stroke
Childhood Cancer: Novel Nanoparticle Shows Early Promise for Brain Tumor
Posted on by Lawrence Tabak, D.D.S., Ph.D.
The human brain is profoundly complex, consisting of tens of billions of neurons that form trillions of interconnections. This complex neural wiring that allows us to think, feel, move, and act is surrounded by what’s called the blood-brain barrier (BBB), a dense sheet of cells and blood vessels. The BBB blocks dangerous toxins and infectious agents from entering the brain, while allowing nutrients and other essential small molecules to pass right through.
This gatekeeping function helps to keep the brain healthy, but not when the barrier prevents potentially life-saving drugs from reaching aggressive, inoperable brain tumors. Now, an NIH-funded team reporting in the journal Nature Materials describes a promising new way to ferry cancer drugs across the BBB and reach the sites of disease [1]. While the researchers have not yet tried this new approach in people, they have some encouraging evidence from studies in mouse models of medulloblastoma, an aggressive brain cancer that’s diagnosed in hundreds of children each year.
The team, including Daniel Heller, Memorial Sloan Kettering Cancer Center, New York, NY, and Praveen Raju, Icahn School of Medicine at Mount Sinai, New York, NY, wanted to target a protein called P-selectin. The protein is found on blood vessel cells at sites of infection, injury, or inflammation, including cancers. The immune system uses such proteins to direct immune cells to the places where they are needed, allowing them to exit the bloodstream and enter other tissues.
Heller’s team thought they could take advantage of P-selectin and its molecular homing properties as a potential way to deliver cancer drugs to patients. But first they needed to package the drugs in particles tiny enough to stick to P-selectin like an immune cell.
That’s when they turned to a drug-delivery construct called a nanoparticle, which can have diameters a thousand times smaller than that of a human hair. But what’s pretty unique here is the nanoparticles are made from chains of sugar molecules called fucoidan, which are readily extracted from a type of brown seaweed that grows in Japan. It turns out that this unlikely ingredient has a special ability to attract P-selectin.
In the new study, the researchers decided to put their novel fucoidan nanoparticles to the test in the brain, while building on their previous animal work in the lungs [2]. That work showed that when fucoidan nanoparticles bind to P-selectin, they trigger a process that shuttles them across blood vessel walls.
This natural mechanism should also allow nanoparticle-packaged substances in the bloodstream to pass through vessel walls in the BBB and into the surrounding brain tissue. The hope was it would do so without damaging the BBB, a critical step for improving the treatment of brain tumors.
In studies with mouse models of medulloblastoma, the team loaded the nanoparticles with a cancer drug called vismodegib. This drug is approved for certain skin cancers and has been tested for medulloblastoma. The trouble is that the drug on its own comes with significant side effects in children at doses needed to effectively treat this brain cancer.
The researchers found that the vismodegib-loaded nanoparticles circulating in the mice could indeed pass through the intact BBB and into the brain. They further found that the particles accumulated at the site of the medulloblastoma tumors, where P-selectin was most abundant, and not in other healthy parts of the brain. In the mice, the approach allowed the vismodegib treatment to work better against the cancer and at lower doses with fewer side effects.
This raised another possibility. Radiation is a standard therapy for children and adults with brain tumors. The researcher found that radiation boosts P-selectin levels specifically in tumors. The finding suggests that radiation targeting specific parts of the brain prior to nanoparticle treatment could make it even more effective. It also may help to further limit the amount of cancer-fighting drug that reaches healthy brain cells and other parts of the body.
The fucoidan nanoparticles could, in theory, deliver many different drugs to the brain. The researchers note their promise for treating brain tumors of all types, including those that spread to the brain from other parts of the body. While much more work is needed, these seaweed-based nanoparticles may also help in delivering drugs to a wide range of other brain conditions, such as multiple sclerosis, stroke, and focal epilepsy, in which seizures arise from a specific part of the brain. It’s a discovery that brings new meaning to the familiar adage that good things come in small packages.
References:
[1] P-selectin-targeted nanocarriers induce active crossing of the blood-brain barrier via caveolin-1-dependent transcytosis. Tylawsky DE, Kiguchi H, Vaynshteyn J, Gerwin J, Shah J, Islam T, Boyer JA, Boué DR, Snuderl M, Greenblatt MB, Shamay Y, Raju GP, Heller DA. Nat Mater. 2023 Mar;22(3):391-399.
[2] P-selectin is a nanotherapeutic delivery target in the tumor microenvironment. Shamay Y, Elkabets M, Li H, Shah J, Brook S, Wang F, Adler K, Baut E, Scaltriti M, Jena PV, Gardner EE, Poirier JT, Rudin CM, Baselga J, Haimovitz-Friedman A, Heller DA. Sci Transl Med. 2016 Jun 29;8(345):345ra87.
Links:
Medulloblastoma Diagnosis and Treatment (National Cancer Institute/NIH)
Brain Basics: Know Your Brain (National Institute of Neurological Disorders and Stroke/NIH)
The Daniel Heller Lab (Memorial Sloan Kettering Cancer Center, New York, NY)
Praveen Raju (Mount Sinai, New York, NY)
NIH Support: National Cancer Institute; National Institute of Neurological Disorders and Stroke
All of Us Research Program Participants Fuel Both Scientific and Personal Discovery
Posted on by Josh Denny, M.D., M.S., All of Us Research Program
The NIH’s All of Us Research Program is a historic effort to create an unprecedented research resource that will speed biomedical breakthroughs, transform medicine and advance health equity. To create this resource, we are enrolling at least 1 million people who reflect the diversity of the United States.
At the program’s outset, we promised to make research a two-way street by returning health information to our participant partners. We are now delivering on that promise. We are returning personalized health-related DNA reports to participants who choose to receive them.
That includes me. I signed up to receive my “Medicine and Your DNA” and “Hereditary Disease Risk” reports along with nearly 200,000 other participant partners. I recently read my results, and they hit home, revealing an eye-opening connection between my personal and professional lives.
First, the professional. Before coming to All of Us, I was a practicing physician and researcher at Vanderbilt University, Nashville, TN, where I studied how a person’s genes might affect his or her response to medications. One of the drug-gene interactions that I found most interesting is related to clopidogrel, a drug commonly prescribed to keep arteries open after a major cardiovascular event, like a heart attack, stroke, or placement of a stent.
People with certain gene variations are not able to process this medication well, leaving them in a potentially risky situation. The patient and their health care provider may think the condition is being managed. But, since they can’t process the medication, the patient’s symptoms and risks are likely to increase.
The impact on patients has been seen in numerous studies, including one that I published with colleagues last year in the Journal of Stroke and Cerebrovascular Disease [1]. We found that stroke risk is three times higher in patients who were poor responders to clopidogrel and treated with the drug following a “mini-stroke”—also known as a transient ischemic attack. Other studies have shown that major cardiovascular events were 50 percent more common in individuals who were poor responders to clopidogrel [2]. Importantly, there are alternative therapies that work well for people with this genetic variant.
Now, the personal. Reading my health-related results, I learned that I carry some of these very same gene variations. So, if I ever needed a medicine to manage my risk of blood clots, clopidogrel would not likely work well for me.
Instead, should I ever need treatment, my provider and I could bypass this common first-line therapy and choose an alternate medicine. Getting the right treatment on the first try could cut my chances of a heart attack in half. The benefits of this knowledge don’t stop with me. By choosing to share my findings with family members who may have inherited the same genetic variations, they can discuss it with their health care teams.
Other program participants who choose to receive results will experience the same process of learning more about their health. Nearly all will get actionable information about how their body may process certain medications. A small percentage, 2 to 3 percent, may learn they’re at higher risk of developing several severe hereditary health conditions, such as certain preventable heart diseases and cancers. The program will provide a genetic counselor at no cost to all participants to discuss their results.
To enroll participants who reflect the country’s diverse population, All of Us partners with trusted community organizations around the country. Inclusion is vitally important in the field of genomics research, where available data have long originated mostly from people of European ancestry. In contrast, about 50 percent of the All of Us’ genomic data come from individuals who self-identify with a racial or ethnic minority group.
More than 3,600 research projects are already underway using data contributed by participants from diverse backgrounds. What’s especially exciting about this “ecosystem” of discovery between participants and researchers is that, by contributing their data, participants are helping researchers decode what our DNA is telling us about health across all types of conditions. In turn, those discoveries will deepen what participants can learn.
Those who have stepped up to join All of Us are the heartbeat of this historic research effort to advance personalized approaches in medicine. Their contributions are already fueling new discoveries in numerous areas of health.
At the same time, making good on our promises to our participant partners ensures that the knowledge gained doesn’t only accumulate in a database but is delivered back to participants to help advance their own health journeys. If you’re interested in joining All of Us, we welcome you to learn more.
References:
[1] CYP2C19 loss-of-function is associated with increased risk of ischemic stroke after transient ischemic attack in intracranial atherosclerotic disease. Patel PD, Vimalathas P, Niu X, Shannon CN, Denny JC, Peterson JF, Chitale RV, Fusco MR. J Stroke Cerebrovasc Dis. 2021 Feb;30(2):105464.
[2] Predicting clopidogrel response using DNA samples linked to an electronic health record. Delaney JT, Ramirez AH, Bowton E, Pulley JM, Basford MA, Schildcrout JS, Shi Y, Zink R, Oetjens M, Xu H, Cleator JH, Jahangir E, Ritchie MD, Masys DR, Roden DM, Crawford DC, Denny JC. Clin Pharmacol Ther. 2012 Feb;91(2):257-263.
Links:
Join All of Us (All of Us/NIH)
NIH’s All of Us Research Program returns genetic health-related results to participants, NIH News Release, December 13, 2022.
NIH’s All of Us Research Program Releases First Genomic Dataset of Nearly 100,000 Whole Genome Sequences, NIH News Release, March 17, 2022.
Funding and Program Partners (All of Us)
Medicine and Your DNA (All of Us)
Clopidogrel Response (National Library of Medicine/NIH)
Hereditary Disease Risk (All of Us)
Preparing for DNA Results: What Is a Genetic Counselor? (All of Us)
Research Projects Directory (All of Us)
Note: Dr. Lawrence Tabak, who performs the duties of the NIH Director, has asked the heads of NIH’s Institutes, Centers, and Offices to contribute occasional guest posts to the blog to highlight some of the interesting science that they support and conduct. This is the 24th in the series of NIH guest posts that will run until a new permanent NIH director is in place.
To Prevent a Stroke, Household Chores and Leisurely Strolls May Help
Posted on by Lawrence Tabak, D.D.S., Ph.D.
As we get older, unfortunately our chances of having a stroke rise. While there’s obviously no way to turn back the clock on our age, fortunately there are ways to lower our risk of a stroke and that includes staying physically active. Take walks, ride a bike, play a favorite sport. According to our current exercise guidelines for American adults, the goal is to get in at least two and a half hours each week of moderate-intensity physical activity as well as two days of muscle-strengthening activity [1].
But a new study, published in the journal JAMA Network Open, shows that reducing the chances of a stroke as we get older doesn’t necessarily require heavy aerobic exercise or a sweat suit [2]. For those who are less mobile or less interested in getting out to exercise, the researchers discovered that just spending time doing light-intensity physical activity—such as tending to household chores—“significantly” protects against stroke.
The study also found you don’t have to dedicate whole afternoons to tidying up around the house to protect your health. It helps to just get up out of your chair for five or 10 minutes at a time throughout the day to straighten up a room, sweep the floor, fold the laundry, step outside to water the garden, or just take a leisurely stroll.
That may sound simple, but consider that the average American adult now spends on average six and a half hours per day just sitting [3]. That comes to nearly two days per week on average, much to the detriment of our health and wellbeing. Indeed, the study found that middle-aged and older people who were sedentary for 13 hours or more hours per day had a 44 percent increased risk of stroke.
These latest findings come from Steven Hooker, San Diego State University, CA, and his colleagues on the NIH-supported Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. Launched in 2003, REGARDS continues to follow over time more than 30,000 Black and white participants aged 45 and older.
Hooker and colleagues wanted to know more about the amount and intensity of exercise required to prevent a stroke. Interestingly, the existing data were relatively weak, in part because prior studies looking at the associations between physical activity and stroke risk relied on self-reported data, which don’t allow for precise measures. What’s more, the relationship between time spent sitting and stroke risk also remained unknown.
To get answers, Hooker and team focused on 7,607 adults enrolled in the REGARDS study. Rather than relying on self-reported physical activity data, team members asked participants to wear a hip-mounted accelerometer—a device that records how fast people move—during waking hours for seven days between May 2009 and January 2013.
The average age of participants was 63. Men and women were represented about equally in the study, while about 70 percent of participants were white and 30 percent were Black.
Over the more than seven years of the study, 286 participants suffered a stroke. The researchers then analyzed all the accelerometer data, including the amount and intensity of their physical activity over the course of a normal week. They then related those data to their risk of having a stroke over the course of the study.
The researchers found, as anticipated, that adults who spent the most time doing moderate-to-vigorous intensity physical activity were less likely to have a stroke than those who spent the least time physically active. But those who spent the most time sitting also were at greater stroke risk, whether they got their weekly exercise in or not.
Those who regularly sat still for longer periods—17 minutes or more at a time—had a 54 percent increase in stroke risk compared to those who more often sat still for less than eight minutes. After adjusting for the time participants spent sitting, those who more often had shorter periods of moderate-to-vigorous activity—less than 10 minutes at a time—still had significantly lower stroke risk. But, once the amount of time spent sitting was taken into account, longer periods of more vigorous activity didn’t make a difference.
While high blood pressure, diabetes, and myriad other factors also contribute to a person’s cumulative risk of stroke, the highlighted paper does bring some good actionable news. For each hour spent doing light-intensity physical activity instead of sitting, a person can reduce his or her stroke risk.
The bad news, of course, is that each extra hour spent sitting per day comes with an increased risk for stroke. This bad news shouldn’t be taken lightly. In the U.S., almost 800,000 people have a stroke each year. That’s one person every 40 seconds with, on average, one death every four minutes. Globally, stroke is the second most common cause of death and third most common cause of disability in people, killing more than 6.5 million each year.
If you’re already meeting the current exercise guidelines for adults, keep up the good work. If not, this paper shows you can still do something to lower your stroke risk. Make a habit throughout the day of getting up out of your chair for a mere five or 10 minutes to straighten up a room, sweep the floor, fold the laundry, step outside to water the garden, or take a leisurely stroll. It could make a big difference to your health as you age.
References:
[1] How much physical activity do adults need? Centers for Disease Control and Prevention. June 2, 2022.
[2] Association of accelerometer-measured sedentary time and physical activity with risk of stroke among US adults. Hooker SP, Diaz KM, Blair SN, Colabianchi N, Hutto B, McDonnell MN, Vena JE, Howard VJ. JAMA Netw Open. 2022 Jun 1;5(6):e2215385.
[3] Trends in sedentary behavior among the US population, 2001-2016. Yang L, Cao C, Kantor ED, Nguyen LH, Zheng X, Park Y, Giovannucci EL, Matthews CE, Colditz GA, Cao Y. JAMA. 2019 Apr 23;321(16):1587-1597.
Links:
Stroke (National Institute of Neurological Disorders and Stroke/NIH)
REGARDS Study (University of Alabama at Birmingham)
NIH Support: National Institute of Neurological Disorders and Stroke; National Institute on Aging
First Comprehensive Census of Cell Types in Brain Area Controlling Movement
Posted on by Dr. Francis Collins
The primary motor cortex is the part of the brain that enables most of our skilled movements, whether it’s walking, texting on our phones, strumming a guitar, or even spiking a volleyball. The region remains a major research focus, and that’s why NIH’s Brain Research Through Advancing Innovative Neurotechnologies® (BRAIN) Initiative – Cell Census Network (BICCN) has just unveiled two groundbreaking resources: a complete census of cell types present in the mammalian primary motor cortex, along with the first detailed atlas of the region, located along the back of the frontal lobe in humans (purple stripe above).
This remarkably comprehensive work, detailed in a flagship paper and more than a dozen associated articles published in the journal Nature, promises to vastly expand our understanding of the primary motor cortex and how it works to keep us moving [1]. The papers also represent the collaborative efforts of more than 250 BICCN scientists from around the world, teaming up over many years.
Started in 2013, the BRAIN Initiative is an ambitious project with a range of groundbreaking goals, including the creation of an open-access reference atlas that catalogues all of the brain’s many billions of cells. The primary motor cortex was one of the best places to get started on assembling an atlas because it is known to be well conserved across mammalian species, from mouse to human. There’s also a rich body of work to aid understanding of more precise cell-type information.
Taking advantage of recent technological advances in single-cell analysis, the researchers categorized into different types the millions of neurons and other cells in this brain region. They did so on the basis of morphology, or shape, of the cells, as well as their locations and connections to other cells. The researchers went even further to characterize and sort cells based on: their complex patterns of gene expression, the presence or absence of chemical (or epigenetic) marks on their DNA, the way their chromosomes are packaged into chromatin, and their electrical properties.
The new data and analyses offer compelling evidence that neural cells do indeed fall into distinct types, with a high degree of correspondence across their molecular genetic, anatomical, and physiological features. These findings support the notion that neural cells can be classified into molecularly defined types that are also highly conserved or shared across mammalian species.
So, how many cell types are there? While that’s an obvious question, it doesn’t have an easy answer. The number varies depending upon the method used for sorting them. The researchers report that they have identified about 25 classes of cells, including 16 different neuronal classes and nine non-neuronal classes, each composed of multiple subtypes of cells.
These 25 classes were determined by their genetic profiles, their locations, and other characteristics. They also showed up consistently across species and using different experimental approaches, suggesting that they have important roles in the neural circuitry and function of the motor cortex in mammals.
Still, many precise features of the cells don’t fall neatly into these categories. In fact, by focusing on gene expression within single cells of the motor cortex, the researchers identified more potentially important cell subtypes, which fall into roughly 100 different clusters, or distinct groups. As scientists continue to examine this brain region and others using the latest new methods and approaches, it’s likely that the precise number of recognized cell types will continue to grow and evolve a bit.
This resource will now serve as a springboard for future research into the structure and function of the brain, both within and across species. The datasets already have been organized and made publicly available for scientists around the world.
The atlas also now provides a foundation for more in-depth study of cell types in other parts of the mammalian brain. The BICCN is already engaged in an effort to generate a brain-wide cell atlas in the mouse, and is working to expand coverage in the atlas for other parts of the human brain.
The cell census and atlas of the primary motor cortex are important scientific advances with major implications for medicine. Strokes commonly affect this region of the brain, leading to partial or complete paralysis of the opposite side of the body.
By considering how well cell census information aligns across species, scientists also can make more informed choices about the best models to use for deepening our understanding of brain disorders. Ultimately, these efforts and others underway will help to enable precise targeting of specific cell types and to treat a wide range of brain disorders that affect thinking, memory, mood, and movement.
Reference:
[1] A multimodal cell census and atlas of the mammalian primary motor cortex. BRAIN Initiative Cell Census Network (BICCN). Nature. Oct 6, 2021.
Links:
NIH Brain Research Through Advancing Innovative Neurotechnologies® (BRAIN) Initiative (NIH)
BRAIN Initiative – Cell Census Network (BICCN) (NIH)
NIH Support: National Institute of Mental Health; National Institute of Neurological Disorders and Stroke
Can Blood Thinners Keep Moderately Ill COVID-19 Patients Out of the ICU?
Posted on by Dr. Francis Collins
One of many troubling complications of infection with SARS-CoV-2, the coronavirus that causes COVID-19, is its ability to trigger the formation of multiple blood clots, most often in older people but sometimes in younger ones, too. It raises the question of whether and when more aggressive blood thinning treatments might improve outcomes for people hospitalized for COVID-19.
The answer to this question is desperately needed to help guide clinical practice. So, I’m happy to report interim results of three large clinical trials spanning four continents and more than 300 hospitals that are beginning to provide critical evidence on this very question [1]. While it will take time to reach a solid consensus, the findings based on more than 1,000 moderately ill patients suggest that full doses of blood thinners are safe and can help to keep folks hospitalized with COVID-19 from becoming more severely ill and requiring some form of organ support.
The results that are in so far suggest that individuals hospitalized, but not severely ill, with COVID-19 who received a full intravenous dose of the common blood thinner heparin were less likely to need vital organ support, including mechanical ventilation, compared to those who received the lower “prophylactic” subcutaneous dose. It’s important to note that these findings are in contrast to results announced last month indicating that routine use of a full dose of blood thinner for patients already critically ill and in the ICU wasn’t beneficial and may even have been harmful in some cases [2]. This is a compelling example of how critical it is to stratify patients with different severity in clinical trials—what might help one subgroup might be of no benefit, or even harmful, in another.
More study is clearly needed to sort out all the details about when more aggressive blood thinning treatment is warranted. Trial investigators are now working to make the full results available to help inform a doctor’s decisions about how to best to treat their patients hospitalized with COVID-19. It’s worth noting that these trials are overseen by independent review boards, which routinely evaluate the data and are composed of experts in ethics, biostatistics, clinical trials, and blood clotting disorders.
These clinical trials were made possible in part by the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership and its ACTIV-4 Antithrombotics trials—along with similar initiatives in Canada, Australia, and the European Union. The ACTIV-4 trials are overseen by the NIH’s National Heart, Lung, and Blood institute and funded by Operation Warp Speed.
This ACTIV-4 trial is one of three Phase 3 clinical trials evaluating the safety and effectiveness of blood thinners for patients with COVID-19 [3]. Another ongoing trial is investigating whether blood thinners are beneficial for newly diagnosed COVID-19 patients who do not require hospitalization. There are also plans to explore the use of blood thinners for patients after they’ve been discharged from the hospital following a diagnosis of moderate to severe COVID-19 and to establish more precise methods for identifying which patients with COVID-19 are most at risk for developing life-threatening blood clots.
Meanwhile, research teams are exploring other potentially promising ways to repurpose existing therapeutics and improve COVID-19 outcomes. In fact, the very day that these latest findings on blood thinners were announced, another group at The Montreal Heart Institute, Canada, announced preliminary results of the international COLCORONA trial, testing the use of colchicine—an anti-inflammatory drug widely used to treat gout and other conditions—for patients diagnosed with COVID-19 [4].
Their early findings in treating patients just after a confirmed diagnosis of COVID-19 suggest that colchicine might reduce the risk of death or hospitalization compared to patients given a placebo. In the more than 4,100 individuals with a proven diagnosis of COVID-19, colchicine significantly reduced hospitalizations by 25 percent, the need for mechanical ventilation by 50 percent, and deaths by 44 percent. Still, the actual numbers of individuals represented by these percentages was small.
Time will tell whether and for which patients colchicine and blood thinners prove most useful in treating COVID-19. For those answers, we’ll have to await the analysis of more data. But the early findings on both treatment strategies come as a welcome reminder that we continue to make progress each day on such critical questions about which existing treatments can be put to work to improve outcomes for people with COVID-19. Together with our efforts to slow the spread of SARS-CoV-2, finding better ways to treat those who do get sick and prevent some of the worst outcomes will help us finally put this terrible pandemic behind us.
References:
[1] Full-dose blood thinners decreased need for life support and improved outcome in hospitalized COVID-19 patients. National Heart, Lung, and Blood Institute. January 22, 2021.
[2] NIH ACTIV trial of blood thinners pauses enrollment of critically ill COVID-19 patients. National Heart, Lung, and Blood Institute. December 22, 2020.
[3] NIH ACTIV initiative launches adaptive clinical trials of blood-clotting treatments for COVID-19. National Heart, Lung, and Blood Institute. September 10, 2020.
[4] Colchicine reduces the risk of COVID-19-related complications. The Montreal Heart Institute. January 22, 2021.
Links:
COVID-19 Research (NIH)
Combat COVID (U.S. Department of Health and Human Services, Washington, D.C.)
Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) (NIH)
NIH Support: National Heart, Lung, and Blood Institute
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