PI5P4Kα promotes glucose and iron acquisition to support metabolic fitness in pancreatic cancer.

Phosphoinositide kinases generate distinct phosphoinositides that regulate pathways to support tumorigenesis. Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) have garnered interest for their role in cancer metabolism; however, their function in pancreatic ductal adenocarcinoma (PDAC) remains unexplored. We identify PI5P4Kα as a critical dependency to support the unique metabolic demands of PDAC cells through its key role in the acquisition of essential metabolic substrates, including glucose and iron.

2025 ADS/ANZCA/GESA/NACOS clinical practice recommendations on the peri-procedural use of GLP-1/GIP receptor agonists.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for the treatment of type 2 diabetes and/or obesity. The physiological actions of endogenous GLP-1, and synthetic GLP-1RAs include inhibition of gastric emptying. This has peri-procedural implications due to the potential increased risk of retained gastric contents which may result in pulmonary aspiration.

ZBTB11 depletion targets metabolic vulnerabilities in KRAS inhibitor-resistant PDAC.

Over 95% of pancreatic ductal adenocarcinomas (PDACs) harbor oncogenic mutations in KRAS. However, upon treatment with KRAS inhibitors, PDAC cells undergo rapid metabolic reprogramming toward an oxidative phosphorylation (OXPHOS)-dependent, drug-resistant state. Here, we demonstrate that this metabolic shift is associated with upregulation of the transcription factor ZBTB11 and both the metabolic state and resistance to KRAS inhibitors can be attenuated by ZBTB11 depletion.

Macropinocytosis maintains CAF subtype identity under metabolic stress in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) tumors are glutamine deficient, and both tumor cells and cancer-associated fibroblasts (CAFs) rely on this amino acid to maintain fitness and induce macropinocytosis as an adaptive response. CAFs play a critical role in sculpting the tumor microenvironment, yet how adaptations to metabolic stress impact the stromal architecture remains elusive. In this study, we find that macropinocytosis sustains the myCAF phenotype under glutamine limitation by preventing inflammatory reprogramming.

Self-amplifying NRF2-EZH2 epigenetic loop converts KRAS-initiated progenitors to invasive pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) emerges from mutant KRAS-harboring but dormant low-grade pancreatic intraepithelial neoplasia (PanIN). To examine the role of oxidative stress, a putative PDAC risk factor, we established an organoid-based transformation system. Although the prototypic oxidant HO induced organoid transformation, its effect was nonmutational and was mediated by the oxidant-responsive transcription factor NRF2, which induced the histone methyltransferase EZH2.

Structural basis for target DNA cleavage and guide RNA processing by CRISPR-Casλ2.

RNA-guided CRISPR-Cas nucleases are widely used as versatile genome-engineering tools. Among the diverse CRISPR-Cas effectors, CRISPR-Casλ-also referred to as Cas12n-is a recently identified miniature type V nuclease encoded in phage genomes. Given its demonstrated nuclease activity in both mammalian and plant cells, Casλ has emerged as a promising candidate for genome-editing applications.

The cell-permeable iron chelator M606 inhibits MYCN-driven neuroblastoma via an E2F3-mediated response.

Despite Myc oncoproteins being major causal factors in human cancer, they remain "undruggable." The oncogene is one of the most powerful prognostic markers for the childhood cancer neuroblastoma and represents an important target for developing novel therapeutics. Here, we report the finding and characterization of M606, a selective small molecule inhibitor of MYCN, which was identified by screening a diverse chemical library.

Initial Characterization of 12 New Subtypes and Variants of Type V CRISPR Systems.

Type V CRISPR systems are highly diverse in sequence, mechanism, and function. Although recent efforts have greatly expanded our understanding of their evolution, the diversity of type V systems remains to be completely explored, and many clades have not been experimentally characterized. In this work, we mined metagenomic databases to identify three new subtypes and nine new variants of Cas12, the effector of Type V systems, and provide experimental and computational characterization of their Protospacer-Adjacent Motif (PAM), interference activity, loci architecture, and tracrRNA dependence.

Metabolic deficiencies underlie reduced plasmacytoid dendritic cell IFN-I production following viral infection.

Type I Interferons (IFN-I) are central to host protection against viral infections, with plasmacytoid dendritic cells (pDC) being the most significant source, yet pDCs lose their IFN-I production capacity following an initial burst of IFN-I, resulting in susceptibility to secondary infections. The underlying mechanisms of these dynamics are not well understood. Here we find that viral infection reduces the capacity of pDCs to engage both oxidative and glycolytic metabolism.

Xenon anaesthesia is associated with a reduction in frontal electroencephalogram peak alpha frequency.

Background: Administration of conventional anaesthetic agents is associated with changes in electroencephalogram (EEG) oscillatory dynamics, including a reduction in the peak alpha frequency. Computational models of neurones can reproduce such phenomena and are valuable tools for investigating their underlying mechanisms. We hypothesised that EEG data acquired during xenon anaesthesia in humans would show similar changes in peak alpha frequency and that computational neuronal models of recognised cellular actions of xenon would be consistent with the observed changes.

Macropinocytosis controls metabolic stress-driven CAF subtype identity in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) tumors are deficient in glutamine, an amino acid that tumor cells and CAFs use to sustain their fitness. In PDAC, both cell types stimulate macropinocytosis as an adaptive response to glutamine depletion. CAFs play a critical role in sculpting the tumor microenvironment, yet how adaptations to metabolic stress impact the stromal architecture remains elusive.

Preoperative Biofluid Biomarkers for Predicting Postoperative Neurocognitive Disorders in Older Adults: A Systematic Review.

Preoperative biofluid biomarkers reflecting pathophysiological, neuronal injury, and inflammation as well as those for Alzheimer's disease (AD) may be valuable tools for the risk stratification of perioperative neurocognitive disorders (PNDs) in older adults. We summarized current evidence relating these preoperative biomarkers to PND beyond 7 days, in older surgical participants aged ≥60 years. Studies that evaluated the association of preoperative biomarkers with cognitive decline as an outcome, beyond 7 days, were identified through searches of 6 databases and 3 trial registries to 17 January 2024.

Tilting the Scales toward EGFR Mutant Selectivity: Expanding the Scope of Bivalent "Type V" Kinase Inhibitors.

Binding multiple sites within proteins with bivalent compounds is a strategy for developing uniquely active agents. A new class of dual-site inhibitors has emerged targeting the epidermal growth factor receptor (EGFR) anchored to both the orthosteric (ATP) and allosteric sites. Despite proof-of-concept successes, enabling selectivity against oncogenic activating mutations has not been achieved and classifying these inhibitors among kinase inhibitors remains underexplored.

A narrative review of gas separation and conservation technologies during xenon anesthesia.

Xenon gas has significant advantages over conventional general anesthetic agents but its use has been limited by the cost associated with its production. Xenon also has significant potential for medical use in the treatment of acquired brain injuries and for mental health disorders. As the demand for xenon gas from other industries increases, the costs associated with its medical use are only likely to increase.

Delineation of global, absolutely essential and conditionally essential pangenomes of Porphyromonas gingivalis.

Porphyromonas gingivalis is a Gram-negative, anaerobic oral pathobiont, an etiological agent of periodontitis and the most commonly studied periodontal bacterium. Multiple low passage clinical isolates were sequenced, and their genomes compared to several laboratory strains. Phylogenetic distances were mapped, a gene absence-presence matrix generated, and core (present in all genomes) and accessory (absent in one or more genomes) genes delineated.

Genetically encoded fluorescent sensors for visualizing polyamine levels, uptake, and distribution.

Polyamines are abundant and physiologically essential biomolecules that play a role in numerous processes, but are disrupted in diseases such as cancer, and cardiovascular and neurological disorders. Despite their importance, measuring free polyamine concentrations and monitoring their metabolism and uptake in cells in real-time remains impossible due to the lack of appropriate biosensors. Here we engineered, characterized, and validated the first genetically encoded biosensors for polyamines, named iPASnFRs.

If the peri-operative patient pathway was right, what would it look like?

Background: Patients undergoing surgery deserve the best possible peri-operative outcomes. Each stage of the peri-operative patient journey offers opportunities to improve care delivery, with shorter lengths of stay, less complications, reduced costs and better value.

Methods: These opportunities were identified through narrative review of the literature, with consultation and consensus at the hidden pandemic (of postoperative complications) summit 2, July 2023 in Adelaide, Australia RESULTS: Before surgery: Some patients who receive timely alternative treatments may not need surgery at all.

Synthesis and Characterization of a Sustained Nitric Oxide-Releasing Orthodontic Elastomeric Chain for Antimicrobial Action.

The acidic byproducts of bacteria in plaque around orthodontic brackets contribute to white spot lesion (WSL) formation. Nitric oxide (NO) has antibacterial properties, hindering biofilm formation and inhibiting the growth of oral microbes. Materials that mimic NO release could prevent oral bacteria-related pathologies.

Prevalence of neurocognitive disorders 5 years after elective orthopaedic surgery.

Background: Peri-operative neurocognitive disorders are one of the most common complications affecting older adults after anaesthesia and surgery. It is not clear how exposure to surgery and anaesthesia contributes to the prevalence of long-term neurocognitive disorders. This study aimed to report the prevalence of neurocognitive disorders, and explore pre-operative factors associated with neurocognitive disorders 5 years after elective orthopaedic surgery.

From hit to vial: Precision discovery and development of an imidazopyrimidine TLR7/8 agonist adjuvant formulation.

Vaccination can help prevent infection and can also be used to treat cancer, allergy, and potentially even drug overdose. Adjuvants enhance vaccine responses, but currently, the path to their advancement and development is incremental. We used a phenotypic small-molecule screen using THP-1 cells to identify nuclear factor-κB (NF-κB)-activating molecules followed by counterscreening lead target libraries with a quantitative tumor necrosis factor immunoassay using primary human peripheral blood mononuclear cells.

ZBTB11 Depletion Targets Metabolic Vulnerabilities in K-Ras Inhibitor Resistant PDAC.

Over 95% of pancreatic ductal adenocarcinomas (PDAC) harbor oncogenic mutations in K-Ras. Upon treatment with K-Ras inhibitors, PDAC cancer cells undergo metabolic reprogramming towards an oxidative phosphorylation-dependent, drug-resistant state. However, direct inhibition of complex I is poorly tolerated in patients due to on-target induction of peripheral neuropathy.