STAT3 blockade ameliorates LPS-induced kidney injury through macrophage-driven inflammation.

BACKGROUND: Signal transducer and activator of transcription 3 (STAT3), a multifaceted transcription factor, modulates host immune responses by activating cellular response to signaling ligands. STAT3 has a pivotal role in the pathophysiology of kidney injury by counterbalancing resident macrophage phenotypes under inflammation conditions. However, STAT3's role in acute kidney injury (AKI), particularly in macrophage migration, and in chronic kidney disease (CKD) through fibrosis development, remains unclear. METHODS: Stattic (a JAK2/STAT3 inhibitor, 5 mg/kg or 10 mg/kg) was administered to evaluate the therapeutic effect on LPS-induced AKI (L-AKI) and LPS-induced CKD (L-CKD), with animals sacrificed 6-24 h and 14 days post-LPS induction, respectively. The immune mechanisms of STAT3 blockade were determined by comparing the macrophage phenotypes and correlated with renal function parameters. Also, the transcriptomic analysis was used to confirm the anti-inflammatory effect of L-AKI, and the anti-fibrotic role was further evaluated in the L-CKD model. RESULTS: In the L-AKI model, sequential increases in BUN and blood creatinine levels were time-dependent, with a marked elevation of 0-6 h after LPS injection. Notably, two newly identified macrophage subpopulations (CD11bhighF4/80low and CD11blowF4/80high), exhibited population changes, with an increase in the CD11bhighF4/80low population and a decrease in the CD11blowF4/80high macrophages. Corresponding to the FACS results, the tubular injury score, NGAL, F4/80, and p-STAT3 expression in the tubular regions were elevated. STAT3 inhibitor injection in L-AKI and L-CKD mice reduced renal injury and fibrosis. M2-type subpopulation with CD206 in CD11blowF4/80high population increased in the Stattic-treated group compared with that in the LPS-alone group in the L-AKI model. Additionally, STAT3 inhibitor reduced inflammation driven by LPS-stimulated macrophages and epithelial cells injury in the co-culture system. Transcriptomic profiling identified 3 common genes in the JAK-STAT, TLR, and TNF signaling pathways and 11 common genes in the LPS with macrophage response. The PI3K-AKT (IL-6, Akt3, and Pik3r1) and JAK-STAT pathways were determined as potential Stattic targets. Further confirmation through mRNA and protein expressions analyses showed that Stattic treatment reduced inflammation in the L-AKI and fibrosis in the L-CKD mice. CONCLUSIONS: STAT3 blockade effectively mitigated inflammation by retrieving the CD11blowF4/80high population, further emphasizing the role of STAT3-associated macrophage-driven inflammation in kidney injury.

This study investigated the role of STAT3 in LPS-induced acute kidney injury (AKI) and its prolonged pathophysiological effect. In a mouse model, blocking STAT3 with Stattic reduced inflammation and fibrosis, decreased the levels of inflammatory and extracellular matrix (ECM) substances, reduced the number of certain immune cells (macrophages), and influenced specific genes related to inflammation. The findings suggest that targeting STAT3 is a promising approach to treat AKI and CKD by controlling the inflammation and the immune response as well as ECM accumulation. This study provides novel insights into AKI and CKD progression and will facilitate the development of new treatments for kidney injuries at various stages.

Ethanolic Extract from Echinacea purpurea (L.) Moench Inhibits Influenza A/B and Respiratory Syncytial Virus Infection in vitro: Preventive Agent for Viral Respiratory Infections.

Among the most frequent causes of respiratory infections in humans are influenza A virus H1N1 (H1N1), influenza B virus (IVB), and respiratory syncytial virus (RSV). Echinacea is a perennial wildflower belonging to the Asteraceae family. Echinacea purpurea (L.) Moench is a species belonging to the Echinacea genus. Its characteristic compound, chicoric acid (CA), is known for its physiological activities, including antiviral effects and immune enhancement. Activities of E. purpurea 60% ethanol extract (EPE) and CA in inhibiting infections caused by H1N1, IVB, and RSV subtype A (RSV-A) were evaluated through plaque inhibition tests, quantification of viral gene expression, and analysis of transmission electron microscopy (TEM) images. Additionally, inhibitory activities of EPE and CA for hemagglutination and neuraminidase (NA) of H1N1 and IVB were determined. In the plaque reduction assays, both EPE and CA reduced infectivity against H1N1, IVB, and RSV-A. Furthermore, quantitative real-time polymerase chain reaction analysis revealed that EPE and CA reduced gene expression levels for H1N1, IVB, and RSV-A, whereas TEM image analysis confirmed their inhibitory effects on host cell infection by these viruses. Hemagglutination assays exhibited the ability of EPE and CA to hinder H1N1 and IVB attachment to host cell receptors. Furthermore, EPE and CA displayed inhibition activity against the NA of H1N1 and IVB. These findings suggest that EPE and CA can suppress the infection and propagation of H1N1, IVB, and RSV-A, demonstrating their potential as preventive and therapeutic agents for viral respiratory infections or as ingredients for health functional foods.

Evaluation of large-scale poultry manure-derived biochar for efficient cadmium removal in zinc smelter wastewater.

Cadmium (Cd), a carcinogen, is released from industrial activities like metal refineries and battery runoff, with significant contamination reported near zinc smelters in Korea. This study addresses the issue using an efficient, economical adsorption process with waste-derived biochar-based adsorbents known for high Cd removal. Poultry manure (PM), typically used as fertilizer, can lead to environmental pollution if mismanaged; therefore, it was pyrolyzed to produce biochar. The resulting poultry manure biochar (PMBC) was produced on a large scale (15 ton/day), demonstrating feasibility for large-scale implementation. The effectiveness of PMBC as an adsorbent for Cd was evaluated using wastewater discharged from a zinc smelter. The Cd adsorption capacity of PMBC (60.39 mg/g) was lower than that (302.0 mg/g) of hen manure biochar produced at a laboratory scale in our previous study but was comparable to other biochars reported in the literature. Response surface methodology analysis indicated that reaction time, dose, and agitation significantly influenced Cd removal by PMBC, whereas pH had a negligible impact. Notable contributions to Cd adsorption include the release of K+ from PMBC and the presence of O-containing functional groups. Under continuous flow conditions with real wastewater, Cd was not detected in the effluent for the initial 8 h, and PMBC sustained a removal efficiency of 40.77% until saturation was reached. The results from wastewater treatment and large-scale biochar production offer valuable insights into the potential of biochar as a medium for addressing environmental issues in real-world applications.

Differential genotoxicity of Polygoni Multiflori in rat and human: insights from Ames test and S9 metabolic activation system.

The Ames test is used worldwide to initially screen the mutagenic potential of new chemicals. In the standard Ames test, S. typhimurium strains (TA100, TA98, TA1535, and TA1537) and Escherichia coli (WP2uvrA) are treated with substances with/without cytochrome P450s (CYPs)-induced rat S9 fractions for identifying mutagens and pro-mutagens. However, many substances show completely different toxicity patterns depending on whether the liver S9 fraction belongs to rats or humans. The natural product Polygoni Multiflori Radix (PMR) can also show bacterial reverse mutation, followed by the rat or human liver S9 fraction. While PMR elicits reverse mutations in the TA1537 strain in rat liver S9 but not in human liver S9, this mechanism has not been verified yet. To explain this, the differences in metabolic enzymes compositions commonly observed between rats and humans have been implicated. This study aimed to explore the key factors that cause differences in the genotoxicity of PMR between rat and human liver S9 metabolic enzymes. The results of next-generation sequencing (NGS) analysis showed that both rat and human metabolic enzymes caused similar mutations in TA1537. However, when the metabolic enzymes in each S9 fraction were analyzed using ion mobility tandem mass spectrometry (IM-MS), rat- and human-specific enzymes were identified among the cytochrome (CYP) family, especially aryl hydrocarbon receptor (AHR)-related CYPs. These findings suggest that CYP1A1 isoforms contribute to the mechanism of PMR in the Ames test. Therefore, an in vitro Ames test might be more reliable in predicting genotoxicity for both rodents and humans. This will also help overcome the limitations of laboratory animal-based toxicity evaluations, which provide unreliable results due to interspecies differences between humans and rodents.

Conceptual review of outcome metrics and measures used in clinical evaluation of artificial intelligence in radiology.

Artificial intelligence (AI) has numerous applications in radiology. Clinical research studies to evaluate the AI models are also diverse. Consequently, diverse outcome metrics and measures are employed in the clinical evaluation of AI, presenting a challenge for clinical radiologists. This review aims to provide conceptually intuitive explanations of the outcome metrics and measures that are most frequently used in clinical research, specifically tailored for clinicians. While we briefly discuss performance metrics for AI models in binary classification, detection, or segmentation tasks, our primary focus is on less frequently addressed topics in published literature. These include metrics and measures for evaluating multiclass classification; those for evaluating generative AI models, such as models used in image generation or modification and large language models; and outcome measures beyond performance metrics, including patient-centered outcome measures. Our explanations aim to guide clinicians in the appropriate use of these metrics and measures.

Targeted delivery of amphotericin B-loaded PLGA micelles displaying lipopeptides to drug-resistant Candida-infected skin.

Amphotericin B (AmB) is an antifungal agent administered for the management of serious systemic fungal infections. However, its clinical application is limited because of its water insolubility and side effects. Herein, to apply the minimum dose of AmB that can be used to manage fungal infections, a targeted drug delivery system was designed using lipopeptides and poly(lactide-co-glycolide) (PLGA). Lipopeptides conjugated with PEGylated distearoyl phosphoethanolamine (DSPE) and short peptides via a maleimide-thiol reaction formed nanosized micelles with PLGA and AmB. The antifungal effects of AmB-loaded micelles containing lipopeptides were remarkably enhanced both in vitro and in vivo. Moreover, the intravenous injection of these micelles demonstrated their in vivo targeting capacity of short peptides in a mouse model infected with drug-resistant Candida albicans. Our findings suggest that short antifungal peptides displayed on the surfaces of micelles represent a promising therapeutic candidate for targeting drug-resistant fungal infections.

The effect of nebulized N-acetylcysteine on the phlegm of chronic obstructive pulmonary disease: the NEWEST study.

BACKGROUND: Phlegm is prevalent symptom in patients with chronic obstructive pulmonary disease (COPD). Few studies have investigated the effectiveness of N-acetylcysteine (NAC) nebulizer therapy in COPD patients. We evaluated the effect of nebulized NAC on the improvement of phlegm symptom in COPD patients. METHODS: This was a 12-week, prospective, single-arm, open-label, phase IV multi-center trial (NCT05102305, Registration Date: 20-October-2021). We enrolled patients aged ≥ 40 years with post bronchodilator forced expiratory volume in one second/forced vital capacity (FEV1/FVC) < 0.7 and COPD assessment test (CAT) phlegm score ≥ 2; the patients were current or ex-smoker with smoking pack-years ≥ 10. The primary endpoint was to determine the change in CAT phlegm score at 12 weeks compared to the baseline. Patients were assessed at baseline, 4, 8, and 12 weeks of treatment using the CAT score. RESULTS: In total, 100 COPD patients were enrolled from 10 hospitals. The mean age of the patients was 71.42 ± 8.20 years, with 19.78% being current-smokers and 80.22% being ex-smokers. The mean smoking pack-years was 40.32 ± 35.18. The mean FVC, FEV1, and FEV1/FVC were 3.94 L (75.44%), 2.22 L (58.50%), and 0.53, respectively. The CAT phlegm score at baseline was 3.47 ± 1.06, whereas after 12 weeks of nebulized NAC it significantly decreased to 2.62 ± 1.30 (p < 0.01). More than half (53.5%) of the patients expressed satisfaction with the effects of nebulized NAC therapy. Adverse events occurred in 8 (8.0%) patients. Notably, no serious adverse drug reactions were reported. CONCLUSION: In this study, we have established the effectiveness and safety of nebulized NAC over 12 weeks.

SrTiO3 and (Ba,Sr)TiO3 Films Epitaxially Grown on SrRuO3 Using Atomic Layer Deposition.

High dielectric constant (k) materials have been investigated to improve the performance of dynamic random access memory (DRAM) capacitors. However, the conventional binary oxides have reached their fundamental limit of k < 100. In this study, we investigated alternative ternary oxides, SrTiO3 (STO) and (Ba,Sr)TiO3 (BSTO), which were epitaxially grown on SrRuO3 (SRO) using atomic layer deposition (ALD). The structural compatibility between SRO and STO enables the in situ crystallization of STO during ALD at a low temperature of 300 °C. Consequently, STO on SRO exhibited no film deformation, a common issue during high temperature postdeposition annealing, and maintained superior crystallinity at a thin thickness down to 50 Å. Furthermore, the dielectric constant of STO can be adjusted by modulating its tunable ferroelectric and dielectric properties through Ba doping. BSTO, with a high dielectric constant (kmax:527) achieved at a Ba doping concentration of approximately 50%, displayed a low leakage current density (3.9 × 10-8 A cm-2 @ 1 V) and demonstrated excellent reliability of 1012 cycles in the metal-insulator-metal capacitors. This study proposes a promising alternative to satisfy the extreme EOT required for next-generation DRAM capacitors.

Discovery of A-910, a Highly Potent and Orally Bioavailable Dual MerTK/Axl-Selective Tyrosine Kinase Inhibitor.

TAM receptor tyrosine kinases have emerged as promising therapeutic targets for cancer treatment due to their roles in both tumor intrinsic survival mechanisms and suppression of antitumor immunity within the tumor microenvironment. Inhibiting MerTK and Axl selectively is believed to hinder cancer cell survival, reverse the protumor myeloid phenotype, and suppress efferocytosis, thereby eliciting an antitumor immune response. In this study, we present the discovery of A-910, a highly potent and selective dual MerTK/Axl inhibitor, achieved through a structure-based medicinal chemistry campaign. The lead compound exhibits favorable oral bioavailability, exceptional kinome selectivity, and significantly improved in vivo target engagement. These findings support the use of A-910 as an orally bioavailable in vivo tool compound for investigating the immunotherapy potential of dual MerTK/Axl inhibition.

Advancing Breast Cancer Therapeutics: Targeted Gene Delivery Systems Unveiling the Potential of Estrogen Receptor-Targeting Ligands.

Although curcumin has been well known as a phytochemical drug that inhibits tumor promotion by modulating multiple molecular targets, its potential was not reported as a targeting ligand in the field of drug delivery system. Here, we aimed to assess the tumor-targeting efficiency of curcumin and its derivatives such as phenylalanine, cinnamic acid, coumaric acid, and ferulic acid. Curcumin exhibited a high affinity for estrogen receptors through a pull-down assay using the membrane proteins of MCF-7, a breast cancer cell line, followed by designation of a polymer-based gene therapy system. As a basic backbone for gene binding, dextran grafted with branched polyethylenimine was synthesized, and curcumin and its derivatives were linked to lysine dendrimers. In vitro and in vivo antitumor effects were evaluated using plasmid DNA expressing anti-bcl-2 short hairpin RNA. All synthesized gene carriers showed excellent DNA binding, protective effects against nuclease, and gene transfection efficiency in MCF-7 and SKBr3 breast cancer cells. Preincubation with curcumin or 17α-estradiol resulted in a marked dose-dependent decrease in gene transfer efficiency and suggested targeting specificity of curcumin. Our study indicates the potential of curcumin and its derivatives as novel targeting ligands for tumor cells and tissues.

Efficacy and Safety of a Home-Use Light-Emitting Diode Neck Device for Improvement in Neck Wrinkles: A Multicenter, Randomized, Double-Blind, Sham Device, Superiority Verification, Confirmatory Clinical Trial.

BACKGROUND: Light-emitting diode (LED) light sources have become an increasingly popular choice for the treatment and rejuvenation of various dermatological conditions. AIMS: This study aimed to evaluate the effects of neck rejuvenation, patient satisfaction, and the safety of LED application to the neck in an Asian population. METHODS: This was a multicenter, randomized, double-blind, sham device study. Seventy participants were enrolled in the study. The participants wore the home-use LED neck device for 9 min a day, 5 times a week, for a total of 60 sessions. The Lemperle Wrinkle Scale (LWS) and Global Aesthetic Improvement Scale (GAIS) were used to evaluate the results of both investigators and participants. The thyroid gland was examined using ultrasonography to evaluate the safety of the investigational device. RESULTS: The percentage of participants with improved LWS at Week 12 was significantly higher in the study group. Additionally, the percentage of participants with improved LWS was significantly higher in the study group at Weeks 8, 12, and 16. The LWS at Week 12 corrected with baseline values was found to be significantly different between the two groups. GAIS showed significant differences at 8, 12, and 16 weeks in the investigators' evaluation but not in the participants' evaluation. Repeated-measures analysis of variance at Weeks 4, 8, 12, and 16 also confirmed a significant difference between the two groups only in investigator assessment. No significant thyroid-related complications were observed. CONCLUSION: LED application to the neck may be considered a satisfactory and safe procedure for neck rejuvenation.

Feasibility of estimating tidal volume from electrocardiograph-derived respiration signal and respiration waveform.

PURPOSE: Estimating tidal volume (VT) from electrocardiography (ECG) can be quite useful during deep sedation or spinal anesthesia since it eliminates the need for additional monitoring of ventilation. This study aims to validate and compare VT estimation methodologies based on ECG-derived respiration (EDR) using real-world clinical data. MATERIALS AND METHODS: We analyzed data from 90 critically ill patients for general analysis and two critically ill patients for constrained analysis. EDR signals were generated from ECG data, and VT was estimated using impedance-based respiration waveforms. Linear regression and deep learning models, both subject-independent and subject-specific, were evaluated using mean absolute error and Pearson correlation. RESULTS: There was a strong short-term correlation between VT and the respiration waveform (r = 0.78 and 0.96), which weakened over longer periods (r = 0.23 and - 0.16). VT prediction models performed poorly in the general population (R2 = 0.17) but showed satisfactory performance in two constrained patient records using measured respiration waveforms (R2 = 0.84 to 0.94). CONCLUSION: Although EDR-based VT estimation is promising, current methodologies are limited by noisy ICU ECG signals, but controlled environment data showed significant short-term correlations with measured respiration waveforms. Future studies should develop reliable EDR extraction procedures and improve predictive models to broaden clinical applications.

Traditional herbal medicine Oryeongsan for heart failure: A systematic review and meta-analysis.

Background and objective: Heart failure (HF) is associated with high mortality and hospitalization rates, and its prevalence increases with age. As congestion is the most common cause of hospitalization for HF, diuretics are the most prescribed drugs. However, these agents have side effects due to electrolyte imbalance. In Asian countries, Oryeongsan (ORS) and its variants are used to manage fluid imbalances, including HF congestion. Therefore, ORS is considered a complementary treatment to overcome the limitations of diuretics. This review aimed to elucidate the safety and effectiveness of ORS combined with conventional Western medicine (CWM) for HF. Materials and methods: A literature search was conducted using the PubMed, Embase, CENTRAL, Scopus, CiNii, CNKI, and ScienceON databases to retrieve relevant studies published up to July 2024. Two independent investigators were involved in the data collection and analysis. Randomized controlled trials (RCTs) that evaluated the effects of ORS and its variants in combination with CWM as treatments for HF were selected. The outcome measures included left ventricular ejection fraction (LVEF), total effective rate (TER), left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), 6-min Walk Test (6MWT), Minnesota Living with Heart Failure Questionnaire (MLHF-Q), serum brain natriuretic peptide (BNP) level, serum N-terminal prohormone of brain natriuretic peptide (NT-proBNP) level, 24-h urine volume, Lee's score, and New York Heart Association (NYHA) grade I ratio for effectiveness; and incidence of adverse events (AEs) for safety. The methodological quality of the included RCTs was assessed using the Cochrane's Risk of Bias tool. Results: Fifty-nine RCTs that comprised 5069 participants and compared CWM combined with ORS and its variants (treatment group) to CWM alone or CWM plus placebo (control group) were included. Based on the meta-analysis, LVEF was found to significantly improve (mean difference: 6.36, 95 % confidence interval: 5.11 to 7.61, P < 0.00001) in the treatment group. TER, LVEDD, LVESD, 6MWT, MLHF-Q, serum BNP and NT-proBNP levels, 24-h urine volume, Lee's score, and NYHA grade I ratio were also significantly improved in the treatment group compared with the control group with CWM alone. LVEF and TER were improved without significance in the treatment group compared with the control group with CWM plus placebo. The incidence of AEs did not significantly differ between the two groups. Conclusions: Combining CWM with ORS or its variants was more effective than CWM alone in managing HF and could serve as a relatively safe treatment for HF. Further studies are required to validate the findings of the present study.

Innovative Multiplex PCR Assay for Detection of tlh, trh, and tdh Genes in Vibrio parahaemolyticus with Reference to the U.S. FDA's Bacteriological Analytical Manual (BAM).

Vibrio parahaemolyticus is an important foodborne bacterium that causes severe gastroenteritis following the consumption of contaminated seafood. To identify V. parahaemolyticus and determine its pathogenicity, the U.S. Food and Drug Administration (FDA)'s Bacteriological Analytical Manual (BAM) recommends a multiplex polymerase chain reaction (PCR) protocol to simultaneously detect the species-specific thermolabile hemolysin (tlh) gene and the pathogenic thermostable-related hemolysin (trh) and thermostable-direct hemolysin (tdh) genes. However, this assay has shown two limitations: difficulty in separating the amplicons of the trh (486 bp) and tlh (450 bp) genes due to their highly similar sizes, and the weaker band exhibited by the tdh gene amplicon (270 bp). The present study aimed to improve the BAM's multiplex PCR assay by separating the three amplicons with similar intensity. A new primer set was applied for the tlh gene (369 bp) alongside the existing primers for the trh and tdh genes. The amplicons for the three genes were effectively separated by electrophoresis on a 2% tris-borate-EDTA (TBE) agarose gel within 45 min. Primer concentrations of 0.25 µM for three genes produced a significant amount of amplicons among various combinations of primer concentrations with 35 PCR cycles. This assay exhibited a detection limit of 10 pg of bacterial DNA, demonstrating its high sensitivity. It did not display amplicons from nine Vibrio species known to be human pathogens or from 18 well-documented foodborne pathogens. Therefore, the present multiplex PCR protocol could help overcome the limitations of existing assays and provide a more reliable method for detecting the three genes of V. parahaemolyticus.

Effect of Severe Fever With Thrombocytopenia Syndrome Virus Genotype on Disease Severity, Viral Load, and Cytokines in South Korea.

Background: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne disease caused by Bandavirus dabieense (SFTS virus [SFTSV]). Recently, at least 6 different genotypes of SFTSV have been identified, with genotypes A, D, and F dominant in China and B dominant in Japan and Korea. This study investigated the effect of SFTSV genotypes circulating in South Korea on disease severity, viral load, and cytokine profile. Methods: We prospectively enrolled 70 patients with SFTS from July 2015 to June 2022. Serial plasma samples were obtained during hospitalization and analyzed. Viral load was measured by real-time reverse-transcription polymerase chain reaction. Partial sequences of the viral genome were analyzed for genotyping. Plasma concentrations of 17 cytokines were measured by multiplex-bead immunoassay. Results: Of 70 samples, 51 could be genotyped. Genotype B was predominant (80.4%) and other genotypes were uncommon. Intensive care unit admission rates (51.2% vs 50.0%) and mortality rates (26.8% vs 40.0%) did not show any significant differences between genotype B and non-B genotypes. The initial viral load did not show any significant differences (3.59 vs 3.64 log copies/µL), whereas viral load measured at hospital day 3-4 tended to be higher in genotype B than non-B genotypes (3.83 vs 1.83 log copies/µL, P = .07). Additionally, the plasma concentrations of interferon-α, interleukin 10, and interferon-γ-induced protein 10, which are closely related to mortality in cases of SFTS, did not show any significant differences. Conclusions: SFTSV genotype B was the prevalent genotype in South Korea, with no genotype-specific difference in clinical outcomes, initial viral load, or cytokine profiles.

SON is an essential RNA splicing factor promoting ErbB2 and ErbB3 expression in breast cancer.

BACKGROUND: In breast cancer, ErbB receptors play a critical role, and overcoming drug resistance remains a major challenge in the clinic. However, intricate regulatory mechanisms of ErbB family genes are poorly understood. Here, we demonstrate SON as an ErbB-regulatory splicing factor and a novel therapeutic target for ErbB-positive breast cancer. METHODS: SON and ErbB expression analyses using public database, patient tissue microarray, and cell lines were performed. SON knockdown assessed its impact on cell proliferation, apoptosis, kinase phosphorylation, RNA splicing, and in vivo tumour growth. RNA immunoprecipitation was performed to measure SON binding. RESULTS: SON is highly expressed in ErbB2-positive breast cancer patient samples, inversely correlating with patient survival. SON knockdown induced intron retention in selective splice sites within ErbB2 and ErbB3 transcripts, impairing effective RNA splicing and reducing protein expression. SON disruption suppressed downstream kinase signalling of ErbB2/3, including the Akt, p38, and JNK pathways, with increased vulnerability in ErbB2-positive breast cancer cells compared to ErbB2-negative cells. SON silencing in ErbB2-positive breast cancer xenografts led to tumour regression in vivo. CONCLUSION: We identified SON as a novel RNA splicing factor that plays a critical role in regulating ErbB2/3 expression, suggesting SON is an ideal therapeutic target in ErbB2-positive breast cancers.

Discovery of selective LATS inhibitors via scaffold hopping: enhancing drug-likeness and kinase selectivity for potential applications in regenerative medicine.

Due to its essential roles in cell proliferation and apoptosis, the precise regulation of the Hippo pathway through LATS presents a viable biological target for developing new drugs for cancer and regenerative diseases. However, currently available probes for selective and highly drug-like inhibition of LATS require further improvement in terms of both activity, selectivity and drug-like properties. Through scaffold hopping aided by docking studies and AI-assisted prediction of metabolic stabilities, we successfully identified an advanced LATS inhibitor demonstrating potent kinase activity, exceptional selectivity against other kinases, and superior oral pharmacokinetic profiles.