Categories : COVIDTags :

Prof Madhi Addresses Omicron Subvariant Concerns

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SARS-CoV-2 virus
SARS-CoV-2 virus. Source: Fusion Medical Animation on Unsplash

In an interview about new Omicron subvariants, leading vaccinologist Prof Shabir Madhi said that “we don’t need to be concerned” about any current threat they may pose to South Africa. However, he stressed that it can still be lethal, particularly in those without underlying T cell immunity. He also noted that boosters are also important for high-risk populations, while some sort of seasonality needs to be observed for COVID for it to make boosters worthwhile for those at low risk due to the way vaccination protection wanes.

The XBB 1.5 SARS-CoV-2 subvariant, nicknamed ‘Kraken’ by researchers, is now accounting for more than half of cases in the United States, and appears much more transmissible and antibody-evasive than the original Omicron variant which evolved in Southern Africa. Prof Pravin Manga, editor of the Wits Journal of Clicnical Medicine interviewed Prof Madhi and asked him what the emergence of Omicron subvariants meant for South Africa.

Prof Madhi, who is the Dean of the Faculty of Health Sciences at Wits University, noted that before this new XBB.1.5 variant, there were BA4 and BA5, which created a “mini surge” in the middle of last year when they arrived in SA. There were concerns that these strains seemed more antibody-resistant than previous ones, stoking fears that they would result in increased hospitalisations and deaths.

In light of the current situation, he says that “the short answer is that we don’t need to be concerned.”

One important aspect of immunity which was becoming apparent was that, although neutralising antibodies were important in protecting against contracting and transmitting the virus, “what seems to be playing a greater role in protecting against severe disease is the T cell immunity, the Natural Killer cell immunity.” This immunity is much more diverse than that from antibodies, instead of merely targeting the Spike protein is rather “multi-epitopic”, targeting the N-protein as well.

“Now this T cell immunity appears to be holding strong. It appears to be less affected by all these mutations. In fact, close to 75 to 80% of vaccine-induced T cell immunity is conserved despite the multiple mutations have arisen in Omicron and its subvariants.”

Differing impacts across countries

With regard to the impact of the virus, Prof Madhi noted that China had pursued its ‘zero COVID’ policy, along with “suboptimal” coverage of vaccines (especially among ages 60+) that were “probably not the best”, meaning that large portions of the population were essentially naïve to the virus.

SA meanwhile, had 90% of the population infected at least once with COVID, and coupled with vaccination, meant that many will have highly robust immunity, which appears to last for 9–12 months compared to vaccine-only immunity where protection starts wanes after 4–6 months.

“What is unlikely to materialise in a country such as South Africa is large numbers of hospitalisations,” he says.

Protecting at-risk populations and the need for new vaccines

At present, he says there is not a strong case for boosters, but people at greater risk, such as those over 60, people with underlying medical conditions, and compromised immune systems, hybrid immunity is likely not enough protection. In these cases probably at least four doses of vaccination. From a public health standpoint, the population under 45 without underlying conditions would require a huge effort for only a nominal benefit as they are no longer at high risk of severe disease.

Timing is also important, due to the waning of vaccine protection, as the best time to get a booster is “probably around two or three weeks before the start of the next resurgence.” Otherwise, it’s useless to get a booster now if the next resurgence is in six months and antibodies will have waned – an obvious logistical challenge for little benefit. Therefore, in order for boosters to be useful, the virus will have to settle into some sort of predictable seasonality such as with influenza.

As for people who are at risk, at least four doses are probably required, though the case for a fifth is thin. Annual boosters are a likely option, and there is a need for a second generation of vaccines. These vaccines would need to be resilient against further mutations that may arise.

Novavax, monoclonal antibodies and Paxlovid

Regarding Novavax, Prof Madhi said that it had been licensed for use in South Africa, but their bivalent vaccine was not yet available. It would not be procured by government but rather by a private company – a situation which needs to change in terms of who is allowed to bring in vaccines. Another issue is whether the no fault compensation used by the government for public sector vaccinations would be used in the private sector as well.

Prof Manga also asked about whether there had been any success with monoclonal antibody treatment, to which Prof Madhi answered that there had been some limited use in the country but overall, monoclonal antibodies were “spectacularly unsuccessful” as they were highly specific and generally unable to keep up with mutations.

In general, antivirals hold much better promise, particularly Paxlovid which is unfortunately not available in South Africa. It was disappointing that it was not available in the country,

Benefits to both pregnant mothers and babies

Regarding pregnant women and children, Prof Madhi said that their own study shows that a substantial amount of transmission takes place between mothers and children. Infants with COVID under six months are often hospitalised, especially in the first month of life. Vaccination reduces the risk of hospitalisation and protects the baby as well, with research showing that babies born to vaccinated mothers were 80% less likely to develop COVID, “which is really a huge benefit,” he noted. This is likely a little reduced with Omicron because the only thing that babies get from the mother is antibodies, not T cell immunity.

Vaccination also reduces the risk of adverse pregnancy outcomes such as stillbirth, and safety “is simply not an issue” as supported by the data. He says there is case for vaccinating pregnant women, even under 45, in the second trimester of the pregnancy so that more antibodies are transferred to the foetus.

Categories : Injury & TraumaTags :

A Handheld Terahertz Scanner Could Accurately Assess Burns

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Ambulance
Photo by Camilo Jimenez on Unsplash

Researchers have developed a handheld terahertz (THz) wave imaging device to assess burns faster and more accurately than current methods. The new device uses neural network model that uses terahertz time-domain spectroscopy (THz-TDS) data for non-invasive burn assessment.

“It is important for healthcare professionals to accurately assess the depth of a burn to provide the most appropriate treatment,” said research team leader M. Hassan Arbab from Stony Brook University. “However, current methods of burn depth evaluation, which rely on visual and tactile examination, have been shown to be unreliable, with accuracy rates hovering around 60–75%. Our new approach could potentially improve the accuracy of burn severity assessments and aid in treatment planning.”

THz-TDS uses short pulses of terahertz radiation, which lies between infrared and microwave wavelengths, to probe a sample. It is being examined for assessing burn injuries because physical changes caused by a burn will produce alterations in the skin’s terahertz reflectivity.

In the journal Biomedical Optics Express, the researchers reported that their artificial neural network classification algorithm was able to accurately predict the ultimate healing outcome of in vivo burns in an animal study with 93% accuracy. Their method needs much less training data, potentially making it more practical to process big data sets obtained over large clinical trials.

“In 2018, approximately 416 000 patients were treated for burn injuries in emergency departments in the United States alone,” said Arbab. “Our research has the potential to significantly improve burn healing outcomes by guiding surgical treatment plans, which could have a major impact on reducing the length of hospital stays and number of surgical procedures for skin grafting while also improving rehabilitation after injury.”

Better burn assessment

Various technologies have been developed to improve burn assessment, but they haven’t been widely adopted in the clinic due to drawbacks such as long acquisition times, high costs and limited penetration depth and field of view. Although THz-TDS looks promising for burn assessment, early demonstrations were limited to point spectroscopy measurements, which don’t account for burn heterogeneity and spatial variations. THz spectroscopy setups also tend to be bulky and difficult to set up.

“To address these challenges, we developed the portable handheld spectral reflection (PHASR) scanner, a user-friendly device for fast hyperspectral imaging of in vivo burn injuries using THz-TDS,” said Arbab. The device allows for “rapid imaging of a 37 x 27 mm2 field of view in just a few seconds.”

Previously, the researchers used numerical methods to extract features from the THz-TDS images and machine learning techniques to estimate the severity grade of in vivo burn injuries using measurements from the PHASR scanner. However, this approach did not consider the physical dynamics and macroscopic changes of the dielectric permittivity of burned skin tissue. Dielectric permittivity describes how a material responds to an electric field, and the researchers used Debye theory to explain how biological material interacts with THz waves.

The researchers tested their method by using the PHASR scanner to obtain spectroscopic images of skin burns and measure the permittivity of the burns. The researchers used this data to create a neural network model based on labelled biopsies. The model estimated the severity of the burns with an average accuracy rate of 84.5% and predicted the outcome of the wound healing process with an accuracy rate of 93%.

The researchers note that clinical testing of both the technique and the handheld imaging device are needed before this technique could be integrated into the existing workflow of clinical burn assessment.

Source: Optica

Categories : Medical Research & TechnologyTags :

New Mathematical Model for Potassium Homeostasis

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Blood samples
Photo by National Cancer Institute on Unsplash

Potassium is essential to normal cellular function, helping the cardiac muscle work correctly and aids in the transmission of electrical signals within cells. A new mathematical model published in PLOS Computational Biology sheds light on the often mysterious process of potassium homeostasis.

Using existing biological data, researchers at the University of Waterloo built a mathematical model that simulates how an average person’s body regulates potassium, both in times of potassium depletion and during potassium intake. Because so many foods contain abundant potassium, the body is continually storing, deploying, and disposing of potassium to keep it in a healthy range, ie the process of potassium homeostasis. Understanding potassium homeostasis is essential in helping diagnose the source of the problem when something goes wrong, for example, when kidney disease or medication leads to dysregulation.

“Too much potassium in the body, or hyperkalaemia, can be just as dangerous as hypokalaemia, or too little,” said study lead author Melissa M. Stadt, a PhD student in applied mathematics. “Dysregulation of potassium can lead to dangerous and potentially fatal consequences.”

The model could be used for a virtual patient trial, allowing researchers to generate dozens of patients and then predict which ones would have hyper- or hypokalaemia based on different controls.

“A lot of our models are pieces of a bigger picture,” said Anita Layton, professor of applied mathematics and Canada 150 Research Chair in mathematical biology and medicine. “This model is one new and exciting piece in helping us understand how our incredibly complex internal systems work.”

The model is especially exciting because it allows scientists to test the muscle-kidney cross-talk signal hypothesis. Scientists have hypothesised that skeletal muscles, which store most of the body’s potassium, can directly signal to the kidneys to dump potassium when there’s too much stores, and vice versa. When the mathematical researchers tested the hypothesis in their model, it more accurately reflected existing biological data regarding potassium homeostasis, suggesting that muscle-kidney cross talk might be an essential piece in the puzzle of potassium regulation.

Source: University of Waterloo

Categories : COVIDTags :

Updated Bivalent Boosters Offer Better Protection against Omicron

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A real-world effectiveness study of updated bivalent mRNA vaccines has shown that bivalent boosters are more effective than original monovalent boosters at preventing hospitalisation and death from the Omicron variant. The study was published today in The New England Journal of Medicine.

“While original COVID vaccines had been demonstrated to be safe and effective prior to the FDA’s authorisation, the Pfizer and Moderna bivalent vaccines that have been deployed in the United States since last fall were approved by the FDA for emergency use on the basis of non-clinical data for those two new vaccines,” explains Dr Danyu Lin, lead author on the study. “We were able to evaluate not only the effectiveness of the two bivalent boosters but also compare their effectiveness to that of monovalent boosters.”

Researchers at the at the University of North Carolina’s Gillings School of Global Public Health compared the incidence of severe Omicron infection resulting in hospitalisation or death for individuals aged 12 and up who received a monovalent or bivalent booster dose to those who did not. The study analysed vaccination and infection data of more than six million North Carolina residents from May to December of 2022, during which the Omicron variant’s BA.4.6/BA.5 and BQ.1/BQ.1.1 strains were predominant in the United States. Both the Pfizer and Moderna bivalent vaccines were included in the study, which also considered different age groups, previous infection status, and the number of booster doses already received.

The effectiveness of the booster was highest at roughly four weeks after administration and decreased afterward. Average effectiveness against severe infection resulting in hospitalisation or death over a three-month period was 25% for one monovalent booster dose and 62% for one bivalent booster dose.

“The increased effectiveness found in this study demonstrates why it’s important for people to protect themselves with the updated booster even if they had already gotten the original booster dose,” says Dr Zack Moore, State Epidemiologist with the North Carolina Department of Health and Human Services.

Source: University of North Carolina at Chapel Hill

Categories : Cardiovascular DiseaseTags :

Gum Infection may be a Risk Factor for Arrhythmia

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Dentist checking teeth
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Periodontitis can lead to a litany of dental issues from bad breath to bleeding and tooth loss, and has long been suspected to be connected to other negative health outcomes in the body. Researchers at Hiroshima University have now found evidence that periodontitis could be connected to atrial fibrosis and arrythmias.

In a study published in JACC: Clinical Electrophysiology, the team found a significant correlation between periodontitis and fibrosis (which is scarring to an appendage of the heart’s left atrium that can lead to an irregular heartbeat called atrial fibrillation) in a sample of 76 patients with cardiac disease.

“Periodontitis is associated with a long-standing inflammation, and inflammation plays a key role in atrial fibrosis progression and atrial fibrillation pathogenesis,” said first author Shunsuke Miyauchi, assistant professor with the Hiroshima University’s Health Service Center. He is also affiliated with the university’s Graduate School of Biomedical and Health Sciences. “We hypothesised that periodontitis exacerbates atrial fibrosis. This histological study of left atrial appendages aimed to clarify the relationship between clinical periodontitis status and degree of atrial fibrosis.”

The left atrial appendages were surgically removed from the patients, and the researchers analysed the tissue to establish the correlation between severity of the atrial fibrosis and severity of the gum disease. They found that the worse the periodontitis, the worse the fibrosis, suggesting that the inflammation of gums may intensify inflammation and disease in the heart.

“This study provides basic evidence that periodontitis can aggravate atrial fibrosis and can be a novel modifiable risk factor for atrial fibrillation,” said corresponding author Yukiko Nakano, professor of cardiovascular medicine in Hiroshima University’s Graduate School of Biomedical and Health Sciences.

According to Nakano, in addition to improving other risk factors such as weight, activity levels, tobacco and alcohol use, periodontal care could aid in comprehensive atrial fibrillation management. However, she cautioned that this study did not establish a causal relationship, meaning that while gum disease and atrial fibrosis degrees of severity appear connected, researchers have not found that one definitively leads to the other.

“Further evidence is required for establishing that periodontitis contributes to the atrial fibrosis in a causal manner and that periodontal care can alter fibrosis,” Nakano said. “One of our goals is to confirm that periodontitis is a modifiable risk factor for atrial fibrillation and to promote dental specialists’ participation in comprehensive atrial fibrillation management. Periodontitis is an easy modifiable target with lower cost among known atrial fibrillation risk factors. Thus, the achievement of this study series may bring benefits for many people worldwide.”

Next, the researchers said they hope to conduct future clinical trials to clarify if periodontal intervention reduces atrial fibrillation occurrence and improves patient outcomes.

Source: Hiroshima University

Categories : Cancer Cardiovascular Disease PaediatricsTags :

First Guideline for Heart Complications in Childhood Cancer Treatment

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Photo by National Cancer Institute on Unsplash

Experts led by researchers from the Murdoch Children’s Research Institute have created the world’s first international clinical guidelines to help prevent and treat heart complications in children undergoing cancer treatment.

Published in JACC:Advances, the guidelines cover cardiovascular disease assessment, screening and follow-up, for paediatric patients receiving cancer treatment with new molecular therapies, immunotherapy, chemotherapy and radiotherapy.

The expert consensus has defined the high-risk group of cancer patients who should undergo a heart check-up, standardised an approach to screening and surveillance during treatment and provided recommendations to protect vulnerable young hearts.

Murdoch Children’s Associate Professor Rachel Conyers said while international guidelines to monitor poor heart side effects during therapy exist for adult patients, none were specific to children.

Associate Professor Conyers said the success of new cancer drugs had increased the chances of cardiac side effects that occur early on during therapy, sometimes within days, which warranted closer heart health surveillance and earlier monitoring.

“Recent advances in treating childhood cancer have resulted in survival rates of more than 80 percent. However, improving serious health outcomes in survivors remains an important and essential focus and prevention is key,” she said.

“Heart complications are a leading cause of death for childhood cancer survivors, second only to cancer relapse. Modern treatments including precision medicine have broadened the agents that can cause heart problems.”

Childhood cancer survivors are 15 times more likely to have heart failure and eight times more likely to have heart disease than the general population.

Associate Professor Conyers said the guidelines would be an indispensable tool for clinicians to significantly reduce the harmful impact of cancer drugs on children’s hearts.

“The guidelines are a major advance for the cardio-oncology field as before this there was no defined approach for surveillance or follow up of pediatric patients during treatment despite new therapeutics having early heart complications such as high blood pressure, abnormal heart beats and heart failure,” she said.

The Australian and New Zealand expert group consisted of pediatric and adult cardiologists and pediatric oncologists who undertook a Delphi consensus approach across 11 areas of cardio-oncology care. The Australian New Zealand Children’s Oncology Group endorsed the study with the guidelines useful for any tertiary institutes treating pediatric oncology patients or initiating cardio-oncology clinics.

Source: Murdoch Children’s Research Institute

Categories : Antibiotics Diseases, Syndromes and ConditionsTags :

Antibiotic Regimen may be Ineffective in TB Meningitis

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Tuberculosis bacteria
Tuberculosis bacteria. Credit: CDC

Research in animal models published in Nature Communications shows that an approved antibiotic regimen for multidrug-resistant (MDR) tuberculosis (TB) may not work for TB meningitis. Limited human studies also provide evidence that a new combination of drugs is needed to develop effective treatments for TB meningitis due to MDR strains.

In the study from Johns Hopkins Children’s Center, the investigators showed that the Food and Drug Administration (FDA)-approved regimen of three antibiotics – bedaquiline, pretomanid and linezolid (BPaL) – used for treating TB of the lungs due to MDR strains, is not effective in treating TB meningitis because bedaquiline and linezolid struggle to cross the blood-brain barrier.

Tuberculosis, caused by the bacteria Mycobacterium tuberculosis, is a global public health threat. About 1%–2% of TB cases progress into TB meningitis, the worst form of TB, which leads to an infection in the brain that causes increased fluid and inflammation.

“Most treatments for TB meningitis are based on studies of treatments for pulmonary TB, so we don’t have good treatment options for TB meningitis,” explains Sanjay Jain, M.D., senior author of the study and director of the Johns Hopkins Medicine Center for Infection and Inflammation Imaging Research.

In 2019, the FDA approved the BPaL regimen to treat MDR strains of TB, specifically those that lead to pulmonary TB. However, there are limited data on how well these antibiotics cross the blood-brain barrier.

In an effort to learn more, the research team synthesised a chemically identical and imageable version of the antibiotic pretomanid. They conducted experiments in mouse and rabbit models of TB meningitis using positron emission tomography (PET) imaging to noninvasively measure pretomanid penetration into the central nervous system as well as using direct drug measurements in mouse brains. In both models, researchers say PET imaging demonstrated excellent penetration of pretomanid into the brain or the central nervous system. However, the pretomanid levels in the cerebrospinal fluid (CSF) that bathes the brain were many times lower than in the brains of mice.

“When we have measured drug concentrations in the spinal fluid, we have found that many times they have no relation to what’s happening in the brain,” says Elizabeth Tucker, MD, a study first author and an assistant professor of anaesthesiology and critical care medicine. “This finding will change how we interpret data from clinical trials and, ultimately, treat infections in the brain.”

Next, researchers measured the efficacy of the BPaL regimen compared with the standard TB treatment for drug-susceptible strains, a combination of the antibiotics rifampin, isoniazid and pyrazinamide. Results showed that the antibacterial effect in the brain using the BPaL regimen in the mouse model was about 50 times lower than the standard TB regimen after six weeks of treatment, likely due to restricted penetration of bedaquiline and linezolid into the brain. The bottom line, says Jain, is that the “regimen that we think works really well for MDR-TB in the lung does not work in the brain.”

In another experiment involving healthy participants, three male and three female aged 20–53 years, first-in-human PET imaging was used to show pretomanid distribution to major organs, according to researchers.

Similar to the work with mice, this study revealed high penetration of pretomanid into the brain or central nervous system with CSF levels lower than those seen in the brain. “Our findings suggest pretomanid-based regimens, in combination with other antibiotics active against MDR strains with high brain penetration, should be tested for treating MDR-TB meningitis,” says study author Xueyi Chen, MD, a paediatric infectious diseases fellow, who is now studying combinations of such therapies.

Limitations included the small quantities of the imageable version of pretomanid per subject (micrograms) used. However, current evidence suggests that studies with small quantities of a drug are a reliable predictor of the drug biodistribution.

Source: Johns Hopkins Medicine

Categories : PaediatricsTags :

Outdoor Play can Mitigate the Worst Effects of Kids’ Screen Time

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Photo by Emily Wade on Unsplash

Children around the world are spending more and more time with screens, which is a great concern for parents and physicians alike. New research from Japan indicates that more screen time at age 2 is associated with poorer communication and daily living skills at age 4 – but playing outdoor seems to reduce some of the negative effects.

For their study, published in JAMA Pediatrics, the researchers followed 885 children from 18 months to 4 years of age. They looked at the relationship between three key features: average amount of screen time per day at age 2, amount of outdoor play at age 2 years 8 months, and neurodevelopmental outcomes at age 4: communication, daily living skills, and socialization scores according to a standardised assessment tool called Vineland Adaptive Behavior Scale-II.

“Although both communication and daily living skills were worse in 4-year-old children who had had more screen time at aged 2, outdoor play time had very different effects on these two neurodevelopmental outcomes,” explains Kenji J. Tsuchiya, Professor at Osaka University and lead author of the study. “We were surprised to find that outdoor play didn’t really alter the negative effects of screen time on communication – but it did have an effect on daily living skills.”

Specifically, almost one-fifth of the effects of screen time on daily living skills were mediated by outdoor play, meaning that increasing outdoor play time could reduce the negative effects of screen time on daily living skills by almost 20%. The researchers also found that, although it was not linked to screen time, socialisation was better in 4-year-olds who had spent more time playing outside at 2 years 8 months of age.

“Taken together, our findings indicate that optimizing screen time in young children is really important for appropriate neurodevelopment,” says Tomoko Nishimura, senior author of the study. “We also found that screen time is not related to social outcomes, and that even if screen time is relatively high, encouraging more outdoor play time might help to keep kids healthy and developing appropriately.”

These results are particularly important given the recent COVID-related lockdowns around the world, which have generally led to more screen time and less outdoor time for children. Because the use of digital devices is difficult to avoid even in very young children, further research looking at how to balance the risks and benefits of screen time in young children is eagerly awaited.

Source: Osaka University

Categories : Diet and Nutrition NeurologyTags :

High-fat Diets Overload the Ability to Moderate Calorie Intake

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Regularly eating a high fat/calorie diet could reduce the brain’s ability to regulate calorie intake, according to a study published in The Journal of Physiology. Rat studies revealed a signalling pathway which causes a quick response to high fat/high calorie intake, reducing food and calorie intake. But continuously eating a high fat/calorie diet seems to disrupt this signalling pathway, sabotaging this short-term protection.

Senior author Dr Kirsteen Browning said, “Calorie intake seems to be regulated in the short-term by astrocytes. We found that a brief exposure (three to five days) of high fat/calorie diet has the greatest effect on astrocytes, triggering the normal signalling pathway to control the stomach. Over time, astrocytes seem to desensitise to the high fat food. Around 10–14 days of eating high fat/calorie diet, astrocytes seem to fail to react and the brain’s ability to regulate calorie intake seems to be lost. This disrupts the signalling to the stomach and delays how it empties.”

Astrocytes initially react when high fat/calorie food is ingested, triggering the release of gliotransmitters, chemicals (including glutamate and ATP) that excite nerve cells and enable normal signalling pathways to stimulate neurons that control stomach function. This ensures the stomach contracts correctly to fill and empty in response to food passing through the digestive system. When astrocytes are inhibited, the cascade is disrupted. The decrease in signalling chemicals leads to a delay in digestion because the stomach doesn’t fill and empty appropriately.

The vigorous investigation used behavioural observation to monitor food intake in rats which were fed a control or high fat/calorie diet for one, three, five or 14 days. This was combined with pharmacological and specialist genetic approaches (both in vivo and in vitro) to target distinct neural circuits, which enabled the researchers to specifically inhibit astrocytes in a particular region of the brainstem. In this way, they assessed the response of individual neurons.

Human studies will need to be carried out to confirm if the same mechanism occurs in humans. If this is the case, further testing will be required to assess if the mechanism could be safely targeted without disrupting other neural pathways.

The researchers have plans to further explore the mechanism. Dr Browning said, “We have yet to find out whether the loss of astrocyte activity and the signalling mechanism is the cause of overeating or that it occurs in response to the overeating. We are eager to find out whether it is possible to reactivate the brain’s apparent lost ability to regulate calorie intake. If this is the case, it could lead to interventions to help restore calorie regulation in humans.”

Source: The Physiological Society

Categories : CancerTags :

Actin Filaments Act as Pipelines for Metastatic Factors

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Lung cancer cells in the process of metastasising. Source: National Cancer Institute on Unsplash

When cancer cells metastasise, they have to break connections with neighbouring cells and migrate to other tissues. Both processes are promoted by signalling molecules released by the cancer cells, which thereby increase the malignancy of tumours. Researchers found that the release of these ‘prometastatic’ factors is influenced by the cellular skeleton – specifically, actin filaments. The study was published in Advanced Science.

Actin’s multiple role functions in cancer propagation

Actin filaments are part of the cell skeleton and essential for stability and motility. They form a network that dynamically builds up and gets broken down by the addition or detachment of building blocks at the filaments’ ends. These processes are precisely regulated by other molecules, such as formins. The dynamics of the actin network enable the movement of cells, for example during development or wound closure, but also that of spreading cancer cells. Actin also plays a role in the transport of substances within the cell. However, this is less well understood than that of other intracellular transport mechanisms.

The research team led by Prof Dr Robert Grosse and Dr Carsten Schwan from the University of Freiburg, now found that the actin network also enables the release of prometastatic factors, such as ANGPTL4 which is an important prometastatic factor that promotes the formation of metastases in various types of cancer. For their study, they used high-resolution microscopy to track the movement of individual transport vesicles within living cancer cells.

“We observed that ANGPTL4-loaded vesicles are conveyed to the periphery of the cell by means of dynamic and localised polymerisation of actin filaments,” says Grosse, who is a member of the Cluster of Excellence CIBSS – Centre for Integrative Biological Signalling Studies at the University of Freiburg.

Transportation along actin filaments

Based on microscopic observations and genetic analyses, the scientists conclude that the vesicles’ movement is controlled by the formin-like molecule FMNL2 by initiating polymerisation (ie elongation) of actin filaments directly at the vesicle. “We already knew that increased FMNL2 activity has prometastatic effects in many types of tumours,” says Grosse. “In our current work we could now demonstrate an important underlying process and a connection to the TGFbeta signalling pathway.” According to the scientist, this knowledge could be used for tumour diagnostics or therapy. for example, by developing an antibody that indicates the presence of active FMNL2 or pharmacologically targets active, phosphorylated FMNL2.

Source: University of Freiburg