Search Results (2,013)

This review explores the biofilm architecture and drug resistance of Enterococcus faecalis in clinical and environmental settings. The biofilm in E. faecalis is a heterogeneous, three-dimensional, mushroom-like or multilayered structure, characteristically forming diplococci or short chains interspersed with water channels for nutrient exchange and waste removal. Exopolysaccharides, proteins, lipids, and extracellular DNA create a protective matrix. Persister cells within the biofilm contribute to antibiotic resistance and survival. The heterogeneous architecture of the E. faecalis biofilm contains both dense clusters and loosely packed regions that vary in thickness, ranging from 10 to 100 µm, depending on the environmental conditions. The pathogenicity of the E. faecalis biofilm is mediated through complex interactions between genes and virulence factors such as DNA release, cytolysin, pili, secreted antigen A, and microbial surface components that recognize adhesive matrix molecules, often involving a key protein called enterococcal surface protein (Esp). Clinically, it is implicated in a range of nosocomial infections, including urinary tract infections, endocarditis, and surgical wound infections. The biofilm serves as a nidus for bacterial dissemination and as a reservoir for antimicrobial resistance. The effectiveness of first-line antibiotics (ampicillin, vancomycin, and aminoglycosides) is diminished due to reduced penetration, altered metabolism, increased tolerance, and intrinsic and acquired resistance. Alternative strategies for biofilm disruption, such as combination therapy (ampicillin with aminoglycosides), as well as newer approaches, including antimicrobial peptides, quorum-sensing inhibitors, and biofilm-disrupting agents (DNase or dispersin B), are also being explored to improve treatment outcomes. Environmentally, E. faecalis biofilms contribute to contamination in water systems, food production facilities, and healthcare environments. They persist in harsh conditions, facilitating the spread of multidrug-resistant strains and increasing the risk of transmission to humans and animals. Therefore, understanding the biofilm architecture and drug resistance is essential for developing effective strategies to mitigate their clinical and environmental impact. Full article

Endometriosis is a disease characterized by the presence of endometrial glands and stroma outside of the uterine corpus, often clinically presenting with pain and/or infertility. Ectopic lesions exhibit features characteristic of epithelial-to-mesenchymal transition (EMT), a process in which epithelial cells lose polarity and acquire mesenchymal traits, including migratory and invasive capabilities. During the process of EMT, epithelial traits are downregulated, while mesenchymal traits are acquired, with cells developing migratory ability, increasing proliferation, and resistance to apoptosis. EMT is promoted by exposure to hypoxia and stimulation by transforming growth factor-β (TGF-β), platelet-derived growth factor (PDGF), and estradiol. Signaling pathways that promote EMT are activated in most ectopic lesions and involve transcription factors such as Snail, Slug, ZEB-1/2, and TWIST-1/2. EMT-specific molecules present in the serum of women with endometriosis appear to have diagnostic potential. Strategies targeting EMT in animal models of endometriosis have demonstrated regression of ectopic lesions, opening the door for novel therapeutic approaches. This review summarizes the current understanding of the role of EMT in endometriosis and highlights potential targets for EMT-related diagnosis and therapeutic interventions. Full article

Efflux is one of the key mechanisms used by Gram-negative bacteria to reduce internal antibiotic concentrations. These active transport systems recognize and expel a wide range of toxic molecules, including antibiotics, thereby contributing to reduced antibiotic susceptibility and allowing the bacteria to acquire additional resistance mechanisms. To date, unlike other resistance mechanisms such as enzymatic modification or target mutations/masking, efflux is challenging to detect and counteract in clinical settings, and no standardized methods are currently available to diagnose or inhibit this mechanism effectively. This review first outlines the structural and functional features of major efflux pumps in Gram-negative bacteria and their role in antibiotic resistance. It then explores various strategies used to curb their activity, with a particular focus on efflux pump inhibitors under development, detailing their structural classes, modes of action, and pharmacological potential. We discuss the main obstacles to their development, including the structural complexity and substrate promiscuity of efflux mechanisms, the limitations of current screening methods, pharmacokinetic and tissue distribution issues, and the risk of off-target toxicity. Overcoming these multifactorial barriers is essential to the rational development of less efflux-prone antibiotics or of efflux pump inhibitors. Full article

Background: Broad-spectrum antibiotics are often used for suspected infections in patients with hematologic malignancies due to the risk of severe infections. Although antibiotic use can lead to antimicrobial resistance and microbiome dysbiosis, the effects of antibiotics on the microbiome and resistome in patients with acute myeloid leukemia (AML) undergoing remission induction chemotherapy (RIC) are not well understood. Methods: Various statistical models were utilized to examine the effects of antibiotic administration on the microbiome and resistome over time, as well as differences in AR-infection (ARI) and colonization (ARC) by important CDC-threats in 119 AML patients. Results: A greater number of unique antibiotic classes administered correlated with a loss of unique antibiotic resistance genes (ARGs) (R = −0.39, p = 0.008). Specifically, although a greater number of oxazolidinone administrations was correlated with a greater loss of diversity (R = −0.58, p < 0.001), each additional day of linezolid reduced the risk of ARC by ~30% (HR: 0.663, p = 0.047) and decreased the odds of acquiring genes predicted to confer macrolide (HR: 0.50, p = 0.026) resistance. Conclusions: The number of antibiotic administrations and the types of antibiotics used can influence the risk of antibiotic resistance gene (ARG) expansion and ARC events in AML patients undergoing RIC. While certain antibiotics may reduce microbial diversity, they are not always linked to an increase in ARGs or ARC events. Full article

Background/Objectives: Non-fermenting Gram-negative bacilli (NFGNB) represent a significant clinical challenge due to their intrinsic and acquired resistance, particularly in immunocompromised patients. Infections cause by NFGNB are associated with high morbidity and mortality, especially among patients with cystic fibrosis and hematologic malignancies. This study aimed to assess the in vitro susceptibility of clinically relevant NFGNB isolates to two newer antibiotics, cefiderocol and aztreonam/avibactam, and an established antibiotic, trimethoprim/sulfamethoxazole. Methods: This retrospective, monocentric study analysed 94 NFGNB isolates (30 Pseudomonas aeruginosa, 30 Acinetobacter sp., 24 Stenotrophomonas maltophilia, and 10 Burkholderia cepacia complex). Susceptibility testing for cefiderocol, aztreonam/avibactam, and trimethoprim/sulfamethoxazole was conducted using gradient strip method. MIC values were interpreted using EUCAST breakpoints, ECOFFs, or alternative criteria when necessary. Results: All S. maltophilia isolates were susceptible to cefiderocol (FCR) and aztreonam/avibactam (A/A) based on ECOFFs, with one strain resistant to trimethoprim–sulfamethoxazole (COT). Burkholderia cepacia complex strains also showed high susceptibility to FCR, with only one isolate exceeding the ECOFF for A/A, and 20% resistant to COT. All Acinetobacter sp. isolates were susceptible to FCR; however, most MIC values clustered at or just below the ECOFF value. In P. aeruginosa, one isolate was resistant to FCR, and three isolates (10%) were resistant to A/A. Interestingly, confirmed carbapenemase producers remained susceptible to both FCR and A/A. Most A/A MIC values for P. aeruginosa were just below the ECOFF. Conclusions: Cefiderocol and aztreonam/avibactam demonstrated promising in vitro activity against clinically relevant NFGNB, including carbapenem-resistant strains. These findings support their potential role as therapeutic options for difficult-to-treat infections, particularly in immunocompromised patients. Full article

Island microgrids are essential for the exploitation and utilization of offshore renewable energy resources. However, voltage regulation and accurate reactive power sharing remain significant technical challenges that need to be addressed. To tackle these issues, this paper proposes an algorithm that integrates a dynamic leader election (DLE) mechanism and model-free reinforcement learning (RL). The algorithm aims to address the issue of fixed leaders restricting reactive power flow between buses during heavy load variations in island microgrids, while also overcoming the challenge of obtaining model parameters such as resistance and inductance in practical microgrids. First, we establish a voltage containment control and reactive power error model for island alternating current (AC) microgrids and construct a corresponding value function based on this error model. Second, a dynamic leader election algorithm is designed to address the issue of fixed leaders restricting reactive power flow between buses due to preset voltage limits under unknown or heavy load conditions. The algorithm adaptively selects leaders based on bus load, allowing the voltage limits to adjust accordingly and regulating reactive power flow. Then, to address the difficulty of accurately acquiring parameters such as resistance and inductance in microgrid lines, a model-free reinforcement learning method is introduced. This method relies on real-time measurements of voltage and reactive power data, without requiring specific model parameters. Ultimately, simulation experiments on offshore island microgrids are conducted to validate the effectiveness of the proposed algorithm. Full article

Background/Objectives: All current FDA-approved antibody–drug conjugates (ADCs) are single-target and single-payload molecules that have limited efficacy in patients due to drug resistance. Therefore, our goal was to generate a novel ADC that was less susceptible to single points of resistance to reduce the likelihood of patient relapse. Methods: We developed a dual-targeting, dual-payload ADC by conjugating a bispecific EGFR x cMET antibody to two payloads (MMAF and SN38) that had separate mechanisms of action using a novel tri-functional linker. This dual-payload ADC was tested for potency and efficacy in dividing and nondividing in vitro cell models using multiple tumor cell types. Efficacy of the dual-payload ADC was confirmed using in vivo models. Results: Our ADC with dual MMAF and SN38 payloads was more efficacious in inhibiting cell proliferation than single-payload ADCs across multiple cancer cell lines. In addition, the dual-payload molecule inhibited nondividing cells, which were more resistant to traditional ADC payloads. The dual-payload ADC also exhibited more potent tumor growth inhibition in vivo compared to that of single-payload ADCs. Conclusions: Overall, the bispecific antibody conjugated with both the MMAF and SN38 payloads inhibited tumor growth more strongly than ADCs conjugated with MMAF or SN38 alone. Developing dual-payload ADCs could limit the impact of acquired resistance in patients as well as lower the effective dose of each payload. Full article

Acinetobacter baumannii is a multidrug-resistant bacterium that has gained significant attention in recent years due to its involvement in a growing number of hospital-acquired infections. The World Health Organization has classified it as a critical priority pathogen, underscoring the urgent need for new therapeutic strategies. Post-translational modifications (PTMs), such as phosphorylation, play essential roles in various bacterial processes, including antibiotic resistance, virulence or biofilm formation. Although proteomics has increasingly enabled their characterization, the identification of phosphorylated peptides remains challenging, primarily due to the enrichment procedures. In this study, we focused on characterizing serine, threonine, and tyrosine phosphorylation in the A. baumannii ATCC 17978 strain. We optimized three parameters for phosphopeptide enrichment using titanium dioxide (TiO₂) beads (number of enrichment fractions between the phosphopeptides and TiO₂ beads, the quantity peptides and type of loading buffer) to determine the most effective conditions for maximizing phosphopeptide identification. Using this optimized protocol, we identified 384 unique phosphorylation sites across 241 proteins, including 260 novel phosphosites previously unreported in A. baumannii. Several of these phosphorylated proteins are involved in critical bacterial processes such as antimicrobial resistance, biofilm formation or pathogenicity. We discuss these proteins, focusing on the potential functional implications of their phosphorylation. Notably, we identified 34 phosphoproteins with phosphosites localized at functional sites, such as active sites, multimer interfaces, or domains important for structural integrity. Our findings significantly expand the current phosphoproteomic landscape of A. baumannii and support the hypothesis that PTMs, particularly phosphorylation, play a central regulatory role in its physiology and pathogenic potential. Full article

The pharmacological treatment of cholangiocarcinoma (CCA) is often hampered by tumor resistance. Improving our understanding of this issue is crucial for developing strategies that can overcome drug refractoriness. We have established and characterized two novel human cell sublines derived from extrahepatic CCA EGI-1 cells that are resistant to cisplatin and 5-fluorouracil (5-FU). Migration and proliferation were analyzed using holographic microscopy. The expression of genes involved in drug uptake and efflux was determined by RT-qPCR. Cross-resistance to commonly used antitumor drugs was assayed using the MTT test. EGI-1 sublines resistant to cisplatin (CR) or 5-FU (FR) exhibited more than a three-fold increase in resistance to cisplatin and 5-FU, respectively, and showed reduced proliferation, migration, and colony-formation rates, along with an altered cell cycle compared to wild-type cells, while retaining tumorigenic capacity. The analysis of the transportome showed downregulation of uptake transporters and upregulation of the export pumps MRP3/4. EGI-1 cells with acquired resistance to 5-FU demonstrated cross-resistance to irinotecan and gemcitabine, while cisplatin-resistant cells showed decreased sensitivity to 5-FU and platinum derivatives. These resistant cell lines offer valuable models for investigating the molecular basis of chemoresistance in CCA, providing a robust platform for the development and evaluation of novel therapeutic strategies. Full article

Pseudomonas aeruginosa is a highly adaptable opportunistic pathogen with significant clinical relevance in both human and veterinary medicine. Despite its well-documented role in hospital-acquired infections in human healthcare settings, its persistence and transmission within veterinary clinics remain underexplored. This review highlights the overlooked status of veterinary facilities as environmental reservoirs and amplification points for multidrug-resistant (MDR) P. aeruginosa, emphasizing their relevance to One Health surveillance. We examine the bacterium’s environmental survival strategies, including biofilm formation, resistance to disinfectants, and tolerance to nutrient-poor conditions that facilitate the long-term colonization of moist surfaces, drains, medical equipment, and plumbing systems. Common transmission vectors are identified, including asymptomatic animal carriers, contaminated instruments, and the hands of veterinary staff. The review synthesizes current data on antimicrobial resistance in environmental isolates, revealing frequent expression of efflux pumps and mobile resistance genes, and documents the potential for zoonotic transmission to staff and pet owners. Key gaps in environmental monitoring, infection control protocols, and genomic surveillance are identified, with a call for standardized approaches tailored to the veterinary context. Control strategies, including mechanical biofilm disruption, disinfectant cycling, effluent monitoring, and staff hygiene training, are evaluated for feasibility and impact. The article concludes with a One Health framework outlining cross-species and environmental transmission pathways. It advocates for harmonized surveillance, infrastructure improvements, and intersectoral collaboration to reduce the risk posed by MDR P. aeruginosa within veterinary clinical environments and beyond. By addressing these blind spots, veterinary facilities can become proactive partners in antimicrobial stewardship and global resistance mitigation. Full article

Triple-negative breast cancer (TNBC) is a highly aggressive subtype known for its rapid metastatic potential. Despite its severity, treatment options for TNBC remain limited. Olaparib, an FDA-approved PARP inhibitor, has been used to treat germline BRCA-mutated TNBC in both metastatic and high-risk early-stage settings. However, acquired resistance to PARP inhibitors and their limited applicability in non-BRCA TNBCs are now two major growing clinical problems. Activation of the IL-6/STAT3 signaling cascade has been implicated in therapeutic resistance. In this study, we evaluated the combined effects of the PARP inhibitor olaparib and the STAT3 inhibitor LLL12B in human TNBC cell lines with both BRCA mutations and wild-type BRCA status. Our results demonstrate that the PARP inhibitor olaparib can induce increased interleukin-6 (IL-6) in TNBC cells, with ELISA showing a 2- to 39-fold increase across five cell lines. MTT assays revealed that knocking down or inhibiting STAT3, a key downstream effector of the IL-6/GP130 pathway, sensitizes TNBC cells to olaparib. Treatment with either olaparib or LLL12B alone reduced TNBC cell viability, migration, and invasion. Notably, their combined administration produced a markedly enhanced inhibitory effect compared to individual treatments, regardless of BRCA mutation status. These findings highlight the potential of dual PARP and STAT3 inhibition as a novel targeted therapeutic strategy for both BRCA-mutant and BRCA-proficient TNBC. Full article

Background: Community-acquired pneumonia (CAP) is the leading cause of death in infants aged 1–59 months. Concurrent with this, there is a need to prescribe antibiotics wisely in Vietnam due to concerns with rising antimicrobial resistance (AMR). Consequently, an urgent need has arisen to treat patients according to agreed guidelines. The aim of this study was to investigate the current management of infants under five years old with CAP in Vietnam as well as identify possible obstacles to adhering to national guidelines. Methods: A mixed-method approach was used incorporating both quantitative and qualitative data analysis in a leading hospital in Vietnam, which influences others. Data from 108 pediatric patient records were collected and analyzed. Subsequently, in-depth interviews were conducted with pediatric doctors treating these patients to ascertain possible reasons for non-adherence to guidelines. Results: The mean age of children diagnosed with CAP was 27.94 ± 12.99 months, with 82.4% having non-severe CAP, and 41.7% of children had previously used antibiotics before hospitalization. The median length of hospital stay was 7 days. All children were prescribed antibiotics, 91.4% of children received these initially intravenously, with third-generation cephalosporins being the most (91.7%) commonly prescribed. Cefoperazone/sulbactam was the most frequently prescribed (48.2%) antibiotic. However, on 96.1% of occasions cefoperazone/sulbactam was given at higher doses than the label instructions. Overall, 73.3% of antibiotics prescribed were “Watch” antibiotics. In addition, the proportion of initial antibiotic regimens that were consistent with current national guidelines was only 4.63%. Conclusions: There were considerable concerns with low adherence rates to current guidelines alongside high rates of prescribing of injectable third-generation cephalosporins due to various internal and external barriers. Antimicrobial stewardship programs with updated national guidelines are urgently needed in Vietnamese hospitals to treat CAP in children as part of ongoing measures to reduce increasing AMR rates. Such activities should also help improve antibiotic use in the community following improved education of trainee ambulatory care physicians regarding appropriate management of children with CAP. Full article

(1) Background: Oral cancer (OC) is one of the most frequently diagnosed human cancers and remains a challenge for biologists and clinicians. More than 90% of OC cases are squamous cell carcinomas (OSCCs). Despite the use of modern diagnostic and prognostic methods, the 5-year survival rate remains unsatisfactory due to the late diagnosis of the neoplastic process and its resistance to treatment. This comprehensive review aims to present the latest literature data on the use and effectiveness of saliva as a non-invasive biomarker in patients with oral cancer. (2) Methods: The article reviews the current literature on the use of salivary omics biomarkers as an effective method in diagnosing and modifying treatment in patients with OSCC; the research corpus was acquired from the PubMed/Google/Scopus/Cochrane Library/Web of Science databases in accordance with the Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA 2020) guidelines. (3) Results: The identification of salivary omics biomarkers involved in carcinogenesis and neoplastic transformation may be a potential alternative to traditional invasive diagnostic methods. Saliva, being both an abundant reservoir of organic and inorganic components derived from epithelial cells as well as a cell-free environment, is becoming an interesting diagnostic material for studies in the field of proteomics, genomics, metagenomics, and metabolomics. (4) Conclusions: Saliva-based analysis is a modern and promising method for the early diagnosis and improvement of treatment outcomes in patients with OSCC and oral potentially malignant disorders (OPMDs), with high diagnostic, therapeutic, and prognostic potential. Full article

Background: Treatment of metastatic cancer remains a challenge, because cancer cells acquire resistance even to the most contemporary therapies. This study analyzed the role of the phosphoprotein Stathmin 1 (STMN1) in regulating cancer cell growth and metastatic potential. Methods: Public datasets with metastatic castration-resistant prostate cancer (mCRPC) and breast cancer (BC) were analyzed to determine the interrelationship between STMN1, hepatocyte growth factor (HGF) and MET proto-oncogene (MET) expression, overall survival, and response to chemotherapy. Site-directed mutagenesis, cell cycle analysis, proliferation, and migration and invasion assays determined the impact of STMN1 phosphorylation on proliferation and metastatic potential. Results: Increased STMN1 associates with HGF and MET gene expression in mCRPC, and taxane chemotherapy further increases HGF expression. STMN1 and HGF are highest, and overall survival is poorest in mCRPC in the liver compared to other sites, implying the metastatic site influences their expression levels and potentially the pattern of metastatic spread. Increased STMN1 and MET also predict taxane responsiveness in BC patients. Analysis of STMN1 serine (S)16, 25, 38, and 63 determined that total (t) STMN1 and STMN1 S16 phosphorylation (pSTMN1^S16) are co-regulated by HGF/MET during cell cycle progression, pSTMN1^S16 alone can promote cell proliferation, and pSTMN1^S16 shortens the cell cycle similar to HGF treatment, while STMN1^S16 dephosphorylation lengthens the cell cycle to arrest cell growth in G2/M, similar to HGF plus the MET inhibitor AMG337. Importantly, STMN1^S16 does not promote metastasis. Conclusions: Selectively inhibiting STMN1^S16 phosphorylation may provide an alternative strategy for inhibiting MET-mediated cell growth to eliminate metastatic cancer cells and inhibit further metastasis. Full article

Immunotherapy has emerged as a transformative approach in gastrointestinal (GI) cancers, addressing historically poor survival rates in advanced-stage disease. Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis demonstrate remarkable efficacy in colorectal cancer with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H), exemplified by trials like NICHE-2 achieving exceptional pathological response rates. However, significant limitations persist, including resistance in some dMMR/MSI-H tumors, minimal efficacy in proficient mismatch repair (pMMR) tumors, and low overall response rates across most GI malignancies due to tumor heterogeneity and immune evasion mechanisms. Predictive biomarkers such as tumor mutational burden (TMB) and PD-L1 expression are crucial for optimizing patient selection, while hypermutated pMMR tumors with POLE mutations represent emerging therapeutic opportunities. In pancreatic adenocarcinoma, where survival remains dismal, combination strategies with chemotherapy and novel approaches like cancer vaccines show promise but lack transformative breakthroughs. Esophagogastric cancers benefit from ICIs combined with chemotherapy, particularly in MSI-H and HER2-positive tumors, while hepatocellular carcinoma has achieved significant progress with combinations like atezolizumab–bevacizumab and durvalumab–tremelimumab surpassing traditional therapies. Biliary tract cancers show modest improvements with durvalumab–chemotherapy combinations. Despite these advances, immunotherapy faces substantial challenges including immune-related adverse events, acquired resistance through cancer immunoediting, and the need for biomarker-driven approaches to overcome tumor microenvironment barriers. This review discusses key clinical trials, therapeutic progress, and emerging modalities including CAR T-cell therapies and combination strategies, emphasizing the critical need to address resistance mechanisms and refine precision medicine approaches to fully realize immunotherapy’s potential in GI malignancies. Full article