To assess feasibility, complications, local tumor recurrences, overall survival (OS) and estimates of cost-effectiveness for multi-site cryoablation (MCA) of oligo-metastatic colorectal cancer (mCRC) in a prospective study.
Category: biotech/medical – Page 44
Cross-species cellular mapping and humanization of Fcγ receptors to advance antibody modeling
A new Science Immunology study highlights the limitations of preclinical models for human antibody-based drugs, and demonstrates how a humanized mouse model may improve study outcomes.
Preclinical modeling of human IgG–based drugs is enhanced through humanized Fcγ receptor and FcRn expression in a murine knockin model.
Pancreatic tumors eliminated in mice without resistance developing
Current drugs for pancreatic cancer lose effectiveness within months because the tumor becomes resistant. Now, a group from Spain’s National Cancer Research Centre (CNIO) has been able to avoid the development of resistance in animal models with a combined triple therapy. Mariano Barbacid, head of the Experimental Oncology Group at the CNIO, has designed a therapy that successfully eliminates pancreatic tumors in mice completely and durably, with no significant side effects.
The study is published in the journal Proceedings of the National Academy of Sciences, with Carmen Guerra as co-lead author and Vasiliki Liaki and Sara Barrambana as first authors.
“These studies open the road to designing novel combination therapies that may improve the survival of PDAC patients [pancreatic ductal adenocarcinoma—the most common type of pancreatic cancer],” the authors state. “These results set the course for developing new clinical trials.”
Enzyme required for transition from monocyte to tissue-resident macrophage identified!
A new study found that an enzyme involved in protein translation is essential for circulating immune cells, called monocytes, to mature into tissue-resident macrophages, a specialized population of immune cells that maintain organ health by clearing dead cells and debris. Without this enzyme, monocytes enter tissues but fail to fully differentiate, leading to impaired tissue maintenance and persistent immune cell infiltration that causes inflammation instead of repair.
The research, published in Nature, showed that deoxyhypusine synthase (DHPS) is required for both the differentiation and long-term survival of macrophages across multiple organs, including the lung, liver, brain, kidney, heart and peritoneal cavity.
Using a series of mouse models, the investigators demonstrated that DHPS controls a core, tissue-agnostic program that enables macrophages to adhere to their local environment, interact with surrounding cells and carry out the essential functions that maintain tissue balance and organ health.
The researchers traced these defects to the polyamine–hypusine pathway. Analyses of gene activity, protein production and protein-making machinery revealed that DHPS is required for efficient translation of a subset of genes involved in cell adhesion (the ability to stick to their surroundings and to other cells so they can stay in the correct place and function properly), signaling, and tissue interaction. Without DHPS, macrophages failed to express key proteins needed to anchor themselves within tissues and respond appropriately to local cues.
Imaging studies showed that DHPS-deficient macrophages had abnormal shape and positioning within tissues, while functional assays demonstrated defects in the clearance of dead cells and tissue maintenance. In the lung, this impairment led to accumulation of surfactant material, a substance in the lungs that keeps air sacs open, and immune cell infiltration, while in the liver, acute macrophage depletion followed by failed restoration resulted in vascular disruption and tissue damage. sciencenewshighlights ScienceMission.
When Familiar Faces Feel Better: A Framework for Social Neurocognitive Aging in a Rat Model
New in eNeuro from Dutta Gupta et al: Some older male rats prefer familiarity over new social situations, which can be reversed via transcranial magnetic stimulation without affecting hippocampus-mediated spatial memory.
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Social cognition, central to emotional and cognitive well-being, is particularly vulnerable to aging, where impairments can lead to isolation and functional decline. Despite compelling evidence that altered social behavior is associated with cognitive decline and dementia risk, experimental strategies for testing causative links remain scarce. To address this gap, we aimed to establish a rat model for research on social neurocognitive aging. We conducted a large-scale behavioral study in 169 male young (6 months) and aged (24−25 months) Long-Evans rats. In order to explore potential relationships among aging outcomes, we first documented individual differences in a widely validated water maze test of hippocampal learning and memory. Sociability and social novelty were then evaluated in the same subjects using the three-chamber social interaction test. Aging induced a selective shift in social novelty preference, marked by a striking familiarity bias in a substantial subpopulation of old rats, while sociability remained entirely normal. Changes in social novelty preference were completely independent of individual differences in spatial memory, and unrelated to anxiety or sensorimotor function. Notably, neuromodulation via TMS enhanced social novelty preference selectively in aged rats that exhibited a social introversion phenotype before treatment, consistent with the possibility that this aging condition reflects a distinct and modifiable neural network state. Together, the results establish a valuable preclinical framework for developing a comprehensive neurobiology of social cognition in aging.
Significance statement Social behavior is a critical yet underexplored component of cognitive aging. While both human and animal studies report age-related narrowing of social networks, the behavioral and neurobiological underpinnings remain unclear. Using a well-powered rat model, here we demonstrate preserved sociability in aging alongside marked individual differences in social novelty preference. A subset of aged rats preferred familiar over novel conspecifics, resembling patterns observed in older humans and non-human primates. Social phenotypes were independent of hippocampal-dependent memory, suggesting a dissociation between these aging outcomes. This dissociation was further validated using transcranial magnetic stimulation, supporting the notion of distinct underlying neurobiological mechanisms. Collectively, the findings lay a powerful foundation for advancing the translational neurobiology of social behavior in cognitive aging and reserve.
Engineering immunotherapy from within
In Science last year, researchers presented a method to safely and preferentially generate CAR T cells directly inside the body using targeted lipid nanoparticles that deliver mRNA directly to T cells.
The approach showed rapid and sustained immune reprogramming in preclinical models, highlighting its promise for treating cancer and autoimmune diseases.
Learn more on WorldCancerDay.
Lipid nanoparticles are designed to generate therapeutic T cells inside living animal models.
Vivek Peche and Stephen Gottschalk Authors Info & Affiliations
Science
Tethered platelets in severe infection
Platelets are cell fragments that plug leaks in blood vessels, preventing bleeding. However, they also form clots that impede blood flow (thrombosis) and increase inflammation.
Activated platelets, which can bind to each other, and hyporesponsive platelets, which do not form clots, are detected in patients with acute severe infections, such as COVID-19 and sepsis. How to uncouple the protective and harmful proinflammatory functions of platelets is a therapeutic dilemma.
In Science, researchers report the formation of platelet-derived integrin-and tetraspanin-enriched tethers (PITTs) in patients with severe infections.
PITTs, which are enriched in specific platelet proteins, remain anchored to the blood vessel wall (endothelium) and promote neutrophil recruitment, inflammation, and tissue damage, whereas the main platelet body shears off and reenters circulation in a hyporesponsive state. PITTs may contribute to blood clotting, immune dysregulation, and bleeding complications that characterize severe infections.
Learn more in a new Science Perspective.
Platelet-derived structures in blood vessel walls increase inflammation and bleeding risk.
Patent Foramen Ovale Closure in Stroke and PASCAL
Among patients with Stroke and PatentForamenOvale, the PASCAL classification system identified those likely to benefit from closure and those at risk of increased atrial fibrillation.
Question Among young and middle-aged individuals (ages 18–60 years) with patent foramen ovale (PFO) and otherwise cryptogenic ischemic stroke enrolled in pivotal trials, can the PASCAL classification system identify those who will experience net benefit and those who will experience net harm from PFO closure in the next 5 years?
Finding This meta-analysis showed that in the PASCAL groups probable and possible, PFO closure reduced recurrent ischemic stroke more often than it caused atrial fibrillation, but in the unlikely group, closure did not reduce stroke and caused a larger amount of atrial fibrillation.
Meaning The PASCAL classification system may identify as many as 4 of 5 patients who will experience net benefit and 1 of 5 who will experience net harm from PFO closure.