Search Results (5,020)

Ferulic acid (FA) is a bioactive compound known for its potent antioxidant and anti-inflammatory properties; however, its poor water solubility significantly limits its bioavailability and therapeutic potential. In this study, a solid dispersion of FA (FA-SD) was developed using Eudragit^® EPO via the solvent evaporation method, achieving a 24-fold increase in solubility (42.7 mg/mL) at a 1:3 drug-to-polymer ratio. Expandable gastroretentive films were subsequently formulated using starches from Hom-Nil rice, glutinous rice, and white rice, combined with chitosan as the primary film-forming agents, via the solvent casting technique. Hydroxypropyl methylcellulose (HPMC) K100 LV was incorporated as an adjuvant to achieve controlled release. At optimal concentrations (3% w/w starch, 2% w/w chitosan, and 2% w/w HPMC), the films exhibited favorable mechanical properties, swelling capacity, and unfolding behavior. Sustained release of FA over 8 h was achieved in formulations containing HPMC with either Hom-Nil or glutinous rice starch. Among the tested formulations (R6, G6, and H6), those incorporating Hom-Nil rice starch demonstrated the most significant antioxidant (10.38 ± 0.23 μg/mL) and anti-inflammatory (9.26 ± 0.14 μg/mL) effects in murine macrophage cell line (RAW 264.7), surpassing the activities of both free FA and FA-SD. These results highlight the potential of anthocyanin-rich pigmented rice starch-based expandable films as effective gastroretentive systems for enhanced FA delivery Full article

Background: Despite clinical and pathological risk tools, predicting outcomes in non-muscle-invasive bladder cancer (NMIBC), particularly high-grade (HG) cases, remains challenging due to its unpredictable recurrence and progression. There is an urgent need for molecular biomarkers to enhance risk stratification and guide treatment. Methods: We assessed the prognostic potential of eight miRNAs (miR-9, miR-143, miR-182, miR-205, miR-27a, miR-369, let-7c, and let-7g) in a cohort of ninety patients with primary bladder cancer. Expression data were retrieved from our previously published studies. Kaplan–Meier’s and Cox’s regression analyses were used to evaluate the associations with overall survival (OS), metastasis-free survival (MFS), and clinical outcomes. Principal component analysis (PCA) was performed to identify informative miRNA combinations. Target gene prediction, pathway enrichment (DAVID), and drug–gene interaction mapping (DGIdb) were conducted in silico. Results: A high expression of let-7g and miR-9 was significantly associated with better OS in HG NMIBC and MIBC, respectively (p = 0.013 and p = 0.000). MiR-9 downregulation correlated with metastasis in MIBC (p = 0.018). Among all combinations, miR-205 and miR-27a best predicted intermediate-risk NMIBC progression and recurrence (r² = 0.982, p = 0.000). A functional analysis revealed that these miRNAs regulate key cancer-related pathways (MAPK, mTOR, and p53) through genes such as TP53, PTEN, and CDKN1A. Drug interaction mapping identified nine target genes (e.g., DAPK1, ATR, and MTR) associated with eight FDA-approved bladder cancer therapies, including cisplatin and gemcitabine. Conclusion: Let-7g, miR-9, miR-143, miR-182, and miR-205 emerged as promising biomarkers for outcome prediction in NMIBC. Their integration into liquid biopsy platforms could support non-invasive monitoring and personalized treatment strategies. These findings warrant validation in larger, prospective studies and through functional assays. Full article

The ribosome in eukaryotic cells is a macromolecular complex composed of four ribonucleic acids and over 80 proteins. This organelle facilitates protein synthesis in cells, and its activity is strongly upregulated in human cancers. Immune cells, a variety of cellular stressors and numerous structurally and mechanistically distinct anti-cancer agents have been shown to induce ribosomal RNA degradation in tumour cells in vitro and in vivo—a phenomenon we termed “RNA disruption”. RNA disruption can be quantified in cultured cell lines and patient samples using the RNA disruption assay (RDA). Unlike well-known high-throughput anti-cancer drug sensitivity assays, RDA can distinguish between dying and arrested tumour cells, making it an attractive assay for anti-cancer drug discovery and development. Low tumour RNA disruption during neoadjuvant chemotherapy (as measured using RDA) is strongly associated with residual disease and reduced disease-free survival, making it a potentially valuable chemo-resistance assessment tool. High RNA disruption may also indicate chemo-responsiveness. RDA holds the prospect of being a useful tool to escalate or de-escalate neoadjuvant chemotherapy in cancer patients. Moreover, the assay’s ability to predict treatment outcomes during neoadjuvant chemotherapy may permit its use in adaptive clinical trials and in drug approval by regulatory agencies. This review provides insight into the cellular processes involved in chemotherapy-induced RNA disruption. It also describes the results of clinical studies on tumour RNA disruption in cancer patients and suggests possible approaches that could be considered for the utilization of RDAs in the clinical management of breast cancer patients undergoing current neoadjuvant chemotherapy regimens. Full article

Malignant melanoma is a highly metastatic skin cancer, representing about 5% of all cancer diagnoses in the United States. Conventional chemotherapy often has limited effectiveness and severe systemic side effects. This study explores a localized, topical delivery system using cisplatin-loaded nanomembranes as a safer and more targeted alternative. Cell viability assays established the safe cisplatin concentrations for tissue culture. Gelatin-based nanomembranes incorporating cisplatin were fabricated via electrospinning. Biocompatibility and therapeutic efficacy were tested by applying the membranes to cultured melanoma and normal skin cells. Controlled drug release profiles were evaluated by adjusting cross-linking times. Cisplatin concentration between 3.125 and 12.5 µg/mL were found safe. Nanomembranes with these doses effectively eliminated melanoma cells with minimal harm to healthy skin cells. Drug-free membranes showed high biocompatibility. Cross-linking duration allowed tunable and stable drug release. Cisplatin-loaded gelatin nanomembranes offer a promising topical therapy for melanoma, enhancing drug targeting while reducing systemic toxicity. This approach may serve as a cost-effective alternative to systemic treatments like immunotherapy. Future research will focus on in vivo testing and clinical application. Full article

This study presents the development of an innovative battery-free, RF-powered implantable microdevice designed for intravesical chemotherapy delivery. The system utilizes a custom-designed RF energy harvesting module that enables wireless energy transfer through biological tissue, eliminating the need for internal power sources. Mechanical and electronic components were co-optimized to achieve full functionality within a compact, biocompatible housing suitable for intravesical implantation. The feasibility of the device was validated through simulation studies and ex vivo experiments using biological tissue models. The results demonstrated successful energy transmission, storage, and sequential actuator activation within a biological environment. The proposed system offers a promising platform for minimally invasive, wirelessly controlled drug delivery applications in oncology and other biomedical fields. Full article

Background/Objectives: Sacituzumab govitecan (SG) is an antibody–drug conjugate targeting Trop-2 that has demonstrated clinical benefits in randomised trials for patients with metastatic triple-negative breast cancer (mTNBC) and metastatic hormone receptor-positive/HER2-negative (HR+/HER2− mBC) disease. However, real-world data on its effectiveness and safety are limited, especially in patients with poor performance status or central nervous system (CNS) involvement. This study aimed to evaluate the real-world outcomes of SG in these two subtypes. Methods: We conducted a retrospective, multicentre, observational study across three tertiary hospitals in Spain. Patients with mTNBC or HR+/HER2− mBC treated with SG between June 2022 and March 2025 were included. Clinical data, treatment history, adverse events (AEs), and survival outcomes were also recorded. The median progression-free survival (mPFS) and median overall survival (mOS) were estimated using Kaplan–Meier analysis. Univariate and multivariate analyses were performed to identify the factors influencing outcomes. The association between granulocyte colony-stimulating factor (G-CSF) prophylaxis and neutropenia was assessed using Fisher’s exact test. Results: A total of 56 patients were included in this study (33 with mTNBC and 23 with HR+/HER2− mBC). In the mTNBC group, mPFS was 4.0 months (95% CI: 1.94–5.98) and mOS was 11.0 months (95% CI: 4.80–17.12). In the HR+/HER2− mBC group, mPFS was 3.7 months (95% CI: 2.02–5.44) and mOS was 20.2 months (95% CI: 3.9–36.5). Fatigue, neutropenia, and gastrointestinal toxicity were the most common AEs. Primary G-CSF prophylaxis was not associated with a reduced incidence of neutropenia (p = 0.434). Conclusions: In routine practice, SG shows effectiveness comparable to that of randomised trials across both subtypes, with a safety profile consistent with pivotal studies. The observed toxicity profile was consistent with that described in pivotal clinical trials and other studies. The prophylactic use of G-CSF was not associated with an impact on the occurrence of neutropenia, but the incidence of neutropenia was lower than that in clinical trials and other studies that did not administer G-CSF prophylactically. Full article

The therapeutic landscape of adults with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is undergoing a paradigm shift, driven by the development of immunotherapy-based “chemo-free” and “chemo-light’ regimens. These strategies aim to achieve high efficacy with reduced toxicity, particularly in older adults who may not tolerate intensive chemotherapy. In Philadelphia chromosome-positive (Ph+) BCP-ALL, the incorporation of ABL tyrosine kinase inhibitors (TKIs) with blinatumomab (CD3/CD19 bispecific T-cell engager) has shown remarkable efficacy, with some studies reporting molecular response rates in the range of 90–100% and long-term survival exceeding 80% without the need for intensive chemotherapy or allogeneic hematopoietic cell transplantation (allo-HCT). In Philadelphia-negative (Ph−) BCP- ALL, an immunotherapy-based combination of blinatumomab and inotuzumab ozogamicin (anti-CD22 antibody-drug conjugate) has demonstrated high rates of complete remission and measurable residual disease (MRD) negativity, with manageable toxicity. While chimeric antigen receptor (CAR) T-cell therapy remains a transformative option for relapsed/refractory B-ALL, its integration into frontline treatment is still under investigation. Ongoing trials are evaluating the optimal sequencing and combinations of these agents and their potential to obviate the need for chemotherapy and/or allo-HCT in selected patients. As evidence continues to accumulate, chemo-free and chemo-light regimens, incorporating minimal chemotherapy with targeted agents to balance efficacy and reduced toxicity, are poised to redefine the standard of care for adults BCP-ALL, offering the possibility of durable remissions with reduced treatment-related morbidity. Full article

Cancer cells can adapt to their surrounding microenvironment by upregulating glucose-regulated protein 78 kDa (GRP78) and vacuolar-type ATPase (V-ATPase) proteins to increase their proliferation and resilience to anticancer therapy. Therefore, targeting these proteins can obstruct cancer progression. A comprehensive computational study was conducted to investigate the inhibitory potential of four proton pump inhibitors (PPIs), dexlasnoprazole (DEX), esomeprazole (ESO), pantoprazole (PAN), and rabeprazole (RAB), against GRP78 and V-ATPase. Molecular docking revealed high-affinity scores for PPIs against both proteins. Moreover, molecular dynamics showed favorable root mean square deviation values for GRP78 and V-ATPase complexes, whereas root mean square fluctuations were high at the substrate-binding subdomains of GRP78 complexes and the α-helices of V-ATPase. Meanwhile, the radius of gyration and the surface-accessible surface area of the complexes were not significantly affected by ligand binding. Trajectory projections of the first two principal components showed similar motions of GRP78 structures and the fluctuating nature of V-ATPase structures, while the free-energy landscape revealed the thermodynamically favored GRP78-RAB and V-ATPase-DEX conformations. Furthermore, the binding free energy was −16.59 and −18.97 kcal/mol for GRP78-RAB and V-ATPase-DEX, respectively, indicating their stability. According to our findings, RAB and DEX are promising candidates for GRP78 and V-ATPase inhibition experiments, respectively. Full article

The integration of organoids with biosensors serves as a miniaturized model of human physiology and diseases, significantly transforming the research frameworks surrounding drug development, toxicity testing, and personalized medicine. This review aims to provide a comprehensive framework for researchers to identify suitable technical approaches and to promote the advancement of organoid sensing towards enhanced biomimicry and intelligence. To this end, several primary methods for technology integration are systematically outlined and compared, which include microfluidic integrated systems, microelectrode array (MEA)-based electrophysiological recording systems, optical sensing systems, mechanical force sensing technologies, field-effect transistor (FET)-based sensing techniques, biohybrid systems based on synthetic biology tools, and label-free technologies, including impedance, surface plasmon resonance (SPR), and mass spectrometry imaging. Through multimodal collaboration such as the combination of MEA for recording electrical signals from cardiac organoids with micropillar arrays for monitoring contractile force, these technologies can overcome the limitations inherent in singular sensing modalities and enable a comprehensive analysis of the dynamic responses of organoids. Furthermore, this review discusses strategies for integrating strategies of multimodal sensing approaches (e.g., the combination of microfluidics with MEA and optical methods) and highlights future challenges related to sensor implantation in vascularized organoids, signal stability during long-term culture, and the standardization of clinical translation. Full article

Background: Hepatitis presents a major health and economic challenge in Saudi Arabia, necessitating insight into its epidemiology, risk factors, and control measures. This review aims to synthesize current evidence on the epidemiology, risk factors, and prevention strategies for viral hepatitis in Saudi Arabia. It evaluates the effectiveness of existing interventions and proposes data-driven approaches to advance national hepatitis elimination goals. Methods: This study reviewed data from 2016 to 2024, sourced from PubMed, Google Scholar, ResearchGate, and ScienceDirect, focusing on hepatitis epidemiology and prevention in Saudi Arabia. Studies relevant to Saudi-specific trends and prevention strategies were included. Results: Saudi Arabia has achieved significant reductions in viral hepatitis prevalence, notably HBV (1.3%) due to universal infant vaccination (98% coverage), and HCV (0.124%) through the Saudi National Hepatitis Program (SNHP), which provides free DAAs (95% cure rate) and has screened 5 million people. However, challenges persist: HAV susceptibility is rising in adults (seroprevalence 33.1%), HDV affects 7.7% of HBV patients, and key risk factors include socioeconomic disparities (higher HAV/HEV in rural/low-income areas), intravenous drug use (30–50% of HCV cases), unsafe medical/cultural practices (e.g., Hijama), and limited healthcare access for migrants/rural populations. While interventions like water sanitation initiatives (58% HAV decline) and prenatal screening are effective, advancing elimination goals requires addressing gaps in HDV/HEV surveillance, outdated seroprevalence data, equitable treatment access (35% lower in rural areas), stigma reduction, and targeted strategies for high-risk groups to meet WHO 2030 targets. Conclusions: Saudi Arabia has made significant progress in hepatitis control through vaccination and public health efforts, but challenges persist. Strengthening healthcare systems, improving community engagement, and ensuring equitable access are key to sustaining elimination efforts. Full article

Background: Multiple myeloma (MM) is an incurable plasma cell dyscrasia with particularly adverse prognosis in relapsed, multi-drug refractory settings. The management of those patients is challenging as treatment options are limited. In this context, bispecific antibodies (BsAbs) have recently emerged as promising therapeutic agents, and several have gained regulatory approval. To better understand their impact in MM landscape, we performed a systematic review and meta-analysis assessing their efficacy and safety in patients with relapsed/refractory MM (RRMM). Methods: A systematic search was conducted in the PubMed, ScienceDirect, Scopus and ClinicalTrials.gov databases for clinical trials investigating BsAbs for RRMM. Pooled estimates in terms of proportions along with 95% confidence intervals were calculated with random-effects models. The present meta-analysis was performed following PRISMA guidelines and was registered in PROSPERO (ID: CRD420251028553). Results: Based on data from six clinical trials involving 850 patients, the pooled overall response and complete response or better rates were 69% and 42%, respectively, whereas the pooled rate of duration of response for at least one year was 71%. The estimated one-year progression-free survival and overall survival were 56% and 72%, respectively. Neutropenia was the most frequently observed severe hematological toxicity, with a pooled incidence of 46%. Grade ≥3 infections occurred in 29%, while any-grade CRS occurred in 69%, as per pooled analysis. Finally, an exploratory minimal residual disease (MRD) analysis in four of the six studies yielded a pooled MRD-negativity rate of 24%. Conclusions: BsAbs demonstrated commendable efficacy in heavily pretreated RRMM patients, in terms of response rates and survival outcomes. However, notable rates of hematologic toxicity, infections, and CRS were recorded. These findings support the clinical utility of BsAbs in RRMM, while highlighting the need for comprehensive toxicity management. Full article

Background: The limited aqueous solubility of BCS Class II drugs, exemplified by itraconazole (ITR), continues to hinder their bioavailability and therapeutic performance following oral administration. The present study investigated the development of amorphous solid dispersions (ASDs) of ITR via continuous manufacturing technologies, such as hot melt extrusion (HME) and spray drying (SD), to improve drug release. Methods: Polymer selection was guided by Hansen solubility parameter (HSP) analysis, film casting, and molecular modeling, leading to the identification of aminoalkyl methacrylate copolymer type A (Eudragit^® EPO), polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer (Soluplus^®), and hypromellose acetate succinate HG (AQOAT^® AS-HG) as suitable carriers. ASDs were prepared at drug-to-polymer ratios of 1:1, 1:2, and 2:1. Comprehensive characterization was performed using ATR-FTIR, NMR, DSC, PXRD, SEM, PLM, and contact angle analysis. Results: HME demonstrated higher process efficiency, solvent-free operation, and superior dissolution enhancement compared to SD. Optimized HME-based ASDs were formulated into tablets. The ITR–Eudragit^® EPO formulation achieved 95.88% drug release within 2 h (Weibull model, R² > 0.99), while Soluplus^® and AQOAT^® AS-HG systems achieved complete release, best described by the Peppas–Sahlin model. Molecular modeling confirmed favorable drug–polymer interactions, correlating with the formation of stable complex and enhanced release performance. Conclusions: HME-based continuous manufacturing provides a scalable and robust strategy for improving the oral delivery of poorly water-soluble drugs. Integrating predictive modeling with experimental screening enables the rational design of ASD formulations with optimized dissolution behavior, offering potential for improved therapeutic outcomes in BCS Class II drug delivery. Full article

Background: Monocarboxylate-transporter-8-(MCT8) deficiency, or Allan–Herndon–Dudley syndrome (AHDS), is a rare X-linked disorder caused by pathogenic variants in the SLC16A2 gene, leading to impaired transport of thyroid hormones, primarily T3 and T4, across cell membranes. The resulting central hypothyroidism and peripheral hyperthyroidism cause neurodevelopmental impairment and thyrotoxicosis. Despite the availability of therapy options, e.g., with triiodothyroacetic acid (TRIAC), diagnosis is often delayed, partly due to normal TSH levels or incomplete genetic panels. MCT8 deficiency is not yet included in newborn-screening programs worldwide. Case Description: We present a case of an infant genetically diagnosed with MCT8 deficiency at 5 months of age after presenting with muscular hypotonia, lack of head control, and developmental delay. Thyroid function testing revealed a normal TSH, low free T4, and significantly elevated free T3 and free T3/T4 ratio. Treatment with TRIAC (Emcitate^®) was initiated promptly, with close drug monitoring. Despite persistent motor deficits and dystonia, some developmental progress was observed, as well as reduction in hyperthyroidism. Discussion/Conclusions: This case underscores the importance of early free T3 and fT3/fT4 ratio testing in infants with unexplained developmental delay. Broader inclusion of SLC16A2 in genetic panels and consideration of newborn screening could improve early diagnosis and outcomes in this rare but treatable condition. Full article

This study systematically explored the interaction mechanisms between two KRAS G12C inhibitors (Sotorasib and Adagrasib) and human serum albumin (HSA) via UV-vis spectroscopy, fluorescence spectroscopy, three-dimensional fluorescence spectroscopy, and molecular docking methods. The experimental findings demonstrated that both drugs caused static quenching of HSA fluorescence, with binding constants of 13.64 × 10³ M⁻¹ (Sotorasib) and 63.67 × 10³ M⁻¹ (Adagrasib), demonstrating significant selectivity differences in their binding affinities. UV spectral analysis demonstrated distinct microenvironmental perturbations: Sotorasib and Adagrasib induced a shift (∆λ = 7 nm and ∆λ = 8 nm, respectively) at 211 nm, consistent with altered polarity in HSA’s binding pockets. Fluorescence spectroscopy confirmed a 1:1 binding stoichiometry, with Stern-Volmer analysis validating static quenching as the dominant mechanism. Three-dimensional fluorescence spectra further highlighted Adagrasib’s stronger conformational impact, reducing tyrosine and tryptophan residue fluorescence intensities by 16% (Peak 1) and 10% (Peak 2), respectively, compared to Sotorasib. Molecular docking revealed divergent binding modes: Sotorasib occupied Sudlow Site I via three hydrogen bonds and hydrophobic interactions (∆G = −24.60 kJ·mol⁻¹), whereas Adagrasib bound through one hydrogen bond and hydrophobic forces (∆G = −30.92 kJ·mol⁻¹), with stability differences attributed to structural characteristics. This study uses multispectral technology and molecular docking to reveal the binding mechanism of Sotorasib and Adagrasib with HSA, providing a theoretical basis for designing highly targeted albumin nanocarriers. The strong binding properties of Adagrasib and HSA may reduce the toxicity of free drugs, providing direction for the development of long-acting formulations. Full article

The escalating crisis of multidrug resistance, together with the persistence of antibiotic residues in clinical and environmental matrices, demands integrated strategies that couple sensitive detection, efficient decontamination, and controlled delivery. However, current techniques for quantifying avibactam (AVI)—a broad-spectrum β-lactamase inhibitor—such as HPLC-UV lack the sensitivity and specificity required for both therapeutic drug monitoring and environmental surveillance. Encapsulation of AVI within cyclodextrins (CDs) may simultaneously enhance its stability, bioavailability, and detectability, while the high binding affinities of CDs position them as molecular traps capable of scavenging residual AVI. In this study, the inclusion complexation of AVI with various CDs was examined through molecular dynamics (MD) simulations, experimental isothermal titration calorimetry (ITC), and non-covalent interaction (NCI) analysis. Stable 1:1 inclusion complexes were observed between AVI and β-cyclodextrin (β-CD), 2,6-dimethyl-β-cyclodextrin (DM-β-CD), and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), with standard Gibbs free energies of binding (ΔG°) of –3.64, –3.24, and –3.11 kcal/mol, respectively. In contrast, γ-cyclodextrin (γ-CD) exhibited significantly weaker binding (ΔG° = –2.25 kcal/mol). DFT-based NCI analysis revealed that cooperative interaction topology and cavity complementarity, rather than the sheer number of localized contacts, govern complex stability. Combined computational and experimental data establish β-CD derivatives as effective supramolecular hosts for AVI, despite an entropic penalty in the DM-β-CD/AVI complex. These CD–AVI affinities support the development of improved analytical methodologies and pharmaceutical formulations, and they also open avenues for decontamination strategies based on molecular trapping of AVI. Full article