Dual-targeting CAR NK cells can prevent cell dysfunction and tumor escape

 Katy Rezvani, M.D., Ph.D
Credit: The University of Texas MD Anderson Cancer Center.

Researchers at The University of Texas MD Anderson Cancer Center have developed a new approach to engineering natural killer (NK) cells with a second chimeric antigen receptor (CAR) to act as a logic gate, requiring two signals to eliminate a target cell. In preclinical studies, these next-generation CAR NK cells improved tumor specificity and enhanced anti-tumor activity by overcoming a process that contributes to NK cell dysfunction and tumor relapse.

This study, published in Nature Medicine, demonstrated that a normal physiological process called trogocytosis contributes to tumor escape and poor responses after CAR NK cell therapy by causing tumor antigen loss, NK cell exhaustion and fratricide — the killing of sibling CAR NK cells.

“We identified a novel mechanism of relapse following CAR NK cell therapy, and we also have developed a strategy to mitigate this process,” said corresponding author Katy Rezvani, M.D., Ph.D., professor of Stem Cell Transplantation & Cellular Therapy. “We engineered CAR NK cells with dual-targeting CARs that are able to ignore tumor antigens on the surface of their sibling NK cells acquired as a result of trogocytosis and selectively eliminate tumor cells.”

Rezvani and Ye Li, M.D., a graduate student in the Rezvani Lab, led the study.

During trogocytosis, surface proteins from a target cell are transferred to the surface of an immune cell, such as an NK cell or T cell, in order to regulate their activity. Using preclinical models, Li and colleagues showed that CAR activation promotes trogocytosis, resulting in the transfer and expression of tumor antigens on CAR NK cells.

Traumatic brain injury ‘remains a major global health problem’ say experts

Photo Credit: Ian Valerio

The report – the 2022 Lancet Neurology Commission – has been produced by world-leading experts, including co-lead author Professor David Menon from the Division of Anesthesia at the University of Cambridge.

 "Over the last decade, large international collaborations have provided important information to improve understanding and care of TBI. However, significant problems remain, especially in low- and middle-income countries"

David Menon

The Commission documents traumatic brain injury (TBI) as a global public health problem, which afflicts 55 million people worldwide, costs over US$400 billion per year, and is a leading cause of injury-related death and disability.

TBI is not only an acute condition but also a chronic disease with long-term consequences, including an increased risk of late-onset neurodegeneration, such as Parkinson’s disease and dementia. Road traffic incidents and falls are the main causes, but while in low- and middle-income countries, road traffic accidents account for almost three times the number of TBIs as falls, in high-income countries falls cause twice the number of TBIs compared to road traffic accidents. These data have clear consequences for prevention.

Over 90% of TBIs are categorized as ‘mild’, but over half of such patients do not fully recover by six months after injury. Improving outcome in these patients would be a huge public health benefit. A multidimensional approach to outcome assessment is advocated, including a focus on mental health and post-traumatic stress disorder. Outcome after TBI is poorer in females compared with males, but reasons for this are not clear.

Molecular chaperones caught in flagrante

For an adequate immune response, it is essential that T lymphocytes recognize infected or degenerated cells. They do so by means of antigenic peptides, which these cells present with the help of specialized surface molecules (MHC I molecules). Using X-ray structure analysis, a research team from Frankfurt has now been able to show how the MHC I molecules are loaded with peptides and how suitable peptides are selected for this purpose.

As task forces of the adaptive immune system, T lymphocytes are responsible for attacking and killing infected or cancerous cells. Such cells, like almost all cells in the human body, present on their surface fragments of all the proteins they produce inside. If these include peptides that a T lymphocyte recognizes as foreign, the lymphocyte is activated and kills the cell in question. It is therefore important for a robust T-cell response that suitable protein fragments are presented to the T lymphocyte. The research team led by Simon Trowitzsch and Robert Tampé from the Institute of Biochemistry at Goethe University Frankfurt has now shed light on how the cell selects these protein fragments or peptides.

Peptide presentation takes place on so-called major histocompatibility complex class I molecules (MHC I). MHC I molecules are a group of very diverse surface proteins that can bind myriads of different peptides. They are anchored in the cell membrane and form a peptide-binding pocket with their outward-facing part. Like all surface proteins, MHC I molecules take the so-called secretory pathway: they are synthesized into the cell's cavity system (endoplasmic reticulum (ER) and Golgi apparatus) and folded there. Small vesicles then bud off from the cavity system, migrate to the cell membrane and fuse with it.

Study reveals how COVID-19 damages the heart

Image Credit: Sanjay k j

University of Queensland researchers have discovered how COVID-19 damages the heart, opening the door to future treatments.

This initial study – featuring a small cohort – found COVID-19 damaged the DNA in cardiac tissue, which wasn’t detected in influenza samples.

UQ Diamantina Institute researcher Dr Arutha Kulasinghe said the team found while COVID-19 and influenza are both severe respiratory viruses, they appeared to affect cardiac tissue very differently.

“In comparison to the 2009 flu pandemic, COVID has led to more severe and long-term cardiovascular disease but what was causing that at a molecular level wasn’t known,” Dr Kulasinghe said.

“During our study, we couldn’t detect viral particles in the cardiac tissues of COVID-19 patients, but what we found was tissue changes associated with DNA damage and repair.

“DNA damage and repair mechanisms foster genomic instability and are related to chronic diseases such as diabetes, cancer, atherosclerosis and neurodegenerative disorders, so understanding why this is happening in COVID-19 patients is important.”

Paleontologists Found Mammoth Baby, Ancient Bear Teeth, and Lair of Cave Hyenas

Scientists will open a new expedition season in spring.
Photo credit: TASS-Ural Press Center / Vladislav Burnashev

Paleontologists of Ural Federal University and the Institute of Plant and Animal Ecology of Ural Branch of Russian Academy of Sciences during summer expeditions found a large number of ancient bones, teeth, as well as wool and skin of a mammoth baby. The study of remains will allow us to recreate the specifics of the flora and fauna of ancient times in detail and to understand the specifics of animal nutrition. Scientists told about the results of summer expeditions at a press conference in TASS.

On the Gyda Peninsula (Far North), paleontologists found the well-preserved remains of a mammoth baby. The uniqueness of the discovery is its age - it is a six-year-old mammoth baby. If previously only single bones were found, now the researchers have found material that will help study mammoth babies, said Pavel Kosintsev, a leading expert of the Laboratory of Natural Science Methods in Humanities of UrFU, a Senior Researcher of the Institute of Plant and Animal Ecology of the Ural Branch of the Russian Academy of Sciences.

Ancient 'Shark' from China Is Humans' Oldest Jawed Ancestor

Life reconstruction of Fanjingshania renovata.
Image Credit: ZHANG Heming)

Paleontologists discover a 439-million-year-old 'shark' that forces us to rethink the timeline of vertebrate evolution

Living sharks are often portrayed as the apex predators of the marine realm. Paleontologists have been able to identify fossils of their extinct ancestors that date back hundreds of millions of years to a time known as the Palaeozoic period. These early "sharks," known as acanthodians, bristled with spines. In contrast to modern sharks, they developed bony "armor" around their paired fins.

A recent discovery of a new species of acanthodian from China surprised scientists with its antiquity. The find predates by about 15 million years the earliest acanthodian body fossils and is the oldest undisputed jawed fish.

These findings were published in Nature.

Reconstructed from thousands of tiny skeletal fragments, Fanjingshania, named after the famous UNESCO World Heritage Site Fanjingshan, is a bizarre fish with an external bony "armor" and multiple pairs of fin spines that set it apart from living jawed fish, cartilaginous sharks and rays, and bony ray- and lobe-finned fish.

Making lab-grown brain organoids ‘brainier

 Slices of mini–brain organoids with neural stem cells (red) and cortical neurons (green).
Credit: Hajime Ozaki, Watanabe lab/UCI

By using stem cells to grow miniature brain-like organs in the lab, scientists have opened a new avenue for studies of neurological development, disease and therapies that can’t be conducted in living people. But not all mini–brain organoids are created equal and getting them to precisely mimic the human brain tissues they’re modeling has been a persistent challenge.

“Right now, it’s like the Wild West because there is no standard method for generating mini–brain organoids,” said Bennett Novitch, a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA and the senior author of a new paper on the topic. “Every neuroscientist wants to make a brain organoid model of their favorite disease, and yet everyone’s organoids do not always look alike.”

In fact, because there is no common protocol for their production and a lack of quality-control guidelines, organoids can vary from lab to lab — and even from batch to batch — which means that a finding made in one organoid may not hold true in another.

“If my lab and another lab down the hall were to conduct drug screens using mini–brain organoid models of the same disorder, we could still get different results,” said Momoko Watanabe, the new paper’s first author and an assistant professor of anatomy and neurobiology at UC Irvine. “We won’t know whose findings are correct because the differences we’re seeing could be reflections of how our models differ rather than reflections of the disease.”

Wildfire smoke exposure hurts learning outcomes

Exposure to fine particle pollution from wildfire smoke during the school day affects average test scores. In this map of the predicted effect on average test scores by district in a relatively high-smoke year, 2016, darker shades indicate a stronger impact.
Image credit: Wen et al. 2022, Nature Sustainability

Pollution from wildfires is linked to lower test scores and possibly lower future earnings for kids growing up with more smoke days at school, a new study finds. Impacts of smoke exposure on earnings are disproportionately borne by economically disadvantaged communities of color.

When wildfire smoke pollutes the air in schoolyards and classrooms, as it does with increasing frequency and severity across the country, it hurts not only children’s health but also their ability to learn and possibly their future earning power, according to new research from Stanford University.

The new analysis, published Sept. 29 in Nature Sustainability, draws on eight years of standardized test scores from nearly 11,700 public school districts across six grades, as well as estimates of daily smoke exposure derived from satellite measurements.

The researchers found test scores in English language arts and math dropped significantly during school years even at low levels of smoke exposure, and that test-score impacts grew as students’ smoke exposure worsened.

The impact on test scores nearly doubled when students were exposed to heavy smoke during the school day compared to the weekend. Underscoring previous studies suggesting that air pollution impacts are particularly harmful for younger students, the study also revealed greater impacts for third to fifth graders compared to sixth to eighth graders.

WVU engineers bring new life to electronics recycling, address supply chain shortfalls affecting national defense

Edward Sabolsky, WVU Benjamin M. Statler College of Engineering and Mineral Resources professor uses ceramic bricks to conduct research at his lab. The U.S. Department of Defense has tasked Sabolsky and Terence Musho with developing a new process for recycling electronic waste in order to extract raw materials that are used to build technology critical to U.S. national defense, such as semiconductors. Photo Credit: WVU /Brian Persinger

West Virginia University researchers are resurrecting discarded electronics, recycling electronic waste and recovering minerals from it to make new products critical for national defense.

Terence Musho, associate professor of mechanical and aerospace engineering at the Benjamin M. Statler College of Engineering and Mineral Resources, is leading the project, which received more than $250,000 from the Defense Advanced Research Projects Agency at the U.S. Department of Defense.

The U.S. currently depends on countries like China to provide raw materials that are essential to electronics enabling its national defense. But according to Musho, that “reliance on foreign national resources has led to the White House identifying a critical shortage in the semiconductor supply chain.”

Musho said that shortage is one reason the DOD is eyeing readily available electronic waste like old “LEDs and microelectronic circuits used for amplifying radio frequencies, which contain critical supply chain materials.”

A Different Kind of Therapy for Stroke

Stroke folders and labels at the Emergency Department at UConn Health in Farmington on Sept. 29, 2020.
Photo Credit: Peter Morenus/UConn

Stroke deprives the brain of oxygen and energy, causing a cascade of spreading cell death. Blocking a specific receptor could contain the damage, researchers from UConn Health and the National Institutes of Health (NIH) report in the Journal of Medicinal Chemistry.

A stroke occurs when a blood vessel in the brain is either ruptured or clogged. The loss of blood flow deprives part of the brain of oxygen, and cells begin to die within minutes. Every 40 seconds someone in the US has a stroke, according to the Centers for Disease Control and Prevention. That’s more than 795,000 people every year. More than half of the survivors will have permanent difficulties walking, talking and caring for themselves.

The faster someone suffering from a stroke gets medical help, the more likely they are to avoid serious lasting disability. Restoring blood flow to the brain as fast as possible to avoid cell death is critical.

But other factors besides blood flow can also contribute to cell death in brain during a stroke. For example, brain cells store lots of energy in the form of the molecule ATP. When a brain cell dies, it releases all of its stored ATP. The spilled ATP triggers a receptor called P2X4 on neighboring brain cells. If the P2X4 receptor is overstimulated, it can trigger a rush of calcium ions that can activate cell death enzymes and set off a destructive cycle of brain damage.