Search Results (9,166)

Background: Breast cancer-related lymphedema (BCRL) is a common and debilitating treatment-related adverse event that can profoundly impact quality of life and financial well-being. Although prospective surveillance and early intervention for BCRL have been shown to reduce the incidence and severity of this chronic condition, diagnostic accuracy of screening, programmatic utilization and efficacy vary widely. We describe the protocol for the BCRL Prospective Surveillance Model (PSM) and Early Intervention Program at the Dana-Farber Brigham Cancer Center that aims to address these issues by augmenting arm measurements (standard of care) with use of patient-reported outcome metrics (PROMs). Methods: Women with newly diagnosed stage I-III breast cancer at high risk for developing BCRL based on tumor and treatment characteristics are eligible for inclusion in our PSM care pathway, which uses both the Breast Cancer and Lymphedema Symptom Experience Index PROMs and arm measurements for screening. Screening begins prior to the initiation of neoadjuvant therapy and continues at regular intervals postoperatively. A positive screen, defined as new patient-reported arm swelling/heaviness and/or relative volume change (RVC) ≥ 5% in the affected limb, triggers consideration for multidisciplinary early intervention. Analysis: The BCRL detection rate will be compared to years previous to protocol development. PSM feasibility will be determined according to the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework. Efficacy of the PSM will be gauged by comparing change in patient-reported outcomes of interest and arm volume measurement pre and post early intervention. Feasibility will be determined by calculating the percentage of PSM-eligible individuals who complete all PSM activities in a 1-year span. Characteristics of participants versus non-participants in the target population will be compared. Furthermore, 1:1 semi-structured interviews with enrolled patients will be performed to understand facilitators and barriers to implementation. Conclusions: The findings from this study will be used to develop a standardized approach to PSM and early intervention that can be adapted to both resource-modest and resource-abundant healthcare infrastructures. Full article

Fusobacterium nucleatum (Fn) has been increasingly recognized as a crucial mediator of colorectal cancer (CRC) biology, particularly in microsatellite-stable (MSS) tumors, where immune checkpoint inhibitors (ICIs) have shown limited efficacy. Rather than representing a passive microbial passenger, Fn actively shapes tumor behavior by adhering to epithelial cells, activating oncogenic signaling, and promoting epithelial–mesenchymal transition (EMT). At the same time, it remodels the tumor microenvironment, driving immune suppression through inhibitory receptor engagement, accumulation of myeloid-derived cells, and metabolic reprogramming of tumor-associated macrophages. These mechanisms converge to impair cytotoxic immunity and contribute to both intrinsic and acquired resistance to ICIs. Beyond immune escape, Fn interferes with conventional chemotherapy by sustaining autophagy and blocking ferroptosis, thereby linking microbial colonization to multidrug resistance. Most of these mechanisms derive from preclinical in vitro and in vivo models, where causal relationships can be inferred. In contrast, human data are mainly observational and provide correlative evidence without proving causality. No interventional clinical studies directly targeting Fn have yet been conducted. Its enrichment across the adenoma–carcinoma sequence and consistent detection in both tumor and fecal samples highlight its potential as a biomarker for early detection and patient stratification. Importantly, multidimensional stool assays that integrate microbial, genetic, and epigenetic markers are emerging as promising non-invasive tools for CRC screening. Therapeutic strategies targeting Fn are also under exploration, ranging from antibiotics and bacteriophages to multifunctional nanodrugs, dietary modulation, and natural microbiota-derived products. These approaches may not only reduce microbial burden but also restore immune competence and enhance the efficacy of immunotherapy in MSS CRC. Altogether, current evidence positions Fn at the intersection of microbial dysbiosis, tumor progression, and therapy resistance. A deeper understanding of its pathogenic role may support the integration of microbial profiling into precision oncology frameworks, paving the way for innovative diagnostic and therapeutic strategies in CRC. Full article

Background/Objectives: Early detection of undiagnosed prediabetes (PD) and type 2 diabetes (T2D) could prevent or delay the onset of diabetes and its complications. The dental setting has been suggested as a location for expanding diabetes screening in primary care. This study aimed to investigate behavioural factors that influence an oral healthcare professional’s (OHP) participation in diabetes screening and their decision to refer individuals at a high risk of diabetes for medical follow-up and confirmatory diagnosis. These factors provide targets for future interventions to encourage screening implementation and increase referral guideline compliance. Methods: This qualitative study utilised OHPs who had participated in a diabetes screening trial in Victoria, Australia. Qualitative, semi-structured interviews were conducted by telephone or videoconferencing and transcribed and analysed thematically. The themes identified were deductively mapped onto the Capability, Opportunity, Motivation, and Behaviour (COM-B) model and the Theoretical Domains Framework (TDF). Results: In total, eight interviews were conducted (seven dentists and one oral health therapist). Five COM-B domains were identified: reflective motivation, automatic motivation, social opportunity, physical opportunity, and psychological capability. Nine TDF domains were associated with issues related to knowledge, the environmental context and resources, memory, attention and decision processes, skills, social influences, beliefs about consequences, emotion, beliefs about capability, and social influence. Conclusions: This is the first study to investigate the factors influencing an OHP’s participation and decision making in diabetes screening and referral processes in the dental setting. The results demonstrate that OHPs need more education and training to screen for diabetes in dental clinics. This study represents the first step in developing interventions to target these factors and improve the effectiveness of diabetes screening in the dental setting. Full article

The accurate prediction of herb–target interactions is essential for the modernization of traditional Chinese medicine (TCM) and the advancement of drug discovery. Nonetheless, the inherent complexity of herbal compositions and diversity of molecular targets render experimental validation both time-consuming and labor-intensive. We propose a graph neural network model, MAMGN-HTI, which integrates metapaths with attention mechanisms. A heterogeneous graph consisting of herbs, efficacies, ingredients, and targets is constructed, where semantic metapaths capture latent relationships among nodes. An attention mechanism is employed to dynamically assign weights, thereby emphasizing the most informative metapaths. In addition, ResGCN and DenseGCN architectures are combined with cross-layer skip connections to improve feature propagation and enable effective feature reuse. Experiments show that MAMGN-HTI outperforms several state-of-the-art methods across multiple metrics, exhibiting superior accuracy, robustness, and generalizability in HTI prediction and candidate drug screening. Validation against literature and databases further confirms the model’s predictive reliability. The model also successfully identified herbs with potential therapeutic effects for hyperthyroidism, including Vinegar-processed Bupleuri Radix (Cu Chaihu), Prunellae Spica (Xiakucao), and Processed Cyperi Rhizoma (Zhi Xiangfu). MAMGN-HTI provides a reliable computational framework and theoretical foundation for applying TCM in hyperthyroidism treatment, providing mechanistic insights while improving research efficiency and resource utilization. Full article

Background: Atherogenic dyslipidemia is defined by the coexistence of high triglyceride concentrations, low levels of high-density lipoprotein cholesterol (HDL-C), and an excess of small, dense particles of low-density lipoprotein cholesterol (LDL-C). This lipid profile is strongly associated with an increased burden of cardiovascular disease and represents a leading cause of global morbidity and mortality. To better capture this risk, composite lipid ratios—including total cholesterol to HDL-C (TC/HDL-C), LDL-C to HDL-C (LDL-C/HDL-C), triglycerides to HDL-C (TG/HDL-C), and the atherogenic dyslipidemia index (AD)—have emerged as robust markers of cardiometabolic health, frequently demonstrating superior predictive capacity compared with isolated lipid measures. Despite extensive evidence linking these ratios to cardiovascular disease, few large-scale studies have examined their association with sociodemographic characteristics, lifestyle behaviors, and social isolation in working populations. Methods: We conducted a cross-sectional analysis of a large occupational cohort of Spanish workers evaluated between January 2021 and December 2024. Anthropometric, biochemical, and sociodemographic data were collected through standardized clinical protocols. Indices of atherogenic risk—namely the ratios TC/HDL-C, LDL-C/HDL-C, TG/HDL-C, and the atherogenic dyslipidemia index (AD)—were derived from fasting lipid measurements. The assessment of lifestyle factors included tobacco use, physical activity evaluated through the International Physical Activity Questionnaire (IPAQ), adherence to the Mediterranean dietary pattern using the MEDAS questionnaire, and perceived social isolation measured by the Lubben Social Network Scale. Socioeconomic classification was established following the criteria proposed by the Spanish Society of Epidemiology. Logistic regression models were fitted to identify factors independently associated with moderate-to-high risk for each lipid indicator, adjusting for potential confounders. Results: A total of 117,298 workers (71,384 men and 45,914 women) were included. Men showed significantly higher odds of elevated TG/HDL-C (OR 4.22, 95% CI 3.70–4.75) and AD (OR 2.95, 95% CI 2.70–3.21) compared with women, whereas LDL-C/HDL-C ratios were lower (OR 0.86, 95% CI 0.83–0.89). Advancing age was positively associated with all lipid ratios, with the highest risk observed in participants aged 60–69 years. Lower social class, smoking, physical inactivity, poor adherence to the Mediterranean diet, and low social isolation scores were consistently linked to higher atherogenic risk. Physical inactivity showed the strongest associations across all indicators, with ORs ranging from 3.54 for TC/HDL-C to 7.12 for AD. Conclusions: Atherogenic dyslipidemia and elevated lipid ratios are strongly associated with male sex, older age, lower socioeconomic status, unhealthy lifestyle behaviors, and reduced social integration among Spanish workers. These findings highlight the importance of workplace-based cardiovascular risk screening and targeted prevention strategies, particularly in high-risk subgroups. Interventions to promote physical activity, healthy dietary patterns, and social connectedness may contribute to lowering atherogenic risk in occupational settings. Full article

Background: Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), remain major causes of morbidity and mortality, yet no targeted pharmacological therapy is available. Excessive neutrophil and macrophage infiltration drives reactive oxygen species (ROS) production and cytokine release, leading to alveolar–capillary barrier disruption and fatal respiratory failure. Methods: We applied an integrative multi-omics strategy combining single-cell transcriptomics, peripheral blood proteomics, and lung tissue proteomics in a lipopolysaccharide (LPS, 10 mg/kg)-induced mouse ALI model to identify key signaling pathways. Harpagide, an iridoid glycoside identified from our natural compound screen, was evaluated in vivo (40 and 80 mg/kg) and in vitro (0.1–1 mg/mL). Histopathology, oxidative stress markers (SOD, GSH, and MDA), cytokine levels (IL-6 and IL-1β), and signaling proteins (HIF-1α, p-PI3K, p-AKT, Nrf2, and HO-1) were quantitatively assessed. Direct target engagement was probed using surface plasmon resonance (SPR), the cellular thermal shift assay (CETSA), and 100 ns molecular dynamics (MD) simulations. Results: Multi-omics profiling revealed robust activation of HIF-1, PI3K/AKT, and glutathione-metabolism pathways following the LPS challenge, with HIF-1α, VEGFA, and AKT as core regulators. Harpagide treatment significantly reduced lung injury scores by ~45% (p < 0.01), collagen deposition by ~50%, and ROS accumulation by >60% relative to LPS (n = 6). The pro-inflammatory cytokines IL-6 and IL-1β were reduced by 55–70% at the protein level (p < 0.01). Harpagide dose-dependently suppressed HIF-1α and p-AKT expression while enhancing Nrf2 and HO-1 levels (p < 0.05). SPR confirmed direct binding of Harpagide to HIF-1α (KD = 8.73 µM), and the CETSA demonstrated enhanced thermal stability of HIF-1α. MD simulations revealed a stable binding conformation within the inhibitory/C-TAD region after 50 ns. Conclusions: This study reveals convergent immune–microenvironmental regulatory mechanisms across cellular and tissue levels in ALI and demonstrates the protective effects of Harpagide through multi-pathway modulation. These findings offer new insights into the pathogenesis of ALI and support the development of “one-drug, multilayer co-regulation” strategies for systemic inflammatory diseases. Full article

Staurosporine (STS) was discovered in 1977 by Omura and colleagues during a chemical screening for microbial alkaloids. It was the first indolocarbazole compound isolated from a soil-dwelling bacterium, Streptomyces staurosporeus. STS was also found to have antifungal activity, but its potent protein kinase (PK) inhibitory properties, perhaps the most extensively characterized biochemical feature of STS, were only revealed nearly a decade after its discovery. Thereafter, STS has been studied mainly for its anticancer potential with foreseen applications ranging from biomedical (e.g., antiparasitic) to agricultural (e.g., insecticidal). Interestingly, the recent discovery that STS induces apoptosis in the filamentous fungus Neurospora crassa renewed interest in this molecule as a scaffold for antifungal drug development. Studies in fungi and mammalian cell lines suggest that, in addition to PK inhibition, other modes of action are possible for STS. These may involve the targeting of membrane lipid domains and/or alterations of membrane biophysical properties. Here, the studies on the action of STS and its natural and synthetic derivatives against diverse fungal species, since its discovery to the present day, are critically reviewed and discussed with the aim of highlighting their advantages, limitations to be overcome, conceivable mechanisms of action, and potential as antifungal chemotherapeutic agents. Full article

Increasing attention has been given to the environmental impact of tire-derived chemicals in aquatic systems, but submerged whole tires remain an overlooked source. This study investigates a previously unexplored underwater tire dump in Hjelmås Bay, Alver Municipality (Norway) where a blast mat manufacturer discarded large quantities of tires into the bay in the 1970s. These tires have remained submerged for over 50 years. We conducted an initial site mapping and collected sediment and water samples to assess tire-related pollutants in comparison with control sites. Sediment analysis revealed elevated levels of Zn, Pb, and Cu, particularly near the tire dump center, with Zn being the most abundant. Bis(2-ethylhexyl) phthalate (DEHP) was the dominant phthalate detected in the sediments, though no clear spatial pattern emerged for phthalates. Non-target chemical screening of water samples identified 20 features potentially linked to tire degradation, with N,N′-Diphenylguanidine (DPG) being the most notable. Our study highlights the long-term environmental persistence of several tire-derived chemicals, which has ramifications for both the regulation of tire-derived chemicals and plans for remediation at Hjelmås. Our initial findings warrant the implementation of a comprehensive chemical and ecological baseline monitoring assessment prior to discussions on remediation. Full article

Background/Objectives: Paramedics frequently encounter potentially traumatic events and workplace violence, increasing their risk of burnout. Resilience may attenuate these effects. We examined the pathways through which post-traumatic stress (PTS) and workplace violence influence burnout and clarified the role of resilience among Korean paramedics. Methods: We studied duty-related trauma and violence experienced by 208 Busan Fire Department paramedics using standardized measures of PTS, workplace violence, resilience, and burnout. Using structural equation modeling, we tested the direct and indirect effects; covariates included sex, nursing license, and intention to stay. Results: PTS was most strongly associated with burnout, whereas workplace violence was indirectly associated with burnout through PTS. Resilience reduced PTS, yielding an indirect protective effect on burnout; however, it had no direct effect on burnout. Holding a nursing license and lack of intention to stay were significantly associated with burnout, and female sex and lack of intention to stay were indirectly associated with burnout via PTS. Conclusions: Burnout is primarily driven by PTS, and workplace violence amplifies PTS and indirectly exacerbates burnout. Strengthening violence prevention/response systems, early PTS screening/treatment, and resilience-building programs is warranted, with targeted support for vulnerable subgroups. Full article

DNA direct reactive impurities (DDRIs) can react with nucleophilic sites of DNA, leading to mutations. The control strategies outlined in International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) M7 are based on the known compound structure of DDRIs. Non-target screening of DDRIs in drugs is still challenging due to the diversity of the species and the poor stability. In this study, a derivatization reagent including a reactive group and report group was designed to screen DDRIs. Based on the electrophilic theory of chemical carcinogenesis, an amine reagent was used as a reactive group to interact with DDRIs. Two derivatization reagents, p-methoxyaniline and p-methoxybenzoyl-β-alaninamide, were employed, each containing different chromatographic modification groups to mitigate matrix effects. The derivatization products were analyzed by ultra-high-performance liquid chromatography coupled to high-resolution mass spectrometry (UPLC-HRMS). Non-target screening for DDRIs was achieved by product ions filtering of the report group. Full article

CRISPR (clustered regularly interspaced short palindromic repeats)-Cas (CRISPR-associated protein) nucleases enable precise genome editing, but off-target cleavage remains a critical challenge. Here, we report the development of MAD7_HF, a high-fidelity variant of the MAD7 nuclease engineered through a bacterial screening system leveraging the DNA gyrase-targeting toxic gene ccdB. This system couples survival to efficient on-target cleavage and minimal off-target activity, mimicking the transient action required for high-precision editing. Through iterative selection and sequencing validation, we identified MAD7_HF, harboring three substitutions (R187C, S350T, K1019N) that enhanced discrimination between on- and off-target sites. In Escherichia coli assays, MAD7_HF exhibited a >20-fold reduction in off-target cleavage across multiple mismatch contexts while maintaining on-target efficiency comparable to wild-type MAD7. Structural modeling revealed that these mutations stabilize the guide RNA-DNA hybrid at on-target sites and weaken interactions with mismatched sequences. This work establishes a high-throughput bacterial screening strategy that allows the identification of Cas12a variants with improved specificity at a given target site, providing a useful framework for future efforts to develop precision genome-editing tools. Full article

Background: Parkinson’s disease (PD) is a neurodegenerative disorder for which no curative therapies currently exist. Experimental models employing 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) reproduce PD features such as striatal dopaminergic dysfunction and motor deficits. Various MPTP dosing regimens are used to screen drug candidates for PD, but their validity is limited because of the predominant use of young male animals. Sex bias is another issue that is underrepresented in PD research, since females are more susceptible to this pathology. Here, we studied the model of bolus administration of MPTP (30 mg/kg) in aged female mice and assessed its sensitivity to the antioxidants fullerene C₆₀ and fullerenol C₆₀(OH)₂₄, given that oxidative stress is a key contributor to PD. Methods: 12-month-old female C57BL/6 mice received fullerene (0.1 mg/kg/day, via diet) or fullerenol (0.15 mg/kg/day, via drinking water). On day 10, mice were injected with MPTP. We studied tremor, piloerection, and behavior in the pole test, rotarod, pole test, and open field. High-performance liquid chromatography (HPLC) was employed to study dopaminergic neurotransmission, and the expression levels of its molecular regulators and nitric oxide synthase (NOS)-related targets were investigated using RT-PCR in the striatum and cortex. Results: MPTP-challenged mice displayed profound impairment in markers of dopaminergic neurotransmission and cellular distress, and showed disrupted motor behavior and vegetative functions. Antioxidant-treated animals that received a bolus injection of MPTP demonstrated partial preservation of tremor response, dopaminergic parameters, and iNOS and nNOS gene expression, although motor performance in the pole test was only modestly improved. Fullerenol appeared more effective in decreasing MPTP-induced neurochemical changes. Conclusions: The applied MPTP model showed its validity in mimicking PD features and was sensitive to low doses of antioxidants, suggesting its usefulness for screening drugs that target oxidative and nitrosative stress. The neuroprotective effects of fullerene-based compounds suggest their potential utility in the treatment of PD. Full article

Background/Objectives: Cardiometabolic risk remains a major challenge in patients with type 2 diabetes mellitus (DMT2). This study aimed to evaluate cardiovascular (CV) risk stratification using advanced glycation end-products (AGEs) measured via skin autofluorescence (SAF) and to assess the achievement of evidence-based ABC targets (HbA1c, blood pressure, low-density lipoprotein (LDL) cholesterol) in adults with DMT2 in Dalmatia. Methods: In this single-center cross-sectional study, 251 adults with DMT2 were stratified by CV risk based on SAF measured AGE levels. Clinical, biochemical, and anthropometric data were collected, including ABC goal attainment and medication use. Statistical analyses compared groups and explored predictors of ABC target achievement using regression models adjusted for clinical factors. Results: Only 17.5% of participants achieved all three ABC goals, indicating suboptimal cardiometabolic control. Those with elevated CV risk had higher hip circumference and lower diastolic blood pressure. Use of sodium-glucose cotransporter 2 (SGLT2) inhibitors was positively associated with ABC goal achievement in patients with prior CV or cerebrovascular events, while higher body mass index was negatively associated. SAF measured AGE levels correlated with cardiometabolic risk but showed no significant differences across LDL cholesterol or other traditional markers. Conclusions: SAF AGE measurement shows potential for CV risk stratification in DMT2 beyond traditional factors. The low rate of ABC goal attainment highlights the need for intensified individualized management incorporating novel biomarkers and therapeutics like SGLT2 inhibitors. Further prospective studies are needed to validate these findings and improve prevention of cardiovascular complications in DMT2. Full article

Nanoparticles (NPs) of noble metals such as gold have garnered significant attention due to their novel optical and catalytic properties, their theranostic properties, as they are biocompatible, and they attract considerable interest in a range of applications including targeted drug delivery. In this study, a fractional factorial design (FFD) is applied to systematically investigate the influence of key synthesis parameters (independent variables) at a low level (−1) and a high level (+1), including the reducing agent type (chitosan or trisodium citrate), concentration of reducing agent (10 to 40 mg), pH (3.5 to 8.5), temperature (60 to 100 °C), agitation time (5 to 15 min), and agitation speed (400 to 1200 rpm), on the dependent parameters—particle size and polydispersity index of gold nanoparticles (GNPs). The goal of this study was to provide a comprehensive understanding of the interplay between these parameters and their interaction effect on the characteristics of gold nanoparticles. A fractional factorial design allowed for efficient screening of the parameter space while minimizing the number of experiments required. The results demonstrated that pH, reducing agent, reducing agent–concentration, reducing agent–concentration of reducing agent–pH, and reducing agent–temperature interactions played significant roles in determining the particle size of the synthesized GNPs. Moreover, pH and reducing agent–concentration were identified as the major factors influencing the dispersity of the NPs. This study sheds light on the complex relationships between synthesis parameters and NP characteristics, offering an insight into the capacity for optimizing the synthesis process in order to tailor the desired properties of GNPs. The findings contribute to the growing field of NP synthesis and advance the understanding of the underlying mechanisms governing the formation of GNPs with specific size and dispersity characteristics. Full article

Introduction: YouTube™ is a widely accessible platform with unfiltered medical information. This study aimed to evaluate the educational value and reliability of YouTube™ videos on Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for advanced epithelial ovarian cancer treatment. Methods: YouTube™ videos were searched using the keywords “ovarian cancer”, “debulking surgery”, “hyperthermic”, and “HIPEC”. Patient Education Materials Assessment Tool for Audiovisual Content (PEMAT A/V) score, DISCERN, Misinformation Scale, and the Global Quality Scale (GQS) were employed to assess the clarity, quality, and reliability of the information presented. Results: Of the 150 YouTube™ videos screened, 71 were suitable for analysis and categorized by target audience (general public vs. healthcare workers). Most (57, 80.2%) were uploaded after the “Ov-HIPEC” trial (18 January 2018), with a trend toward more videos for healthcare workers (p = 0.07). Videos for the general public were shorter (p < 0.001) but received more views (p = 0.06) and likes (p = 0.09), though they were of lower quality. The DISCERN score averaged 50 (IQR: 35–60), with public-targeted videos being less informative (p < 0.001), a trend mirrored by the Misinformation Scale (p < 0.001) and GQS (p < 0.001). The PEMAT A/V scores showed 80% Understandability (IQR: 62–90) and 33% Actionability (IQR: 25–100), with no significant difference between groups (p = 0.15, p = 0.4). Conclusions: While YouTube™ provides useful information for healthcare professionals, it cannot be considered a reliable source for patients seeking information on HIPEC for ovarian cancer. Many videos contribute to misinformation by not properly explaining treatment indications, timing, adverse effects, multimodal approaches, or clinical trial findings. Full article