Search Results (965)

Objectives: In this research study, we introduce a novel approach to develop an innovative nanocarrier system comprising gold nanoparticles (GNPs) loaded with doxorubicin (D) in combination with natural molecules, such as trans-resveratrol (R), piperine (P), and icariin (Ic), against human cervical cancer. The final objective is to improve the anticancer efficacy of doxorubicin on HeLa and CaSki cell lines. Methods: Resveratrol was also used for the synthesis of GNP_R1 nanoparticles. Multi-functional GNPs loaded with D, R, P, and Ic (e.g., GNP_R1@D/R/P/Ic) were successfully prepared and fully characterized by SPR, TEM, HR-TEM, XRD, AFM, DLS, and zeta potential. They were investigated for in vitro stability in various biological media. The cytotoxicity activity was tested on HeLa and CaSki cell lines, using the MTT assay, for their applications as anticancer agents. Results: Our results demonstrate that the novel multi-functional GNPs (such as GNP_R1@D/R and GNP_R1@D/R/P/Ic) can effectively target the cervical cancer cells, improving the bioavailability of therapeutic agents and enhancing their cytotoxicity against cervical cancer cells. In vitro assessments demonstrated that the multi-functional GNPs exhibited improved stability and potential anticancer efficacy on human cervical cancer cells. Conclusions: The described strategy connects the benefits of biomolecules with functional nanoparticles toward the development of various GNP_R1@D/R/P/Ic nanocarriers for their applications as anticancer agents against human cervical cancer. This study provides compelling evidence that the innovative nanoparticles can enhance the therapeutic efficacy of doxorubicin against cervical cancer and offer a more advantageous alternative compared to doxorubicin monotherapy. Full article

Introduction and Aim: Sarcopenia has emerged as a key prognostic factor in patients with chronic limb-threatening ischemia (CLTI), with potential implications for clinical decision-making. This study aimed to assess the association between sarcopenia and clinical outcomes, mortality, and amputation, using simple, accessible screening tools in a CLTI population. Methods: In this prospective, single-center study conducted between December 2023 and December 2024, 170 patients with CTLI were enrolled. Sarcopenia screening was performed using the SARC-F (strength, assistance in walking, rising from a chair, climbing stairs, falls) questionnaires, handgrip strength measurement, and calf circumference, adjusted for body mass index and sex. The primary outcome was 6-month all-cause mortality and/or major amputation. Results: Sarcopenia was identified in 77 patients (45.3%). Compared to non-sarcopenic individuals, sarcopenic patients were significantly older. They exhibited greater functional impairment, as well as poorer nutritional and muscle status. They also had significantly higher in-hospital mortality (16.9% vs. 3.2%, p = 0.002), 30-day mortality (24.7% vs. 4.3%, p = 0.001), and 6-month mortality (50.6% vs. 15.1%, p = 0.001). Sarcopenia was significantly associated with the primary outcome in univariate analysis (HR: 2.05; 95% CI: 1.31–3.20; p = 0.002) and remained an independent predictor after multivariate adjustment (HR: 1.95; 95% CI: 1.01–3.79; p = 0.048). Conclusions: Sarcopenia is a strong, independent predictor of poor outcome in patients with CLTI. Its detection through simple tools offers an easy and cost-effective strategy to improve risk stratification and guide early intervention through exercise-based therapy. Full article

Background and Objectives: Emerging evidence indicates that individuals exposed to adverse childhood experiences (ACEs) face elevated risks for various chronic illnesses. However, the association between ACEs and osteoporosis risk remains underexplored, particularly regarding potential modifications by genetic susceptibility. This prospective cohort study aims to examine the relationship of ACEs with incident osteoporosis and investigate interactions with polygenic risk score (PRS). Materials and Methods: This study analyzed 124,789 UK Biobank participants initially free of osteoporosis. Cumulative ACE burden (emotional neglect, emotional abuse, physical neglect, physical abuse, sexual abuse) was ascertained through validated questionnaires. Multivariable-adjusted Cox proportional hazards models assessed osteoporosis risk during a median follow-up of 12.8 years. Moderation analysis examined genetic susceptibility interactions using a standardized PRS incorporating osteoporosis-related SNPs. Results: Among 2474 incident osteoporosis cases, cumulative ACEs showed dose–response associations with osteoporosis risk (adjusted hazard ratio [HR]_{per one-unit increase} = 1.07, 95% confidence interval [CI] 1.04–1.11; high ACEs [≥3 types] vs. none: HR = 1.26, 1.10–1.43). Specifically, emotional neglect (HR = 1.14, 1.04–1.25), emotional abuse (HR = 1.14, 1.03–1.27), physical abuse (HR = 1.17, 1.05–1.30), and sexual abuse (HR = 1.15, 1.01–1.31) demonstrated comparable effect sizes. Sex-stratified analysis revealed stronger associations in women. Joint exposure to high ACEs/high PRS tripled osteoporosis risk (HR = 3.04, 2.46–3.76 vs. low ACEs/low PRS) although G × E interaction was nonsignificant (P-interaction = 0.10). Conclusions: These results suggest that ACEs conferred incremental osteoporosis risk independent of genetic predisposition. These findings support the inclusion of ACE screening in osteoporosis prevention strategies and highlight the need for targeted bone health interventions for youth exposed to ACEs. Full article

Background: While timely blood transfusion is critical for restoring oxygen-carrying capacity after coronary artery bypass grafting (CABG), allogeneic blood product transfusions are independently associated with increased long-term mortality, necessitating a risk-stratified approach to balance oxygen delivery against immunological complications and infection risks. Methods: We retrospectively analyzed 3376 patients undergoing isolated CABG between 2005 and 2023 at a single tertiary center. Patients who died during their perioperative hospital stay within 30 days were excluded. Transfusion burden was assessed both as the absolute number of blood product units (packed red blood cells, platelet transfusion, fresh frozen plasma) and as a percentage of calculated patient blood volume. The primary outcome was all-cause mortality at 5 years. Flexible Cox regression with penalized smoothing splines, adjusted for EuroSCORE II, was used to model dose–response relationships. Results: From our cohort of 3376 patients, a total of 137 patients (4.05%) received >10 units of packed red blood cells (PRBC) perioperatively. These patients were older (median 71 vs. 68 years, p < 0.001), more often female (29% vs. 15%, p < 0.001), and had higher preoperative risk (EuroSCORE II: 2.53 vs. 1.41, p < 0.001). After 5 years, mortality was 42% in the massive transfusion group versus 10% in controls. Spline regression revealed an exponential increase in mortality with transfused units: 14 units yielded a 1.5-fold higher hazard of death (HR 1.46, 95% CI 1.31–1.64), rising to HR 2.71 (95% CI 2.12–3.47) at 30 units. When transfusion was indexed to blood volume, this relationship became linear and more tightly correlated with mortality, with lower maximum hazard ratios and narrower confidence intervals. Conclusions: Indexing transfusion burden to the percentage of patient blood volume replaced provides a more accurate and clinically actionable predictor of 5-year mortality after CABG than absolute unit counts. Our findings support a shift toward individualized, volume-based transfusion strategies to optimize patient outcomes and resource stewardship in a time of limited availability of blood products. Full article

This study investigates the relationships between proactive personality, psychological capital, work engagement, work well-being, and innovative work behavior among employees in Saudi public authorities, based on the conservation of resources theory and the job demands-resources model. Using a sequential mediation model, data from 457 public employees were analyzed through structural equation modeling. The results show that a proactive personality and psychological capital significantly predict work engagement, but neither is significantly related to work well-being. Notably, while a proactive personality does not directly impact innovative work behavior, psychological capital does. Additionally, work well-being partially mediates the relationship between work engagement and innovative work behavior. These findings suggest that enhancing psychological capital and fostering engagement are key to promoting innovation. The mediating role of well-being highlights the importance of employee welfare in this process. This study provides practical implications for HR managers in the Saudi public sector and emphasizes strategies for building internal psychological resources. However, as data were collected from a single source, future research should include multiple key informants to enhance generalizability. This study builds on theory by demonstrating how proactive personality and psychological capital jointly stimulate innovative behavior through engagement and well-being, enriching the job demands-resources model with personal resource dynamics in public sector organizations. Full article

Objective: To investigate the effect of an 8-week inspiratory muscle training (IMT) intervention on respiratory muscle strength and cardiovascular autonomic regulation in obese young men. Methods: The study included 36 obese young men who met the inclusion and exclusion criteria. Participants were randomly divided into two groups: the IG (inspiratory muscle training group, n = 17), which underwent high-intensity IMT intervention for 8 weeks, 5 times a week, and the CG (control group, n = 18), which was not given any additional intervention. Assessed parameters included maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP), systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR), as well as heart rate variability metrics such as the standard deviation of normal-to-normal intervals (SDNN), root mean square of successive differences (RMSSD), standard deviation of successive differences (SDSD), low-frequency power component (LF), high-frequency power component (HF), and LF/HF ratio. These measurements were taken both at baseline and following the completion of the 8-week intervention period. Results: After 8 weeks of IMT, the MIP and MEP of the IG increased by 31.8% and 26.5%, respectively (p < 0.01). In addition, SBP, DBP, and HR decreased by 2.2%, 3.2%, and 2.1%, respectively (p < 0.01). In the HRV time domain, SDNN and RMSSD increased by 54.1% and 33.5%, respectively (p < 0.01), and there was no significant improvement in SDSD (p > 0.05); in the HRV frequency domain, LF decreased by 40.5%, HF increased by 59.4% (p < 0.01), and the LF/HF ratio decreased by 58.2% (p < 0.05). Conclusion: An 8-week 80%MIP IMT intervention significantly improves respiratory muscle strength and cardiovascular autonomic regulation in obese young men, suggesting that IMT is a promising non-pharmacological strategy for mitigating obesity-related cardiovascular risk. Full article

Lysosomal storage disorders (LSDs) are inherited metabolic conditions characterized by lysosomal enzyme deficiencies leading to substrate accumulation. As genetic diseases, LSDs can be treated with gene therapies (GT), including the CRISPR/Cas systems. The CRISPR/Cas systems enable precise and programmable genome editing, leading to targeted modifications at specific genomic loci. While the classical CRISPR/Cas9 system has been extensively used to generate LSD disease models and correct disease-associated genetic alterations through homologous recombination (HR), recently described Cas proteins as well as CRISPR/Cas9-derived strategies such as base editing, prime editing, and homology-independent targeted integration (HITI) offer a novel way to develop innovative treatments for LSDs. The direct administration of the CRISPR/Cas9 system remains the primary strategy evaluated in several LSDs; nevertheless, the ex vivo CRISPR/Cas9-based approach has been recently explored, primarily in central nervous system-affecting LSDs. Ex vivo approaches involve genetically modifying, in theory, any patient cells in the laboratory and reintroducing them into the patient to provide a therapeutic effect. This manuscript reviews the molecular aspects of the CRISPR/Cas technology and its implementation in ex vivo strategies for LSDs while discussing novel approaches beyond the classical CRISPR/Cas9 system. Full article

Despite the increased mortality due to ST-segment elevation myocardial infarction (STEMI) in South Africa (SA), SA lacks comprehensive data on STEMI clinical outcomes. This study aimed to determine the 30-day and one-year all-cause mortality rates of STEMI patients presenting to our hospital. This was a one-year prospective single-centre study of STEMI patients presenting to the Charlotte Maxeke Johannesburg Hospital in SA between December 2021 and August 2023. We compared the baseline clinical characteristics, reperfusion strategies, and in-hospital, 30-day, and one-year clinical outcomes of survivors and non-survivors. This cohort included 378 STEMI participants. The in-hospital, 30-day, and one-year all-cause mortality rates were 6.6% (n = 25), 10.1% (n = 38), and 17.2% (n = 65), respectively. The pharmacoinvasive strategy was the most used reperfusion therapy (n = 150, 39.7%). On adjusted multivariate Cox regression analysis, a Killip class >2 was the strongest independent predictor of 30-day [HR 5.61, 95% CI 2.83–11.12; p < 0.001] and one-year all-cause mortality [HR 1.72, 95% CI 1.26–2.34; p = 0.001]. Although mortality has increased, our mortality rates were comparable to outcomes from high-income countries but significantly lower than reports from other low- or middle-income countries. Importantly, there were no significant differences in 30-day and one-year survival outcomes between the different reperfusion strategies. Full article

Background: Circadian rhythms regulate critical cellular processes, including DNA repair and cell cycle dynamics, potentially influencing the effectiveness of radiotherapy (RT). This study evaluated whether RT timing impacts clinical outcomes and symptom burden in prostate cancer patients. Patients/Methods: This retrospective study (n = 336, median follow-up 55 months) included men who received curative intent external beam RT between 2010 and 2019 (median age 69, 69% black, median PSA 11.3, 40% with Gleason 8–10). Treatment times (TTs) were averaged and analyzed by quartile/median. Outcomes included freedom from biochemical failure (FFBF) and distant metastasis (FFDM), GI and GU toxicity, and quality of life (QOL). Subgroup analyses by race and hormone therapy status were performed. Results: Across the overall cohort, TT was not associated with FFBF or FFDM. However, in white men, earlier TTs were significantly associated with higher 5-year FFBF (89% vs. 67%, p = 0.0139) and FFDM (93% vs. 72%, p = 0.0268). In the multivariate analysis (MVA), TT was not associated with FFBF or FFDM for all men, but in white men, earlier TT was associated with improved FFBF (HR 2.8, p = 0.06) in a model also including risk category (p = 0.21). Overall, no significant differences were observed for grade 2–3+ toxicity and TT. Trends for inferior QOL, and worse grade 2+ (p = 0.2) and 3+ GU toxicity (p = 0.1) were observed for later TTs. In white men, bowel, urinary continence, and irritative/obstructive urinary QOL were worse with later TTs (p < 0.05). Conclusions: TT may influence clinical outcomes and symptom burden, particularly in white men. These findings underscore the potential of chronoradiotherapy as a personalized treatment strategy and highlight the need for prospective trials. Full article

Background: Staphylococcus spp. represent the most prevalent Gram-positive organisms in children with malignancies or undergoing haematopoietic cell transplantation (HCT), contributing to significant morbidity and mortality. This study aimed to assess the epidemiology, risk factors, treatment strategies, and outcomes of staphylococcal infections (SIs) in paediatric haemato-oncology (PHO) and HCT patients in Poland over a 12-year period. Methods: A retrospective, multicentre study was conducted across 17 paediatric oncology centres in Poland. The clinical and microbiological data of patients under the age of 18, diagnosed with malignancies or post-HCT, were analysed for confirmed SI between 2012 and 2023. The variables assessed included demographics, underlying conditions, infection type and source, antimicrobial susceptibility, treatment, and 30-day infection-free survival. Results: Among 1725 patients with SI, 1433 were PHO and 292 were HCT patients. The cumulative incidence of SI was 12.7% in PHO and 14.3% in HCT patients (p = 0.008). The 30-day survival rate was significantly higher in PHO compared to HCT patients (98.4% vs. 93.2%, p < 0.001). Most deaths were caused by S. epidermidis, S. haemolyticus, and S. hominis, predominantly involving methicillin-resistant coagulase-negative Staphylococci (MRCNS). Multivariate Cox regression identified undergoing HCT (HR = 3.0, 95% CI: 1.6–5.6, p < 0.001) and treatment of infection > 10 days (HR = 2.0, 95% CI: 1.1–3.6, p = 0.019) as independent risk factors for mortality. Conclusions: Staphylococcal infections pose a significant challenge in paediatric oncology and transplant populations. Optimising prevention, diagnostics, and antimicrobial therapy is crucial for improving outcomes in these high-risk groups. Full article

Leymus chinensis (Trin.) Tzvel., a vital native forage grass in northern China for ecological restoration and livestock production, faces severe yield losses and grassland degradation due to rust (Puccinia spp.) infection. Current control strategies, reliant on chemical interventions, are limited by evolving resistance risks and environmental concerns, while rust-resistant breeding remains hindered by insufficient molecular insights. To address this, we systematically evaluated rust resistance in 24 L. chinensis germplasms from diverse geographic origins, identifying six highly resistant (HR) and five extremely susceptible (ES) genotypes. Integrating transcriptomics and metabolomics, we dissected molecular responses to Puccinia infection, focusing on contrasting HR (Lc71) and ES (Lc5) germplasms at 48 h post-inoculation. Transcriptomic analysis revealed 1012 differentially expressed genes (DEGs: 247 upregulated, 765 downregulated), with enrichment in cell wall biosynthesis and photosynthesis pathways but suppression of flavonoid synthesis. Metabolomic profiling identified 287 differentially accumulated metabolites (DAMs: 133 upregulated, 188 downregulated), showing significant downregulation of pterocarpans and flavonoids in HR germplasms, alongside upregulated cutin synthesis-related metabolites. Multi-omics integration uncovered 79 co-enriched pathways, pinpointing critical regulatory networks: (1) In the nucleotide metabolism pathway, genes Lc5Ns011910, Lc1Xm057211, and Lc4Xm043884 exhibited negative cor-relations with metabolites Deoxycytidine and Cytosine. (2) In flavonoid biosynthesis, Lc2Xm054924, Lc4Xm044161, novel.8850, Lc2Ns006303, and Lc7Ns021884 were linked to naringenin and naringenin-7-O-glucoside accumulation. These candidate genes likely orchestrate rust resistance mechanisms in L. chinensis. Our findings advance the molecular understanding of rust resistance and provide actionable targets for breeding resilient germplasms. Full article

Targeted radionuclide therapy (TRT) utilizes radiopharmaceuticals to deliver radiation directly to cancer cells while sparing healthy tissues. Beyond the absorbed dose of ablative radiation, TRT induces non-targeted effects (NTEs) that significantly enhance its therapeutic efficacy. These effects include radiation-induced bystander effects (RIBEs), abscopal effects (AEs), radiation-induced genomic instability (RIGI), and adaptive responses, which collectively influence the behavior of cancer cells and the tumor microenvironment (TME). TRT also modulates immune responses, promoting immune-mediated cell death and enhancing the efficacy of combination therapies, such as the use of immune checkpoint inhibitors. The molecular mechanisms underlying TRT involve DNA damage, oxidative stress, and apoptosis, with repair pathways like homologous recombination (HR) and non-homologous end joining (NHEJ) playing critical roles. However, challenges such as tumor heterogeneity, hypoxia, and radioresistance limit the effectiveness of this approach. Advances in theranostics, which integrate diagnostic imaging with TRT, have enabled personalized treatment approaches, while artificial intelligence and improved dosimetry offer potential for treatment optimization. Despite the significant survival benefits of TRT in prostate cancer and neuroendocrine tumors, 30–40% of patients remain unresponsive, which highlights the need for further research into molecular pathways, long-term effects, and combined therapies. This review outlines the dual mechanisms of TRT, direct toxicity and NTEs, and discusses strategies to enhance its efficacy and expand its use in oncology. Full article

Background: Primary sclerosing cholangitis (PSC) accounts for 10–15% of liver transplants but is the leading cause of retransplant. This study evaluates whether PSC patients have different survival and graft outcomes when receiving grafts from donors after brain death (DBD) versus circulatory (DCD) death. Methods: Using the SRTR database (2004–2024), we compared PSC patients receiving DCD vs. DBD grafts. Demographics and outcomes including graft loss, mortality, and retransplant were analyzed using multivariable logistic and Cox regression, along with propensity-matched analysis. Results: Among 5762 PSC patients, 391 (6.8%) received DCD grafts. Patients receiving DCD grafts were older but had lower MELD scores (19 vs. 22; p < 0.001) and were less often functionally dependent (11.3% vs. 24.4%; p < 0.001). Multivariable Cox regression demonstrated that receipt of a DCD graft was independently associated with time to graft loss (HR 1.59; CI 1.10–2.31; p = 0.013. Similarly, DCD graft receipt significantly increased the likelihood of requiring retransplant (HR 3.25; CI: 1.93–5.46; p < 0.001) but did not increase the likelihood of mortality. Propensity matched analysis further supported these finding with significantly higher graft loss with DCD grafts at one and two years and higher retransplant rates at all time points including 5-years (+7.9%, CI 4.4 to 11.4%; p < 0.001). Conclusions: DCD grafts in PSC patients are linked to worse graft survival and higher retransplant rates. They may be best suited for older, lower-MELD patients, but further studies on perfusion strategies are needed. Full article

Background/Objectives: Acute myeloid leukemia (AML) with FLT3 internal tandem duplication (FLT3-ITD) mutations carries a poor prognosis. While FLT3 inhibitors like midostaurin show benefits in combination with chemotherapy, the role of allelic ratio (AR), NPM1 mutation status, and hematopoietic stem cell transplantation (HSCT) remains uncertain. Real-world data can help refine prognostic classification and treatment strategies. Methods: We retrospectively analyzed 37 fit patients with FLT3-ITD AML treated with standard “7+3” chemotherapy, with and without midostaurin, between 2013 and 2022. Patients were stratified by FLT3-ITD AR, NPM1 status, and treatment approach. Outcomes assessed included complete remission (CR), disease-free survival (DFS), and overall survival (OS). Results: Overall, 67.6% achieved CR/CRi. Response rates did not differ significantly by AR (low vs. high: 66.7% vs. 69.2%) or midostaurin use (72.6% vs. 60%; p = 0.49). NPM1 mutations were associated with improved DFS (10.3 vs. 3 months, p = 0.036) but not OS. HSCT, performed in 54.1% of patients, mainly in first remission (CR1), significantly prolonged DFS (not reached vs. 5.3 months, p = 0.005) and remained an independent predictor in multivariate analysis (HR: 0.160, p = 0.039). OS (median 15.1 months) did not vary significantly across subgroups. Among patients achieving CR1, OS was significantly longer in those who underwent HSCT after midostaurin-based induction compared to those not transplanted (median OS not reached vs. 12.8 months; 95% CI, 6.9–18.7; p = 0.045), whereas no significant benefit was observed after standard induction. In a landmark analysis restricted to patients transplanted in CR1, those who had received midostaurin-based induction showed a trend toward improved OS compared to those treated with standard induction (median OS not reached vs. 11.5 months; 95% CI, 0.5–25.0; p = 0.086). Conclusions: This real-life study supports the importance of NPM1 mutations and HSCT in CR1, especially in the midostaurin era, for improving DFS in FLT3-ITD AML. These findings support updated guidelines for reducing the prognostic weight of AR and highlight the need for improved post-remission strategies in this setting. Full article

Background: Sex differences play a significant role in the epidemiology, biology, and outcomes of many cancers, including glioblastoma (GB), the most common and aggressive primary brain tumor. GB is more frequent in males, while females tend to have longer survival, though the underlying reasons for these differences remain poorly understood. Potential contributors include hormonal influences, sex-specific risk factors, and treatment disparities. Understanding these differences is critical for optimizing personalized treatment strategies. Methods: We conducted a retrospective analysis of patients with gliomas from a neuro-oncological database, with a primary focus on GB cases. Variables collected included sex, age, tumor type, molecular biomarker, and treatment modalities. The primary objective was to assess sex-based differences in tumor characteristics and outcomes, while the secondary objective was to identify predictors of time to progression and mortality. Results: The cohort comprised 125 GB, 48 astrocytomas, and 16 oligodendrogliomas, with no significant sex-based differences in age or tumor type distribution. Among GB patients, multifocality was more prevalent in females (14% vs. 8%; p = 0.01); also, EGFR amplification was more frequent in females (25.5% vs. 52.5%; p = 0.007). Males received chemotherapy (80% vs. 63%; p = 0.04) and radiotherapy (84% vs. 67%; p = 0.03) more frequently than females. Survival was positively associated with MGMT methylation (p = 0.002) and negatively associated with TERT mutation (p = 0.01). Multivariable analysis identified TERT mutation as a predictor of increased mortality (HR = 4.1; 95% CI: 1.2–14; p = 0.025), while multifocality predicted both mortality (HR = 2.3; 95% CI: 1.3–3.9; p = 0.003) and reduced time to progression (HR = 3.3; 95% CI: 1.02–10.6; p = 0.04). Conclusions: This study underscores the importance of sex and molecular profiling in GB management, revealing distinct patterns in tumor characteristics and treatment administration between males and females. Our findings advocate for the integration of sex-specific considerations and molecular profiling into clinical decision-making to improve outcomes for GB patients. Full article