How Pathogens Hijack Immune System to Cause Vaccine-Enhanced Disease

Associate Professor Steven Szczepanek (standing, left) with graduate students Tyler Gavitt (seated) and Arlind Mara (standing, right).
Photo Credit: Jason Sheldon/UConn

Researchers in the College of Agriculture, Health and Natural Resources are working to unlock a decades-long mystery that has hampered development of a walking pneumonia vaccine.

Associate Professor Steven Szczepanek and Professor Steven Geary from the Department of Pathobiology and Veterinary Science, along with former graduate students Tyler Gavitt and Arland Mara, published findings that help explain how Mycoplasma pneumoniae (Mp) hijacks our immune system following vaccination.

They shared their findings in two recent publications in Nature journal npj Vaccines.

Mp is a common pathogen that causes walking pneumonia. While this respiratory infection is not typically severe, it is a common co-pathogen with illnesses that spread in the same way, like the flu or COVID-19, which can cause more severe illnesses, especially in older or immunocompromised adults.

In the 1960s, scientists began working to develop an Mp vaccine. They killed the bacteria and injected it into human subjects, thinking it would provide protection from actual infection. But that’s not what happened.

A new nanoparticle to act at the heart of cells

This electron micrograph documents the porous nature of silica nanoparticles. These pores are large enough to allow entrance of a large number of NSA molecules. Here, they are protected until being taken up by the immune cells. At this point NSA is released and can stop the inflammatory processes.
Credit: UNIGE - Carole Bourquin

How can a drug be delivered exactly where it is needed, while limiting the risk of side effects? The use of nanoparticles to encapsulate a drug to protect it and the body until it reaches its point of action is being increasingly studied. However, this requires identifying the right nanoparticle for each drug according to a series of precise parameters. A team from the University of Geneva (UNIGE) and the Ludwig Maximilians Universität München (LMU) has succeeded in developing a fully biodegradable nanoparticle capable of delivering a new anti-inflammatory drug directly into macrophages - the cells where uncontrolled inflammatory reactions are triggered - ensuring its effectiveness. In addition, the scientists used an invitro screening methodology, thus limiting the need for animal testing. These results, recently published in the Journal of Controlled Release, open the way to an extremely powerful and targeted anti-inflammatory treatment.

Inflammation is an essential physiological response of the body to defend itself against pathogens such as bacteria. It can, however, become problematic when it turns into a chronic condition, such as in cancers, autoimmune diseases or certain viral infections. Many treatments already exist, but their action is often not very targeted, high doses are required and deleterious side effects are frequent. Macrophages, large immune cells whose natural function is to absorb pathogens and trigger inflammation to destroy them, are often involved in inflammatory diseases. When overactivated, they trigger an excessive inflammatory response that turns against the body instead of protecting it.

New experimental treatment can stop the growth of schwannoma tumors

Researchers showed that after just 21 days of the drugs being administered, tumor growth can be strongly and significantly reduced.
Photo Credit: MART PRODUCTION

Two novel and orally administered drugs can not only block the growth, but also shrink the size, of a tumor type found in the nervous system, new research has shown.

The tumors, schwannomas, most frequently grow on the nerves that bring hearing and balance information into the brain. Schwannomas are the most common nerve sheath tumor, and can occur in anyone but are also linked to a hereditary condition known as Neurofibromatosis Type II (NF2).

In NF2, where the function of the protein Merlin is lost in cells, patients frequently develop not only schwannomas, but also meningioma tumors associated with the brain and spinal cord.

The treatment of both tumor types is difficult, with surgery being the current mainstay but also carrying a high risk of damage to the surrounding normal nervous system tissue.

With an urgent need for new treatments, an international team of scientists focused on the Hippo signaling pathway, which normally controls organ size in human tissues and cells, but is dysregulated in multiple types of cancer.

Therapeutic HIV vaccine with Oxford technology achieves encouraging results

Artist illustration of the HIV virus.
Illustration Credit: Darwin Laganzon

A phase I/IIa clinical trial that the University of Oxford collaborated on has demonstrated that a T-cell therapeutic HIV vaccine was associated with better control of the virus rebound when antiretroviral therapy (ART) was temporarily withdrawn.

Researchers carrying out the AELIX-002 study, whose results have been published in Nature Medicine, reported that two fifths of participants without any genetic background associated with spontaneous HIV control were able to stay off ART for the six-month duration of the supervised ART pause.

The vaccine in the study – developed by AELIX Therapeutics – delivered the HIVACAT T-cell Immunogen (HTI) using a combination of DNA vector, modified vaccinia virus Ankara (MVA) vector and simian adenovirus vector ChAdOx1. The latter two vaccines were constructed at Oxford.

Tomáš Hanke, Professor of Vaccine Immunology at the Jenner Institute, Nuffield Department of Medicine, who leads on HIV vaccine development, said:

‘This result provides further encouragement that active immunization against HIV may be possible, slowing HIV replication, providing a window of treatment holidays for people living with HIV and eventually leading to HIV cure. T cells/T-cell vaccines are likely to play an important part in the final package for HIV cure and, perhaps, other advanced therapies for difficult diseases.’

A new weapon against antibiotic-resistant bacteria

This inoculated MacConkey agar culture plate cultivated colonial growth of Gram-negative, small rod-shaped and facultatively anaerobic Klebsiella pneumoniae bacteria. K. pneumoniae bacteria are commonly found in the human gastrointestinal tract, and are often the cause of hospital acquired, or nosocomial infections involving the urinary and pulmonary systems.
Credit: CDC

The unreasonable use of antibiotics has pushed bacteria to develop resistance mechanisms to this type of treatment. This phenomenon, known as antibiotic resistance, is now considered by the WHO as one of the greatest threats to health. The lack of treatment against multi-resistant bacteria could bring us back to a time when millions of people died of pneumonia or salmonella. The bacterium Klebsiella pneumoniae, which is very common in hospitals and particularly virulent, is one of the pathogens against which our weapons are becoming blunt. A team from the University of Geneva (UNIGE) has discovered that edoxudine, an anti-herpes molecule discovered in the 60s, weakens the protective surface of Klebsiella bacteria and makes them easier to eliminate for immune cells. These results can be read in the journal PLOS One.

Klebsiella pneumoniae causes many respiratory, intestinal and urinary tract infections. Due to its resistance to most common antibiotics and its high virulence, some of its strains can be fatal for 40% to 50% of infected people. There is an urgent need to develop new therapeutic molecules to counter it. “Since the 1930s, medicine has relied on antibiotics to get rid of pathogenic bacteria,” explains Pierre Cosson, professor in the Department of Cell Physiology and Metabolism at the UNIGE Faculty of Medicine, who led this research. “But other approaches are possible, among which trying to weaken the bacteria’s defense system so that they can no longer escape the immune system. This avenue seems all the more promising as the virulence of Klebsiella pneumoniae stems largely from its ability to evade attacks from immune cells.”

Bulking Up to Beat Bacteria

The inhibitor-binding site of the wild-type MexB pump. (a) The crystal structure of the inhibitor ABI-PP bound to the MexB trimer. Three MexB monomers are shown in green, blue, and red, representing the access, binding, and extrusion monomer, respectively. ABI-PP is shown as a yellow space-filling model. (b) A close-up view of the inhibitor binding site. The substrate translocation pathway is shown as a solid gray surface. The proximal and distal binding pockets are indicated in green and blue circles, respectively. The inhibitor binding pit is shown as a red surface. The ABI-PP molecule is represented as a yellow stick model. (c) A detailed view of the inhibitor-binding site. Carbon atoms of ABI-PP are indicated in yellow while amino acid residues are indicated in green. The classification of these amino acids is shown on the right side of the panel.
Image Credit: 2022 Yamasaki et al., Spatial Characteristics of the Efflux Pump MexB Determine Inhibitor Binding, Antimicrobial Agents and Chemotherapy

The medical profession is in the midst of losing an arms race. Bacterial antibiotic resistance doesn’t just threaten our ability to treat infection but our ability to carry out any treatment where infection is a risk. This includes a raft of life-saving surgeries ranging from coronary bypass operations to organ transplantation. In fact, the number of new antimicrobials being developed is declining each year. Understanding how bacteria resist the influence of antibiotics is essential to winning this arms race: it is time to make up ground.

In a study published this month in Antimicrobial Agents and Chemotherapy, researchers at Osaka University have produced new insights into the structure of a particular bacterial protein known as an efflux pump. This protein is involved in antibiotic resistance and its structure influences the ability of drugs to target it.

Overcoming resistance to colon cancer treatment

Colorectal cancer cells after treatment with FOLFORIXI chemotherapy for 34 weeks. Cell fibers (in green) and nuclei (in blue).
Credit: UNIGE-Nowak-Sliwinka

Colorectal cancer is one of the most common cancers. Its treatment is mainly based on chemotherapy. However, over time, chemotherapy induces resistance in the majority of patients, who end up being unresponsive to the drugs. As a result, the five-year survival rate for those affected is still low. After succeeding in reproducing this resistance in the laboratory, a team from the University of Geneva (UNIGE) has found a way to overcome it. The team has used an optimized combination of drugs belonging to the class of tyrosine kinase inhibitors, which take different pathways to attack cancer cells than chemotherapy. These results, to be found in the journal Cancers, open up new avenues for overcoming treatment resistance and for developing new therapies that are more targeted than chemotherapy.

Colorectal cancer is the third most diagnosed cancer in the world and second only to lung cancer in terms of mortality. It most often develops from the age of 50 in the terminal part of the colon. It results from a change in the DNA of certain cells present in this organ. These cells become cancerous and proliferate in an uncontrolled manner until they form a primary tumor. As in many cancers, these cells can migrate to other parts of the body and form secondary tumors. This is known as metastatic cancer.

While genetics play a role in the development of the disease, the presence of inflammatory bowel diseases (e.g. Crohn’s disease) and certain dietary habits (alcohol, red meat) are also risk factors. In the case of a primary tumor, treatment is based on surgery and chemotherapy. In the case of secondary tumors, it is based on a combination of chemotherapies. These treatments are non-targeted and aggressive. They cause significant side effects. They also lead to progressive resistance to treatment in the majority of patients.

Sand serves up a possible cure for obesity

Engineered particles of purified sand could be the next anti-obesity therapy as new research from the University of South Australia published in journal MPDI Pharmaceutics shows that porous silica can prevent fats and carbohydrates from being adsorbed in the body.

The engineered silica particles are made from purified sand and are optimally designed with a high surface area that enables them to soak up large amounts of digestive enzymes, fats, and sugars within the gastrointestinal tract.

Funded by the Channel 7 Children’s Research Foundation, the study is the first to validate how porous silica particles can impede digestive processes and stop fat and sugar adsorption.

Developed in partnership with Glantreo Limited, the new silica-based therapy will be gentler on the stomach with fewer of the unpleasant side effects associated with the mainstream anti-obesity drug, Orlistat.

Lead researcher, UniSA’s Dr Paul Joyce says this breakthrough finding could change the health outcomes for billions of people struggling with obesity.

A revolutionary method to observe cell transport

Nanobodies (grey) with magnetic probes (red stars) target the desired membrane protein.
Credit: Bordignon, Enrica

Membrane proteins are key targets for many drugs. They are located between the outside and inside of our cells. Some of them, called ‘‘transporters’’, move certain substances in and out of the cellular environment. Yet, extracting and storing them for observation is particularly complex. A team from the University of Geneva (UNIGE), in collaboration with the University of Zurich (UZH), has developed an innovative method to study their structure in their native environment: the cell. The technique is based on electron spin resonance spectroscopy. These results, just published in the journal Science Advances, may facilitate future development of new drugs.

In living organisms, each cell is surrounded by a cell membrane (or ‘‘cytoplasmic membrane’’). This membrane consists of a double layer of lipids. It separates the contents of the cell from its direct environment and regulates the substances that can enter or leave the cell. The proteins attached to this membrane are called ‘‘membrane proteins’’.

Located at the interface between the outside and inside of the cell, they carry various substances across the membrane - into or out of the cell - and play a crucial role in cell signaling, i.e. in the communication system of cells that allows them to coordinate their metabolic processes, development and organization. As a result, membrane proteins represent more than 60% of current drug targets.

Study Finds No Benefit to Taking Fluvoxamine for COVID-19 Symptoms

A study led by the Duke Clinical Research Institute (DCRI) in partnership with Vanderbilt University found no symptomatic or clinical benefit to taking the antidepressant fluvoxamine 50 mg twice daily for 10 days for the treatment of mild-to-moderate COVID-19 symptoms.

“There was no evidence of improvement in time to recovery in participants who took this dose of fluvoxamine versus those who took a placebo,” said Adrian Hernandez, M.D., the study’s administrative principal investigator and executive director of the DCRI.

Findings appear on medRxiv, a pre-publication server, and have been submitted to a peer-reviewed journal.

Researchers looked at the rate of sustained recovery, defined as three days without symptoms, in ACTIV-6. While 75% of participants were still reporting symptoms on day 7, the majority (82%) of these participants reported no limitation in activities.

Covid-19 is linked to increased degradation of connections between nerve cells in a new brain model

Postdoctoral fellow Samudyata and doctoral student Susmita Malwade.
Source: Karolinska Institutet

Researchers at Karolinska Institutet have used cellular reprogramming in a new study to create human three-dimensional brain models and infected them with SARS-CoV-2. In infected models, the brain's immune cells showed an excessive elimination of connections between the nerve cells. The gene expression of these cells also mimicked changes observed in neurodegenerative diseases. The results hope to identify new treatments for cognitive symptoms after Covid-19 infection.

Several studies have reported persistent cognitive symptoms following a covid-19 infection, but the underlying mechanisms for this are still unknown. The researchers behind the study, published in the journal Molecular Psychiatry, have created from human induced pluripotent stem cells (iPS) three-dimensional models of the brain in test tubes, so-called brain organoids. The model differs from previous organoid models in that they also contain microglia - the brain's immune cells. In the infected models, microglia regulated genes involved in phagocytosis, "cell-eating," the researchers could also see how microglia contained an increased amount of proteins from brain cell connections, so-called synapses. The developed model and results of the study can help guide future efforts to address cognitive symptoms in the aftermath of COVID-19 and other neuroinvasive viral infections.

Ural Scientists Developed a Drug to Combat Post-Covidal Complications

According to the scientists, the university and the Ural Branch of the Russian Academy of Sciences are developing world-class materials.
Photo credit: TASS-Ural Press Center, Vladislav Burnashev

Scientists from the Ural Federal University and the Postovsky Institute of Organic Synthesis have developed a drug to combat post-covidal complications, namely, the formation of blood clots. The drug blocks the release of clot-forming compounds caused by coronavirus infection. As the scientists point out, this is a world-class achievement, as new classes of compounds capable of combating the effects of coronavirus have been discovered. Representatives of the Ural Branch of the Russian Academy of Sciences talked about this, as well as about other developments aimed at ensuring the scientific and technological sovereignty of Russia, at a press conference at TASS.

"We develop unique things. This is important to note, because now the concept of import substitution is pushed to the background, and we are talking about the scientific and technological sovereignty of the country. The fact is that import substitution implies reproduction, copying of foreign technologies. We are catching up beforehand. Scientific and technological sovereignty implies independence from external conditions and supremacy in the development of industrial samples and new materials which are superior to foreign analogues in their characteristics. Therefore, it is certain that the Ural scientists successfully solve the task of ensuring scientific and technological progress," emphasizes Victor Rudenko, Academician and Chairman of the Ural Branch of the Russian Academy of Sciences.

Scientists develop a new kind of printable, wearable insect repellent

This is what the ring looks like that could help repel insects.
Photo credit: Uni Halle / Fanfan Du

A new type of insect-repellent delivery device has been developed by scientists from the Martin Luther University Halle-Wittenberg (MLU). With the help of a 3D printer, the active ingredient is first "encapsulated" and formed into the desired shape, such as a ring, which can then be worn and releases an agent designed to repel mosquitoes for a long time. The team has presented its work in the "International Journal of Pharmaceutics".

The researchers have developed their prototypes using "IR3535", an insect repellent developed by MERCK. "Mosquito sprays containing IR3535 are very gentle on the skin and have been used all over the world for many years. That’s why we’ve been using the agent for our experiments", says Professor René Androsch from the MLU. It is usually applied as a spray or lotion and offers several hours of protection. However, Androsch and his team are looking for ways to release the agent over a much longer period, such as by encapsulating it in a wearable ring or bracelet.

Repurposing existing drugs to fight new COVID-19 variants

Photo Credit: Myriam Zilles

MSU researchers are using big data and AI to identify current drugs that could be applied to treat new COVID-19 variants

Finding new ways to treat the novel coronavirus and its ever-changing variants has been a challenge for researchers, especially when the traditional drug development and discovery process can take years. A Michigan State University researcher and his team are taking a hi-tech approach to determine whether drugs already on the market can pull double duty in treating new COVID variants.

“The COVID-19 virus is a challenge because it continues to evolve,” said Bin Chen, an associate professor in the College of Human Medicine. “By using artificial intelligence and really large data sets, we can repurpose old drugs for new uses.”

Chen built an international team of researchers with expertise on topics ranging from biology to computer science to tackle this challenge. First, Chen and his team turned to publicly available databases to mine for the unique coronavirus gene expression signatures from 1,700 host transcriptomic profiles that came from patient tissues, cell cultures and mouse models. These signatures revealed the biology shared by COVID-19 and its variants.

How the secrets of the ‘water bear’ could improve lifesaving drugs like insulin

A tardigrade, or water bear, floating in water. The tiny organism can endure some of the most extreme conditions on Earth — and even space.
Credit: Schokraie E, Warnken U, Hotz-Wagenblatt A, Grohme MA, Hengherr S, et al. licensed under the Creative Commons Attribution 2.5 Generic license.

UCLA chemist Heather Maynard had to wonder: How do organisms like the tardigrade do it?

This stocky microscopic animal, also known as a water bear, can survive in environments where survival seems impossible. Tardigrades have been shown to endure extremes of heat, cold and pressure — and even the vacuum of space — by entering a state of suspended animation and revitalizing, sometimes decades later, under more hospitable conditions. 

If she could understand the mechanism behind this extraordinary preservation, Maynard reckoned, she might be able to use the knowledge to improve medicines so that they remain potent longer and are less vulnerable to typical environmental challenges, ultimately broadening access and benefiting human health.

It turns out that one of the processes protecting tardigrades is spurred by a sugar molecule called trehalose, commonly found in living things from plants to microbes to insects, some of which use it as blood sugar. For a few select organisms, such as the water bear and the spiky resurrection plant, that can revive after years of near-zero metabolism and complete dehydration, trehalose’s stabilizing power is the secret to their unearthly fortitude.

A potential new treatment for brain tumors

Featured photo at top of Pankaj Desai, left, and senior graduate research assistant Aniruddha Karve, right, in the lab.
Photo credit: Andrew Higley | University of Cincinnati

A research question posed in Pankaj Desai’s lab has led to a decade of research, a clinical trial and major national funding to further investigate a potential new treatment for the deadliest form of brain tumors.

Desai, PhD, and his team at the University of Cincinnati recently received a $1.19 million grant from the National Institutes of Health/National Institute of Neurological Disorders and Stroke to continue research into the use of a drug called letrozole to treat glioblastomas (GBM).

Research progression

GBMs are aggressive brain tumors that patients often are unaware of until symptoms emerge and the tumor is substantial. Current treatments include immediate surgery to safely remove as much tumor as possible, radiation and chemotherapy, but the tumor often recurs or becomes resistant to treatments. The average patient survives no more than 15 months after diagnosis.

The medication letrozole was approved by the U.S. Food and Drug Administration as a treatment for postmenopausal women with breast cancer in 2001. The drug works by targeting an enzyme called aromatase that is present in breast cancer cells and helps the cancer grow.

Fighting fungal infections with metals

A Petri dish with red agar on which grows a fungal strand in the shape of the element symbol for platinum (Pt).
Credit: CO-ADD

An international collaboration led by researchers from the University of Bern and the University of Queensland in Australia has demonstrated that chemical compounds containing special metals are highly effective in fighting dangerous fungal infections. These results could be used to develop innovative drugs which are effective against resistant bacteria and fungi.

Each year, more than one billion people contract a fungal infection. Although they are harmless to most people, over 1.5 million patients die each year as a result of infections of this kind. While more and more fungal strains are being detected that are resistant to one or more of the available drugs, the development of new drugs has come to a virtual standstill in recent years. Today, only around a dozen clinical trials are underway with new active agents for the treatment of fungal infections. “In comparison with more than a thousand cancer drugs that are currently being tested on human subjects, this is an exceptionally small number,” explains Dr. Angelo Frei of the Department of Chemistry, Biochemistry and Pharmacy at the University of Bern, lead author of the study. The results have been published in the journal JACS Au.

Boosting antibiotics research with crowd sourcing

The CO-ADD Team at work in the laboratory.
Credit: CO-ADD

To encourage the development of anti-fungal and antibacterial agents, researchers at the University of Queensland in Australia have founded the Community for Open Antimicrobial Drug Discovery, or CO-ADD. The ambitious goal of the initiative is to find new antimicrobial active agents by offering chemists worldwide the opportunity to test any chemical compound against bacteria and fungi at no cost. As Frei explains, the initial focus of CO-ADD has been on “organic” molecules, which mainly consist of the elements of carbon, hydrogen, oxygen and nitrogen, and do not contain any metals.

However, Frei, who is trying to develop new metal-based antibiotics with his research group at the University of Bern, has found that over 1,000 of the more than 300,000 compounds tested by CO-ADD contained metals. “For most folks, when used in connection with the word ‘people’, the word metal triggers a feeling of unease. The opinion that metals are fundamentally harmful to us is widespread. However, this is only partially true. The decisive factor is which metal is used and in which form,” explains Frei, who is responsible for all the metal compounds in the CO-ADD database.

Low toxicity demonstrated

Dr. Angelo Frei at work in the laboratory.
Credit: Angelo Frei

In their new study, the researchers turned their attention to the metal compounds which showed activity against fungal infections. Here, 21 highly-active metal compounds were tested against various resistant fungal strains. These contained the metals cobalt, nickel, rhodium, palladium, silver, europium, iridium, platinum, molybdenum and gold. “Many of the metal compounds demonstrated a good activity against all fungal strains and were up to 30,000 times more active against fungi than against human cells,” explains Frei. The most active compounds were then tested in a model organism, the larvae of the wax moth. The researchers observed that just one of the eleven tested metal compounds showed signs of toxicity, while the others were well tolerated by the larvae. In the next step, some metal compounds were tested in an infection model, and one compound was effective in reducing the fungal infection in larvae.

Considerable potential for broad application

Metal compounds are not new to the world of medicine: Cisplatin, for example, which contains platinum, is one of the most widely used anti-cancer drugs. Despite this, there is a long way to go before new antimicrobial drugs that contain metals can be approved. “Our hope is that our work will improve the reputation of metals in medical applications and motivate other research groups to further explore this large but relatively unexplored field,” says Frei. “If we exploit the full potential of the periodic table, we may be able to prevent a future where we don’t have any effective antibiotics and active agents to prevent and treat fungal infections.”

The study was supported by the Swiss National Science Foundation, the Wellcome Trust and the University of Queensland, among others.

Source/Credit: University of Bern

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Brain Injury Model Created to Find New Medication

The experiments on the fish were conducted non-invasively, using a laser machine.
Photo credit: Danil Lomovskikh

Scientists from Russia and Taiwan (China) have developed and successfully tested a new model of traumatic brain injury (TBI) in zebradanio fish (Danio rerio). The method is based on irradiating the brains of adult individuals of these popular aquarium and laboratory fish with a unique laser system with precise aiming, which was specially developed by scientists. The application of this model allowed the researchers to simulate the TBI and identify molecular targets promising for the treatment of neurotrauma and its consequences. This paves the way for preclinical zebrafish testing of new neuroprotective medications.

The work was financially supported by the Russian Science Foundation (grant № 20-65-46006). An article describing the research was published in the highly rated scientific journal Pharmaceutics. The subject of the research was explained by Alan Kaluev, professor of the Russian Academy of Sciences, member of the European Academy, leading researcher of the Research Institute of Neuroscience and Medicine, professor of the St. Petersburg State University and Sirius Scientific-Technological University, leading researchers of the Ural Federal University and the Moscow Institute of Physics and Technology. Professor Kaluev is a leading scientist within the framework of research conducted at the Scientific Novosibirsk Research Institute of Neuroscience and Medicine (laboratory of Tamara Amstislavskaya and Maria Tikhonova).

The most common experimental models of brain injury in both rodents and zebrafish, such as mechanical blows to the head or needle piercing of the brain, involve penetrating brain tissue damage. However, these models do not correctly reproduce TBI. In the created model, due to the fact that the skin and skull of the used zebradanio species are transparent, it was possible to hit directly the brain, and non-invasively.

‘Drug factory’ implants eliminate mesothelioma tumors in mice

Tiny alginate bead implants invented in the laboratory of Rice University bioengineer Omid Veiseh can be loaded with cells that produce cytokine, proteins that play a major role in immune response. A new study found a treatment combining the implants and checkpoint inhibitor drugs eradicated advanced mesothelioma tumors in all seven mice in which it was tested.
Photo credit: Jeff Fitlow/Rice University

Rice University and Baylor College of Medicine researchers have shown they can eradicate advanced-stage mesothelioma tumors in mice in just a few days with a treatment combining Rice’s cytokine “drug factory” implants and a checkpoint inhibitor drug.

The researchers administered the drug-producing beads, which are no larger than the head of a pin, next to tumors where they could produce continuous, high doses of interleukin-2 (IL-2), a natural compound that activates white blood cells to fight cancer.

The study, published online today in Clinical Cancer Research, is the latest in a string of successes for the drug-factory technology invented in the lab of Rice bioengineer Omid Veiseh, including Food and Drug Administration (FDA) approval to begin clinical trials of the technology this fall in ovarian cancer patients.

“From the beginning, our objective was to develop a platform therapy that can be used for multiple different types of immune system disorders or different types of cancers,” said Rice graduate student Amanda Nash, who spent several years developing the implant technology with study co-lead author Samira Aghlara-Fotovat, a fellow student in Veiseh’s lab.

First Structure of Key COVID Enzyme at Human Body Temperature

Scientists used x-rays to decipher the three-dimensional structure of the main protease of the virus that causes COVID-19 at different temperatures. The background image shows the full structure at 240 Kelvin (-28°F, cyan stick figure) and 100 K (-280°F, dark blue). The red and green blobs represent differences in the structure at these distinct temperatures. The study allowed the scientists to zero in on subtle shifts that occur in the structure as the temperature changes (inset), potentially pointing to areas of the enzyme that could be targeted with inhibitor drugs to impair its function.
 Source/Credit: Brookhaven National Laboratory

Daniel Keedy, City University of New York

Scientists studying a COVID-19 coronavirus enzyme at temperatures ranging from frosty to human-body warm discovered subtle structural shifts that offer clues about how the enzyme works. The findings, published in IUCrJ, the journal of the International Union of Crystallography, may inspire the design of new drugs to counteract COVID-19—and possibly help head off future coronavirus pandemics.

“No previous study has looked at this important coronavirus enzyme at physiological (or body) temperature,” said Daniel Keedy, a structural biologist at the City University of New York (CUNY), who conducted the study in collaboration with scientists at the U.S. Department of Energy’s Brookhaven National Laboratory.

Most structures to date come from frozen samples—far from the temperatures at which the molecules operate within living cells. “If you are working at physiological temperature, you should get a more realistic picture of what’s happening during an actual infection, because that’s where biology happens,” Keedy said.

In addition, he added, the team used temperature as a tool. “By turning that knob and seeing how the protein reacts, we can learn about its mechanics—how it physically works."