Search Results (16,760)

Objectives: Diabetic foot infections are a major cause of morbidity and amputation, and increasing antibiotic resistance complicates their management. This study aimed to evaluate longitudinal changes in antibiotic resistance among bacterial pathogens isolated from patients undergoing toe amputation due to diabetic foot infections. Methods: This retrospective, single-center study included patients who underwent toe amputation for diabetic foot infections between 2013 and 2024. Microbiological culture results and antimicrobial susceptibility data were analyzed across three consecutive time periods: 2013–2016, 2017–2020, and 2021–2024. Results: A total of 351 patients were included (mean age, 64.1 years; 64% male). A history of dialysis was present in 30% of patients, and 54% had a history of prior hospitalization. A total of 351 patients were included in the study. A total of 378 bacterial isolates recovered from positive microbiological cultures were included in the antimicrobial susceptibility analysis. The most frequently isolated microorganisms were Escherichia coli, Enterococcus spp., coagulase-negative Staphylococcus, and Staphylococcus aureus. Among Enterobacterales isolates, statistically significant increases in resistance across the three consecutive time periods were observed for amoxicillin–clavulanate (p = 0.009), piperacillin–tazobactam (p = 0.002), trimethoprim–sulfamethoxazole (p = 0.012), and meropenem (p = 0.027), whereas the increase in imipenem resistance did not reach statistical significance (p = 0.054). Within Staphylococcus spp., a statistically significant increase in resistance across the three consecutive time periods was observed only for ciprofloxacin (p = 0.047). Conclusions: Changes in antimicrobial resistance rates were observed among bacterial isolates recovered from diabetic foot infections across the three consecutive time periods, highlighting the importance of regional surveillance and up-to-date local resistance data for guiding empirical antibiotic therapy. Full article

The prognostic significance of next-generation sequencing (NGS) findings during the hormone-sensitive phase of prostate cancer remains incompletely characterized. This retrospective cohort study included 92 patients who underwent NGS analysis on tumor tissue between 2019 and 2025. The primary endpoint was time to castration-resistant prostate cancer (CRPC) from androgen deprivation therapy (ADT) initiation; secondary endpoints were overall survival from ADT initiation (OS-ADT) and from diagnosis. Kaplan-Meier and Cox regression analyses were performed. CRPC developed in 66 patients (71.7%) at a median of 21.1 months. The most frequently altered genes were ATR (35.9%), PTEN (28.3%), TP53 (26.1%), and BRCA2 (15.2%). KMT2C alteration (5.4%) was the strongest independent genomic predictor of shorter time to CRPC (HR = 6.804, p = 0.003) and OS-ADT (HR = 4.730, p = 0.019). TP53 alteration independently predicted shorter OS-ADT (HR = 1.810, p = 0.038). High genomic burden independently predicted shorter time to CRPC (HR = 1.917, p = 0.032). Homologous recombination repair deficiency was not associated with outcomes, attributable to high ATR alteration frequency introducing pathway heterogeneity. Mismatch repair deficiency showed a borderline association with shorter OS-ADT (20.7 vs. 44.0 months; p = 0.060). An exploratory composite risk score stratified patients into three prognostic groups with markedly different outcomes (HR = 7.904, p = 0.001). NGS analysis during the hormone-sensitive phase identifies independent predictors of castration resistance, supporting its integration at ADT initiation for risk stratification and biomarker-guided treatment planning. Full article

Breast cancer is a highly heterogeneous malignancy with multiple molecular subtypes and variable treatment responses. Despite advances in endocrine therapy, HER2-targeted therapy, chemotherapy, and immunotherapy, treatment resistance and disease recurrence remain major clinical challenges. There is growing evidence that transcriptional plasticity and enhancer relinking contribute to tumor progression and treatment adaptation, highlighting the powerful role of epigenetic regulators. CREB-binding protein (CBP) and E1A-associated protein p300 (EP300) are transcriptional coactivators that regulate breast cancer enhancer activity and lineage-specific gene expression. Emerging research suggests that CBP/p300 is more of a context-dependent vulnerability point than a universal carcinogenic driver. ER-positive tumors exhibit a strong dependence on CBP/p300-mediated transcriptional programs, while the triple-negative breast cancer subgroup, including androgen receptor-positive and immunosuppressive tumors, may rely on CBP/p300-dependent signaling to maintain survival and treatment resistance. This is in contrast to their role in HER2-positive breast cancer. This review summarizes the biological functions of CBP/p300 in breast cancer and discusses subtype-specific vulnerability, biomarker-directed patient stratification, drug resistance mechanisms, rational combination strategies, and current translational challenges, emphasizing the need for precise treatment of breast cancer. Full article

Immune checkpoint inhibitors (ICIs) have improved clinical outcomes in recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), including oral squamous cell carcinoma (OSCC). However, many patients eventually develop resistance to systemic therapy, highlighting the need for novel strategies that can restore or sustain antitumor immunity. Near-infrared photoimmunotherapy (PIT) has emerged as a tumor-selective locoregional treatment that not only induces targeted tumor cell death but also promotes antitumor immune activation through immunogenic cell death. This narrative review summarizes current evidence regarding PIT for recurrent oral cancer and explores the immunological rationale for sequential ICI–PIT–ICI therapy (ICI–PIT–ICI sequence). Within this framework, PIT-induced tumor antigen release and inflammatory activation may reinitiate elements of the cancer-immunity cycle, whereas continued PD-1 blockade may help sustain newly activated tumor-reactive T-cell responses. To illustrate this concept, we present two cases of recurrent oral cancer treated with the ICI–PIT–ICI sequence. Both patients achieved durable clinical and radiological complete responses following PIT and subsequent nivolumab continuation. Longitudinal analyses of peripheral immune surrogate markers demonstrated a biphasic temporal pattern characterized by transient increases in inflammatory markers, including neutrophil-to-lymphocyte ratio, C-reactive protein, platelet-to-lymphocyte ratio, and systemic immune-inflammation index, followed by recovery trends in absolute lymphocyte count and lymphocyte-to-monocyte ratio during continued PD-1 blockade. These observations support the biological plausibility of PIT as an immune-modulating intervention with potential immune-reprogramming effects. Although hypothesis-generating, the ICI–PIT–ICI sequence may represent a promising strategy integrating locoregional tumor destruction with systemic immune modulation in recurrent oral cancer. Further prospective studies incorporating peripheral and tissue-based immune profiling are warranted. Full article

The spread of multidrug-resistant (MDR) bacteria has renewed interest in combining the targeted killing of bacteriophages with immunomodulatory antimicrobial peptides (AMPs). AMPs offer broad antimicrobial, antibiofilm, and immunomodulatory effects, although their efficacy is limited by stability, delivery, and toxicity. Phage-based systems may help address some of these limitations by localizing antimicrobial activity and improving bacterial targeting. In this perspective, we treat engineered phages as programmable “Trojan horses” that deliver AMPs into their bacterial targets, framing this concept alongside the rapid growth of AI-guided AMP design as well as phage–host matching. The evidence thus far is largely preclinical. AMP-armed phages have shown activity in vitro and in animal models, while engineered phages have only recently entered early-phase clinical trials. Reasons why phage-delivered AMPs remain largely in the preclinical and early translational stages are delineated. We argue that the primary hurdle lies in the gap between the separate advancement of AMP design on one end and phage–host matching on the other. The alignment of these interests, along with manufacturing and regulatory efforts, will likely be what allows this therapy to reach the bedside. Full article

Nanotechnology is rapidly advancing as a promising approach in ovarian cancer management, addressing key challenges such as late diagnosis, drug resistance, and systemic toxicity of conventional therapies. Nanoparticles—engineered at the 1–100 nm scale—possess unique physical and biological properties that make them well-suited for targeted drug delivery, imaging, and biomarker detection. In diagnostics, platforms such as gold nanoparticles, quantum dots, superparamagnetic iron oxide nanoparticles (SPIONs), and carbon-based nanomaterials have demonstrated the ability to improve sensitivity and specificity, enabling the detection of low-abundance biomarkers and enhancing imaging contrast. These advances could significantly improve the early-stage detection, where survival outcomes are most favorable. Therapeutically, nanoparticles offer controlled and sustained drug release, targeted delivery to specific tumor sites, and the ability to co-deliver multiple agents, including siRNA and mRNA, in order to overcome resistance pathways. Clinically, liposomal formulations such as Doxil, already demonstrate reduced toxicity and improved drug bioavailability, while polymeric, silica, gold, and magnetic nanoparticles continue to show encouraging results in preclinical and early clinical studies. Although challenges remain—including large-scale production, long-term safety evaluation, and regulatory complexity—the current body of evidence highlights nanotechnology’s transformative potential in ovarian cancer care. By enabling earlier detection, more precise targeting, and reduced systemic toxicity, nanomedicine represents a critical step toward improving both survival and quality of life in affected patients. Full article

Hepatocellular carcinoma (HCC), a leading cause of cancer-related mortality worldwide, is driven by complex interactions between genetic mutations and reversible epigenetic alterations. Among these, aberrant DNA methylation, histone modifications, and dysregulated noncoding RNAs (ncRNAs) play central roles in hepatocarcinogenesis, tumor progression, and therapy resistance. Epigenetic changes not only regulate key oncogenic pathways, including JAK/STAT and RAS, but also contribute to tumor immune evasion and heterogeneity. Unlike genetic mutations, epigenetic alterations are reversible, offering unique opportunities for therapeutic targeting. This review highlights recent advances in understanding the epigenetic landscape of HCC, identifies promising biomarkers for early detection and prognosis, and evaluates emerging epigenetic therapies (including DNMT, HDAC, and BET inhibitors as well as ncRNA-based strategies). Although these therapies have shown tumor-suppressive or treatment-sensitizing effects in preclinical models, their clinical translation remains limited by modest efficacy, small early-phase trials, treatment-related adverse events, and insufficient biomarker-guided patient selection. These insights may support more precise diagnostic and therapeutic strategies for HCC. Full article

Huanglongbing (HLB), caused by Candidatus Liberibacter asiaticus (CLas) and vectored by Asian citrus psyllid (Diaphorina citri), remains a major constraint to sustainable citrus production. In Florida, individual protective covers (IPCs) have been adopted as an effective psyllid exclusion tool by shielding young trees from this vector of the phloem-dwelling bacterium CLas. Brassinosteroids (BRs), a class of plant steroid hormones, are being explored as a treatment to mitigate HLB and are approved for commercial use in the state. We investigated the effect of IPCs combined with homobrassinolide (HBr) applied as a foliar spray on CLas titer, canopy volume, tree growth, yield, fruit quality, and defense-related gene expression of the salicylic acid (SA) pathways in ‘Tango’ mandarin grafted on sour orange (SO) or US-942 rootstocks. After being covered with IPCs in the field for three years, trees were subjected to monthly foliar application of HBr upon IPC removal. The experiment included four treatment groups: trees with IPC and HBr spray (IPC HBr+), IPC without HBr (IPC HBr-), no-IPC with HBr (no-IPC HBr+), and no-IPC without HBr (no-IPC HBr-). IPCs effectively delayed bacterial infection for six to nine months after IPC removal, maintaining higher cycle threshold (Ct) values (lower CLas titers) than in no-IPC trees, confirming the protective effect of IPCs against early CLas colonization. The combination of IPCs and HBr spray significantly enhanced canopy volume, particularly in trees grafted on SO. This effect was sustained over one year and was consistently greater in IPC HBr+ trees than in IPC HBr- and no-IPC HBr+ or HBr- trees, suggesting a synergistic effect of the combined therapy on enhancing tree growth. The tree height and trunk diameter were primarily improved by IPC, regardless of HBr treatment. IPC-treated trees exhibited significantly greater height and trunk diameters (scion and rootstock) than no-IPC trees across one or both rootstocks, indicating that IPCs alone contribute to these horticultural growth improvements. IPC trees also showed reduced preharvest fruit drop compared to the no-IPCs trees, resulting in higher yields, with additional gains observed in IPC HBr+ trees on SO. Fruit quality attributes, including °Brix, titratable acidity, peel color, and size, did not differ significantly among treatments. Importantly, gene expression analysis revealed early and sustained upregulation of key SA pathway genes in IPC HBr+ trees, indicating that HBr effectively activated systemic acquired resistance (SAR), particularly on SO rootstock. This study highlights the complementary roles of IPCs and HBr in the management of HLB. While IPCs provided essential early protection against CLas and promoted long-term horticultural growth, HBr enhanced early canopy development, activated host defense mechanisms, and enhanced yield. The integration of both approaches offers a sustainable and effective strategy to protect young citrus trees, delay CLas infection, and improve tree health and productivity under endemic HLB. Full article

Head and neck squamous cell carcinoma (HNSCC) is characterized by marked intratumoral heterogeneity and complex tumor–immune–stromal interactions, which shape therapeutic response and clinical outcome. Despite extensive transcriptomic efforts, bulk RNA sequencing has faced significant limitations, often failing to generate robust prognostic or predictive biomarkers, highlighting the need for approaches capable of resolving the cellular and spatial complexity of the tumor ecosystem. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) have refined our understanding of HNSCC biology by enabling high-resolution mapping of malignant, stem-like, immune, and stromal compartments. Three major spatial domains have been defined in HNSCC: tumor core (TC), tumor invasion front (TIF), and leading edge (LE). Each ecosystem exhibits distinct cellular programs that promote immune evasion, tumor dissemination, and therapy resistance, particularly in high-risk clinical settings. In this Review, we integrate recent single-cell and spatial studies and propose a translational framework linking ecosystem architecture with clinical stratification across resectable locally advanced (r-LAD), unresectable locally advanced (u-LAD), and recurrent/metastatic (R/M) disease. We further discuss how spatially resolved transcriptomic approaches may support biomarker discovery and hypothesis generation for risk stratification and trial design, while emphasizing that clinical implementation remains limited by cohort size, methodological heterogeneity, and the need for large-scale prospective validation. Finally, we outline key methodological and translational challenges that must be addressed before these technologies can reliably inform precision oncology and decision-making in HNSCC. Full article

Cardiometabolic residual risk in type 2 diabetes mellitus (T2D) persists despite major advances in glucose-lowering therapy, lipid management, blood pressure control, weight reduction, and organ-protective strategies. This residual burden should not be interpreted solely as the consequence of incomplete achievement of conventional therapeutic targets, but rather as the clinical expression of persistent molecular activity involving multiple interconnected organs and pathways. Insulin resistance, metaflammation, oxidative stress, mitochondrial dysfunction, lipotoxicity, endothelial impairment, hepatic metabolic dysregulation, renal inflammation, fibrotic remodeling, and metabolic memory interact within a dynamic network linking adipose tissue, liver, kidney, immune cells, and vasculature. In this review, we discuss the biochemical and molecular drivers of cardiometabolic residual risk in T2D, with particular emphasis on impaired insulin receptor substrate/PI3K/Akt signaling, stress-kinase activation, NLRP3 inflammasome priming and assembly, MASLD-related lipotoxicity and fibrogenesis, podocyte and tubular injury, endothelial nitric oxide synthase uncoupling, AGE-RAGE signaling, and thrombo-inflammatory vascular injury. These pathways explain why biological vulnerability may persist even when conventional clinical parameters appear adequately controlled. We also examine the role of translational biomarkers and simple clinical indices, including TyG-derived indices, adiposity markers, hepatic steatosis and fibrosis scores, albuminuria, eGFR, and lipid-related markers, as accessible windows into active biological pathways. Finally, we review how contemporary therapeutic strategies may modulate selected components of this residual-risk network. A pathway-centered interpretation of T2D may support more precise residual-risk phenotyping and help move cardiometabolic care beyond isolated target control toward mechanism-based prevention. This review further links these mechanisms to the contemporary cardiovascular–kidney–metabolic (CKM) framework, as defined by the 2026 AHA/ACC/ADA/ASN CKM Guideline, and disaggregates the underlying molecular network into organ-specific pathway cascades that make the causal relationships between metabolic, inflammatory, hepatic, renal, and vascular injury more explicit. Full article

Background/Objectives: Antimicrobial resistance (AMR) is a major global health threat that has outpaced the development of new antibiotics. Drug repurposing has emerged as a promising strategy for identifying alternative antimicrobial therapies. Antidepressants have attracted interest because experimental studies suggest they possess off-target antimicrobial activity, although growing evidence indicates they may also promote antimicrobial resistance. This review critically examines both the therapeutic potential and risks of antidepressant–microbial interactions. Methods: A structured narrative review was conducted using literature identified from major biomedical databases. Experimental, animal, microbiome, environmental, and clinical studies were synthesized according to antidepressant class, antimicrobial mechanisms, interactions with conventional antibiotics, microbiome modulation, and antimicrobial resistance. Results: Experimental evidence demonstrates that several antidepressants inhibit bacterial and fungal pathogens through mechanisms including membrane disruption, oxidative stress induction, efflux pump inhibition, and biofilm interference. Some agents also enhance the activity of conventional antibiotics. However, current evidence is largely preclinical. Multiple studies indicate that antidepressants may also promote antimicrobial resistance through reactive oxygen species-mediated mutagenesis, efflux pump activation, horizontal gene transfer, microbiome dysbiosis, and environmental exposure. Conclusions: Antidepressants represent both a promising drug-repurposing opportunity and a potential contributor to antimicrobial resistance. Although their antimicrobial properties are encouraging, current evidence remains predominantly preclinical, and clinically effective and safe antimicrobial dosing has not been established. At present, their antimicrobial use should be regarded as proof-of-concept rather than a clinically validated therapeutic strategy. Further pharmacokinetic, pharmacodynamic, animal, and clinical studies are required before routine antimicrobial application can be considered. Full article

Background: High-risk (HR) prostate cancer has a propensity for local and distant progression with ultimate death, mandating aggressive locoregional and systemic treatment approaches to maximize oncologic outcomes. Although brachytherapy (BT) with supplemental therapies has demonstrated favorable biochemical and quality of life outcomes, improvements in overall survival have been hampered by an excessive incidence of non- prostate cancer deaths. In this HR study, we report on biochemical failure (BF), prostate cancer-specific mortality (PCSM), overall mortality (OM) and patterns of death with recommendations for the mitigation of non-prostate cancer deaths. Materials and Methods: From April 1995 to November 2018, 577 consecutive HR patients were treated with LDR BT (97.9% Pd-103). Patients were stratified into three age cohorts: ≤ 59, 60–69 and ≥70 years. The BT prescription dose was prescribed to the prostate gland with generous peri-prostatic margins and the proximal 10mm of the seminal vesicles. 94.6% received supplemental EBRT (45–50.4 Gy) and 63.3% received androgen deprivation therapy (ADT) (median duration 12 months). Post-implant CT-based dosimetry was performed on day 0. BF was defined as a PSA > 0.40 ng/mL after nadir. The cause of death was determined for each patient. Patients with metastatic prostate cancer or non-metastatic castrate resistant prostate cancer who died of any cause were classified as dead of prostate cancer. All other deaths were attributed to the immediate cause. Multiple clinical, pathologic and treatment were evaluated for impact on patient outcomes. Results: Of the patients, 87.5% (median follow-up 8.9 years) presented with a single HR factor. The day 0 D90 was 122.5%. Overall, the 15-year BF, PCSM and OM were 12.4%, 5.6% and 51.7%. When stratified by age, there was no significant difference in BF or PCSM. The median post- treatment PSA in biochemically controlled patients was <0.01 ng/mL. In all three cohorts, OM increased linearly for the first 10 years and then approximately doubled from years 10 to 15. Moreover, 239 patients died: 10.9% due to prostate cancer, 38.1% from cardiovascular (CV) disease and 28.4% from other malignancies (to include one rectal and three bladder cancers). In MVA, BF was most closely related to percent positive biopsies (p < 0.001, SHR 1.018), PCSM to Gleason score (p = 0.004, SHR 2.884) and percent positive biopsies (p = 0.005, SHR 1.021) and OM to age (p < 0.001, HR 1.075) and tobacco (p < 0.001, HR 2.374). Conclusions: Despite high cancer control rates, overall survival was limited by a preponderance of CV and non-prostate cancer deaths, which were 6 times more likely than prostate cancer deaths. The implementation of a comprehensive multidisciplinary survivorship program will be essential to impact longevity in this patient population. Full article

Severe treatment-resistant asthma (STRA) in children is often sustained by type 2 inflammation and eosinophil-dependent airway disease that persists despite optimized inhaled therapy and the mitigation of modifiable factors. This review summarizes the clinical and translational evidence on monoclonal antibodies targeting the interleukin-5 (IL-5) axis (anti-IL-5 and anti-IL-5Rα) available in pediatric severe asthma. PubMed/MEDLINE was searched up to January 2026 for English-language studies in patients aged 0–18 years addressing mepolizumab and benralizumab, including randomized trials, high-quality observational studies, meta-analyses, and international guidance. Mepolizumab has the most robust pediatric data, showing consistent reductions in exacerbations and blood eosinophils, and improvements in symptom control and quality of life, with safety broadly comparable to adults. The pediatric evidence for benralizumab is more limited but shows rapid eosinophil depletion, improved outcomes in selected children, and acceptable safety; further trials are ongoing. Overall, IL-5–directed biologics represent a key add-on option for carefully selected children with severe eosinophilic asthma, while pediatric-specific predictors of response, comparative effectiveness, and standardized long-term monitoring and stopping criteria remain priorities. Full article

Background/Objectives: Antimicrobial resistance (AMR) is a major global public health threat, compromising prevention and treatment of infectious diseases. This narrative review examines AMR as a multifactorial and transnational crisis through epidemiological, One Health, social and bioethical perspectives, and discusses emerging non-antibiotic preventive and therapeutic strategies. Methods: PubMed and Scopus were searched using terms related to AMR, epidemiology, public health, surveillance, One Health, bioethics, equity and alternative therapies. Peer-reviewed medical and public health articles were considered, together with selected reports from international organizations and public health agencies. Results: AMR is driven by inappropriate antibiotic use in human medicine, livestock, aquaculture and agriculture, combined with weaknesses in infection prevention, stewardship, environmental control and surveillance. Epidemiological evidence shows a substantial global burden, marked regional inequalities in resistance patterns, surveillance capacity and policy response, and major consequences, including increased mortality, prolonged hospitalization, rising healthcare costs and disproportionate effects on vulnerable populations. Key bioethical concerns include collective responsibility, equitable access to effective treatment, stewardship, global justice and intergenerational accountability. Emerging non-antibiotic strategies vary in translational maturity: vaccines and selected microbiome-based interventions have preventive or supportive roles in defined settings, bacteriophage therapy is used mainly in compassionate or specialized contexts, and many antimicrobial peptides and nanotechnology-based platforms remain experimental or early translational. Conclusions: AMR requires coordinated global action grounded in One Health, strong public health systems, integrated surveillance, responsible antimicrobial use and sustained innovation. Effective containment must also address social inequalities, ethical stewardship, equitable access to diagnostics and treatment, and responsibility toward future generations. Full article

Upper-limb impairments affect a substantial portion of the global population, often limiting the ability to perform daily activities. Robotic rehabilitation systems offer a promising solution by enabling high-dose, task-oriented therapy with consistent and objective feedback. However, user acceptance and perceived comfort are critical for their successful adoption. This work presents a feasibility, performance, and comfort evaluation of a 2-degree-of-freedom upper-limb rehabilitation exoskeleton capable of performing elbow flexion/extension and forearm pronation/supination. A total of 47 healthy participants were enrolled and tested across three rehabilitation modalities: passive assist, active assist, and active resist. Passive assist enabled full range-of-motion execution, active assist supported movement, and active resist provided variable resistance via a sliding bar (0–100%). Objective performance metrics, including position, current, and temperature, were recorded and analyzed, revealing trajectory-tracking errors during passive assistance of 4.82° ± 0.02° for forearm movement and 1.20° ± 0.04° for elbow movement, with actuator temperatures remaining below their rated limits throughout the study. The active assist mode did not achieve a true assist-as-needed performance, indicating a need for further refinement. Subjective evaluation included the System Usability Scale, yielding a score of 87.1 ± 9.6, indicating excellent usability, and a safety and comfort assessment averaging 4.4 ± 0.4 out of 5. Perceived effort was assessed using the Borg CR-10 scale and generally scaled appropriately across modalities, although some variability suggests the need for further investigation. Qualitative feedback identified areas for improvement, particularly in ergonomics and control behavior. Overall, the results support the feasibility, usability, and safe operation of the proposed exoskeleton and provide insights for future device refinement and evaluation with target user populations. Full article