FLT1 activation in cancer cells promotes PARP-inhibitor resistance in breast cancer.

Acquired resistance to PARP inhibitors (PARPi) remains a treatment challenge for BRCA1/2-mutant breast cancer that drastically shortens patient survival. Although several resistance mechanisms have been identified, none have been successfully targeted in the clinic. Using new PARPi-resistance models of Brca1- and Bard1-mutant breast cancer generated in-vivo, we identified FLT1 (VEGFR1) as a driver of resistance. Unlike the known role of VEGF signaling in angiogenesis, we demonstrate a novel, non-canonical role for FLT1 signaling that protects cancer cells from PARPi in-vivo through a combination of cell-intrinsic and cell-extrinsic pathways. We demonstrate that FLT1 blockade suppresses AKT activation, increases tumor infiltration of CD8+ T cells, and causes dramatic regression of PARPi-resistant breast tumors in a T-cell-dependent manner. Moreover, PARPi-resistant tumor cells can be readily re-sensitized to PARPi by targeting Flt1 either genetically (Flt1-suppression) or pharmacologically (axitinib). Importantly, a retrospective series of breast cancer patients treated with PARPi demonstrated shorter progression-free survival in cases with FLT1 activation at pre-treatment. Our study therefore identifies FLT1 as a potential therapeutic target in PARPi-resistant, BRCA1/2-mutant breast cancer.

Correction: Liu et al. Emergent Peptides of the Antifibrotic Arsenal: Taking Aim at Myofibroblast Promoting Pathways. Biomolecules 2023, 13, 1179.

There was an error in the original publication [...].

Layer-by-Layer Assembly of Renal-Targeted Polymeric Nanoparticles for Robust Arginase-2 Knockdown and Contrast-Induced Acute Kidney Injury Prevention.

The mitochondrial enzyme arginase-2 (Arg-2) is implicated in the pathophysiology of contrast-induced acute kidney injury (CI-AKI). Therefore, Arg-2 represents a candid target for CI-AKI prevention. Here, layer-by-layer (LbL) assembled renal-targeting polymeric nanoparticles are developed to efficiently deliver small interfering RNA (siRNA), knockdown Arg-2 expression in renal tubules, and prevention of CI-AKI is evaluated. First, near-infrared dye-loaded poly(lactic-co-glycolic acid) (PLGA) anionic cores are electrostatically coated with cationic chitosan (CS) to facilitate the adsorption and stabilization of Arg-2 siRNA. Next, nanoparticles are coated with anionic hyaluronan (HA) to provide protection against siRNA leakage and shielding against early clearance. Sequential electrostatic layering of CS and HA improves loading capacity of Arg-2 siRNA and yields LbL-assembled nanoparticles. Renal targeting and accumulation is enhanced by modifying the outermost layer of HA with a kidney targeting peptide (HA-KTP). The resultant kidney-targeting and siRNA loaded nanoparticles (PLGA/CS/HA-KTP siRNA) exhibit proprietary accumulation in kidneys and proximal tubular cells at 24 h post-tail vein injection. In iohexol-induced in vitro and in vivo CI-AKI models, PLGA/CS/HA-KTP siRNA delivery alleviates oxidative and nitrification stress, and rescues mitochondrial dysfunction while reducing apoptosis, thereby demonstrating a robust and satisfactory therapeutic effect. Thus, PLGA/CS/HA-KTP siRNA nanoparticles offer a promising candidate therapy to protect against CI-AKI.

Emergent Peptides of the Antifibrotic Arsenal: Taking Aim at Myofibroblast Promoting Pathways.

Myofibroblasts are the principal effector cells driving fibrosis, and their accumulation in tissues is a fundamental feature of fibrosis. Essential pathways have been identified as being central to promoting myofibroblast differentiation, revealing multiple targets for intervention. Compared with large proteins and antibodies, peptide-based therapies have transpired to serve as biocompatible and cost-effective solutions to exert biomimicry, agonistic, and antagonistic activities with a high degree of targeting specificity and selectivity. In this review, we summarize emergent antifibrotic peptides and their utilization for the targeted prevention of myofibroblasts. We then highlight recent studies on peptide inhibitors of upstream pathogenic processes that drive the formation of profibrotic cell phenotypes. We also briefly discuss peptides from non-mammalian origins that show promise as antifibrotic therapeutics. Finally, we discuss the future perspectives of peptide design and development in targeting myofibroblasts to mitigate fibrosis.

Improving detection of impacted animal bones on lateral neck radiograph using a deep learning artificial intelligence algorithm.

OBJECTIVE: We aimed to develop a deep learning artificial intelligence (AI) algorithm to detect impacted animal bones on lateral neck radiographs and to assess its effectiveness for improving the interpretation of lateral neck radiographs. METHODS: Lateral neck radiographs were retrospectively collected for patients with animal bone impaction between January 2010 and March 2020. Radiographs were then separated into training, validation, and testing sets. A total of 1733 lateral neck radiographs were used to develop the deep learning algorithm. The testing set was assessed for the stand-alone deep learning AI algorithm and for human readers (radiologists, radiology residents, emergency physicians, ENT physicians) with and without the aid of the AI algorithm. Another radiograph cohort, collected from April 1, 2020, to June 30, 2020, was analyzed to simulate clinical application by comparing the deep learning AI algorithm with radiologists' reports. RESULTS: In the testing set, the sensitivity, specificity, and accuracy of the AI model were 96%, 90%, and 93% respectively. Among the human readers, all physicians of different subspecialties achieved a higher accuracy with AI-assisted reading than without. In the simulation set, among the 20 cases positive for animal bones, the AI model accurately identified 3 more cases than the radiologists' reports. CONCLUSION: Our deep learning AI model demonstrated a higher sensitivity for detection of animal bone impaction on lateral neck radiographs without an increased false positive rate. The application of this model in a clinical setting may effectively reduce time to diagnosis, accelerate workflow, and decrease the use of CT.

Targeting S100A9-ALDH1A1-Retinoic Acid Signaling to Suppress Brain Relapse in EGFR-Mutant Lung Cancer.

The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib has significantly prolonged progression-free survival (PFS) in patients with EGFR-mutant lung cancer, including those with brain metastases. However, despite striking initial responses, osimertinib-treated patients eventually develop lethal metastatic relapse, often to the brain. Although osimertinib-refractory brain relapse is a major clinical challenge, its underlying mechanisms remain poorly understood. Using metastatic models of EGFR-mutant lung cancer, we show that cancer cells expressing high intracellular S100A9 escape osimertinib and initiate brain relapses. Mechanistically, S100A9 upregulates ALDH1A1 expression and activates the retinoic acid (RA) signaling pathway in osimertinib-refractory cancer cells. We demonstrate that the genetic repression of S100A9, ALDH1A1, or RA receptors (RAR) in cancer cells, or treatment with a pan-RAR antagonist, dramatically reduces brain metastasis. Importantly, S100A9 expression in cancer cells correlates with poor PFS in osimertinib-treated patients. Our study, therefore, identifies a novel, therapeutically targetable S100A9-ALDH1A1-RA axis that drives brain relapse. SIGNIFICANCE: Treatment with the EGFR TKI osimertinib prolongs the survival of patients with EGFR-mutant lung cancer; however, patients develop metastatic relapses, often to the brain. We identified a novel intracellular S100A9-ALDH1A1-RA signaling pathway that drives lethal brain relapse and can be targeted by pan-RAR antagonists to prevent cancer progression and prolong patient survival. This article is highlighted in the In This Issue feature, p. 873.

Bioinspired enzymatic compartments constructed by spatiotemporally confined in situ self-assembly of catalytic peptide.

Enzymatic compartments, inspired by cell compartmentalization, which bring enzymes and substrates together in confined environments, are of particular interest in ensuring the enhanced catalytic efficiency and increased lifetime of encapsulated enzymes. Herein, we constructed bioinspired enzymatic compartments (TPE-Q18H@GPs) with semi-permeability by spatiotemporally controllable self-assembly of catalytic peptide TPE-Q18H in hollow porous glucan particles (GPs), allowing substrates and products to pass in/out freely, while enzymatic aggregations were retained. Due to the enrichment of substrates and synergistic effect of catalytic nanofibers formed in the confined environment, the enzymatic compartments exhibited stronger substrate binding affinity and over two-fold enhancement of second-order kinetic constant (kcat/Km) compared to TPE-Q18H nanofibers in disperse system. Moreover, GPs enabled the compartments sufficient stability against perturbation conditions, such as high temperature and degradation. This work opens an intriguing avenue to construct enzymatic compartments using porous biomass materials and has fundamental implications for constructing artificial organelles and even artificial cells.

Myofibroblasts: Function, Formation, and Scope of Molecular Therapies for Skin Fibrosis.

Myofibroblasts are contractile, α-smooth muscle actin-positive cells with multiple roles in pathophysiological processes. Myofibroblasts mediate wound contractions, but their persistent presence in tissues is central to driving fibrosis, making them attractive cell targets for the development of therapeutic treatments. However, due to shared cellular markers with several other phenotypes, the specific targeting of myofibroblasts has long presented a scientific and clinical challenge. In recent years, myofibroblasts have drawn much attention among scientific research communities from multiple disciplines and specialisations. As further research uncovers the characterisations of myofibroblast formation, function, and regulation, the realisation of novel interventional routes for myofibroblasts within pathologies has emerged. The research community is approaching the means to finally target these cells, to prevent fibrosis, accelerate scarless wound healing, and attenuate associated disease-processes in clinical settings. This comprehensive review article describes the myofibroblast cell phenotype, their origins, and their diverse physiological and pathological functionality. Special attention has been given to mechanisms and molecular pathways governing myofibroblast differentiation, and updates in molecular interventions.

Ultrasound-Guided Moving Shot Radiofrequency Ablation of Benign Soft Tissue Neoplasm.

Background and Objective: To evaluate the effectiveness of radiofrequency ablation (RFA) using the moving-shot technique for benign soft tissue neoplasm. Materials and Methods: This retrospective study reviewed eight patients with benign soft tissue neoplasm presenting with cosmetic concerns and/or symptomatic issues who refused surgery. Six patients had vascular malformation, including four with venous malformation and two with congenital hemangioma. The other two patients had neurofibroma. All patients underwent RFA using the moving-shot technique. Imaging and clinical follow-up were performed in all patients. Follow-up image modalities included ultrasound (US), computed tomography (CT), and magnetic resonance (MR) imaging. The volume reduction ratio (VRR), cosmetic scale (CS), and complications were evaluated. Results: Among the seven patients having received single-stage RFA, there were significant volume reductions between baseline (33.3 ± 21.2 cm3), midterm follow-up (5.1 ± 3.8 cm3, p = 0.020), and final follow-up (3.6 ± 1.4 cm3, p = 0.022) volumes. The VRR was 84.5 ± 9.2% at final follow-up. There were also significant improvements in the CS (from 3.71 to 1.57, p = 0.017). The remaining patient, in the process of a scheduled two-stage RFA, had a 33.8% VRR after the first RFA. The overall VRR among the eight patients was 77.5%. No complications or re-growth of the targeted lesions were noted during the follow-up period. Of the eight patients, two received RFA under local anesthesia, while the other six patients were under general anesthesia. Conclusions: RFA using the moving-shot technique is an effective, safe, and minimally invasive treatment for benign soft tissue neoplasms, achieving mass volume reduction within 6 months and significant esthetic improvement, either with local anesthesia or with general anesthesia under certain conditions.

Design and Evaluation of a Polypeptide that Mimics the Integrin Binding Site for EDA Fibronectin to Block Profibrotic Cell Activity.

Fibrosis is characterized by excessive production of disorganized collagen- and fibronectin-rich extracellular matrices (ECMs) and is driven by the persistence of myofibroblasts within tissues. A key protein contributing to myofibroblast differentiation is extra domain A fibronectin (EDA-FN). We sought to target and interfere with interactions between EDA-FN and its integrin receptors to effectively inhibit profibrotic activity and myofibroblast formation. Molecular docking was used to assist in the design of a blocking polypeptide (antifibrotic 38-amino-acid polypeptide, AF38Pep) for specific inhibition of EDA-FN associations with the fibroblast-expressed integrins α4ß1 and α4ß7. Blocking peptides were designed and evaluated in silico before synthesis, confirmation of binding specificity, and evaluation in vitro. We identified the high-affinity EDA-FN C-C' loop binding cleft within integrins α4ß1 and α4ß7. The polypeptide with the highest predicted binding affinity, AF38Pep, was synthesized and could achieve specific binding to myofibroblast fibronectin-rich ECM and EDA-FN C-C' loop peptides. AF38Pep demonstrated potent myofibroblast inhibitory activity at 10 µg/mL and was not cytotoxic. Treatment with AF38Pep prevented integrin α4ß1-mediated focal adhesion kinase (FAK) activation and early signaling through extracellular-signal-regulated kinases 1 and 2 (ERK1/2), attenuated the expression of pro-matrix metalloproteinase 9 (MMP9) and pro-MMP2, and inhibited collagen synthesis and deposition. Immunocytochemistry staining revealed an inhibition of α-smooth muscle actin (α-SMA) incorporation into actin stress fibers and attenuated cell contraction. Increases in the expression of mRNA associated with fibrosis and downstream from integrin signaling were inhibited by treatment with AF38Pep. Our study suggested that AF38Pep could successfully interfere with EDA-FN C-C' loop-specific integrin interactions and could act as an effective inhibitor of fibroblast of myofibroblast differentiation.