Search Results (241)

RKIP and LKB1, encoded by PEBP1 and STK11, respectively, have emerged as key regulators of cancer pathophysiology. However, their role in shaping tumor progression through modulation of the tumor microenvironment (TME) is not yet fully understood. To address this, we performed a comprehensive pan-cancer analysis using TCGA transcriptomic data across 33 cancer types, grouped by their tissue of origin. We investigated PEBP1/STK11 co-expression and its association with transcriptomic reprogramming in major TME components, including immune, mechanical, metabolic, and hypoxic subtypes. Our results revealed both positive and inverse correlations between PEBP1/STK11 co-expression and TME-related molecular signatures, which did not align with classical cancer categorizations. In a subset of tumors, PEBP1/STK11 co-expression was significantly associated with improved overall survival and reduced mortality (HR < 1). Notably, we predominantly observed inverse correlations with pro-inflammatory and immunosuppressive chemokines, immune checkpoints, extracellular matrix components, and key regulators of epithelial-to-mesenchymal transition. In contrast, we found positive associations with anti-inflammatory chemokines and their receptors. Importantly, PEBP1/STK11 co-expression was consistently linked to reduced expression of drug resistance genes and greater chemosensitivity across multiple tumor types. Our findings underscore the co-expression of PEBP1 and STK11 as a promising target for future studies aimed at elucidating its potential as a biomarker for prognosis and therapeutic response in precision oncology. Full article

Pancreatic cancer, specifically pancreatic ductal adenocarcinoma (PDAC), ranks among the most lethal malignancies, with a 5-year survival rate of under 10%. The most prevalent KRAS mutations occur in three hotspot residues: glycine-12 (G12), glycine-13 (G13), and glutamine-61 (Q61), leading to the constant activation of the Ras pathway, making them the primary focus in oncologic drug development. Selective KRAS G12C inhibitors (e.g., sotorasib, adagrasib) have demonstrated moderate efficacy in clinical trials; however, this mutation is infrequent in PDAC. Emerging therapies targeting KRAS G12D and G12V mutations, such as MRTX1133, PROTACs, and active-state inhibitors, show promise in preclinical studies. Pan-RAS inhibitors like ADT-007, RMC-9805, and RMC-6236 compounds provide broader coverage of mutations. Their efficacy and safety are currently being investigated in several clinical trials. A major challenge is the development of resistance mechanisms, including secondary mutations and pathway reactivation. Combination therapies targeting the RAS/MAPK axis, SHP2, mTOR, or SOS1 are under clinical investigation. Immunotherapy alone has demonstrated limited effectiveness, attributed to an immunosuppressive tumor microenvironment, although synergistic effects are noted when paired with KRAS-targeted agents. Furthermore, KRAS mutations reprogram cancer metabolism, enhancing glycolysis, macropinocytosis, and autophagy, which are being explored therapeutically. RNA interference technologies have also shown potential in silencing mutant KRAS and reducing tumorigenicity. Future strategies should emphasize the combination of targeted therapies with metabolic or immunomodulatory agents to overcome resistance and enhance survival in KRAS-mutated PDAC. Full article

Vibrio parahaemolyticus is a pathogenic bacterium widely distributed in marine environments, posing significant threats to aquatic organisms and human health. The overuse and misuse of antibiotics has led to the development of multidrug- and pan-resistant V. parahaemolyticus strains. There is an urgent need for novel antibacterial therapies with innovative mechanisms of action. In this work, a genome-scale metabolic network model (GMSN) of V. parahaemolyticus, named VPA2061, was reconstructed to predict the metabolites that can be explored as potential drug targets for eliminating V. parahaemolyticus infections. The model comprises 2061 reactions and 1812 metabolites. Through essential metabolite analysis and pathogen–host association screening with VPA2061, 10 essential metabolites critical for the survival of V. parahaemolyticus were identified, which may serve as key candidates for developing new antimicrobial strategies. Additionally, 39 structural analogs were found for these essential metabolites. The molecular docking analysis of the essential metabolites and structural analogs further investigated the potential value of these metabolites for drug design. The GSMN reconstructed in this work provides a new tool for understanding the pathogenic mechanisms of V. parahaemolyticus. Furthermore, the analysis results regarding the essential metabolites hold profound implications for the development of novel antibacterial therapies for V. parahaemolyticus-related disease. Full article

Urogenital infections contribute greatly to both hospital- and community-acquired infections. In Ghana, the prevalence of resistance to commonly used antibiotics is relatively high. This study sought to evaluate the antibiotic sensitivity of bacterial urogenital pathogens from patient samples in a regional and district hospital in the Volta Region of Ghana. A retrospective cross-sectional study was conducted using data obtained between January and December 2023 from Volta Regional Hospital and Margret Marquart Catholic Hospital. Bacteria were isolated from urine, urethral swabs, and vaginal swabs from 204 patients. Data on culture and sensitivity assays performed using the Kirby–Bauer disc diffusion method were extracted and analyzed using WHONET. The most prevalent organisms isolated from the samples from both facilities were Escherichia coli (24.9%), Staphylococcus aureus (21.5%), and Klebsiella oxytoca (8.8%). The isolates were mostly resistant to amoxicillin/clavulanic acid (n = 75, 95% CI [91.8–99.9]), meropenem (n = 61, 95% CI [87.6–99.4]), cefuroxime (n = 54, 95% CI [78.9–96.5]), ampicillin (n = 124, 95% CI [61.2–77.9]), and piperacillin (n = 43, 95% CI [82.9–99.2]). Multidrug-resistant (MDR, 70 (34.1%)), extensively drug-resistant (XDR, 63 (30.7%)), and pandrug-resistant (PDR, 9 (4.3%)) strains of S. aureus, E. coli, and Pseudomonas aeruginosa were identified from the patient samples. The study highlights the presence of high-priority resistant urogenital pathogens of public health significance to varied antibiotic groups. Full article

Klebsiella pneumoniae can acquire resistance mechanisms to colistin and present a pan-resistant phenotype. Therefore, new alternative agents are imperative to control this pathogen, and the peptide Jelleine-I stands out as a promising prototype. Here, the antibacterial activity of Jelleine-I against clinical isolates of colistin-resistant K. pneumoniae (CRKP) was investigated. Antimicrobial activity was assessed by determining the minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC) and time kill-curve assay. The release of 260 nm-absorbing materials (DNA/RNA) and the release of proteins were used in the lysis assay. Anti-biofilm activity was studied in microplates. In vivo activity was determined by the lethality assay using Tenebrio molitor larvae. The results show that the MIC of Jelleine-I ranged from 16 to 128 µM and the MBC was on average 128 µM. Jelleine-I at 200 µM killed all CRKP cells in suspension (10⁶ colony-forming units (CFU)/mL) after 150 min of incubation. Jelleine-I acts on the CRKP cell membrane inducing lysis. Biomass and viability of CRKP-induced biofilms are reduced after treatment with Jelleine-I, and the use of this peptide in T. molitor larvae infected with CRKP reduces lethality and improves overall larval health. In conclusion, Jelleine-I is a potential prototype for the development of new antimicrobial agents. Full article

VIRMA (also known as KIAA1429), as a core regulatory subunit of the m6A methyltransferase complex, plays a key role in tumorigenesis and progression by dynamically regulating RNA methylation modifications. Studies have shown that VIRMA is aberrantly overexpressed in more than 20 types of malignant tumors, including liver cancer, breast cancer, and lung cancer, and is significantly associated with chromosome 8q amplification and poor prognosis. Its mechanism of action involves regulating the expression of tumor-associated genes through both m6A-dependent and m6A-independent pathways, thereby promoting tumor proliferation, metastasis, and drug resistance. These findings suggest that VIRMA has the potential to serve as a pan-cancer diagnostic and prognostic biomarker. This review summarizes the role of VIRMA in malignant tumors from multiple perspectives and explores its potential applications in clinical diagnosis and treatment. Full article

The objective of this study was to determine the epidemiological, clinical, and laboratory characteristics of newborns with sepsis in northwestern Mexico, identify the microorganisms causing early- and late-onset sepsis, and assess antimicrobial resistance. Additionally, it sought to associate neonatal characteristics with antimicrobial resistance or mortality. A retrospective study was conducted from August 2021 to April 2023, during which 8382 neonatal clinical records were analyzed to collect epidemiological, clinical, and laboratory characteristics, as well as microorganisms isolated from neonates and their antimicrobial resistance profiles. Of these, 314 neonates with sepsis were included. The incidence of neonatal sepsis was 4% (314/8382), and the mortality was 12.7% (40/314); late-onset sepsis (65.3%) was more frequent than early-onset sepsis (34.7%). Staphylococcus epidermidis was the most frequently isolated bacterium in neonates with sepsis (both early- and late-onset). Gram-positive bacteria, such as Staphylococcus hominis and Enterococcus faecium, were associated with early-onset sepsis, whereas fungi, particularly Candida albicans, were associated with late-onset sepsis. Of the microorganisms, 52.6% were multidrug resistant (MDR), 10.8% were extensively drug resistant (XDR), and 5.5% were pan-drug resistant (PDR). Low birth weight, prematurity, cesarean section, mechanical ventilation, tachycardia, and low hemoglobin and platelet levels, among others, were associated with XDR or MDR microorganisms. In contrast, low birth weight, mechanical ventilation, stroke, unexpected delivery, respiratory distress, tachycardia, convulsive crisis, high procalcitonin, urea, and AST/TGO levels, among others, were associated with mortality. The incidence, types of sepsis, antimicrobial resistance, and associations identified in this study will aid in diagnosing neonatal sepsis earlier and may reduce mortality in our region. Full article

Nowadays, antimicrobial resistance (AMR) is a growing global health threat, with carbapenem-resistant Enterobacteriaceae (CRE) posing particular concern due to limited treatment options. In fact, CRE have been classified as a critical priority by the World Health Organization (WHO). Carbapenem resistance results from complex mechanisms, often combining the production of hydrolytic enzymes such as β-lactamases with reduced membrane permeability and efflux system induction. The Ambler classification is an effective tool for differentiating the characteristics of serine-β-lactamases (SβLs) and metallo-β-lactamases (MβLs), including ESβLs (different from carbapenemases), KPC, NDM, VIM, IMP, AmpC (different from carbapenemases), and OXA-48. Recently approved inhibitor drugs, such as diazabicyclooctanones and boronic acid derivatives, only partially address this problem, not least because of their ineffectiveness against MβLs. However, compared with taniborbactam, xeruborbactam is the first bicyclic boronate in clinical development with a pan-β-lactamase inhibition spectrum, including the IMP subfamily. Recent studies explore strategies such as chemical optimization of β-lactamase inhibitor scaffolds, novel β-lactam/β-lactamase inhibitor combinations, and siderophore–antibiotic conjugates to enhance bacterial uptake. A deeper understanding of the mechanistic properties of the active sites enables rational drug design principles to be established for inhibitors targeting both SβLs and MβLs. This review aims to provide a comprehensive overview of current therapeutic strategies and future perspectives for the development of carbapenemase inhibitor drug candidates. Full article

Background/Objectives: Clostridium perfringens is a normal inhabitant of the intestinal tract of poultry, and it has the potential to induce cholangiohepatitis and necrotic enteritis (NE). The poultry industry suffers significant financial losses because of NE, and treatment becomes more challenging due to resistant C. perfringens strains. Methods: The antimicrobial and antibiofilm activities of cellulose nanocrystals/zinc oxide nanocomposite (CNCs/ZnO) were assesses against pan drug-resistant (PDR) C. perfringens isolated from chickens and turkeys using phenotypic and molecular assays. Results: The overall prevalence rate of C. perfringens was 44.8% (43.75% in chickens and 58.33% in turkeys). Interestingly, the antimicrobial susceptibility testing of C. perfringens isolates revealed the alarming PDR (29.9%), extensively drug-resistant (XDR, 54.5%), and multidrug-resistant (MDR, 15.6%) isolates, with multiple antimicrobial resistance (MAR) indices ranging from 0.84 to 1. All PDR C. perfringens isolates could synthesize biofilms; among them, 21.7% were strong biofilm producers. The antimicrobial potentials of CNCs/ZnO against PDR C. perfringens isolates were evaluated by the agar well diffusion and broth microdilution techniques, and the results showed strong antimicrobial activity of the green nanocomposite with inhibition zones’ diameters of 20–40 mm and MIC value of 0.125 µg/mL. Moreover, the nanocomposite exhibited a great antibiofilm effect against the pre-existent biofilms of PDR C. perfringens isolates in a dose-dependent manner [MBIC50 up to 83.43 ± 1.98 for the CNCs/ZnO MBC concentration (0.25 μg/mL)]. The transcript levels of agrB quorum sensing gene and pilA2 type IV pili gene responsible for biofilm formation were determined by the quantitative real time-PCR technique, pre- and post-treatment with the CNCs/ZnO nanocomposite. The expression of both genes downregulated (0.099 ± 0.012–0.454 ± 0.031 and 0.104 ± 0.006–0.403 ± 0.035, respectively) when compared to the non-treated isolates. Conclusions: To the best of our knowledge, this is the first report of CNCs/ZnO nanocomposite’s antimicrobial and antibiofilm activities against PDR C. perfringens isolated from chickens and turkeys. Full article

Background/Objectives: TIGD1 (Trigger Transposable Element Derived 1) is a recently identified oncogene with largely unexplored biological functions. Emerging evidence suggests its involvement in multiple cellular processes across cancer types. This study aimed to perform a comprehensive pan-cancer analysis of TIGD1 to evaluate its expression patterns, diagnostic utility, prognostic value, and association with immunotherapy response and drug resistance. Methods: Transcriptomic and clinical data from TCGA and GTEx were analyzed using various bioinformatic tools. Expression profiling, survival analysis, immune correlation studies, gene set enrichment, single-cell sequencing, and drug sensitivity assessments were performed. Results: TIGD1 was found to be significantly upregulated in various tumor types, with notably high expression in colon adenocarcinoma. Elevated TIGD1 expression was associated with poor prognosis in several cancers. TIGD1 levels correlated with key features of the tumor immune microenvironment, including immune checkpoint gene expression, TMB, and MSI, suggesting a role in modulating anti-tumor immunity. GSEA and single-cell analyses implicated TIGD1 in oncogenic signaling pathways. Furthermore, high TIGD1 expression was linked to resistance to several therapeutic agents, including Zoledronate, Dasatinib, and BLU-667. Conclusions: TIGD1 may serve as a promising diagnostic and prognostic biomarker, particularly in colon, gastric, liver, and lung cancers. Its strong associations with immune modulation and therapy resistance highlight its potential as a novel target for precision oncology and immunotherapeutic intervention. Full article

Background: The efflux system is one of the resistance mechanisms that bacteria use to reduce the effectiveness of antibiotics, leading to the development of multidrug resistance. To evaluate other treatment choices, esomeprazole (ESO), omeprazole (OME), pantoprazole (PAN), vitamin D (VD), and vitamin K (VK) were tested for potential efflux pump (EP)-inhibiting activity. Methods: The minimum inhibitory concentrations (MICs) of the tested drugs were determined against K. pneumoniae ATCC 51503 and P. aeruginosa PAO1. Quantitative estimation of the EP-inhibiting activity of the tested medications was phenotypically investigated with a semi-automated fluorometric system and genotypically confirmed by real-time polymerase chain reaction (RT-PCR). Data were confirmed through docking study. Results: K. pneumoniae ATCC 51503 and P. aeruginosa PAO1 were positive efflux standard strains. VD and VK revealed an MIC_VD of 625–1250 µg/mL and MIC_VK of 2500–5000 µg/mL, lower than what was detected for PPIs (MIC_PPIs = 16,000–32,000 µg/mL). Vitamins showed powerful anti-efflux activity with remarkable ethidium bromide accumulation in K. pneumoniae ATCC 51503 and P. aeruginosa PAO1. Also, VD and VK significantly lowered the MIC of ciprofloxacin by 64-fold. On the molecular level, OME showed a notable decrease in the relative expression of the efflux-encoding genes acrB and mexA by 91.5% and 99.7% in ATCC 51503 and PAO1, respectively. Conclusion: This study highlights the anti-efflux activity of ESO, OME, PAN, VD, and VK against the tested Gram-negative strains. Hence, these PPIs and vitamins could be valuable adjuvant treatments to enhance the effectiveness of curing infections caused by MDR strains. Full article

Background: Lung adenocarcinoma is the most common NSCLC and is associated with metabolic dysregulation. Purine biosynthesis, regulated by PAICS, plays a key role in tumor progression and therapy resistance. Methods: We focused on LUAD using pan-cancer and KEGG enrichment analyses. TCGA-LUAD and three GEO datasets were analyzed to confirm the prognostic relevance of purine biosynthesis. A prognostic model, the Purine Biosynthesis-Related Score (PBRS), was developed using LASSO regression and validated in independent cohorts. Gene set variation analysis, immune profiling, tumor mutational burden analysis, and drug sensitivity analysis were conducted. PAICS expression was validated in LUAD tissues, and its role was assessed via proliferation and migration assays. Results: PBRS classified LUAD patients into high-risk (PBRS-high) and low-risk (PBRS-low) subgroups, with distinct prognostic outcomes. PBRS-high patients showed enrichment in cell cycle regulation and DNA repair pathways and had higher TMB, suggesting potential sensitivity to immunotherapy, although immune escape mechanisms may limit the efficacy of immune checkpoint inhibitors. PBRS-low patients were more responsive to metabolic inhibitors. PAICS overexpression correlated with poor prognosis, while its knockdown suppressed LUAD progression. Conclusion: PBRS is a prognostic tool in LUAD, identifying PBRS-high patients who may benefit from immunotherapy or DDR-targeted therapies. PBRS-low patients exhibit sensitivity to metabolic inhibitors. PAICS is a potential therapeutic target. Full article

Background: The mutation rate of p53 in breast cancer is around 20%. Specific p53 mutations exhibit prion-like abnormal misfolding and aggregation and gain oncogenic function, causing resistance to the chemotherapy drug doxorubicin. In this study, we identified key upstream regulatory molecules that inhibit the aggregation of p53 with the aim of increasing the anticancer effect of doxorubicin. Methods: Thioflavin T was employed as a fluorescent probe to detect prion-like protein aggregates within cells, the response to various inhibitors was evaluated using CCK8 assay, and the coefficient of drug interaction was calculated. The cell apoptosis ratio was evaluated using Caspase-3/7 based flow cytometry assay. Results: MDA-MB-231 cells (with p53 R280K mutation) and T47D cells (with p53 L194F mutation) had a strong Thioflavin T staining signal, but MDA-MB-468 cells (with p53 R273H mutation) had a weak Thioflavin T signal. Compared to MDA-MB-468 cells, which had a good response to doxorubicin, both MDA-MB-231 and T47D showed high doxorubicin drug resistance. Co-treatment with various misfolding p53 aggregation inhibitors and doxorubicin found that only the HSP70 inhibitor and doxorubicin had synergistic anticancer activity in both MDA-MB-231 and T47D cells. Furthermore, this co-treatment induced cell apoptosis in MDA-MB-231, which was reversed by a pan-caspase inhibitor. Conclusions: Doxorubicin resistance caused by specific p53 mutants can be resolved by co-treatment with a HSP70 inhibitor in breast cancer cells. Full article

This study analyzed eleven isolates of colistin-resistant Pseudomonas aeruginosa, originating from Portugal and Taiwan, which are associated with various pathologies. The results revealed significant genetic diversity among the isolates, with each exhibiting a distinct genetic profile. A prevalence of sequence type ST235 was observed, characterizing it as a high-risk clone, and serotyping indicated a predominance of type O11, associated with chronic respiratory infections in cystic fibrosis (CF) patients. The phylogenetic analysis demonstrated genetic diversity among the isolates, with distinct clades and complex evolutionary relationships. Additionally, transposable elements such as Tn3 and IS6 were identified in all isolates, highlighting their importance in the mobility of antibiotic resistance genes. An analysis of antimicrobial resistance profiles revealed pan-drug resistance in all isolates, with a high prevalence of genes conferring resistance to β-lactams and aminoglycosides. Furthermore, additional analyses revealed mutations in regulatory networks and specific loci previously implicated in colistin resistance, such as pmrA, cprS, phoO, and others, suggesting a possible contribution to the observed resistant phenotype. This study has a strong impact because it not only reveals the genetic diversity and resistance mechanisms in P. aeruginosa but also identifies mutations in regulatory genes associated with colistin resistance. Full article

Background: ESR1 mutations are biomarkers in breast cancer patients who develop metastatic disease after endocrine therapy (ET). Recently, the Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved Elacestrant, a selective estrogen receptor degrader for patients harboring ESR1 mutations. This has necessitated the establishment of reliable and sensitive NGS- or PCR-based assays to detect these ESR1 resistance mutations in liquid biopsy samples. Methods: We evaluated NGS results of a pan-cancer cohort of almost 6000 patients from two major German institutes of pathology, to show that the occurrence of ESR1 mutations is extremely rare (<1%) in ET-naïve patients. This suggests that ESR1 mutations arise almost exclusively under the pressure of ET. Therefore, we designed a breast cancer-specific hybrid capture-based NGS liquid biopsy assay covering 12 breast cancer-related genes, including ESR1, PIK3CA, AKT1, ERBB2, BRCA1/2, and TP53. We validated the HS2-Mamma-LIQ assay extensively using reference material to detect mutations to 0.1% variant allele frequency (VAF) and compared the performance to a commercially available ESR1 ddPCR assay. Results: We show the results of routine diagnostic analysis of the first consecutive 354 patients with activating ESR1 mutations rate of 43%, with 20% of patients harboring co-mutations in PIK3CA and other genes underlining the relevance of tumor heterogeneity. Our study highlights liquid biopsy as a preferred approach for monitoring ESR1 mutations in breast cancer patients by showing cases where NGS analysis suggests complex tumor heterogeneity with multiple ESR1 as well as PIK3CA mutations at different VAFs. Conclusions: Our findings not only corroborate prior research concerning the rarity of these mutations in unselected patients but also emphasize the importance of robust and broad molecular assays rather than single gene assays in their detection and characterization in the diagnostic setting. Advantages of different approaches are discussed to address the current clinical need. Full article