Search Results (7,555)

Background/Objectives: Skin and soft tissue infections (SSTIs) represent a significant clinical challenge, largely due to the high prevalence of antibiotic-resistant Staphylococcus aureus, particularly methicillin-resistant S. aureus (MRSA). Treatment is further complicated by biofilm formation, which reduces antibiotic efficacy. The limitations of conventional therapies highlight the need for alternative approaches. Phage therapy has emerged as a promising biological strategy; however, its effectiveness may be constrained by factors such as phage instability and biofilm regrowth. This study aimed to enhance phage-based treatment by combining a newly isolated phage, vB_Sau-E, with lactoferrin (Lf), a multifunctional protein of the innate immune system. Methods: Phage vB_Sau-E was characterized in terms of its infection dynamics and lytic activity. Biocompatibility was further examined using human skin cell lines. The potential effect of Lf was assessed by evaluating its impact on phage infectivity and stability under a range of environmental conditions and by checkerboard assay. Results: Phage vB_Sau-E belongs to the Silviavirus genus in the Herelleviridae family. It was shown to infect 12 out of 22 tested clinical MRSA isolates, with 10 strains identified as good hosts. The phage has a ~30 min life cycle, and ~50 progeny virions are released after bacterial cell lysis. We have also observed that Lf increased plating efficiency and enhanced phage stability at a pH of 5.5 and at −20° C. It also proved to have an additive antibacterial effect, though this was observed to be strain-dependent. Conclusions: Lactoferrin functions as a stabilizing adjuvant for phage vB_Sau-E. Its additive effect supports the development of more effective, biofilm-targeting therapies for staphylococcal SSTIs. Full article

Background: Allogeneic hematopoietic stem cell transplantation (allo-HCT) is the only curative therapy for myelofibrosis (MF), but its use is limited by substantial transplant related morbidity and mortality, particularly in older or comorbid patients. Treosulfan has emerged as a less toxic alternative to busulfan, with potential advantages in myeloablative and reduced intensity conditioning. Methods: We conducted a comprehensive, multi-database literature search (PubMed, Scopus/EMBASE, Cochrane Library, Web of Science, and grey literature) for studies published between 2000 and 2025 evaluating treosulfan-based conditioning in MF patients undergoing allo-HCT. Data on patient characteristics, conditioning regimens, engraftment, graft-versus-host disease (GVHD), and survival outcomes were synthesized. Results: Eight studies including more than 800 patients were analyzed. Treosulfan was most commonly combined with fludarabine, with or without additional agents. Engraftment rates were consistently high at 94 to 100%, with low non-relapse mortality (NRM) and favorable progression-free survival (PFS). An EBMT registry study demonstrated superior survival and significantly lower NRM compared with busulfan based regimens. Benefits were observed across older patients, alternative donors, and second transplants. Higher treosulfan doses were associated with increased toxicity in some cohorts. Conclusions: Treosulfan based conditioning offers an effective and better tolerated option for MF transplantation. Prospective trials are needed to refine dosing and patient selection. Full article

This review summarizes mechanisms regulating mRNA translation under cellular stress and highlights design strategies to improve translation efficiency and stability in the gene therapy of human diseases. mRNA-based therapeutics are emerging as a versatile gene therapy platform enabling transient and controllable expression of therapeutic proteins for the treatment of cancer, genetic disorders, and inflammatory diseases. The efficacy of mRNA-based gene therapy is strongly influenced by sequence design, chemical modifications, and structural features. Evidence shows that rational mRNA engineering can significantly enhance translation efficiency even under stress conditions that impair canonical protein synthesis, as observed in many pathological states. Cellular stress activates regulatory pathways that suppress global translation; however, optimized mRNA constructs can partially bypass these inhibitory mechanisms, enabling sustained protein expression. By improving mRNA stability and resistance to stress-responsive translational control, robust therapeutic protein production can be achieved even in challenging cellular environments. This article was prepared as a narrative review focused on translational regulation mechanisms relevant to therapeutic mRNA design under cellular stress conditions. Literature was collected from PubMed, Google Scholar, and Web of Science using keywords including “mRNA therapeutics,” “cellular stress,” “translation regulation,” “UTR engineering,” and “cap-independent translation.” Studies published mainly between 2010 and 2025 were considered. Original articles and reviews related to stress-responsive translation and therapeutic mRNA optimization were included, while studies outside the scope of translational control and mRNA engineering were excluded. Priority was given to recent and mechanistically relevant publications. Full article

Antibiotic resistance is a growing global health threat. However, its evolution cannot be fully understood without considering antibiotic tolerance and persistence. Persister cells are phenotypic variants that survive lethal antibiotic exposure without heritable resistance, primarily through growth arrest, metabolic slowdown, and stress-adaptive states. Although persistence has been viewed as a transient survival phenomenon, increasing evidence suggests that it may also have a genetic basis by preserving populations during antibiotic-induced bottlenecks and enabling regrowth, mutation, and selection under certain conditions. This review examines the molecular mechanisms underlying persister formation, including toxin–antitoxin systems, stringent-response signaling, ATP depletion, translational arrest, and stress-response networks. We discuss how persistence contributes to antibiotic tolerance in biofilms, host environments, and recurrent infections, and how repeated antibiotic exposure may promote stepwise evolution from phenotypic survival to stable resistance in specific contexts. Evidence from experimental evolution, clinical observations, and system-level analyses supports a potential but context-dependent link between persistence and resistance. We also highlight therapeutic strategies targeting persister cells, including antipersister compounds, metabolic activation, combination therapies, bacteriophages, and alternative approaches. Finally, we outline future research directions, emphasizing single-cell technologies, systems biology, longitudinal clinical studies, and evolution-informed treatment design. A comprehensive understanding of persistence and its evolutionary implications is essential for improving treatment efficacy and limiting the emergence of long-term antibiotic resistance. Full article

The term bacterial biofilm refers to a complex community of microorganisms embedded within a self-produced matrix of extracellular polymeric substances. This structural organization creates an environment that, when present in an infectious context within a living organism, limits the effectiveness of conventional antibiotic therapy. Consequently, such conditions substantially promote the development of antibiotic resistance. The decline in the discovery of novel antibiotic agents, coupled with a concurrent increase in the prevalence of multidrug-resistant microorganisms, has intensified the search for alternative strategies to combat such infections. At the same time, advances in nanoscience have stimulated substantial research into the use of micro/nanorobots for the eradication of bacterial biofilms. These devices, engineered at the micro- to nanoscale, are capable of targeted intervention in otherwise inaccessible sites. However, the development of such “microscopic therapeutic agents” is still at an early stage. To date, the vast majority of available data has been derived from in vitro studies, while evidence regarding their feasibility, safety, and therapeutic effects in living organisms remains limited. This review discusses their antimicrobial mechanisms and critically evaluates the current evidence concerning their in vivo applications. Full article

Bacterial sexually transmitted and sexually associated infections remain a major global health concern, increasingly complicated by antimicrobial resistance and the limited effectiveness of existing therapies. In this context, bacteriophage-based and phage-derived approaches have re-emerged as potential alternative antibacterial strategies. This narrative review examines their applicability across key bacterial pathogens associated with sexually transmitted infections, including Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma genitalium, Treponema pallidum and biofilm-associated bacterial vaginosis, with a particular focus on pathogen-specific biological barriers. Available evidence indicates that the success of phage-based interventions is strongly dependent on factors such as intracellular localisation, structural characteristics of the bacterial envelope and the presence of polymicrobial biofilms. While phage-derived platforms, including endolysins, depolymerases and engineered phages, demonstrate antibacterial activity in experimental settings, their effectiveness is uneven across different pathogens. Biofilm-associated infections appear more accessible to these approaches, whereas intracellular and structurally atypical bacteria are currently considered more challenging targets based on available mechanistic and experimental evidence. These observations highlight the need for pathogen-specific engineering strategies and delivery systems. Overall, phage-based therapeutics in this field should be considered within a framework that integrates biological constraints with targeted antimicrobial design. Full article

Colorectal cancer (CRC) is the third most frequently diagnosed malignancy and the second leading cause of cancer-related mortality worldwide, underscoring the need for the development of more effective and durable therapeutic strategies. A key mechanism of tumor immune evasion involves activation of immune checkpoint pathways through the upregulation of inhibitory ligand expression within the tumor microenvironment, leading to lymphocyte exhaustion and impaired antitumor immunity. Consequently, immune checkpoints have emerged as important targets for immunotherapeutic intervention, with significant advances over the past decade. Nevertheless, despite demonstrated clinical benefits in selected patient subpopulations, the overall therapeutic efficacy of immune checkpoint inhibitors remains limited, particularly in the context of CRC. In this review, we provide a comprehensive overview of currently approved immune checkpoint-based immunotherapies for cancer treatment, with a specific focus on CRC, as well as ongoing clinical trials and evolving trends in this area. Furthermore, we discuss emerging targets and novel therapeutic strategies, with particular emphasis on innovative small-molecule inhibitors as potential alternatives to monoclonal antibody-based approaches. Finally, we outline future perspectives and potential directions for advancing immune checkpoint-targeted therapies in CRC. Full article

Background: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) represents a group of rare systemic autoimmune disorders marked by inflammation and damage to small- and medium-sized blood vessels. The clinical presentation of AAV is highly variable, ranging from isolated organ involvement to severe, life-threatening multisystem disease, posing significant challenges in diagnosis, treatment, and prognosis. Objective: To demonstrate the clinical heterogeneity and different outcomes in three pediatric cases of ANCA-positive disease and emphasize the importance of integrating clinical findings with laboratory and imaging investigations for accurate diagnosis. Methods: We present three pediatric patients (ages 12–15 years) with ANCA-positive results but distinct clinical presentations, evaluated at the Children’s Emergency Hospital “Louis Turcanu”, Timisoara, between 2020 and 2024. All cases were investigated according to EULAR/PRINTO/PReS criteria for pediatric vasculitis. Results: Case 1 (PR3-ANCA positive) developed severe multi-organ involvement, including granulomatosis with polyangiitis (GPA) with pulmonary hemorrhage, pericarditis, thrombotic events, and renal impairment, requiring intensive immunosuppression with cyclophosphamide, rituximab, and mycophenolate mofetil, ultimately developing chronic kidney disease stage 3a. Case 2 (BPI-ANCA positive) presented with purpuric lesions and painless joint swelling, responding favorably to corticosteroid therapy with subsequent remission. Case 3 (MPO-ANCA) manifested as polyarticular arthritis without other organ involvement and was ultimately diagnosed as seronegative juvenile idiopathic arthritis (JIA), achieving complete remission with adalimumab therapy. Conclusions: This case series highlights the diverse clinical and biological features of ANCA-positive conditions in children, emphasizing that ANCA positivity requires careful clinical correlation as it may indicate true vasculitis requiring aggressive treatment or alternative diagnoses such as JIA with incidental ANCA positivity. Tailored therapeutic strategies based on clinical presentation and continued research are essential to improve patient outcomes. Full article

Pharmacomicrobiomics is the study of drug–microbiome interactions. It examines the dynamic relationship between the drug, the host, and the microbiome, and has become a rapidly evolving area in the realm of pharmacology and personalized medicine. Emerging evidence demonstrates that the gut microbiome can influence the pharmacodynamics and pharmacokinetics of drugs through various mechanisms, while drugs can simultaneously alter microbial composition. Treatment approaches include regular targeted pharmaceutical therapies (e.g., antibiotics, antidepressants) and alternative treatment approaches (e.g., CAM treatments such as supplements and herbs). Microbiome-based medication treatment is an alternative treatment approach that has been studied extensively in the last decade. This article reviews the current knowledge on drug–microbiome interactions across multiple therapeutic systems, including cardiovascular, central nervous system, gastrointestinal, respiratory, endocrine, oncologic, musculoskeletal, anti-infective therapies, and supplements (such as melatonin). We also highlight the various pathways by which microbes can alter the mechanisms (such as drug absorption), bioavailability, efficacy, and incidence of adverse effects, along with highlighting the clinical implications of drug-induced dysbiosis. Full article

Triple-negative breast cancer (TNBC) is a clinically aggressive malignancy with extremely limited effective targeted therapies. Natural products are promising alternatives for anticancer drug discovery, whereas integrated computational approaches serve as efficient tools for novel lead identification. Herein, four novel spiro-polycyclic sesquiterpene [4+2] trimers (Inubritantrimers A–D) and eight synthetic derivatives from Inula britannica L. were investigated via DFT calculations at the ωB97xD/6-311++G(2d,p) level (for geometric, electronic, spectral, and reactivity parameters), network pharmacology, molecular docking against seven core breast cancer-related targets, 500 ns all-atom molecular dynamics (MD) simulation, and MM/PBSA analysis. The results showed that the endo-type cycloaddition products had superior structural stability, with all reactions thermodynamically spontaneous (ΔG < 0). Compound 11 exhibited the most potent and balanced binding activity, with a docking free energy of −13.45 kcal/mol to MTOR; MD and MM/PBSA confirmed stable complex formation (total binding free energy −21.13 kcal/mol), driven predominantly by hydrophobic interactions. This study first established a comprehensive stereochemistry–electronic structure–property–activity relationship for this rare sesquiterpene trimer class and identified compound 11 as a promising MTOR-targeted TNBC lead. It provided a theoretical basis for developing high-efficiency, low-toxicity natural anticancer agents. Full article

Silver nanoparticles (AgNPs) have attracted substantial scientific interest in biomedical research owing to their unique physicochemical characteristics, broad-spectrum antimicrobial activity, plasmonic properties, and therapeutic versatility. Although conventional physicochemical synthesis methods enable controlled NPs fabrication, their dependence on hazardous reagents, elevated energy input, and environmentally detrimental processing conditions has stimulated the development of sustainable biogenic alternatives. Biological synthesis utilizing plants, microorganisms, fungi, algae, and purified biomolecules has emerged as an eco-friendly and bio-compatible strategy for AgNP fabrication, enabling simultaneous reduction, stabilization, and intrinsic biofunctionalization of NPs. However, traditional biogenic synthesis remains constrained by limited mechanistic understanding, poor batch reproducibility, inadequate control over physicochemical properties, and challenges in large-scale manufacturing. Recent advances in bioengineering have transformed this field through the integration of metabolic engineering, synthetic biology, microfluidic-assisted synthesis, artificial intelligence-guided process optimization, and continuous-flow biomanufacturing, collectively enabling precision fabrication of biogenic AgNPs with enhanced uniformity, scalability, and functional tunability. Furthermore, strategic surface engineering and functionalization have expanded the applicability of biogenic AgNPs across targeted anticancer therapy, antimicrobial intervention, wound healing, regenerative medicine, drug delivery, and theranostic imaging. Despite these advancements, critical challenges remain regarding nano–bio interactions, toxicological safety, regulatory compliance, and translational scalability. Unlike conventional reviews focused primarily on green synthesis approaches, this review critically highlights emerging bioengineering paradigms that enable programmable, scalable, and precision-controlled biogenic AgNP fabrication. This review comprehensively examines next-generation paradigms and strategies for AgNPs biosynthesis, elucidates the molecular mechanisms governing their formation, highlights emerging functionalization and biomedical application paradigms, and discusses current translational barriers. Forming biogenic composites of AgNPs and heteroatom doped carbon nanodots needs intense research in near future. Full article

Background: Biofilm-associated urinary tract infections (UTIs) pose a significant therapeutic challenge due to the increased tolerance of biofilm-embedded bacteria to antimicrobial agents and the high risk of infection recurrence. The increasing prevalence of multidrug-resistant uropathogens necessitates the evaluation of alternative therapeutic strategies, including antibiotic combination therapy. This study aimed to assess the antibiofilm activity of selected antibiotics used individually and in combination against biofilms formed by clinically relevant uropathogens. Methods: Biofilms of Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, and Enterococcus faecalis isolated from patients with UTIs were developed on polystyrene microtiter plates and exposed to ciprofloxacin, nitrofurantoin, amikacin, and imipenem applied as monotherapy and in combinations. Biofilm biomass reduction was quantified spectrophotometrically using crystal violet staining and expressed as a percentage relative to untreated controls. Results: Antibiotic monotherapy produced moderate reductions in biofilm biomass, with efficacy dependent on bacterial species and antibiotic concentration. In contrast, antibiotic combinations demonstrated enhanced antibiofilm activity. The ciprofloxacin–nitrofurantoin combination showed increased biofilm biomass reduction compared with monotherapy against P. aeruginosa and E. coli. The imipenem–amikacin combination reduced P. mirabilis biofilm biomass by over 80%. Conclusions: These findings suggest that rationally selected antibiotic combinations may represent a more effective strategy than monotherapy for controlling biofilm-associated UTIs. Full article

Background: Standardized operating procedures (SOPs) for intravenous vancomycin therapy have been shown to improve population-level trough target attainment and to reduce nephrotoxicity in orthopedic inpatients. However, mean target attainment on a population level does not capture how stably an individual patient remains within the therapeutic window. Intra-individual variability of vancomycin trough concentrations has remained underreported as a patient-level quality indicator in the orthopedic stewardship literature, despite its direct clinical relevance, as alternating sub- and supratherapeutic phases compromise both efficacy and safety independently of the mean exposure. Methods: We conducted a secondary analysis of the prospectively and retrospectively collected data of the Halle Vancomycin SOP cohort. Pre-SOP (n = 58) and post-SOP (n = 23) patient cohorts were compared with respect to patient-level variability metrics, including the coefficient of variation (CV%), swing index, mean absolute successive difference (MSSD), range of trough values, zone-transition frequencies, and the proportion of “stable” patients defined as CV% below 20%. First-order Markov transition matrices were computed to characterize the directionality of trough movements between subtherapeutic, target, and supratherapeutic zones. The primary analysis was restricted to patients with at least three documented trough measurements. Results: The median CV% decreased from 43.5% (IQR 33.5–51.5) pre-SOP to 32.5% (IQR 21.9–38.6) post-SOP (Mann–Whitney U, p = 0.011). The swing index decreased from 1.09 to 0.75 (p = 0.002), and the median range of individual trough concentrations shrank from 19.1 mg/L to 13.2 mg/L (p = 0.029). The absolute number of zone transitions per patient did not differ significantly between cohorts, but their directionality differed substantially: target-zone persistence increased from 37.8% to 57.6%. Across all 403 measurements, subtherapeutic values declined from 38.5% to 26.6%, while target-zone measurements rose from 28.5% to 44.7%. In the post-SOP cohort, longer therapy duration was associated with lower CV% (Spearman ρ = −0.52, p = 0.032). Conclusions: In addition to improvements in population-level target attainment, implementation of the SOP was associated with stabilization of the individual exposure profile of orthopedic inpatients receiving intravenous vancomycin. Intra-individual variability was lower in the post-SOP cohort, and transitions between zones were more often oriented toward the target range. These findings, derived from a single-centre secondary analysis with a small post-SOP cohort, support patient-level variability metrics as a complementary quality indicator in protocolized vancomycin management and warrant prospective multicentre validation. Full article

Background: Gastroparesis is characterised by prolonged gastric emptying in the absence of mechanical gastric obstruction. When symptomatic, gastroparesis significantly impacts quality of life. While current consensus emphasises medical, surgical, or nutritional therapies, data evaluating the efficacy of alternative therapies remains scarce. Here, we review the efficacy of alternative therapies; acupuncture, electroacupuncture, moxibustion, and herbal medicine as management strategies. Methods: A systematic literature review of the literature was performed until February 2025. All papers were published from 2001 to 2024. This search focusses on the efficacy of acupuncture, electroacupuncture, moxibustion, and herbal medicines for management of gastroparesis. A comprehensive search was performed in PubMed, Embase, Medline, Google Scholar, Science Direct, and Web of Science. There were no language restrictions. Study outcomes were compared in a narrative synthesis and quality was assessed using Critical Appraisal Skills Programme (CASP) checklists. Results: We identified 68 studies of acupuncture, electroacupuncture, moxibustion, and herbal medicine as alternate therapies for gastroparesis. The total patient sample size of included studies was 4566, with a mean sample of 70.25 per study. The focus of studies comprising our review was electroacupuncture (11%), moxibustion (11%), acupuncture (29%), and herbal medicine (49%). Control comparisons were made with Mosapride, Metoclopramide, Domperidone, and Itopride. Conclusions: We found that alternative therapies are effective for the management of gastroparesis. However, the review was limited by heterogeneous study designs, incomplete methodological reporting, and publication bias. Future investigations must focus on long-term randomised control trials encompassing large sample sizes. Full article

Focused ultrasound (FUS)-mediated therapies have evolved with the advent of modern ultrasound-guided technology and MRI imaging, moving from their initial use as thermal ablation to a multifunctional platform for thermal and non-thermal ablation, immunomodulation, and targeted drug delivery. This narrative review explores the potential, limitations, and challenges of ablative high-intensity focused ultrasound (HIFU) therapies: HIFU thermal ablation and non-thermal ablation, histotripsy, as well as non-ablative low-intensity focused ultrasound (LIFU) applications in the management of hepatobiliary cancers. HIFU and histotripsy are reviewed as alternative or complementary treatment options in liver tumors, as well as their potential as bridging therapy. Histotripsy is addressed as a theranostic tool, not only by combining ablation with real-time ultrasound imaging guidance, but also by integrating it with sonobiopsy. It facilitates a liquid sonobiopsy of the ablated tumor by releasing intact tumor antigens and damage-associated molecular patterns, leading to potential molecular profiling. LIFU-induced targeted drug delivery (sono-chemotherapy), sonodynamic therapy, radiosensitization, immunomodulation of the immunosuppressive tumor microenvironment (sono-immunotherapy), and the potential to enhance the effect of immune checkpoint inhibitors in these malignancies are discussed. Since FUS-assisted procedures exhibit dual actions through therapeutic functionality associated with intra- and post-procedural ultrasound imaging guidance, they could have value as a theranostic tool in hepatobiliary interventional oncology. Although promising, the available clinical evidence for FUS-mediated therapies in hepatobiliary malignancies consists predominantly of early-stage feasibility studies, retrospective observational cohorts, and non-randomized comparative analyses. Further studies focused on standardized protocols, validation through large-scale, multicenter, prospective randomized clinical trials comparing FUS-based therapies with established treatments, and long-term follow-up of oncological efficacy could define their future role in multimodal oncological strategies. Full article