Search Results (2,087)

Background/Objectives: Multidrug resistant (MDR) Salmonella represents a major global public health challenge within the One Health interface. This study aimed to characterize the genomic epidemiology of Salmonella isolates from Colombia and resolve the genetic architecture of novel MDR plasmids identified in foodborne strains. Methods: A total of 90 Salmonella isolates collected between 2002 and 2009 from various food sources and food-producing animals in Colombia were analyzed using whole-genome sequencing (WGS). Bioinformatics tools were employed for serotype prediction, multi-locus sequence typing (MLST), and resistome/virulome profiling. Long-read sequencing was utilized to close the complete sequences of representative MDR plasmids. Results: 45.6% of isolates exhibited antimicrobial resistance, with seven being classified as MDR. The major serotypes identified were Uganda (n = 20), Newport (n = 10), and Braenderup (n = 10). We characterized a novel 229,037 bp IncHI1 plasmid (pCFS0255-1) harboring a copper homeostasis and silver resistance island (CHASRI) integrated with tetracycline and macrolide resistance clusters. Additionally, a 99,288 bp IncI1 plasmid (pCFS0255-2) carrying a unique aminoglycoside resistance module was resolved. Conclusions: Our findings highlight the persistence of specific Salmonella lineages in the Colombian food chain and the role of hybrid plasmids in the co-selection of metal and antibiotic resistance. The study underscores the necessity of implementing WGS-based surveillance to track emerging MDR threats. Full article

Glioma, the most common and aggressive primary brain tumor, presents significant clinical management challenges due to difficulties in blood–brain barrier penetration, high tumor heterogeneity, and susceptibility to drug resistance and recurrence, leading to an extremely poor prognosis. Traditional Chinese Medicine (TCM), particularly its derived active ingredients and herbal formulations, with its advantages of multi-component, multi-target, and holistic regulation, demonstrates significant potential in the comprehensive treatment of this disease. This review systematically outlines the research progress in TCM for combating glioma. Regarding mechanisms of action, active TCM components not only directly inhibit tumors by inducing cell apoptosis but also exert synergistic therapeutic effects via multiple pathways. These include remodeling the immunosuppressive microenvironment, activating novel cell death programs such as ferroptosis and immunogenic cell death, intervening in tumor metabolic reprogramming, and reversing chemotherapy resistance. In terms of overcoming delivery barriers, drug delivery systems represented by nanocarriers, liposomes, and extracellular vesicles, combined with the penetration-enhancing effects of aromatic orifice-opening herbs (a class of TCM medicinals traditionally used to “open the orifices” and awaken the mind, now recognized to transiently enhance BBB permeability), have significantly improved the brain-targeting efficiency and bioavailability of TCM components. For clinical translation, a number of innovative drugs derived from TCM, such as elemene, cinobufagin, and ACT001, are currently under clinical investigation, with initial results showing efficacy in prolonging survival and improving quality of life. In the future, by integrating the analysis of multi-target synergistic mechanisms, promoting the clinical translation of intelligent drug delivery systems, and conducting high-quality clinical research on integrated Chinese and Western medicine, TCM is expected to provide a new generation of integrated treatment strategies for glioma that combines holistic and precision medicine. Full article

Prostate adenocarcinoma (PRAD) poses a significant challenge due to therapy resistance and an immunosuppressive tumor microenvironment (TME). Ferroptosis has emerged as a therapeutic vulnerability, yet its immunomodulatory role in PRAD remains elusive. Here, we employed a multi-omics approach—integrating bulk RNA-seq (498 tumors), single-cell RNA-seq (68,322 cells), and spatial transcriptomics (19,483 spots)—to decode the ferroptosis-immune landscape. We derived a robust 16-gene ferroptosis signature that predicted biochemical recurrence (C-index = 0.76) and validated it in two independent cohorts. Crucially, high-risk tumors exhibited a “cold” immunosuppressive TME enriched in regulatory T cells and M2 macrophages, alongside elevated immune checkpoints (HAVCR2, CTLA4, PDCD1). Single-cell and virtual knockout analyses revealed that cancer epithelial cells evade ferroptosis via NFE2L2-associated antioxidant defenses, which strongly correlates with immune exclusion. Spatial transcriptomics further demonstrated spatially organized vulnerabilities, with ferroptosis-resistant tumor cores and immune-infiltrated invasive margins. To identify therapeutic interventions, we utilized drug response modeling and molecular docking, prioritizing RSL3, Atovaquone (targeting NOX4 (NADPH oxidase 4)/DHODH), and Sorafenib (targeting TrxR1 (thioredoxin reductase 1, encoded by TXNRD1)) as potent agents with potential ferroptosis-modulatory activity. Collectively, our findings demonstrate that NFE2L2-associated ferroptosis resistance shapes immune evasion in PRAD. Targeting ferroptosis regulators provides a compelling therapeutic rationale to remodel the TME and synergize with immune checkpoint blockade. Full article

We present a modular microfluidic platform for constructing miniaturized, compartmentalized cell culture systems that support monoculture, co-culture, and organ-on-a-chip models of human tissues. The devices provide architecturally defined three-dimensional microenvironments in which heterogeneous cell populations can be cultured in close proximity while maintaining precise spatial organization and independent access to each compartment. In vivo-like perfusion into, from, and between adjacent chambers is achieved via micro-engineered porous barriers that act as perfusion microchannels, enabling controlled convective and diffusive transport and recapitulating paracrine signaling between tissue units. As a proof of concept, we implement an adipose–immune co-culture model that reproduces key features of inflamed, insulin-resistant adipose tissue, including altered cytokine secretion and glucose uptake. Together, these features establish a versatile platform for the biofabrication of customizable single-organ and multi-organ in vitro models that more faithfully recapitulate human tissue structure and function for applications in disease modeling, immunometabolic studies, and preclinical drug testing. Full article

Listeria monocytogenes is already a well-known foodborne bacterial pathogen, ubiquitously dispersed not only in the food production environment but also in the primary animal production environment as well. The present study performed whole-genome characterization of the multidrug-resistant (MDR) L. monocytogenes strain BF11, previously isolated from raw pet food and phenotypically described for antimicrobial resistance. To this end, the genomic analysis performed on the isolate confirmed the pathogen’s designation as a serotype 1/2b strain belonging to ST5 and CC5 (Lineage I), carrying multiple MDR genes, stress-related genes, and mobile genetic elements, despite the absence of plasmids. The strain is phylogenetically closely related to Lineage I epidemic strains (e.g., F2365), as it has a full-length inlA and a functional prfA, rendering it capable of invading human cells and marking its high virulence. Overall, this strain may represent a potentially novel genomic profile when core genome multilocus sequence typing (cgMLST) is used, although further data from additional isolates would be required to confirm its classification within a new Complex Type, while displaying a hybrid unique profile. It is an evolved ST5 L. monocytogenes strain that has acquired genetic material conferring a “clinical signature” (Lineage I-like) and an extensive resistance network. Therefore, presence of L. monocytogenes strain BF11 in pet food is alarming, since such hybrid strains often evade surveillance monitoring as they do not fit strictly into classical categories, posing a serious food safety and public health threat in the concept of One Health. Full article

Protein–protein interactions (PPIs) are critical for cellular signaling, apoptosis regulation, and immune function in the body, and dysregulation is a hallmark of cancer. The large, dynamic, and shallow nature of PPI interfaces rendered them “undruggable” by conventional small molecules in the past. Recent advances in structural biology, chemical innovation, and artificial intelligence have revolutionized the landscape of PPI-directed drug discovery. This review summarizes the mechanistic roles of PPIs in oncogenesis, critically discusses novel therapeutic interventions, such as small molecules, peptidomimetics, stapled peptides, proteolysis-targeting chimeras (PROTACs), molecular glues, and AI-based drug optimization strategies, altering the druggable proteome in oncology. Therapeutics with clinically well-validated action, including Venetoclax and AMG 510, and next-generation candidates demonstrate the translational applications of these approaches. Some of the key challenges, such as interface complexity, specificity, bioavailability, and resistance, are addressed together with countermeasures like rational design, combination therapies, enhanced delivery systems, and biomarker-based patient selection. To this end, the incorporation of multi-omics data and artificial-intelligence (AI)-driven modeling technologies is revolutionizing the personalized cancer therapeutics development space. Collectively, these advances mark a paradigm shift: PPIs, once considered inaccessible, are now at the forefront of precision oncology, offering new hope for patients with previously intractable malignancies. Full article

Background/Objectives: Klebsiella pneumoniae is a major pathogen involved in both acute and chronic infections, characterized by high incidence and significant clinical severity. Over the past decade, resistance to traditional antimicrobial treatments has risen rapidly, highlighting the urgent need for innovative approaches. Light-based antimicrobial strategies, including antimicrobial photodynamic therapy (aPDT), offer a promising approach for addressing drug-resistant bacteria. Combining two photosensitizers (PSs) with antibiotics synergistically enhances ROS generation and multi-target bacterial damage, achieving superior antimicrobial efficacy at reduced PS, light and antibiotic doses while limiting resistance development. We evaluated the efficacy of aPDT using the photosensitizers (PSs) methylene blue (MB) and Photodithazine (PDZ), either alone or in combination with the antibiotic ciprofloxacin (CIP), gentamicin (GEN), or ceftriaxone (CEF), against K. pneumoniae. Methods: Bacterial suspensions were treated with PDZ (25–200 µg/mL) and/or MB (5–20 µg/mL) in the presence of CIP (0.005–4 µg/mL), GEN (0.5–16 µg/mL), or CEF (0.5–16 µg/mL), followed by irradiation at either 15 J/cm² or 30 J/cm². Bacterial survival was assessed by colony-forming unit (CFU/mL) quantification. Results: The combined application of photosensitizers and antibiotics demonstrated a synergistic bactericidal effect against planktonic K. pneumoniae. The combined use of two PSs with antibiotics markedly reduced the antibiotic dose required to achieve a comparable bactericidal effect. Conclusions: This study highlights the potential of combining aPDT with conventional antibiotics as a promising strategy to combat drug-resistant infections, offering enhanced antimicrobial efficacy while allowing for reduced antibiotic dosages to achieve comparable therapeutic outcomes. Full article

Introduction: Heat shock proteins (HSPs) are stress-responsive molecular chaperones that are frequently dysregulated in cancer and contribute to tumorigenesis, invasion, metastasis, immune interactions, and resistance to therapy. Distinct HSP families, including HSP27, HSP60, HSP70, HSP90, and HSP110, promote malignant progression through complementary effects on apoptosis regulation, mitochondrial function, proteostasis, and stabilization of oncogenic signaling pathways. This makes HSPs attractive therapeutic targets. Their coordinated roles within stress-adaptive chaperone networks further garner interest in targeting multiple HSP families in cancer therapy. Discussion: Preclinical and clinical studies have established multiple HSP families as promising anticancer targets; however, clinical translation of HSP-directed therapies has been challenged by toxicity, compensatory heat shock responses, and resistance mechanisms. Many N-terminal HSP90 inhibitors have shown clinical utility but have also highlighted the need for alternative approaches, including C-terminal inhibition, HSP70-directed therapies, and rational combination strategies targeting compensatory survival pathways. Emerging inhibitors targeting HSP27, HSP60, and HSP110, as well as HSP-based vaccines, further expand therapeutic opportunities across cancer subtypes. Collectively, these approaches highlight the growing therapeutic relevance of disrupting interconnected HSP networks rather than targeting individual chaperones in isolation. Conclusions: Future development of heat shock protein-targeted therapies will require a deeper understanding of HSP-mediated chemoresistance. Clinical trial and drug development approaches may benefit from combination or multi-targeted strategies that simultaneously disrupt multiple components of the heat shock protein network to achieve more durable anticancer responses. Full article

Cancers are intricate and multifactorial diseases. Despite progress in medicine, there are still some obstacles in their treatment due to drug resistance, the toxicity of combination therapy and lack of drug selectivity toward cancer cells. The solution to this may be multi-target directed ligands (MTDLs), which have gained more and more popularity over the years. This review presents a comprehensive overview of novel potential multi-targeted derivatives of nitrogen-containing heterocycles, as imidazole, pyrazole, 1,2,3-triazole and 1,2,4-triazole. The review gathers the selected literature from 2006 to 2026. The analysis focuses on the potency of the inhibitory activity of selected molecules against a variety of molecular targets, as well as on their interactions with protein binding sites. Additionally, the structure-activity relationship (SAR) studies within the collected series are included. The discussion may contribute to the development of new multi-target anticancer agents. Full article

Background/Objectives: Acinetobacter baumannii is a critical opportunistic pathogen causing severe healthcare-associated infections, particularly in intensive care units. The global dissemination of carbapenem-resistant A. baumannii (CRAB) and its environmental persistence necessitate continuous genomic surveillance to monitor high-risk clones. Methods: We conducted whole-genome sequencing (WGS), core genome multi-locus sequence typing (cgMLST), and phylogenomic analyses on 26 CRAB isolates collected at the National Institute for Infectious Diseases (INMI) “Lazzaro Spallanzani” IRCCS (September 2023–September 2024). Antimicrobial resistance determinants, virulence-related genes, and capsular (KL) and lipooligosaccharide outer core (OCL) loci were characterized by interrogation of comprehensive bioinformatic pipelines. Results: All CRAB isolates displayed an extensively drug-resistant (XDR) phenotype, with a shared resistance pattern to carbapenems, aminoglycosides, fluoroquinolones, fosfomycin, and sulfonamides, while being susceptible only to colistin and cefiderocol. The carbapenemase gene bla_OXA-23 was detected in all CRAB isolates, together with clone-specific bla_OXA-51-like variants. For all isolates, the resistome profile fully matched the observed resistance phenotype. All isolates belonged to the International Clonal Lineage II (ICL II), Pasteur Sequence Type (ST) 2, and Oxford ST369, ST208, and ST455. Integration of cgMLST data with phylogenomic analyses and genome-based classification of KL and OCL loci revealed five distinct clusters, each one including nearly identical isolates, indicating both intra-hospital dissemination and possible inter-hospital transmission. Virulome profiling revealed heterogeneous repertoires of virulence-associated genes, resulting in cluster-specific patterns, while patristic analysis identified phylogenetic clusters linking the study isolates to other Italian and other European lineages. Conclusions: This study underscores the complex genomic landscape of CRAB in our setting, driven by the circulation of different ICL II clonal types, and reinforces the urgency of integrated genomic surveillance and robust antimicrobial stewardship to mitigate the spread of high-risk XDR A. baumannii clones. Full article

Background: Acquired resistance to the third-generation EGFR tyrosine kinase inhibitor osimertinib, often mediated by EGFR triple mutations, poses a major clinical challenge in non-small cell lung cancer (NSCLC) treatment. Among these, some rare mutations, such as L858R/T790M/L792H and L858R/T790M/G796R, create steric hindrance that directly interferes with osimertinib binding, yet effective targeted therapeutic strategies for these specific mutations remain lacking. Cudratricusxanthone A (CTXA), a natural xanthone derivative isolated from Cudrania tricuspidata Bur., has demonstrated various pharmacological activities, but its effects against EGFR triple-mutant NSCLC have not been systematically investigated. Methods: Stable Ba/F3 and NIH/3T3 cell lines expressing EGFR L858R/T790M/L792H or L858R/T790M/G796R triple mutations were generated via electroporation. The antiproliferative effects of CTXA were evaluated by MTT/MTS assays, colony formation, and wound healing assays. Cell cycle distribution and apoptosis were analyzed by flow cytometry. Protein expression of EGFR signaling pathway components (p-EGFR, p-ERK, p-AKT, p-STAT3) and cell cycle regulators (Cyclin D1, CDK4) were examined by Western blotting. Molecular docking and 200 ns molecular dynamics simulations were performed to investigate the stability and binding modes of CTXA to the mutant EGFR kinase domains. Results: The successfully established triple-mutant cell lines exhibited high EGFR expression, IL-3-independent growth, and significant resistance to osimertinib. CTXA inhibited the proliferation of all triple-mutant cell lines in a time- and concentration-dependent manner, with 48 h IC₅₀ values ranging from 0.362 to 2.488 μM. Mechanistically, CTXA suppressed EGFR autophosphorylation and downregulated downstream p-ERK, p-AKT, and p-STAT3. CTXA induced G1 phase cell cycle arrest by downregulating Cyclin D1 and CDK4, significantly promoted apoptosis, and inhibited cell migration. Molecular docking revealed that while osimertinib binding was blocked by steric hindrance from His-792 or Arg-796, CTXA adapted to the mutated ATP-binding pockets through multiple hydrogen bonds and extensive hydrophobic interactions. Molecular dynamics simulations confirmed the stable binding of CTXA to both mutant EGFR proteins over the 200 ns simulations. Conclusions: This study demonstrates for the first time that the natural compound CTXA possesses antitumor efficacy against EGFR L858R/T790M/L792H and L858R/T790M/G796R mutants by regulating EGFR-ERK/AKT/STAT3 signaling. Our findings position CTXA as a promising lead compound for tackling this challenging form of acquired resistance and highlight the value of natural products in multi-target antitumor drug discovery. Full article

This study investigated the epidemiology, antimicrobial resistance, and transmission risks of β-lactamase, cefotaxime-hydrolyzing, Munich (bla_CTX-M)-positive Escherichia coli (CTX-M-EC) in large-scale pig farms in Jiangxi Province (China). In total, 278 samples (manure, wastewater, drinking water, and flies) were collected. CTX-M-EC strains were isolated and analyzed using antimicrobial susceptibility testing, resistance gene profiling, multilocus sequence typing, and genetic environment analysis with gene transfer assessed by transduction experiments. Twenty-seven CTX-M-EC strains (9.71%) were isolated, all exhibiting multi-drug resistance with 100% resistance to cefotaxime, ciprofloxacin, and tetracycline, and >90% resistance to ceftazidime, florfenicol, and trimethoprim-sulfamethoxazole. Four bla_CTX-M subtypes were identified. bla_CTX-M-55 was the predominant subtype (70.37%) and was distributed across diverse sequence types and serotypes. Each strain harbored multiple antibiotic resistance genes, plasmids, and virulence genes. Mobile elements such as ISEcp1 and IS26 were detected surrounding the bla_CTX-M gene, and 96.29% of strains successfully transferred the bla_CTX-M gene via transduction. Clones highly homologous to pig manure strains were detected in flies and sewage, suggesting that this resistance gene can spread between animals, the environment, and vectors. These findings highlight the high transmission risk of bla_CTX-M and underscore the need for rational antibiotic use, waste management, and vector control within a One Health framework. Full article

Cardiometabolic diseases, encompassing obesity, insulin resistance, type 2 diabetes (T2D), metabolic dysfunction-associated steatotic liver disease (MASLD), hypertension, and atherosclerotic cardiovascular disease (ASCVD), represent a vast continuum driven by multi-organ network dysregulation. Clinical risk assessment remains dominated by late-stage measures (e.g., fasting glucose, HbA1c, standard lipids). While these assessments predominate the literature and clinical trial endpoints, each incompletely capture early mechanistic risk, inter-individual heterogeneity, and differential response to interventions. Multiomics (genomics, epigenomics, transcriptomics, proteomics, metabolomics, lipidomics, microbiomics, and extracellular vesicle/exosome cargo profiling) expands the biomarker landscape but introduces translational barriers: high dimensionality, cohort heterogeneity, limited causal inference, and insufficient validation pipelines. AI-driven systems biology platforms can support cardiometabolic biomarker discovery and therapeutic translation by enabling systems-level biological inference across heterogeneous datasets, prioritizing mechanism and traceability over purely correlation-based models. GATC Health’s Operon™ platform is described as a proprietary, AI-driven internal scientific computing platform designed to support therapeutic discovery and development decision-making across the pharmaceutical lifecycle, including evaluation of drug efficacy, safety, off-target effects, pharmacokinetics (PK), pharmacodynamics (PD), and overall development risk. Operon evolved from earlier generations of GATC Health’s internal multiomic modeling systems (formerly referred to as the Multiomics Advanced Technology, MAT) and incorporates expanded data types, orchestration layers, validation workflows, and productization frameworks. Operon is operated by GATC scientists and generates structured, productized outputs (e.g., formal assessments, analyses, and decision frameworks) that are reviewed by experts. Operon methodologies have undergone internal validation and independent academic evaluation under blinded conditions, with reported classification performance (true positive rate 86% and true negative rate 91%) in controlled evaluation settings; these performance metrics should not be interpreted as guarantees of clinical success. This review provides a T2D-centered cardiometabolic biomarker landscape with cardiovascular extension and outlines how Operon-enabled multiomic integration and scenario-based simulation can support early screening, endotype stratification, mechanistic interpretation, and precision intervention design, including AI-guided polypharmacology strategies. Full article

Background/Objectives: Antimicrobial resistance (AMR) is a global threat to human, animal, and environmental health. Among bacteria, E. coli is frequently used as a key indicator of AMR. Despite their genetic proximity to humans, studies on AMR in Non-Human Primates (NHPs) remain limited, particularly in semi-anthropized environments. This study aims to characterize the antibiotic resistance profiles and phylo-groups of E. coli isolated from NHPs and humans at a primatology center. Methods: A total of 143 stool samples were collected, including 125 from NHPs and 18 from humans. Isolates were cultured on Eosin Methylene Blue agar and then identified by MALDI-TOF mass spectrometry. Antibiotic susceptibility was assessed using the Kirby–Bauer disk diffusion method, with 30 antibiotics following CASFM-EUCAST recommendations. E. coli phylo-groups were characterized by quadruplex PCR according to the Clermont method, targeting the genes. Results: A total of 122 E. coli isolates (85.31%) were recovered, with comparable prevalence observed across NHPs and human staff. More than half of the isolates (55.74%) were resistant to at least one antibiotic tested, and 12.3% were classified as multi-drug resistant (MDR). Resistance rates of isolates in Mandrillus sphinx, Pan troglodytes, and humans were 50.6%, 57.7%, and 80.0%, respectively, with no significant statistical difference (p = 0.11). A single Extended-Spectrum Beta-Lactamase (ESBL) producing isolate was identified in the mandrill. Phylo-group analysis revealed the dominance of group A (50%), followed by groups B1, D, and C. Conclusions: Resistance profiles and phylo-group distribution among NHPs could suggest bacterial exchange and potential for cross-transmission of AMR within the shared environment. Full article

Fucosylation, the enzymatic addition of fucose residues to glycans, modulates receptor signalling and cellular identity in the intestinal epithelium. Its role as an integrative determinant of cancer cell fate in colorectal cancer (CRC) remains undefined. Transcriptomic and clinicopathological data from 976 CRC patients across three independent cohorts (TCGA-CRC, CPTAC2-CRC, Sidra-LUMC) were analysed. A curated fucosylation gene set was used to calculate tumour fucosylation scores. Associations with histogenetic status, genomic features, microenvironmental phenotypes, drug resistance programmes, and survival were evaluated using gene set enrichment analysis, multivariable Cox regression, and integrated molecular subtyping. High-fucosylation tumours exhibited elevated epithelial differentiation, MSI-H/BRAF-mutant enrichment, oxidative phosphorylation dominance, the complete absence of EMT and invasion programmes, and favourable prognosis (HR = 0.633, 95% CI: 0.470–0.853, p = 0.003). Low-fucosylation tumours demonstrated mesenchymal phenotypes, TP53 mutations, chromosomal instability, comprehensive multi-family RTK signalling, immune-excluded microenvironments, and poor outcomes. Distinct multidrug resistance programmes emerged: drug efflux in low-fucosylation tumours versus xenobiotic sensing, target bypass, and drug sequestration in high-fucosylation tumours. Tumour fucosylation status defines two fundamentally distinct CRC cell states with mutually exclusive engagement of invasion programmes, metabolic pathways, immune phenotypes, and resistance mechanisms. Fucosylation represents an independent prognostic biomarker and integrative determinant of cancer cell fate, with significant implications for risk stratification and personalised therapeutic strategies. Full article