Researchers Discover New Particle in The Blood of Septic Patients (Medicine)

LJI scientists get first glimpse of how mysterious particles break off of immune cells.

Researchers at La Jolla Institute for Immunology (LJI) have found that people with sepsis have never-before-seen particles in their blood. The scientists are the first to show that these particles, called elongated neutrophil-derived structures (ENDS), break off of immune cells and change their shape as they course through the body.

This timelapse image shows the appearance of an ENDS and how it curls over time. ©Alex Marki, Ph.D., Ley Laboratory, La Jolla Institute for Immunology

“We actually found a new particle in the human body that had never been described before,” explains LJI Instructor Alex Marki, M.D., who served as first author of the study. “That’s not something that happens every day.”

The research, published December 4, 2020 in the Journal of Experimental Medicine shows the importance of understanding how immune cells change over the course of a disease.

“ENDS are not normal–they are not detectable in healthy people or mice,” says LJI Professor Klaus Ley, M.D., who served as senior author of the study. “But ENDS are very high in sepsis, and I would not be surprised if they were high in other inflammatory diseases.”

The beginning of the ENDS

The discovery of ENDS started with an odd observation.

Marki was studying neutrophils, a kind of immune cell that moves through the bloodstream and slips into tissues to fight infections. At the time, he was studying living mice to confirm the presence of tubes called tethers. These tethers are attached to neutrophils as they roll on the blood vessel wall.

During these experiments Marki noticed long, thin objects of neutrophil origin sticking to the vessel wall. Since no such structure was described in the scientific literature, the team had to come up with a name for them. The initial lab slang name “sausages” was eventually replaced by the elongated neutrophil-derived structures or ENDS.

Desperate for learning more about these new objects, the LJI team developed a series of new techniques to study how ENDS form and degrade–and to detect them in human and mouse blood plasma.

Thanks to sophisticated imaging techniques, the LJI team figured out that tethers become ENDS. As the neutrophils flop and roll along, their tethers get longer and longer. Eventually the tethers become too thin–just 150 nanometers (around 1/500th the width of a human hair). Then they break in the middle. Part of the tether stays with the neutrophil, but the broken fragment flies away in the bloodstream, off to form an ENDS.

The researchers showed that these ENDS curl against the vessel wall until they get a rounded shape. It’s likely that the ENDS stay intact for a while, but not for long. Without any life-sustaining organelles inside, the ENDS begin to die. In fact, the researchers found that the ENDS secrete tell-tale signaling molecules that promote inflammation.

Compared with healthy subjects, the researchers showed that ENDS are around 100-fold more detectable in septic patients.

What this means for sepsis

Sepsis can occur when the immune system overreacts to an infection by flooding the body with dangerous chemicals. Instead of just fighting the infection, these chemicals trigger organ damage as they course through the bloodstream. The mortality rate for septic “shock” is 30 percent.

“Once you’re in the hospital, sepsis is the most common cause of death,” Ley says.

Ley and Marki are still not sure why ENDS form in patients with sepsis. To learn more, Marki hopes to collect more patient samples to track ENDS formation and frequency over time. “I’d like to study blood from several time points from each patient–to see the dynamics of how ENDS change,” he says.

Ley says it is theoretically possible that ENDS could one day serve as a biomarker for early sepsis detection, but it is currently impossible to detect them in a clinical setting. “Right now, the assay is not practical because it takes specialized instrumentation,” says Ley.

Rather than serving as a diagnostic, Ley thinks studying ENDS could reveal secrets to how the immune system evolved. He’s curious to learn how the process to form ENDS evolved–and why.

“Neutrophils are very soft cells that can deform to reach almost any place in the body,” says Ley. “So one hypothesis I have is that ENDS might be the price you pay for having such a soft cell–that if you pull too hard, it falls apart.”

Reference: Alex Marki et al.,”Elongated neutrophil-derived structures are blood-borne microparticles formed by rolling neutrophils during sepsis”, Journal of Experimental Medicine, 2020. https://doi.org/10.1084/jem.20200551 https://apps.crossref.org/pendingpub/pendingpub.html?doi=10.1084%2Fjem.20200551

Provided by LA Jolla Institute for Immunology

About La Jolla Institute for Immunology

The La Jolla Institute for Immunology is dedicated to understanding the intricacies and power of the immune system so that we may apply that knowledge to promote human health and prevent a wide range of diseases. Since its founding in 1988 as an independent, nonprofit research organization, the Institute has made numerous advances leading toward its goal: life without disease.

Inouye Solar Telescope Releases First Image of a Sunspot (Planetary Science)

The world’s largest solar observatory, the U.S. National Science Foundation’s Daniel K. Inouye Solar Telescope, just released its first image of a sunspot. Although the telescope is still in the final phases of completion, the image is an indication of how the telescope’s advanced optics and four-meter primary mirror will give scientists the best view of the Sun from Earth throughout the next solar cycle.

This is the first sunspot image taken on Jan. 28, 2020, by the NSF’s Inouye Solar Telescope’s Wave Front Correction context viewer. The image reveals striking details of the sunspot’s structure as seen at the sun’s surface. The sunspot is sculpted by a convergence of intense magnetic fields and hot gas boiling up from below. This image uses a warm palette of red and orange, but the context viewer took this sunspot image at the wavelength of 530 nanometers — in the greenish-yellow part of the visible spectrum. This is not the same naked eye sunspot group visible on the sun in late November and early December 2020. ©NSO/AURA/NSF

The image, taken January 28, 2020, is not the same naked eye sunspot currently visible on the Sun. This sunspot image accompanies a new paper by Dr. Thomas Rimmele and his team. Rimmele is the associate director at NSF’s National Solar Observatory (NSO), the organization responsible for building and operating the Inouye Solar Telescope. The paper is the first in a series of Inouye-related articles featured in Solar Physics. The paper details the optics, mechanical systems, instruments, operational plans and scientific objectives of the Inouye Solar Telescope. Solar Physics will publish the remaining papers in early 2021.

Read Daniel K. Inouye Solar Telescope – Observatory Overview, by Thomas R. Rimmele et al. – Solar Physics volume 295, issue 12, 2020

“The sunspot image achieves a spatial resolution about 2.5 times higher than ever previously achieved, showing magnetic structures as small as 20 kilometers on the surface of the sun,” said Rimmele.

The image reveals striking details of the sunspot’s structure as seen at the Sun’s surface. The streaky appearance of hot and cool gas spidering out from the darker center is the result of sculpting by a convergence of intense magnetic fields and hot gasses boiling up from below.

The National Science Foundation’s Inouye Solar Telescope. ©NSF/NSO/AURA

The concentration of magnetic fields in this dark region suppresses heat within the Sun from reaching the surface. Although the dark area of the sunspot is cooler than the surrounding area of the Sun, it is still extremely hot with a temperature of more than 7,500 degrees Fahrenheit.

This sunspot image, measuring about 10,000 miles across, is just a tiny part of the Sun. However, the sunspot is large enough that Earth could comfortably fit inside.

Sunspots are the most visible representation of solar activity. Scientists know that the more sunspots that are visible on the Sun, the more active the Sun is. The Sun reached solar minimum, the time of fewest sunspots during its 11-year solar cycle, in December 2019. This sunspot was one of the first of the new solar cycle. Solar maximum for the current solar cycle is predicted in mid-2025.

“With this solar cycle just beginning, we also enter the era of the Inouye Solar Telescope,” says Dr. Matt Mountain, president of the Association of Universities for Research in Astronomy (AURA), the organization that manages NSO and the Inouye Solar Telescope. “We can now point the world’s most advanced solar telescope at the Sun to capture and share incredibly detailed images and add to our scientific insights about the Sun’s activity.”

Sunspots, and associated solar flares and coronal mass ejections, cause many space weather events, which frequently impact the Earth, a consequence of living inside the extended atmosphere of a star. These events affect technological life on Earth. The magnetic fields associated with solar storms can impact power grids, communications, GPS navigation, air travel, satellites and humans living in space. The Inouye Solar Telescope is poised to add important capabilities to the complement of tools optimized to study solar activity particularly magnetic fields.

NSF’s Inouye Solar Telescope is located on the island of Maui in Hawai?i. Construction began in 2013 and is slated to be completed in 2021.

“While the start of telescope operations has been slightly delayed due to the impacts of the COVID-19 global pandemic,” said Dr. David Boboltz, NSF Program Director for the Inouye Solar Telescope, “this image represents an early preview of the unprecedented capabilities that the facility will bring to bear on our understanding of the Sun.”

The Daniel K. Inouye Solar Telescope is a facility of the National Science Foundation operated by the National Solar Observatory under a cooperative agreement with the Association of Universities for Research in Astronomy, Inc. The Inouye Solar Telescope is located on land of spiritual and cultural significance to Native Hawaiian people. The use of this important site to further scientific knowledge is done so with appreciation and respect.

References: Rimmele, T.R., Warner, M., Keil, S.L. et al. The Daniel K. Inouye Solar Telescope – Observatory Overview. Sol Phys 295, 172 (2020). https://link.springer.com/article/10.1007%2Fs11207-020-01736-7 https://doi.org/10.1007/s11207-020-01736-7

Provided by Association of Universities for Research in Astronomy

Rochester Researchers Uncover Key Clues About the Solar System’s History (Astronomy)

New clues lead to a better understanding of the evolution of the solar system and the origin of Earth as a habitable planet.

In a new paper published in the journal Nature Communications Earth and Environment, researchers at the University of Rochester were able to use magnetism to determine, for the first time, when carbonaceous chondrite asteroids–asteroids that are rich in water and amino acids–first arrived in the inner solar system. The research provides data that helps inform scientists about the early origins of the solar system and why some planets, such as Earth, became habitable and were able to sustain conditions conducive for life, while other planets, such as Mars, did not.

Illustration of solar wind flowing over asteroids in the early solar system. The magnetic field of the solar wind (white line/arrows) magnetizes the asteroid (red arrow). Researchers at the University of Rochester used magnetism to determine, for the first time, when carbonaceous chondrite asteroids first arrived in the inner solar system. ©University of Rochester illustration / Michael Osadciw

The research also gives scientists data that can be applied to the discovery of new exoplanets.

“There is special interest in defining this history–in reference to the huge number of exoplanet discoveries–to deduce whether events might have been similar or different in exo-solar systems,” says John Tarduno, the William R. Kenan, Jr., Professor in the Department of Earth and Environmental Sciences and dean of research for Arts, Sciences & Engineering at Rochester. “This is another component of the search for other habitable planets.”

SOLVING A PARADOX USING A METEORITE IN MEXICO

Some meteorites are pieces of debris from outer space objects such as asteroids. After breaking apart from their “parent bodies,” these pieces are able to survive passing through the atmosphere and eventually hit the surface of a planet or moon.

Studying the magnetization of meteorites can give researchers a better idea of when the objects formed and where they were located early in the solar system’s history.

“We realized several years ago that we could use the magnetism of meteorites derived from asteroids to determine how far these meteorites were from the sun when their magnetic minerals formed,” Tarduno says.

In order to learn more about the origin of meteorites and their parent bodies, Tarduno and the researchers studied magnetic data collected from the Allende meteorite, which fell to Earth and landed in Mexico in 1969. The Allende meteorite is the largest carbonaceous chondrite meteorite found on Earth and contains minerals–calcium-aluminum inclusions–that are thought to be the first solids formed in the solar system. It is one of the most studied meteorites and was considered for decades to be the classic example of a meteorite from a primitive asteroid parent body.

In order to determine when the objects formed and where they were located, the researchers first had to address a paradox about meteorites that was confounding the scientific community: how did the meteorites gain magnetization?

Recently, a controversy arose when some researchers proposed that carbonaceous chondrite meteorites like Allende had been magnetized by a core dynamo, like that of Earth. Earth is known as a differentiated body because it has a crust, mantle, and core that are separated by composition and density. Early in their history, planetary bodies can gain enough heat so that there is widespread melting and the dense material–iron–sinks to the center.

New experiments by Rochester graduate student Tim O’Brien, the first author of the paper, found that magnetic signals interpreted by prior researchers was not actually from a core. Instead, O’Brien found, the magnetism is a property of Allende’s unusual magnetic minerals.

DETERMINING JUPITER’S ROLE IN ASTEROID MIGRATION

Having solved this paradox, O’Brien was able to identify meteorites with other minerals that could faithfully record early solar system magnetizations.

Tarduno’s magnetics group then combined this work with theoretical work from Eric Blackman, a professor of physics and astronomy, and computer simulations led by graduate student Atma Anand and Jonathan Carroll-Nellenback, a computational scientist at Rochester’s Laboratory for Laser Energetics. These simulations showed that solar winds draped around early solar system bodies and it was this solar wind that magnetized the bodies.

Using these simulations and data, the researchers determined that the parent asteroids from which carbonaceous chondrite meteorites broke off arrived in the Asteroid Belt from the outer solar system about 4,562 million years ago, within the first five million years of solar system history.

Tarduno says the analyses and modeling offers more support for the so-called grand tack theory of the motion of Jupiter. While scientists once thought planets and other planetary bodies formed from dust and gas in an orderly distance from the sun, today scientists realize that the gravitational forces associated with giant planets–such as Jupiter and Saturn–can drive the formation and migration of planetary bodies and asteroids. The grand tack theory suggests that asteroids were separated by the gravitational forces of the giant planet Jupiter, whose subsequent migration then mixed the two asteroid groups.

He adds, “This early motion of carbonaceous chondrite asteroids sets the stage for further scattering of water-rich bodies–potentially to Earth–later in the development of the solar system, and it may be a pattern common to exoplanet systems.”

References: O’Brien, T., Tarduno, J.A., Anand, A. et al. Arrival and magnetization of carbonaceous chondrites in the asteroid belt before 4562 million years ago. Commun Earth Environ 1, 54 (2020). https://doi.org/10.1038/s43247-020-00055-w

Provided by University of Rochester

Reusing Face Masks: Are Microwaves The Answer? (Medicine)

Researchers from Cardiff University have been testing the feasibility of using microwave ovens and dry heat to decontaminate crucial PPE being used to combat the coronavirus pandemic.

Credit: Cardiff University

Reporting their findings in the Journal of Hospital Infection, the team have shown that certain types of respirators can be effectively decontaminated in just 90 seconds using an industrial-grade microwave oven and a baby bottle sterilizer containing water.

It has been widely reported that access to respirators and surgical face masks has become restricted in many facilities over the course of the pandemic.

“Being unable to access adequate PPE puts frontline workers and patients at risk of contracting coronavirus. Whilst masks are usually considered to be single use items, we wanted to find out whether they could be safely disinfected and used again,” said co-author of the study Prof Jean-Yves Maillard, from the School of Pharmacy and Pharmaceutical Sciences.

The researchers believe microwave decontamination could be used in emergency situations to address supply issues and dramatically increase the number of respirators available to frontline staff.

In the study, respirators were exposed to three microwave disinfection cycles and were shown to retain their ability to filter bacteria and viral-sized aerosols. However, the researchers reported that microwaving surgical masks led to a complete loss of their aerosol filtering capacity.

Michael Pascoe, co-author of the study from the School of Pharmacy and Pharmaceutical Sciences, said: “Surgical masks are known to lose effectiveness once they become moist—we suspected that microwave disinfection would lead to a similar loss in their ability to filter aerosols and this was confirmed by our lab observations.”

The team, which also includes academics from the School of Engineering, also investigated using dry heat ovens as an alternative approach. Dry heat sterilization does not involve any water and so is compatible with items which are damaged by moisture.

Exposure to 70°C dry heat for 90 minutes was effective at decontaminating both surgical masks and respirators. After three dry heat cycles, both types of mask retained their aerosol filtering properties.

It is essential that PPE is effectively decontaminated between uses. Whilst microwave-generated steam and dry heat have both been shown to effectively kill coronaviruses, the researchers wanted to ensure that this method was also effective against bacteria encountered in healthcare environments.

In the study, respirators and surgical masks were purposely contaminated with Staphylococcus aureus, a bacterial species highly prevalent in human airways which can cause soft tissue infections and sepsis. Staphylococcus aureus is also the accepted biological indicator to test the integrity of a mask.

Both methods effectively reduced the number of bacteria on masks to a safe level.

As a result of the study, the team have developed a protocol to determine which types of PPE would be suitable for different treatments with dry heat incubators or microwave ovens.

“Mask and respirator models vary considerably and so it is important to ensure the method of decontamination does not compromise their function.”

The team warns against members of the public using a similar approach at home. Professor Adrian Porch, from the School of Engineering, said: “Domestic microwave ovens typically have much lower power, around 800 W, and use rotating turntables rather than a rotating antenna. Significantly longer exposure times would be needed to achieve similar results and it is unknown how this would affect the functioning of the mask. Masks which contain thin wires can even catch fire when placed in a microwave.”

Reference: M.J. Pascoe et al. Dry heat and microwave-generated steam protocols for the rapid decontamination of respiratory personal protective equipment in response to COVID-19-related shortages, Journal of Hospital Infection (2020). DOI: 10.1016/j.jhin.2020.07.008

Provided by Cardiff University

Mediterranean Diet Reduces the Risk of Having Another Heart Attack (Cardiology / Medicine)

Heart disease is the main cause of death in developed countries. There is evidence that shows that factors related to lifestyle, such as diet, have an influence on developing these kinds of diseases. But, do they have any effect on patients who are already ill?

Part of the research team. Credit: Maimonides Biomedical Research Institute of Cordoba (IMIBIC)

A team from the University of Córdoba, Queen Sofia University Hospital and the Maimonides Biomedical Research Institute of Cordoba (IMIBIC) has published a study in PLOS Medicine. This study compares the effects of two different healthy diets on the endotheliem, the walls that cover the arteries. 1002 patients who had previously had an acute myocardial infarction took part in the study and were monitored over the course of a year.

The research group had previously worked on a similar study with healthy patients, however, this is the first time it has been done with ill patients, who are more likely to have other heart attacks. “The degree of endothelial damage predicts the occurrence of future cardiovascular events, as in acute myocardial infarctions. If we can take action at the inital stages, prompting endothelium regeneration and better endothelial function, we can help to prevent heart attacks and heart disease from reoccurring,” explains José López Miranda, researcher on the study and coordinator of the “Nutritional Genomics and Metabolic Syndrome” research group at the Maimonides Biomedical Research Institute of Cordoba, made up of researchers belonging to the Internal Medicine Clinical Management Unit at Queen Sofia University Hospital, to the University of Córdoba (UCO) and to CIBERobn, the Online Biomedical Research Centre for Obesity and Nutrition.

During the study, half of the patients were told to follow a Mediterranean diet, based on using plenty of virgin olive oil, eating fruit and vegetables every day, and having three servings of legumes, three of fish and three of nuts a week. In addition, they were told to cut down on eating meat, especially red meat, and to avoid additional fats such as margarine and butter as well as food that is high in sugar.

In contrast, the other group was told to follow a low-fat diet, based on limiting all kinds of fat, both animal and plant, and increasing their intake of complex carbohydrates. They were told to cut down on red meat, to choose low-fat dairy products, to avoid eating nuts and to reduce their intake of sweets and pastries.

In the first place, the vasodilation capacity that the patients’ arteries had was analyzed, which is very important in order to adapt to different circumstances, like exercise or stressful situations. Secondly, the degree of permanent endothelium damage was assessed. Lastly, the reparation ability of the arteries by means of endothelial progenitor cells, or stem cells, was measured.

“We observed that the Mediterranean diet model induced better endothelial function, meaning that the arteries were more flexible in adapting to different situations in which greater blood flow is required. Besides, the endothelium’s ability to regenerate was better and we detected a drastic reduction in damage to the endothelium, even in patients at severe risk,” explains José López Miranda.

Though the Mediterranean diet, rich in monounsaturated fatty acids, had already been proven to be a good strategy in order to improve endothelial function in overweight patients as well as patients with high cholesterol, this is the first time that the benefits of following a Mediterranean diet have been shown among patients with heart disease, helping them to reduce the likelihood of having another heart attack.

Reference: Elena M. Yubero-Serrano et al, Mediterranean diet and endothelial function in patients with coronary heart disease: An analysis of the CORDIOPREV randomized controlled trial, PLOS Medicine (2020). DOI: 10.1371/journal.pmed.1003282 https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1003282

Provided by University of Córdoba

Kidney Injury in Diabetic Ketoacidosis Linked to Brain Injury (Medicine)

Researchers from a consortium of hospitals including Children’s Hospital of Philadelphia (CHOP) have identified factors that make children with diabetic ketoacidosis more likely to experience acute kidney injury. Analyzing data from a large, multicenter clinical trial, the researchers also found that children who experience acute kidney injury are more likely to also experience subtle cognitive impairment and demonstrate lower IQ scores, suggesting a pattern of multiple organ injury. The findings were published online today in JAMA Network Open.

Multiple recent studies have shown that organ injuries in children with diabetic ketoacidosis occur more frequently than previously thought. One recent retrospective study found that acute kidney injury commonly occurs in these children. Earlier analysis of a large, multicenter study demonstrated cerebral injury commonly occurs in diabetic ketoacidosis. Together, these studies raised the possibility of an underlying pathophysiology that connects these injuries across the body if the presence of these injuries were linked in patients.

“We wanted to look at these issues in a more prospective manner,” said Sage Myers, MD, an attending physician in the Emergency Department at CHOP and first author of the study. “With 13 participating emergency departments in the Pediatric Emergency Care Applied Research Network, we had the ability to not only study the frequency of acute kidney injury in these children, but also the underlying factors associated with injury and whether there is an association between the occurrence of acute kidney injury and cerebral injury, which would suggest a possible linkage between the mechanisms of injury underlying both.”

The researchers studied 1,359 episodes of diabetic ketoacidosis in children. Acute kidney injury occurred in 584 (43%) of those episodes, and 252 of those episodes (43%) were classified as either stage 2 or 3, representing more severe cases of kidney injury. When assessing whether acute kidney injury was associated with cognitive issues, children with kidney injuries had lower scores on short-term memory tests during diabetic ketoacidosis, as well as lower IQ scores three to six months after recovering from the condition. These differences persisted after adjusting for the severity of diabetic ketoacidosis and demographic factors like socioeconomic status.

“If we can identify the mechanisms of kidney injury after diabetic ketoacidosis, it can help in the development of new therapeutic and preventive strategies,” said Nathan Kuppermann, MD, professor and chair of emergency medicine at UC Davis Health, and senior author and co-principal investigator of the study. “We’re also hoping to focus future research on how diabetic ketoacidosis causes simultaneous, multi-organ injuries such as what we demonstrated in this study.”

Reference: Myers et al, “Acute Kidney Injury During Diabetic Ketoacidosis in Children: Frequency, Risk Factors, and Association with Neurocognitive Outcomes.” JAMA Network Open (2020). DOI: 10.1001/jamanetworkopen.2020.25481

Provided by Children’s Hospital of Philadelphia

Inducing Accurately Controlled ‘Fever’ in Tumors to Fight Cancer (Medicine)

Heating tumors can greatly enhance the effect of radio- and chemotherapies for cancer. This increases the chances of recovery and helps reduce the use of radiation and drugs, leading to fewer side effects for patients. An effective way of heating tumors is via ultrasound, which is noninvasive and ensures pinpoint accuracy. To optimize the cancer-killing effects of radio- and chemotherapies using thermal ultrasound treatments, Ph.D. candidate Daniel Deenen has developed self-learning algorithms that automatically steer the beams based on the current tumor temperature measurements. This new method could drastically improve patients’ chances for curing from cancer. Deenen defended his thesis on Thursday 3 December.

Using ultrasound to heat up tumors decreases the need for toxic treatments like radiation and chemotherapy. Credit: Eindhoven University of Technology

With more than 18 million new cases and 9 million deaths each year, cancer is the second most significant cause of death globally. In fact, in the Netherlands it is the leading cause, with almost one out of every three deaths being due to cancer. In addition to surgery, cancer treatments typically consist of radio- and chemotherapy, which due to their toxicity are limited in their admissible dose and can lead to severe side effects for the surviving patients.

Fever temperatures

In hyperthermia therapy, tumors are heated to fever temperatures of about 42 °C for 60 minutes or more, which significantly enhances the therapeutic efficacy of radio- and chemotherapies without causing additional toxicity or side effects. As a result, hyperthermia can be used to substantially improve the chance for disease-free and long-term survival, or allows for the use of lower systemic doses of radiation and drugs to reduce the severity of the negative side effects typically associated with cancer treatment. However, accurately controlling the tumor temperature is essential for a successful hyperthermia treatment outcome.

In magnetic-resonance-guided high-intensity focused ultrasound (MR-HIFU) hyperthermia treatments, powerful and millimeter-accurate heating is applied via ultrasound waves, while the tumor temperature is measured in real time using an MRI scanner. This allows for a completely noninvasive treatment, which greatly contributes to the patients’ comfort and well-being.

Controllers

The goal of Deenen’s Ph.D. research was to develop algorithms or ‘controllers’ that automatically steer the HIFU beams based on the current tumor temperature measurements in such a manner that the tumor temperature and, therefore the cancer-killing effects, are optimized. These algorithms learn the tumor’s thermal behavior from measurement data and then adapt the HIFU steering correspondingly. The result is personalized hyperthermia treatments in which accurate and safe heating is ensured.

This is extremely important in practice, since each patient and tumor is different, and may even change over time. Furthermore, he designed controllers that enable the optimal treatment of larger tumors than previously possible. The researcher tested these algorithms on a clinical MR-HIFU setup at, and in collaboration with, the University Hospital of Cologne (Germany) using artificial tissue-mimicking models (so-called phantoms) and in real-life in-vivo experiments for large animals, proving that they can be applied successfully in clinics.

Clinical trials

This Ph.D. research is an important step towards enabling optimal, safe, and effective hyperthermia treatments for people that suffer from cancer. In fact, clinical trials for MR-HIFU hyperthermia are currently being prepared at the University Hospital of Cologne. This is a true advancement in the medical field, and in turn could drastically improve patients’ chances of recovery from cancer.

Reference: Daniel Deenen, “Model predictive control for MR-guided ultrasound hyperthermia in cancer therapy”, Technische Universiteit Eindhoven, 2020. https://research.tue.nl/en/publications/model-predictive-control-for-mr-guided-ultrasound-hyperthermia-in

Provided by Eindhoven University of Technology

Beta2-AR Agonist Therapy Puts the Brakes on Oral Cancer Progression (Oncology / Medicine)

Affecting almost 600,000 people worldwide every year, and with only a 50% survival rate, oral squamous cell carcinoma (OSCC) is one of the more common and deadly forms of cancer. The poor prognosis of OSCC patients is mainly attributed to a lack of therapies that block the metastasis, or spread, of cancer cells from the primary tumor to other sites in the body.

In this study researchers identified isoxsuprine, a β2-adrenergic receptor agonist as an effective inhibitor of mesenchymal phenotypes and migration of oral squamous cell carcinoma cells suggesting that β2-adrenergic receptor signal is a new promising therapeutic target for treatment of oral cancer. Credit: Department of Biochemistry,TMDU

Prior to metastasis, cancer cells undergo a series of changes that cause them to become motile and more invasive. This process, called epithelial-mesenchymal transition (EMT), equips cancer cells with everything they need to travel through the lymphatic system and form secondary tumors. Furthermore, recent reports imply that EMT also confers cancer cells with tumor initiation activity and drug resistance.

Working on the theory that disrupting EMT should prevent cancer progression and therefore reduce OSCC mortality rates, researchers from Tokyo Medical and Dental University (TMDU) screened a panel of small chemical compounds for their ability to reverse the process of EMT in oral cancer cells. The results, published this month in Cancer Science, may represent an exciting new avenue for the treatment of OSCC.

“We identified a beta2-adrenergic receptor (β2-AR) agonist called isoxsuprine that effectively interfered with EMT,” says lead author of the study Shintaro Sakakitani. “Interestingly, previous studies have provided conflicting results regarding the involvement of β-ARs in tumorigenesis—some reports suggest that β-AR signaling is important in tumor progression, while others point to a protective role for β-AR induction.”

After treating a range of oral cancer cell types with isoxsuprine, the researchers found that the resulting increase in β2-AR expression significantly impaired EMT and reduced cell motility. A non-selective agonist called isoprenaline, which enhances the expression of all types of β adrenergic receptor not just β2, produced a similar result.

Confirming the protective role of β-AR activation, the researchers then pre-treated cells with a chemical that prevents receptor expression, resulting in enhanced EMT. Further, deletion of the gene coding for β2-AR completely abolished the protective effects of isoxsuprine.

As a further test of treatment efficacy, the researchers established tumors in mice and provided daily treatment with either isoxsuprine or a placebo. Not surprisingly, at the end of the treatment period, mice that received isoxsuprine had significantly smaller tumors compared with the placebo group, confirming the tumor-suppressive effects of isoxsuprine.

“These results are hugely encouraging,” says senior author Katarzyna Anna Podyma-Inoue. “The efficacy of β-AR-agonist therapy in both the in vitro and in vivo models suggests that this group of compounds may be the answer to preventing metastasis in OSCC and could potentially even inhibit tumor growth, offering a much better prognosis for OSCC patients worldwide.”

References: Shintaro Sakakitani et al, Activation of β2‐adrenergic receptor signals suppresses mesenchymal phenotypes of oral squamous cell carcinoma cells, Cancer Science (2020). DOI: 10.1111/cas.14670 https://onlinelibrary.wiley.com/doi/10.1111/cas.14670

Provided by Tokyo Medical and Dental University

Researchers find ‘Missing Link’ Between Stress And Infertility (Neuroscience)

Otago researchers have found the “missing link between stress and infertility.” Published in The Journal of Neuroscience, and led by Professor Greg Anderson of the Centre for Neuroendocrinology, the research has confirmed in laboratory testing that a population of nerve cells near the base of the brain—the RFRP neurons—become active in stressful situations and then suppress the reproductive system.

“A revolutionary step forward that has become available to neuroscientists in recent years is the ability to control the activity of selected groups of neurons—to either silence or ramp up their activity, and then monitor the outcomes,” Professor Anderson says.

“We used cutting edge transgenic techniques to show that when the activity of the RFRP cells is increased, reproductive hormones are suppressed—in a similar manner to what happens during stress, or during exposure to the stress hormone cortisol.

“Amazingly, when we used cortisol to suppress the reproductive hormones but also silenced the RFRP neurons, the reproductive system continued to function as if cortisol wasn’t there at all—proving that the RFRP neurons are a critical piece of the puzzle in stress-induced suppression of reproduction.”

The reaction was most evident in females.

Professor Anderson started researching the role of RFRP neurons in controlling fertility in mammals about a decade ago.

“I became interested in whether these neurons might be what causes fertility to be suppressed during chronic stress, after reading that these cells become active during stress. This is a question that has remained stubbornly unanswered over the past decades.

“Although it is known that stress steroids—like cortisol—are probably part of the mechanism involved, it is also known that the brain cells that control reproduction are unable to respond to cortisol, so there seemed to be a missing link in the circuit somewhere.

“We have now shown that the RFRP neurons are indeed the missing link between stress and infertility. They become active in stressful situations—perhaps by sensing the increasing levels of cortisol—and they then suppress the reproductive system.”

It is possible drugs could be used to block the actions of the RFRP neurons, and that will be the focus of further research for Professor Anderson.

“We’d like to see if we can overcome stress-induced infertility using drugs which block the actions of the RFRP neurons.

“For women struggling with infertility, drugs which block the actions of the RFRP neurons may prove to be a novel therapy. From what we know about these neurons, such a drug wouldn’t have any side-effects.

“There are such drugs available, but they’re not approved for human use and they would likely need refining,” he says.

Reference: Asha Mamgain et al. RFamide-related peptide neurons modulate reproductive function and stress responses, The Journal of Neuroscience (2020). DOI: 10.1523/JNEUROSCI.1062-20.2020 https://www.jneurosci.org/content/early/2020/11/20/JNEUROSCI.1062-20.2020

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