New Material Could Better Protect Soldiers, Athletes and Motorists (Material Science)

Soldiers, athletes, and motorists could lead safer lives thanks to a new process that could lead to more efficient and re-useable protection from shock and impact, explosion, and vibration, according to a new study.

Pressurised insertion of aqueous solutions into water-repellent nanoporous materials, such as zeolites and metal-organic frameworks, could help to create high-performance energy absorbing systems.

An international research team experimented with hydrothermally stable zeolitic imidazolate frameworks (ZIFs) with a ‘hydrophobic’ cage-like molecular structure – finding that such systems are remarkably effective energy absorbers at realistic, high-rate loading conditions, and this phenomenon is associated with the water clustering and mobility in nanocages.

Researchers from the Universities of Birmingham and Oxford, together with Ghent University, Belgium, published their findings today in Nature Materials.

Dr Yueting Sun, Lecturer in Engineering at the University of Birmingham, commented: “Rubber is widely used for shock absorption nowadays, but the process we have discovered creates a material that can absorb more mechanical energy per gram with very good reusability due to its unique nanoscale mechanism.

“The material has great significance for vehicle crash safety for both occupants and pedestrians, military armoured vehicles and infrastructures as well as human body protection.

“Soldiers and police could benefit from better body armour and bomb suits, athletes might wear more effective helmets, knee pads and shoe insoles as the material is liquid-like and flexible to wear.”

The reusability of the material, stemming from the spontaneous liquid extrusion, also enables the material to be suitable for damping purposes, meaning that it could be used to create vehicles with lower noise and vibration, as well as better ride comfort.

The material could also be incorporated into machinery to reduce harmful vibrations and noise – reducing maintenance costs. It could also be used to reduce the vulnerability to earthquakes of bridges and buildings.

Current state-of-the-art energy absorption materials rely on processes such as extensive plastic deformation, cell buckling, and viscoelastic dissipation – making it difficult to create materials that can provide efficient protection from multiple impacts.

Notes to editors:

  • ‘High rate nanofluidic energy absorption in porous zeolitic frameworks’ – Yueting Sun, Sven M.J. Rogge, Aran Lamaire, Steven Vandenbrande, Jelle Wieme, Clive R. Siviour, Veronique Van Speybroeck and Jin-Chong Tan is published in Nature Materials.

Featured image: Cyclists and other athletes could benefit from better protective equipment © University of Birmingham


Provided by University of Birmingham

SMART Breakthrough in Materials Discovery Enables ‘Twistronics’ for Bulk Systems (Material Science)

The findings allow manipulation of materials for the first time by stacking films at a twist angle, allowing a new way to control light emitting from materials

● Recent discoveries focused on manipulation of atomically-thin 2D materials, while the new breakthrough can be used to stack technologically-relevant 3D materials at a twist angle

● Method allows continuous, systematic control of optical emission intensity and energy, and can produce ultraviolet emissions at room temperature for bulk systems

● The discovery can be significant for applications in medicine, environmental or information technologies.

Researchers from the Low Energy Electronic Systems (LEES) Interdisciplinary Research Group (IRG) at Singapore-MIT Alliance for Research and Technology (SMART), MIT’s research enterprise in Singapore together with Massachusetts Institute of Technology (MIT) and National University of Singapore (NUS) have discovered a new way to control light emission from materials.

Controlling the properties of materials has been the driving force behind most modern technologies – from solar panels, computers, smart vehicles or life-saving hospital equipment. But materials properties have traditionally been adjusted based on their composition, structure, and sometimes size, and most practical devices that produce or generate light use layers of materials of different compositions that can often be difficult to grow.

The breakthrough by SMART researchers and their collaborators offers a new paradigm-shifting approach to tune the optical properties of technologically-relevant materials by changing the twist angle between stacked films, at room temperature. Their findings could have a huge impact on various applications in the medical, biological, and quantum information fields. The team explain their research in a paper titled “Tunable Optical Properties of Thin Films Controlled by the Interface Twist Angle” recently published in the prestigious journal Nano Letters.

“A number of new physical phenomena – such as unconventional superconductivity – have been discovered recently by stacking individual layers of atomically-thin materials on top of each other at a twist angle, which results in the formation of what we call moiré superlattices,” says corresponding author of the paper, Professor Silvija Gradecak from the Department of Materials Science and Engineering at NUS and Principal Investigator at SMART LEES. “The existing methods focus on stacking only thin individual monolayers of film which is laborious, while our discovery would be applicable to thick films as well – making the process of materials discovery much more efficient.”

Their research can also be meaningful for developing the fundamental physics in the field of “twistronics” – the study of how the angle between layers of two-dimensional materials can change their electrical properties. Professor Gradecak points out the field has so far focused on stacking individual monolayers, which requires careful exfoliation and may suffer from relaxation from a twisted state, thus limiting their practical applications. The team’s discovery could make this groundbreaking twist-related phenomenon applicable to thick film systems as well, which are easy to manipulate and industrially relevant.

“Our experiments showed that the same phenomena leading to formation of moiré superlattices in two-dimensional systems can be translated to tune optical properties of three-dimensional, bulk-like hexagonal boron nitride (hBN) even at room temperature,” said Hae Yeon Lee, the lead author of the paper and a Materials Science and Engineering Ph.D. candidate at MIT. “We found that both the intensity and colour of stacked, thick hBN films can be continuously tuned by their relative twist angles and intensity increased by more than 40 times.”

The research results open up a new way to control optical properties of thin films beyond the conventionally used structures especially for applications in medicine, environmental or information technologies.

The research is carried out by SMART and supported by the National Research Foundation (NRF) Singapore under its Campus for Research Excellence And Technological Enterprise (CREATE) programme.

Featured image: Phenomena of moiré superlattices formation in 2D systems translated for use in 3D materials. Nano Letters, Volume 21, Issue 7 © SMART MIT

Provided by Singapore-MIT

Stress Test Finds Cracks in the Resistance of Harmful Hospital Bugs (Biology)

Research has identified critical factors that enable dangerous bacteria to spread disease by surviving on surfaces in hospitals and kitchens.

The study into the mechanisms which enable the opportunistic human pathogen Pseudomonas aeruginosa to survive on surfaces, could lead to new ways of targeting harmful bacteria.

To survive outside their host, pathogenic bacteria must withstand various environmental stresses. One mechanism is the sugar molecule, trehalose, which is associated with a range of external stresses, particularly osmotic shock – sudden changes to the salt concentration surrounding cells.

Researchers at the John Innes Centre analysed how trehalose is metabolised by P. aeruginosa to define its role in protection against external stresses.

Combining analytical biochemistry and reverse genetics – using mutated bacteria lacking key functions – they show that trehalose metabolism in P. aeruginosa is connected to biosynthesis of the carbon storage molecule glycogen.

Experiments showed that disruption of either trehalose or glycogen pathways significantly reduced the ability of P. aeruginosa to survive on man-made surfaces such as kitchen or hospital counters.

The study found that while both trehalose and glycogen are important for stress tolerance in P. aeruginosa they counter distinct stresses: trehalose helps the bacteria to survive in conditions of elevated salt; glycogen contributes to survival in dry (desiccated) environments.

The findings raise the possibility of targeting the trehalose and glycogen pathways to limit pathogen survival on man-made surfaces.

“We have shown how a dangerous human pathogen Pseudomonas aeruginosa responds to environmental challenges, such as salt stress or drying out. Disrupting the production of certain stress-tolerance sugars in this bug significantly reduces its ability to survive on kitchen and hospital worksurfaces,” said corresponding author of the study Dr Jacob Malone.

An unexpected finding was how the bacteria operates different pathways for different stresses, said Dr Malone: “Conventional wisdom says that trehalose was responsible for both phenotypes, but we have shown that trehalose only protects against osmo-stress and glycogen is needed to protect against desiccation. We were also surprised to see such a marked drop in surface survival when we disrupted the pathways in the bugs.”

The next step for the research is to understand how trehalose and glycogen metabolic pathways are regulated in P. aeruginosa and closely related species. The group also wants to understand how glycogen accumulation allows the bacteria to survive in dry environments and provide more explanation of how and when different parts of the pathways are turned on and off.

P. aeruginosa is a significant pathogen in animals as well as humans. In humans it primarily affects immunocompromised individuals, where it is a major cause of pneumonia and hospital-acquired infections. Chronic P. aeruginosa infections occur in 80% of adult cystic fibrosis patients, where it is the primary cause of morbidity and mortality.

The study: Trehalose and α-glucan mediate distinct abiotic stress responses in Pseudomonas aeruginosa appears in PLOS Genetics

This research was funded by UK Research and Innovation | Biotechnology and Biological Sciences Research Council (BBSRC) Institute Strategic Program Grants BB/J004553/1 (Biotic Interactions) and BBS/E/J/000PR9797 (Plant Health) to the John Innes Centre and by two BBSRC DTP PhD studentships. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Featured image: The opportunistic human pathogen Pseudomonas aeruginosa © John Innes Centre


Provided by John Innes Centre

Study Finds Stereotactic Body Radiotherapy is Safe For Treating Multiple Metastases (Medicine)

A phase 1 clinical trial led by investigators at the University of Chicago Medicine testing the effects of stereotactic body radiotherapy for treating multiple metastases has determined that treatments used for single tumors can also be safely used for treating patients with multiple metastases. The study was run through NRG Oncology and sponsored by the National Cancer Institute. The results were published on April 22 in JAMA Oncology.

Cancer is traditionally treated with a combined approach, with clinicians using surgery, chemotherapy and radiation therapy to kill and remove cancerous tumors. Systemic treatments such as chemotherapy often are not enough to stop the cancer’s growth.

Stereotactic body radiation therapy (SBRT) is a type of radiation therapy that uses precisely targeted beams of very high doses of radiation to destroy tumors. The higher doses are more effective at killing cancer cells than traditional radiation therapy, while the careful targeting of tumors reduces damage to noncancerous tissue.

This approach has been used successfully to treat small, early stage tumors, but until now, it was not clear if such high doses of radiation would be safe in patients with multiple tumors due to metastatic cancer. Because SBRT uses multiple, high-intensity radiation beams, physicians have to be especially careful in locating tumors and targeting the radiation beams to maximize benefits and minimize risks — a challenge that Steven Chmura, MD, PhD, likened to trying to “cross the beams” in the “Ghostbusters” movie.

“Part of the difficulty is working out the logistics for testing this approach in patients across multiple institutions,” said Chmura, Professor of Radiation and Cellular Oncology at UChicago Medicine. “We’ve thought for a long time that you could treat three or four metastases at the same time, but it’s very technically complicated to do so. But before we could test this in something like a large, phase 3 clinical trial, we had to prove that we could get multiple institutions together and come up with a ‘cook book’ for how to do this right, ensuring that treatment was the same across the board. This was really like seven phase 1 clinical trials rolled into one.”

A phase 1 clinical trial, led by Chmura, set out to test the safety of such an approach. In a trial of 39 patients who had breast, prostate or non-small cell lung cancer with at least three metastases or two metastases in close proximity, the investigators determined that there were no treatment-related deaths and that the approach was safe enough to begin phase 2/3 clinical trials in a larger group of patients.

“At the end of the trial, the primary endpoint of six-month dose limiting toxicity was 0%,” Chmura said. “This shows us that treating three or four sites of metastases throughout the body with these high-ablative doses of radiotherapy is safe.”

Radiation therapy is not without risks. While the study found that no patients experienced side effects severe enough to call off the study, several adverse events were linked to the treatment, including gastric ulcers, broken bones and bone pain, and pneumonitis. In many cases during the four-year trial, these side effects appeared months to years following treatment, highlighting the importance of maintaining long-term follow-up contact with these patients. Overall, however, none of these treatments or side effects led to increased risk of death.

“People have been saying for years that if we used SBRT in patients with multiple, limited metastases, we could potentially cure more patients,” said Chmura. “But we needed to conduct these large-scale, phase 2/3 clinical trials to prove that. And before we can do those large trials, we had to set up the infrastructure. The greatest challenge was having a whole team of people come together and figure out how we could define the doses and manage the real-time quality assurance to make sure every single patient had the best treatment possible.”

With this collaborative infrastructure in place, the investigators have launched additional trials to test the efficacy of stereotactic body radiation therapy for treating patients with multiple metastases. The group is currently enrolling patients in a phase 2/3 trial for using SBRT for the treatment of metastatic breast cancer, with the goal of treating up to 450 people.

The study, “Evaluation of Safety of Stereotactic Body Radiotherapy for the Treatment of Patients With Multiple Metastases,” was supported by NRG Oncology (UG1CA189867, U10CA180868, U10CA180822) and the National Cancer Institute (U24CA180803). Additional authors include Hania Al-Hallaq and Yasmin Hasan of the University of Chicago Medicine, Kathryn Winter and Jennifer Moughan of NRG Oncology, Clifford Robinson of Washington University, Thomas Pisansky and Sean Park of the Mayo Clinic, Virginia Borges of the University of Colorado-Anschutz Medical Center, Martha Matuszak of the University of Michigan, Sun Yi of the University of Arizona Medical Center, Jose Bazan and Julia White of the Ohio State University, Philip Wong of the Centre Hospitalier de L’Universite de Montréal, Harold Yoon of the Heartland Cancer Research National Cancer Institute, Janet Horton and Joseph Salama of the Duke University Medical Center, Gregory Gan of the New Mexico Minority Underserved National Cancer Institute Community Oncology Research Program, Michael Milano of the University of Rochester, and Elin Ruth Sigurdson of the Fox Chase Cancer Center.


Reference: Steve Chmura, Kathryn A. Winter et al., “Evaluation of Safety of Stereotactic Body Radiotherapy for the Treatment of Patients With Multiple Metastases”, JAMA Oncol. Published online April 22, 2021. doi:10.1001/jamaoncol.2021.0687


Provided by University of Chicago Medical Center

Researchers Find Repetitive Head Impacts Can Result in Functional Brain Impairments (Neuroscience)

Brain Vital Signs Concussion Study in Bantam and Junior A Ice-Hockey Detects Significant Subconcussive Changes in Cognitive Brain Function

Neuroscience researchers at Mayo Clinic Orthopedics and Sports Medicine in Rochester, Minnesota, U.S., the Health and Technology District and Simon Fraser University (SFU) in Surrey, British Columbia, Canada have published the latest results of their ongoing multi-year hockey concussion study examining changes in subconcussive cognitive brain function in male youth ice hockey players.

The research team monitored brain vital signs during pre- and post-season play in 23 Bantam (age 14 or under) and Junior A (age 16 to 20) male ice-hockey players in Rochester, Minnesota.

“Brain vital signs” translates complex brain waves measured using portable electroencephalography (EEG) at the rink-side, into simple, fast, user-friendly and intuitive results that provide an objective evaluation of cognitive brain function. Called the ABCs of brain function, brain vital signs track three well-established neural responses for Auditory sensation (using a response called the N100), Basic attention (using a response called the P300), and Cognitive processing (using a response called the N400).

The study builds on 2019 results published in Brain: A Journal of Neurology that confirmed significant brain vitals sign changes shortly after concussions were diagnosed in Junior A players. Key results of this study showed undetected impairments remained when players were cleared to return to play using current clinical concussion protocols. Notably, the initial study also reported sensitivity to subconcussive impairments in those players who did not sustain a concussion diagnosis over the course of the season.

The current second phase of the study replicated these results and added the Bantam age group. The latest findings were recently published in the peer-reviewed journal Brain Communications in the advanced articles section.

The results of this new Brain Communications study showed:

  • Significant brain vital sign changes in N100 Auditory sensation and N400 Cognitive processing responses for the pre-to-post season comparison across both groups.
  • Differences between the Bantam and Junior A ice hockey players showed more changes in the Junior A group.
  • Importantly, the subconcussive changes were significantly correlated with the number of head impacts over the season across both age groups and consequently showed more subconcussive changes in brain vital signs.

A subconcussive impact is a mechanical force transmitted to the brain below the threshold for a diagnosis of an acute concussive injury. The effects of these low-magnitude impacts may not even be noticeable to the player or to observers on the sideline. Head impacts in the sport of ice hockey typically result from player-to-player or player-to-boards contact due to body checking, collisions and fighting[i]. Some of these impacts are the consequence of foul play, but many of these events also result from routine, legal on-ice behavior.

“Concussion in sports is a major concern for many and our research has shown that having an objective physiological measure of brain function at rink-side is key to detection and managing concussive impacts,” says Dr. Aynsley Smith, principal investigator of the study and Associate Professor of Orthopedics at Mayo Clinic in Rochester, Minnesota.

The study, funded in part by USA Hockey, was co-led by Dr. Michael Stuart, Professor of Orthopedics at Mayo Clinic in Rochester, Minnesota. It is also part of a larger concussion research team within Mayo Clinic that includes neurology research leadership from Dr. David Dodick, Professor of Neurology at Mayo Clinic in Phoenix, Arizona, U.S.

Canadian collaborators include neuroscientist Dr. Ryan C. N. D’Arcy, an SFU professor and co-founder of the Health and Technology District in Surrey B.C. and Dr. Shaun Fickling, a biomedical engineer, a recent SFU PhD graduate and lead author of the study.

“Our research has shown that repetitive subconcussive impacts triggered compounding effects in brain function changes, which underscores the importance of shifting our thinking and understanding of concussions as a singular acute-injury model to a spectrum of head-impact exposure and effects over time,” says Dr. Fickling.

The US-Canadian concussion research team is continuing to advance their collaborative effort.

Says Dr. D’Arcy, “In medicine: you can’t treat what you can’t measure. With breakthroughs on measurement challenges, we hope to now accelerate treatment innovations for prevention, acute care and extended care concussion management – for all people across a range of different applications. Our partnership is moving into incredibly exciting future steps – stay tuned.”

The research study was designed and carried out by the Mayo Clinic Sports Medicine Ice Hockey Research team, partially funded by USA Hockey Foundation and the Johannson-Gund Endowment. Financial support was also provided by the Mathematics of Information Technology and Complex Systems (MITACS), Natural Sciences and Engineering Council Canada (NSERC) and the Canadian Institutes for Health Research (CIHR).

Featured image: Hockey player gets his brain vital signs checked. Researchers find repetitive head impacts can result in functional brain impairments in youth hockey.


Reference: Shaun D Fickling, Aynsley M Smith, Michael J Stuart, David W Dodick, Kyle Farrell, Sara C Pender, Ryan C N D’Arcy, Subconcussive brain vital signs changes predict head-impact exposure in ice hockey players, Brain Communications, Volume 3, Issue 2, 2021, fcab019, https://doi.org/10.1093/braincomms/fcab019


Provided by HealthTech Connex

Freeze! Executioner Protein Caught in the Act (Biology)

A new molecular ‘freeze frame’ technique has allowed WEHI researchers to see key steps in how the protein MLKL kills cells.

Small proteins called ‘monobodies’ were used to freeze MLKL at different stages as it moved from a dormant to an activated state, a key process that enables an inflammatory form of cell death called necroptosis. The team were able to map how the three-dimensional structure of MLKL changed, revealing potential target sites that might be targets for drugs – a potential new approach to blocking necroptosis as a treatment for inflammatory diseases.

The research, which was published in Nature Communications, was led by Associate Professor James Murphy and PhD students Ms Sarah Garnish and Mr Yanxiang Meng, in collaboration with Assistant Professor Akiko Koide and Professor Shohei Koide from New York University, US.

At a glance

  • The ‘executioner’ protein MLKL kills cells through an inflammatory process called necroptosis.
  • Monobody technology has enabled WEHI researchers to capture different forms of MLKL as it becomes activated and moves to kill the cell.
  • Understanding how the three-dimensional shape of MLKL changes may lead to the development of drugs that prevent necroptosis, as a treatment for inflammatory diseases.

Key steps in necroptosis

MLKL is a key protein in necroptosis, being the ‘executioner’ that kills cells by making irreparable holes in their exterior cell membrane. This allows the cell contents to leak out and triggers inflammation – alerting nearby cells to a threat, such as an infection.

Ms Garnish said MLKL was activated within a protein complex called a ‘necrosome’ which responded to external signals.

A cell in yellow is shown dying by necroptosis, a process requiring the protein MLKL © WEHI Australia

“While we know which proteins activate MLKL, and that this involves protein phosphorylation, nobody had been able to observe any detail about how this changes MLKL at the structural level. It happens so fast that it’s essentially a ‘molecular blur’,” she said.

A new technology – monobodies – developed by Professor Koide’s team, was key to revealing how MLKL changed.

Monobodies that specifically bound to different ‘shapes’ of MLKL were used to capture these within cells, Mr Meng said.

“These monobodies prevented MLKL from moving out of these shapes – so we could freeze MLKL into its different shapes,” he said.

“We then used structural biology to generate three-dimensional maps of these shapes which could be compared. This revealed that MLKL passed through distinct shape changes as it transitioned from being activated through to breaking the cell membrane.”

An important step

Associate Professor Murphy said the structures provided the first formal evidence for how MLKL changed its shape after it was activated.

“Until now, we’ve speculated that this happens, but it was only with monobodies that we could actually prove there are distinct steps in MLKL activation,” he said.

“Necroptosis is an important contributor to inflammatory conditions such as inflammatory bowel disease. There is intense interest in MLKL as a key regulator of necroptosis – and how it could be blocked by drugs as a potential new anti-inflammatory therapy.”

The research was supported by the Australian Government National Health and Medical Research Council and Department of Education, Skills and Employment, a Melbourne Research Scholarship, the Wendy Dowsett Scholarship, an Australian Institute of Nuclear Science and Engineering Postgraduate Research Award, the Australian Cancer Research Foundation, the US National Institutes of Health and the Victorian Government.

The Australian Synchrotron’s MX beamlines were critical infrastructure for the project.

WEHI authors: Ms Sarah Garnish, Mr Yanxiang Meng, Dr Jarrod Sandow, Ms Annette Jacobsen, Dr Andre Samson, Dr Christopher Horne, Dr Cheree Fitzgibbon, Mr Samuel Young, Ms Phoebe Smith, Associate Professor Andrew Webb, Dr Emma Petrie, Dr Joanne M. Hildebrand, Associate Professor Peter Czabotar, Associate Professor James Murphy

Featured image: PhD students Mr Yanxiang Meng (L) and Ms Sarah
Garnish (R) have discovered a key step in how the protein MLKL kills cells


Reference: Garnish, S.E., Meng, Y., Koide, A. et al. Conformational interconversion of MLKL and disengagement from RIPK3 precede cell death by necroptosis. Nat Commun 12, 2211 (2021). https://doi.org/10.1038/s41467-021-22400-z


Provided by WEHI

New Therapy Target For Malignant Melanomas in Dogs (Medicine)

Scientists have shown that the biological molecule PD-L1 is a potential target for the treatment of metastasized oral malignant melanoma in dogs.

There are a number of cancers that affect dogs, but there are far fewer diagnosis and treatment options for these canine cancers. However, as dogs and humans are both mammals, it is likely that strategies and treatments for cancers in humans can be used for canine cancer, with minor modifications.

A team of scientists, including Associate Professor Satoru Konnai from the Faculty of Veterinary Medicine at Hokkaido University, have demonstrated that an anti-cancer therapy that targets the cancer marker PD-L1—a target that has shown great promise for treating cancer in humans—is effective for canine cancer as well. Their findings were published in the journal npj Precision Oncology.

The proteins Programmed Cell Death 1 (PD-1) and its associated molecule, PD-ligand 1 (PD-L1) are involved in the immune response in humans. PD-L1 is overexpressed by many types of cancer in humans, enabling these cancers to suppress the immune response. Studies in mice models and in human cell lines have shown that PD-1 and PD-L1 have great promise in the treatment of cancer as blocking them strengthens the immune response to cancer.

Antitumor effect of anti-PD-L1 antibody. CT images of oral malignant melanoma (upper left) and its lung metastases (lower left) observed in a Pomeranian (12 years old, male). As a result of treatment with anti-PD-L1 antibody, all detectable tumors disappeared (right panels; Naoya Maekawa, et al. npj Precision Oncology. February 12, 2021).

Malignant melanomas are a canine cancer that is both relatively common and fatal. In particular, oral malignant melanomas (OMMs) are highly invasive and metastatic; with treatment, the median survival time is less than two months. As new treatments are needed for this cancer, the scientists chose to explore the options available.

The scientists first developed a novel anti-PD-L1 monoclonal antibody to detect PD-L1 in various canine cancers by immunohistochemical staining. Using this antibody, they demonstrated that malignant canine cancers expressed PD-L1; out of 20 samples for each cancer tested, nasal adenocarcinoma, transitional cell carcinoma, osteosarcoma and mammary adenocarcinoma had a 100% positive rate, while anal sac gland carcinoma and OMM had a 95% positive rate.

A prior pilot study had shown that another canine chimeric anti-PD-L1 monoclonal antibody had anti-tumor effect against OMM, when tested on nine dogs. For the current study scientists selected 29 dogs with primary OMM and pulmonary metastasis, where the melanoma has spread to the lungs, and most of which had been subjected to at least one round of treatment. These dogs were treated with the chimeric antibody every two weeks, and other interventions to achieve local control of cancer were allowed.

The survival time of dogs treated with the chimeric antibody was significantly longer, with a median survival time of 143 days, compared to 54 days for the control group, from historical data. Thirteen dogs had measurable cancer (i.e., at least one tumor >10 mm in diameter in CT scan), while 16 had non-measurable cancer (all tumors < 10 mm in diameter in CT scan). Five dogs showed tumor response, where the tumor reduced or disappeared due to the treatment. In one of these, all detectable tumors disappeared. In two other dogs, all detectable tumors disappeared, resulting in survival times longer than a year. In the last two dogs, all tumors in the lungs disappeared, but oral and lymph node tumors persisted. The increase in survival time correlated positively with radiation therapy that was simultaneous or began within eight weeks of treatment with the chimeric antibody. 

“Our findings are limited by the small size of the historical control group,” says Satoru Konnai. “Nevertheless, as there is no systemic therapy that prolongs the survival of dogs with pulmonary metastatic OMM, the increased survival time encourages the further development of anti-PD-L1 therapy in dogs.”

From the left: Yusuke Izumi, Naoya Maekawa, Satoshi Takagi, Tatsuya Deguchi and Satoru Konnai, members of the research team (Photo: Hokkadio University).

Original Article:

Naoya Maekawa, et al. PD-L1 immunohistochemistry for canine cancers and clinical benefit of anti-PD-L1 antibody in dogs with pulmonary metastatic oral malignant melanomanpj Precision Oncology. February 12, 2021. DOI: 10.1038/s41698-021-00147-6

Funding:

This work was supported by the Grant-in-Aid for Scientific Research (16K15042, 19H03114, and 19K15969) and Grant-in-aid for JSPS Fellows (15J01989) from the Japan Society for the Promotion of Science (JSPS) and by Japan Agency for Medical Research and Development (AMED; JP20am0101078).

Featured image: PD-L1 immunohistochemical staining in typical oral malignant melanoma (left) and squamous cell skin cancer (right). The tumor cells are stained brown, indicating that they are PD-L1 positive (Naoya Maekawa, et al. npj Precision Oncology. February 12, 2021).


Provided by Hokkaido University

AI Model Pre­dicts Which Key of the Im­mune Sys­tem Opens the Locks of Coronavirus (Medicine)

With an artificial intelligence (AI) method developed by researchers at Aalto University and University of Helsinki, researchers can now link immune cells to their targets and for example uncouple which white blood cells recognize SARS-CoV-2. The developed tool has broad applications in understanding the function of immune system in infections, autoimmune disorders, and cancer.

The human immune defense is based on the ability of white blood cells to accurately identify disease-causing pathogens and to initiate a defense reaction against them. The immune defense is able to recall the pathogens it has encountered previously, on which, for example, the effectiveness of vaccines is based. Thus, the immune defense the most accurate patient record system that carries a history of all pathogens an individual has faced. This information however has previously been difficult to obtain from patient samples.

The learning immune system can be roughly divided into two parts, of which B cells are responsible for producing antibodies against pathogens, while T cells are responsible for destroying their targets. The measurement of antibodies by traditional laboratory methods is relatively simple, which is why antibodies already have several uses in healthcare.

”Although it is known that the role of T cells in the defense response against for example viruses and cancer is essential, identifying the targets of T cells has been difficult despite extensive research,” says Satu Mustjoki, Professor of Translational Hematology.

AI helps to identify new key-lock pairs

T cells identify their targets in a key and a lock principle, where the key is the T cell receptor on the surface of the T cell and the key is the protein presented on the surface of an infected cell. An individual is estimated to carry more different T cell keys than there are stars in the Milky Way, making the mapping of T cell targets with laboratory techniques cumbersome.

Researchers at Aalto University and the University of Helsinki have therefore studied previously profiled key-lock pairs and were able to create an AI model that can predict targets for previously unmapped T cells.

JANI HUUHTANEN (BIORENDER.COM)

”The AI model we created is flexible and is applicable to every possible pathogen – as long as we have enough experimentally produced key-lock pairs. For example, we were quickly able to apply our model to coronavirus SARS-CoV-2 when a sufficient number of such pairs were available,” explains Emmi Jokinen, M.Sc. and a Ph.D. student at Aalto University.

The results of the study help us to understand how a T cell applies different parts of its key to identify its locks. The researchers studied which T cells recognize common viruses such as influenza-, HI-, and hepatitis B -virus. The researchers also used their tool to analyze the role of T-cells recognizing hepatitis B, which had lost their killing ability after the progression of hepatitis to hepatic cell cancer.

The study has been published in the scientific journal PLOS Computational Biology.

A new life for pub­lished data with novel AI mod­els

Tools generated by AI are cost-effective research topics.

“With the help of these tools, we are able to make better use of the already published vast patient cohorts and gain additional understanding of them,” points out Harri Lähdesmäki, Professor of Computational Biology and Machine Learning at Aalto University.

Using the artificial intelligence tool, the researchers have figured out, among other things, how the intensity of the defense reaction relates to its target in different disease states, which would not have been possible without this study.

”For example, in addition to COVID19 infection, we have investigated the role of the defense system in the development of various autoimmune disorders and explained why some cancer patients benefit from new drugs and some do not”, reveals M.D. Jani Huuhtanen, a Ph.D. student at the University of Helsinki, about the upcoming work with the new model.

Featured image credit: mostphotos


Original article: Jokinen E, Huuhtanen J, Mustjoki S, Heinonen M, Lähdesmäki H (2021) Predicting recognition between T cell receptors and epitopes with TCRGP. PLOS Computational Biology 17(3): e1008814. DOI: 10.1371/journal.pcbi.1008814


Provided by University of Helsinki

A New Study Identifies Interleukin 11 As A Marker of Cancer-associated Fibroblasts (Medicine)

Interleukin 11-producing fibroblasts are potential candidates for new therapeutic targets in human colorectal cancer

IL-11 is known to promote the development of colorectal cancer in humans and mice, but when and where IL-11 is expressed during cancer development is unknown. “To address these questions experimentally, we generated reporter mice that express the green fluorescent protein (EGFP) gene in interleukin 11 (IL-11)-producing (IL11+) cells in vivo. We found IL-11+ cells in the colons of this murine colitis-associated colorectal cancer model,” said Dr. Nishina, the lead author of a study published April 16 in Nature Communications. “The IL-11+ cells were absent from the colon under normal conditions but rapidly appeared in the tissues of mice with colitis and colorectal cancer.”

In the study, Dr. Nishina and colleagues characterized the IL-11+ cells by flow cytometry and found that most IL-11+ cells express stromal cell surface markers, such as Thy1, podoplanin, and Sca-1, suggesting that IL-11+ cells are stromal fibroblasts. RNA-seq analysis revealed that the expression of approximately 350 genes was elevated in IL-11+ fibroblasts compared IL-11- fibroblasts. These genes were also elevated in murine and human colorectal cancer tissues in vivo. IL-11 released from IL-11+ cells induced activation signals in nearby tumor cells and fibroblasts in a paracrine or autocrine manner. Thus, IL-11+ fibroblasts and tumor cells constitute the tumor microenvironment that supports tumor growth.

“We looked at human cancer databases and found that elevated expression of genes enriched in IL-11+ fibroblasts correlate with short duration of disease-free survival. We think IL-11+ fibroblasts can be new therapeutic targets for treating human colorectal cancer,” said Prof. Nakano, the senior author of the study.

These results were published in Nature Communications on April 16, 2021 (10.1038/s41467-021-22450-3). This research was conducted in collaboration with Associate Professors Nobuhiro Tada and Hideo Yagita of Juntendo University, Professor Masato Ohtsuka of Tokai University, Professors Koji Matsushima and Chiharu Nishiyama of Tokyo University of Science, Professor Masanobu Oshima of Kanazawa University, and Naohiro Inohara of Michigan University.

Featured image: Colon tumor sections from ApcMin/+;Il11-Egfp mice were stained with anti-GFP (IL-11+ cells, green), anti-E-cadherin (white), anti-CD31 (endothelial cells, red), and DAPI (nuclei). © Hiroyasu Nakano


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