A multidisciplinary research team at the University of California, Irvine has revealed that the circadian clock can be leveraged to enhance the efficacy of checkpoint inhibitor cancer therapy. Checkpoint inhibitors block different proteins from binding to tumour cells, allowing the immune system’s T cells to kill the tumour.
The study, published online today in the journal Nature Immunology, provides deeper insights into the intricate relationship among the circadian clock, immune regulation and tumour development and found that a therapeutic approach optimising time-of-day delivery based on an individual’s unique circadian patterns offers new avenues for prevention and treatment.
“Disruption of the internal biological pacemaker is an inherent aspect of modern society that may contribute to the rising incidence of many cancer types. We found that proper regulation of circadian rhythms is necessary to suppress inflammation and support peak immune function,” said corresponding author Selma Masri, UC Irvine associate professor of biological chemistry. “Understanding precisely how circadian disruption promotes disease progression could lead to behaviour modification to reduce cancer risk.”
Team members used an advanced single-cell RNA sequencing technique in a genetic model of colorectal cancer and identified clock-dependent changes controlling the number of myeloid-derived cells that suppress T cell activation. They discovered that disruption of the internal clock in the epithelial cells lining the intestine alters secretion of cytokine proteins, leading to heightened inflammation, increased numbers of immunosuppressive myeloid cells and cancer progression. These findings were leveraged to demonstrate that providing immunotherapy at the time of day when these immunosuppressive myeloid cells are most abundant significantly enhanced the efficacy of immune checkpoint blockades in solid tumours.
“As we enhance our understanding of the fundamental mechanism of circadian regulation of immunity, we will be able to harness the power of the body’s natural rhythms to fight cancer and develop more personalised and effective treatment strategies,” said lead author Bridget Fortin, a UC Irvine doctoral student in the Department of Biological Chemistry.
While this study represents a significant step forward in defining circadian control of anti-tumour immunity, the team believes future research should focus on exploring additional factors and cell types influencing time-of-day response to checkpoint inhibitor therapy.
Researchers have identified the primary cause of sensory hypersensitivity related to autism spectrum disorders (ASD), in an area of the brain called the anterior cingulate cortex – a region often examined for cognitive and emotional disorders but overlooked for sensory ones. The results are published in the journal Molecular Psychiatry.
Autism affects approximately 1 in 36 individuals and is marked by significant challenges in social interaction and communication. Around 90% of autism patients also suffer from abnormal sensory hypersensitivity that deeply affects their daily functioning. This hypersensitivity results in exaggerated or dampened responses to common sensory stimuli such as sound, light, and touch, which leads to considerable stress and further social withdrawal. The precise brain region responsible for this sensory dysfunction is unknown, which hinders treatment efforts.
To find out more, a research team led by Director KIM Eunjoon of the Center for Synaptic Brain Dysfunctions and Director KIM Seong-Gi of the Center for Neuroscience Imaging Research within the Institute for Basic Science (IBS) studied a mouse model of ASD.
The ASD mouse model has a mutation in the Grin2b gene, which encodes the GluN2B subunit of NMDA receptors. NMDA receptors, a type of glutamate receptor in the brain, have garnered attention in the context of autism due to their crucial role in synaptic transmission and neural plasticity. It was hypothesised that the Grin2b gene mutation in mice would induce ASD-like phenotypes, including sensory abnormalities, and that certain brain mechanisms may play important roles.
The researchers monitored neural activity and functional connectivity in the brains of these mice using activity-dependent markers and functional magnetic resonance imaging (fMRI). In these mice, the researchers discovered increased neuronal activity in the anterior cingulate cortex (ACC). The ACC is one of the higher-order cortical regions that have been extensively studied for cognitive and emotional brain functions, but have been understudied for brain disease-related sensory abnormalities.
Interestingly, when the hyperactivity of ACC neurons was inhibited using chemogenetic methods, sensory hypersensitivity were normalised, indicating the pivotal role of ACC hyperactivity in sensory hypersensitivity associated with autism.
Director KIM Eunjoon states, “This new research demonstrates the involvement of the anterior cingulate cortex (ACC), which has been known for its deep association with cognitive and social functions, in sensory hypersensitivity in autism.”
The hyperactivity of the ACC was also associated with the enhanced functional connectivity between the ACC and other brain areas. It is believed both hyperactivity and the hyperconnectivity of the ACC with various other brain regions are involved with sensory hypersensitivity in Grin2b-mutant mice.
Director KIM Seong-Gi states, “Past studies attributed peripheral neurons or primary cortical areas to be important for ASD-related sensory hypersensitivity. These studies often only focused on the activity of a single brain region. In contrast, our study investigates not only the activity of ACC but also the brain-wide hyperconnectivity between the ACC and various cortical/subcortical brain regions, which gives us a more complete picture of the brain.”
The researchers plan to study the detailed mechanisms underlying the increased excitatory synaptic activity and neuronal hyperconnectivity. They suspect that the lack of Grin2b expression may inhibit the normal process of weakening and pruning synapses that are less active so that relatively more active synapses can participate in refining neural circuits in an activity-dependent manner. Other areas of research interest is studying the role of ACC in other mouse models of ASD.
In a potentially game-changing development, scientists at Virginia Tech have revealed a new understanding of sometimes fatal viral infections that affect the heart.
The focus has mostly been on myocarditis, which is often triggered by the body’s immune response to a viral infection. Now, a new study led by James Smyth, associate professor at the Fralin Biomedical Research Institute, sheds new light on this notion, revealing that the virus itself creates potentially dangerous conditions in the heart before inflammation sets in.
The discovery, now online and set to appear in the March 29 issue of Circulation Research, suggests completely new directions to diagnose and treat viral infections affecting the heart.
Given the high incidence of viral-related myocarditis leading to sudden cardiac death, the insight is crucial. Up to 42% of sudden cardiac deaths in young adults are attributed to myocarditis, and of these cases viral infection is the leading cause.
“From a clinical perspective, our understanding of viral infection of the heart has focused on inflammation, causing problems with the rate or rhythm of the heartbeat,” Smyth said. “But we have found an acute stage when the virus first infects the heart and before the body’s immune response causes inflammation. So even before the tissue is inflamed, the heart is being set up for arrhythmia.”
To make this discovery, researchers focused on adenovirus, a common culprit in cardiac infection and myocarditis, using Mouse Adenovirus Type-3 to replicate the human infection process.
They found that early in the infection, the virus disrupts critical components of the heart’s communication and electrical systems.
As a result, even before symptoms appear, the adenoviral infection creates conditions that disrupt the heart’s gap junctions and ion channels, according to virologist Rachel Padget, the study’s first author who worked in the Smyth lab while completing a doctoral degree from the Virginia Tech Translational Biology, Medicine, and Health graduate program.
Gap junctions are like tiny tunnels between heart cells that allow them to communicate, and ion channels are like gates in the cell membranes that help maintain the right balance of ions needed for the heart to generate normal patterns of electrical activity that allow it to beat properly.
When adenoviral infection disturbs these communication bridges and gatekeepers, it creates a situation where the heart might develop irregular patterns of electrical activity called arrhythmias affecting its mechanical beating and blood pumping capacity, and that can lead to sudden cardiac problems, especially in people with active infections.
Now, by targeting specific heart changes induced by viral infections at the molecular level, researchers aim to reduce the risk of cardiac issues in people grappling with viral illnesses.
“Individuals who have acute infections can look normal by MRI and echocardiography, but when we delved into the molecular level, we saw that something very dangerous could occur,” Smyth said. “In terms of diagnostics, we can now work with our colleagues here to start looking ways to analyse blood for a biomarker of the more serious problem. People get cardiac infections all the time and they recover. But can we identify what’s different about individuals that are at a higher risk to have the arrhythmia, possibly through a simple blood test in the doctor’s office.”
Studies at MIT and elsewhere are producing mounting evidence that light flickering and sound clicking at the gamma brain rhythm frequency of 40Hz can reduce Alzheimer’s disease (AD) progression and treat symptoms in human volunteers as well as lab mice. In a new study in Natureusing a mouse model of the disease, researchers at The Picower Institute for Learning and Memory of MIT reveal a key mechanism that may contribute to these beneficial effects: clearance of amyloid proteins, a hallmark of AD pathology, via the brain’s glymphatic system, a recently discovered “plumbing” network parallel to the brain’s blood vessels.
“Ever since we published our first results in 2016, people have asked me how does it work? Why 40Hz? Why not some other frequency?” said study senior author Li-Huei Tsai, Professor of Neuroscience at Picower. “These are indeed very important questions we have worked very hard in the lab to address.”
The new paper describes a series of experiments, led by Mitch Murdock when he was a Brain and Cognitive Sciences doctoral student at MIT, showing that when sensory gamma stimulation increases 40 Hz power and synchrony in the brains of mice, that prompts a particular type of neuron to release peptides. The study results further suggest that those short protein signals then drive specific processes that promote increased amyloid clearance via the glymphatic system.
“We do not yet have a linear map of the exact sequence of events that occurs,” said Murdock, who was jointly supervised by Tsai and co-author and collaborator Ed Boyden, Professor of Neurotechnology at MIT. “But the findings in our experiments support this clearance pathway through the major glymphatic routes.”
From gamma to glymphatics
Because prior research has shown that the glymphatic system is a key conduit for brain waste clearance and may be regulated by brain rhythms, Tsai and Murdock’s team hypothesised that it might help explain the lab’s prior observations that gamma sensory stimulation reduces amyloid levels in Alzheimer’s model mice.
Working with “5XFAD” mice, which genetically model Alzheimer’s, Murdock and co-authors first replicated the lab’s prior results that 40Hz sensory stimulation increases 40Hz neuronal activity in the brain and reduces amyloid levels. Then they set out to measure whether there was any correlated change in the fluids that flow through the glymphatic system to carry away wastes. Indeed, they measured increases in cerebrospinal fluid in the brain tissue of mice treated with sensory gamma stimulation compared to untreated controls. They also measured an increase in the rate of interstitial fluid leaving the brain. Moreover, in the gamma-treated mice he measured increased diameter of the lymphatic vessels that drain away the fluids and measured increased accumulation of amyloid in cervical lymph nodes, which is the drainage site for that flow.
To investigate how this increased fluid flow might be happening, the team focused on the aquaporin 4 (AQP4) water channel of astrocyte cells, which enables the cells to facilitate glymphatic fluid exchange. When they blocked APQ4 function with a chemical, that prevented sensory gamma stimulation from reducing amyloid levels and prevented it from improving mouse learning and memory. And when, as an added test they used a genetic technique for disrupting AQP4, that also interfered with gamma-driven amyloid clearance.
In addition to the fluid exchange promoted by APQ4 activity in astrocytes, another mechanism by which gamma waves promote glymphatic flow is by increasing the pulsation of neighbouring blood vessels. Several measurements showed stronger arterial pulsatility in mice subjected to sensory gamma stimulation compared to untreated controls.
One of the best new techniques for tracking how a condition, such as sensory gamma stimulation, affects different cell types is to sequence their RNA to track changes in how they express their genes. Using this method, Tsai and Murdock’s team saw that gamma sensory stimulation indeed promoted changes consistent with increased astrocyte AQP4 activity.
Prompted by peptides
The RNA sequencing data also revealed that upon gamma sensory stimulation a subset of neurons, called “interneurons,” experienced a notable uptick in the production of several peptides. This was not surprising in the sense that peptide release is known to be dependent on brain rhythm frequencies, but it was still notable because one peptide in particular, VIP, is associated with Alzheimer’s-fighting benefits and helps to regulate vascular cells, blood flow and glymphatic clearance.
Seizing on this intriguing result, the team ran tests that revealed increased VIP in the brains of gamma-treated mice. The researchers also used a sensor of peptide release and observed that sensory gamma stimulation resulted in an increase in peptide release from VIP-expressing interneurons.
But did this gamma-stimulated peptide release mediate the glymphatic clearance of amyloid? To find out, the team ran another experiment: they chemically shut down the VIP neurons. When they did so, and then exposed mice to sensory gamma stimulation, they found that there was no longer an increase in arterial pulsatility and there was no more gamma-stimulated amyloid clearance.
“We think that many neuropeptides are involved,” Murdock said. Tsai added that a major new direction for the lab’s research will be determining what other peptides or other molecular factors may be driven by sensory gamma stimulation.
Tsai and Murdock added that while this paper focuses on what is likely an important mechanism – glymphatic clearance of amyloid – by which sensory gamma stimulation helps the brain, it’s probably not the only underlying mechanism that matters. The clearance effects shown in this study occurred rather rapidly but in lab experiments and clinical studies weeks or months of chronic sensory gamma stimulation have been needed to have sustained effects on cognition.
With each new study, however, scientists learn more about how sensory stimulation of brain rhythms may help treat neurological disorders.
Photo by Pixabay: https://www.pexels.com/photo/broccoli-161514/
Cycles of a diet that mimics fasting can reduce signs of immune system ageing, as well as insulin resistance and liver fat in humans, resulting in a lower biological age, according to a new study in Nature Communications. The USC Leonard Davis School of Gerontology-led study adds to the body of evidence supporting the beneficial effects of the fasting-mimicking diet (FMD).
The FMD is a five-day diet high in unsaturated fats and low in overall calories, protein, and carbohydrates and is designed to mimic the effects of a water-only fast while still providing necessary nutrients and making it much easier for people to complete the fast.
The diet was developed by the laboratory of USC Leonard Davis School Professor Valter Longo, the senior author of the new study.
“This is the first study to show that a food-based intervention that does not require chronic dietary or other lifestyle changes can make people biologically younger, based on both changes in risk factors for aging and disease and on a validated method developed by the Levine group to assess biological age,” Longo said.
Previous research led by Longo has indicated that brief, periodic FMD cycles are associated with a range of beneficial effects, including: promoting stem cell regeneration, lessening chemotherapy side effects, and reducing the signs of dementia in mice. In addition, the FMD cycles can lower the risk factors for cancer, diabetes, heart disease and other age-related diseases in humans.
The Longo lab also had previously shown that one or two cycles of the FMD for five days a month increased the healthspan and lifespan of mice on either a normal or Western diet, but the effects of the FMD on aging and biological age, liver fat, and immune system aging in humans were unknown until now.
Lower disease risks & more youthful cells
The study analysed the diet’s effects in two clinical trial populations, each with men and women between the ages of 18 and 70. Patients randomised to the fasting-mimicking diet underwent 3-4 monthly cycles, adhering to the FMD for 5 days, then ate a normal diet for 25 days.
The FMD is comprised of plant-based soups, energy bars, energy drinks, chip snacks, and tea portioned out for 5 days as well as a supplement providing high levels of minerals, vitamins, and essential fatty acids.
Patients in the control groups were instructed to eat either a normal or Mediterranean-style diet.
An analysis of blood samples from trial participants showed that patients in the FMD group had lower diabetes risk factors, including less insulin resistance and lower HbA1c results.
Magnetic resonance imaging also revealed a decrease in abdominal fat as well as fat within the liver, improvements associated with a reduced risk of metabolic syndrome.
In addition, the FMD cycles appeared to increase the lymphoid-to-myeloid ratio – an indicator of a more youthful immune system.
Further statistical analysis of the results from both clinical studies showed that FMD participants had reduced their biological age, a measure of how well one’s cells and tissues are functioning, by 2.5 years on average.
“This study shows for the first time evidence for biological age reduction from two different clinical trials, accompanied by evidence of rejuvenation of metabolic and immune function,” Longo said.
The study, conducted by first authors Sebastian Brandhorst, USC Leonard Davis research associate professor, and Morgan E. Levine, founding principal investigator of Altos Labs and USC Leonard Davis PhD alumna, lends more support to the FMD’s potential as a short-term periodic, achievable dietary intervention that can help people lessen their disease risk and improve their health without extensive lifestyle changes, Longo said.
“Although many doctors are already recommending the FMD in the United States and Europe, these findings should encourage many more healthcare professionals to recommend FMD cycles to patients with higher than desired levels of disease risk factors as well as to the general population that may be interested in increased function and younger age,” Longo said.
Credit: Darryl Leja National Human Genome Research Institute National Institutes Of Health
Combining testosterone-blocking drugs in patients with prostate cancer relapse prevents the spread of cancer better than treatment with a single drug, a multi-institution, Phase 3 clinical trial led by UC San Francisco researchers has found.
The approach can extend the time between debilitating drug treatments without prolonging the time it takes to recover from each treatment.
Prostate cancer affects 1 in 8 men, and is usually treated with one of several testosterone-lowering drugs for a set period of time.
“This adds to a growing body of evidence in favour of more intensive testosterone-blocking therapy in patients with higher-risk prostate cancer,” said Rahul Aggarwal, MD, professor in the UCSF School of Medicine and lead author of the paper.
The researchers’ findings were published in the Journal of Clinical Oncology. They were first announced in September 2022 at the annual meeting of the European Society for Medical Oncology.
A case for intensifying prostate cancer treatment
The new study focused on patients who had surgery for prostate cancer, and yet the cancer relapsed and was detected through a sudden jump in the blood levels of a protein called prostate-specific antigen (PSA).
“We looked at patients who had a fast rise in their PSA – an indicator of a higher-risk form of relapsed prostate cancer,” Aggarwal said.
“Our goal was to test several different hormone therapy strategies to find the best approach in terms of delaying the cancer’s progression.”
Between 2017 and 2022, 503 patients were randomly assigned to take a single testosterone-lowering therapy chosen by their oncologist, or to combine it with one or two other testosterone-lowering drugs.
The additional drugs were already FDA-approved for other cancers but hadn’t been tested in this way with prostate cancer.
The patients stayed on the assigned therapy for a year. Whether given singly or in combination, the drugs caused their testosterone to plummet.
That put the brakes on their cancer but also caused fatigue, hot flashes, decreased libido and other problems for patients, according to Aggarwal.
Compared to the prostate cancer patients who only received a single drug therapy during their year of treatment, patients who received either one or two additional drugs stayed cancer-free, with low PSA levels, for longer.
Once off the treatment, patients who took the combination therapies saw their testosterone levels recover just as fast as others who took the single drug.
The researchers are following up with a more detailed analysis of how patients fared on the different treatments – which side effects they experienced and for how long, and how they felt overall as they recovered.
“New cancer therapies must clear a high bar to make their way to patients,” Aggarwal said. “With the evidence in this study and others, combination hormone therapy should be considered a standard of care in prostate cancer patients with high-risk relapse after prior treatment.”
Studies have recently begun to reveal that the lines of communication between the body’s organs are key regulators of aging. When these lines are open, the body’s organs and systems work well together. But with age, communication lines deteriorate, and organs don’t get the molecular and electrical messages they need to function properly.
A new study from Washington University School of Medicine in St. Louis identifies, in mice, a critical communication pathway connecting the brain and fat tissue in a feedback loop that appears central to energy production throughout the body. The research suggests that the gradual deterioration of this feedback loop contributes to the increasing health problems that are typical of natural aging.
The study, which appears in Cell Metabolism, has implications for developing future interventions that could maintain the feedback loop longer and slow the effects of advancing age.
The researchers identified a specific set of neurons in the brain’s hypothalamus that, when active, sends signals to the body’s fat tissue to release energy. Using genetic and molecular methods, the researchers studied mice that were programmed to have this communication pathway constantly open after they reached a certain age. The scientists found that these mice were more physically active, showed signs of delayed aging, and lived longer than mice in which this same communication pathway gradually slowed down as part of normal aging.
“We demonstrated a way to delay aging and extend healthy life spans in mice by manipulating an important part of the brain,” said senior author Shin-ichiro Imai, MD, PhD, the Theodore and Bertha Bryan Distinguished Professor in Environmental Medicine and a professor in the Department of Developmental Biology at Washington University. “Showing this effect in a mammal is an important contribution to the field; past work demonstrating an extension of life span in this way has been conducted in less complex organisms, such as worms and fruit flies.”
These specific neurons, in a part of the brain called the dorsomedial hypothalamus, produce an important protein: Ppp1r17. When this protein is present in the nucleus, the neurons are active and stimulate the sympathetic nervous system, which governs the body’s fight or flight response.
The fight-or-flight response is well known for having broad effects throughout the body, including causing increased heart rate and slowed digestion. As part of this response, the researchers found that the neurons in the hypothalamus set off a chain of events that triggers neurons that govern white adipose tissue stored under the skin and in the abdominal area. The activated fat tissue releases fatty acids into the bloodstream for fuelling physical activity, as well as another important protein, an enzyme called eNAMPT, which returns to the hypothalamus and allows the brain to produce fuel for its functions.
This feedback loop is critical for fuelling the body and the brain, but it slows down over time. With age, the researchers found that the protein Ppp1r17 tends to leave the nucleus of the neurons, and when that happens, the neurons in the hypothalamus send weaker signals. With less use, the nervous system wiring throughout the white adipose tissue gradually retracts, and what was once a dense network of interconnecting nerves becomes sparse. The fat tissues no longer receive as many signals to release fatty acids and eNAMPT, leading to fat accumulation, weight gain and less energy for the brain and other tissues.
The researchers, including first author Kyohei Tokizane, PhD, a staff scientist and a former postdoctoral researcher in Imai’s lab, found that when they used genetic methods in old mice to keep Ppp1r17 in the nucleus of the neurons in the hypothalamus, the mice were more physically active, with increased wheel-running, and lived longer than control mice. They also used a technique to directly activate these specific neurons in the hypothalamus of old mice, and they observed similar anti-aging effects.
The high end of the life span of a typical laboratory mouse is generally about 900–1000 days. In this study, all of the control mice that had aged normally died by 1000 days of age. Those that underwent interventions to maintain the brain-fat tissue feedback loop lived 60 to 70 days longer than control mice. This is a roughly 7% increase in lifespan, which translates to a 75-year human lifespan being extended about five more years. The mice receiving the interventions also were more active and looked younger, with thicker and shinier coats, at later ages, suggesting more time with better health as well.
Imai and his team are continuing to investigate ways to maintain the feedback loop between the hypothalamus and the fat tissue. One route they are studying involves supplementing mice with eNAMPT, the enzyme produced by the fat tissue that returns to the brain and fuels the hypothalamus, among other tissues. When released by the fat tissue into the bloodstream, the enzyme is packaged inside compartments called extracellular vesicles, which can be collected and isolated from blood.
“We can envision a possible anti-aging therapy that involves delivering eNAMPT in various ways,” Imai said. “We already have shown that administering eNAMPT in extracellular vesicles increases cellular energy levels in the hypothalamus and extends life span in mice. We look forward to continuing our work investigating ways to maintain this central feedback loop between the brain and the body’s fat tissues in ways that we hope will extend health and life span.”
Coup and contrecoup brain injury. Credit: Scientific Animations CC4.0
Researchers have created a new brain imaging method that allows to be diagnosed, even when existing imaging techniques like magnetic resonance imaging (MRI) The technique involves loading gadolinium, a standard MRI contrast agent, into ‘backpacks’ that are attached macrophages. mTBIs cause inflammation, attracting macrophages there. Coupling the gadolinium contrast agent to these cells enables MRI to reveal brain inflammation and increase the number of correctly diagnosed mTBI cases, improving patient care. The method is described in a new paper in Science Translational Medicine.
“70-90% of reported TBI cases are categorised as ‘mild,’ yet as many as 90% of mTBI cases go undiagnosed, even though their effects can last for years and they are known to increase the risk of a host of neurological disorders including depression, dementia, and Parkinson’s disease,” said senior author Samir Mitragotri, PhD, in whose lab the research was performed. “Our cell-based imaging approach exploits immune cells’ innate ability to travel into the brain in response to inflammation, enabling us to identify mTBIs that standard MRI imaging would miss.”
Using immune cells to identify inflammation
Most of us know someone who has had a concussion (another name for an mTBI), sometimes even more than one. But the vast majority of people who experience an mTBI are never properly diagnosed. Without that diagnosis, they can exacerbate their injuries by returning to normal activity before they’re fully recovered, which can lead to further damage. Some studies even suggest that repeated mTBIs can lead to chronic traumatic encephalopathy (CTE), the neurodegenerative disease that has been found to afflict more than 90% of professional American football players.
Because the effects of mTBI are believed to be caused by “invisible” brain inflammation, members of the Mitragotri lab decided to leverage their experience with immune cells to create a better diagnostic. “Our previous projects have focused on controlling the behaviour of immune cells or using them to deliver drugs to a specific tissue. We wanted to exploit another innate ability of immune cells – homing to sites of inflammation in the body – to carry imaging agents into the brain, where they can provide a visible detection signal for mTBI,” said first author Lily Li-Wen Wang, Ph.D.. Wang is a former Research Fellow in the Mitragotri Lab at the Wyss Institute and SEAS who is now a scientist at Landmark Bio.
Gadolinium needs water to show up on MRI
The team planned to use their cellular backpack technology to attach gadolinium molecules to macrophages, known to infiltrate the brain in response to inflammation. But right away, they ran into a problem: in order to function as a contrast agent for MRI scans, gadolinium needs to interact with water. Their original backpack microparticles are made of a hydrophobic polymer called PLGA. So Wang and her co-authors started developing a new backpack made out of a hydrogel material that could be manufactured at a large scale in the lab.
After years of hard work, they finally created a new hydrogel backpack that could produce a strong gadolinium-mediated MRI signal, attach stably to both mouse and pig macrophages, and maintain their cargo for a sustained period of time in vitro. They named their new microparticles M-GLAMs, short for “macrophage-hitchhiking Gd(III)-Loaded Anisotropic Micropatches.” Now, it was time to test them in a more realistic setting, for which they partnered with researchers and clinicians at Boston Children’s Hospital.
First, they injected mouse M-GLAMs macrophages into mice to see if they could visualize them in vivo. They were especially interested to see if they accumulated in the kidney, as existing gadolinium-based contrast agents like Gadavist® can cause health risks for patients with kidney disease. Their M-GLAMs did not accumulate in the mice’s kidneys, but persisted in their bodies for over 24 hours with no negative side effects. In contrast, mice injected with Gadavist® showed substantial accumulation of the contrast agent in their kidneys within 15 minutes of injection, and the substance was fully cleared from their bodies within 24 hours.
Then, they tested porcine M-GLAMs in a pig model of mTBI. They injected the M-GLAMs into the animals’ blood two days after a mock mTBI, then used MRI to evaluate the concentration of gadolinium in the brain. They focused on a small region called the choroid plexus, which is known as a major conduit of immune cells into the brain. Pigs that received the M-GLAMs displayed a significant increase in the intensity of gadolinium present in the choroid plexus, while those injected with Gadavist® did not, despite confirmation of increased inflammation macrophage density in the brains of both groups. The animals showed no toxicity in any of their major organs following administration of the treatments.
“Another important aspect of our M-GLAMs is that we are able to achieve better imaging at a much lower dose of gadolinium than current contrast agents – 500-1000-fold lower in the case of Gadavist®,” said Wang. “This could allow the use of MRI for patients who are currently unable to tolerate existing contrast agents, including those who have existing kidney problems.”
The Vikings, famous as raiders who terrorised many parts of Europe, may have been quite ruthless, but their society seems to have had access to surprisingly advanced dental care for the era. A University of Gothenburg analysis of Viking Age teeth showed that although caries and toothache were widespread, there was also evidence of dental practices not too dissimilar from modern ones.
The study examined 3293 teeth from 171 individuals among the Viking Age population of Varnhem in Västergötland, Sweden.
The site is known for extensive excavations of Viking and medieval environments, including tombs where skeletons and teeth have been preserved well in favourable soil conditions.
The research team from the University of Gothenburg’s Institute of Odontology worked with an osteologist from Västergötland’s Museum. The skulls and teeth underwent clinical examinations at Gothenburg using standard dentistry tools under bright light.
A number of X-ray examinations were also performed using the same technique used in dentistry, where the patient bites down on a small square imaging plate in the mouth.
Caries and tooth loss
The results, which have been published in the journal PLOS ONE, show that 49% of the Viking population had one or more caries lesions.
Of the adults’ teeth, 13% were affected by caries – often at the roots. Children with milk teeth or a mix of milk and adult teeth, were entirely caries-free however. (Presumably sweets for the kids were not high on the Viking raiders’ lists.)
Tooth loss was also common among adults. The studied adults had lost an average of 6% of their teeth, excluding wisdom teeth, over their lifetimes. The risk of tooth loss increased with age.
The findings suggest that caries, tooth infections, and toothache were common among the Viking population in Varnhem – but the study also reveals examples of tooth care.
“There were several signs that the Vikings had modified their teeth, including evidence of using toothpicks, filing front teeth, and even dental treatment of teeth with infections,” says Carolina Bertilsson, a dentist and Associate Researcher, and the study’s first-named and corresponding author.
Not unlike today’s treatments
One sign of more sophisticated procedures was molars with filed holes, from the crown of the tooth and into the pulp, probably in order to relieve pressure and alleviate severe toothache due to infection.
“This is very exciting to see, and not unlike the dental treatments we carry out today when we drill into infected teeth. The Vikings seem to have had knowledge about teeth, but we don’t know whether they did these procedures themselves or had help.”
The filed front teeth may have been a form of identity marker. In both this and previous studies, the cases found were male.
Carolina Bertilsson continues: “This study provides new insights into Viking oral health, and indicates that teeth were important in Varnhem’s Viking culture. It also suggests that dentistry in the Viking Age was probably more sophisticated than previously thought.”
New experimental evidence suggests that substances known as narrow-spectrum Wnt signaling inhibitors can suppressing breast cancer tumour growth in mice. These substances, which are derived from Clostridioides difficile bacteria, could have fewer side effects than existing treatments. Aina He of Shanghai Jiaotong University Affiliated Sixth People’s Hospital, China, and colleagues published these findings in the open access journal PLOS Biology.
While certain subtypes of breast cancer can be targeted with special medications, others can only be treated with standard chemotherapy. For some patients, chemotherapy may lead to the growth of stem cell-like cancer cells that are drug resistant. Previous studies suggest that medications that inhibit a specific biological process called Wnt signaling could potentially combat these cells, but so far, the potential benefits of Wnt signaling inhibitors have been hampered by their damaging side effects, particularly on bone density.
These side effects arise from the fact that humans have ten different versions of the Wnt signaling receptor, Frizzled, with distinct functions. Researchers have therefore recently developed new Wnt signaling inhibitors that could reduce side effects by targeting just three of these receptors. However, it has been unclear how effective these narrow-spectrum Wnt signaling inhibitors might be at treating cancer.
To shed new light, He and colleagues conducted a series of experiments with a specific narrow-spectrum Wnt signaling inhibitor known as TcdBFBD, which was derived from a toxin found naturally in the bacterial species Clostridioides difficile. They tested TcdBFBD in several different mouse models that mimic different types of breast cancer – basal-like and luminal-like – found in humans.
The researchers found evidence suggesting that TcdBFBD suppressed tumour growth and reduced the activity of stem cell-like cancer cells in the mice, without side effects on bone density. They also found evidence that TcdBFBD can synergise with the standard chemotherapy drug cisplatin to inhibit both basal-like and luminal-like breast cancer tumours in mice.
These findings provide preliminary evidence for the potential therapeutic promise of narrow-spectrum Wnt signaling inhibitors like TcdBFBD. However, more research will be needed to investigate their effectiveness in humans, examine how they might synergise with other cancer treatments beyond cisplatin, and explore their effects in additional types of cancer, such as serous ovarian cancer and oral squamous cell carcinoma.
The authors add, “A bacterial toxin fragment targets and suppresses breast cancer tumour-initiating and chemo-resistant cells.”
