Search Results (584)

Background/Objectives: Metastatic colorectal cancer (mCRC) remains difficult to treat, largely due to chemotherapy resistance. Mutations in TP53 impair apoptosis and are associated with poor response to irinotecan. This study aimed to determine whether targeting Survivin, a key inhibitor of apoptosis, and using the disulfiram-derived compound CuET could restore apoptotic signaling and improve irinotecan efficacy. Methods: Human CRC cell lines with varying TP53 status and murine tumor models were treated with irinotecan (or its active metabolite SN-38), the Survivin inhibitor YM-155, and CuET, alone or in combination. Cell viability, clonogenic survival, and apoptotic signaling were assessed using cytotoxicity assays, flow cytometry, confocal microscopy, and Western blotting. In vivo efficacy was evaluated in xenograft and syngeneic mouse models through tumor growth measurements and histological analyses. Results: Inhibition of Survivin with YM-155 enhanced irinotecan-induced cytotoxicity and promoted caspase-dependent apoptosis in CRC cells. Irinotecan treatment induced Survivin expression, suggesting an adaptive resistance mechanism that was reversed by YM-155. CuET demonstrated potent cytotoxic activity independent of TP53 status and partially suppressed Survivin expression. Importantly, CuET restored sensitivity to irinotecan in TP53-deficient models and significantly enhanced antitumor efficacy in vivo, leading to reduced tumor growth, decreased proliferation, and increased apoptosis. Conclusions: These findings identify Survivin-mediated apoptotic resistance as a key determinant of irinotecan response in CRC. Targeting this pathway, either directly through Survivin inhibition or through CuET-induced stress responses, restores apoptotic sensitivity and enhances chemotherapy efficacy. This study supports the development of combination strategies incorporating CuET to overcome resistance in TP53-mutant CRC. Full article

We present a brief review that highlights the importance of III-Nitride semiconductor compounds according to their structural, compositional, morphological, and optical properties, which have significant applications in new semiconductor devices and play a fundamental role in modern electronic and optoelectronic technologies. The importance of sputtering as a viable alternative for obtaining III-Nitride semiconductor compounds is discussed. This is due to its versatility, cost, ease of handling, and advantages provided by the physics of its operation in obtaining thin films compared to techniques such as metal–organic chemical vapor deposition (MOCVD), atomic layer deposition (ALD), and molecular beam epitaxy (MBE). The physics of the sputtering method is briefly and clearly described, including magnetron configurations, plasma generation, energy dependence of sputtering, reactive sputtering, hysteresis effects, target types, and the importance of temperature and working distance between the substrate and target. In addition, the review of the literature on the application of sputtering for obtaining III-Nitride semiconductor compounds is presented. Furthermore, this review also highlights the future of sputtering, which is moving towards high-power pulsation, atomic-level precision, and AI-driven automation due to the miniaturization of electronics, advances in green technology, and innovations in plasma control to increase film density and reduce target material loss. Full article

Background/Objectives: The advent of immune checkpoint inhibitors (ICIs) and targeted therapies has revolutionized advanced melanoma treatment but introduced unique immune-related adverse events (irAEs). Hematological irAEs (Hem-irAEs) are rare but carry disproportionately high morbidity and mortality. This review systematically synthesizes current literature to comprehensively understand the incidence, pathophysiology, clinical presentation, and management of Hem-irAEs in modern melanoma therapy. Methods: A comprehensive Web of Science literature search (January 2015 to January 2026) identified studies reporting hematological adverse events associated with melanoma immunotherapy and targeted therapies. After screening 2274 records, 130 relevant studies were included for quantitative data extraction, focusing on incidence rates and toxicity grading. Results: Hem-irAEs occur infrequently (under 4% overall incidence for ICIs) but possess staggering mortality rates between 12% and 15.5%. The most common manifestations are immune thrombocytopenia (ITP), autoimmune hemolytic anemia, and neutropenia. Combination regimens significantly amplify toxicity frequency and severity. Diagnosis requires meticulous baseline monitoring and bone marrow biopsies to differentiate peripheral destruction from central marrow failure. First-line management mandates ICI discontinuation and high-dose corticosteroids, utilizing targeted second-line immunosuppressants for refractory syndromes. Conclusions: Hem-irAEs embody a profound clinical paradox: while mild toxicities often herald a robust anti-tumor response, severe hematological events drastically increase non-cancer mortality, negating these oncological benefits. Navigating this “double-edged sword” demands a paradigm shift toward proactive risk stratification. Integrating predictive biomarkers including baseline autoantibodies, Human Leukocyte Antigens (HLA) profiling, and systemic inflammatory indices is crucial to identify vulnerable populations before treatment. Optimizing outcomes requires highly personalized vigilance to balance the life-saving efficacy of immunotherapy against the catastrophic threat of hematopoietic failure. Full article

Carrier-based fixed-wing UAV landing is challenged by deck motion, carrier airwake, gust disturbances, strong trajectory–attitude coupling, and actuator constraints. To address these issues, this paper proposes a Predefined-Time Direct Lift/Side-Force-Integrated Approach Landing (PTDIAL) method. An integrated direct-force architecture is constructed using the trailing-edge flap for direct lift and the spoiler for direct side force, thereby reducing the dependence of trajectory correction on angle-of-attack- and bank-angle/sideslip-mediated regulation. A preview-based reference glide slope is generated from the predicted Ideal Touch Point (ITP) sequence to improve the response to deck motion. Predefined-time control laws are developed for the cascaded position, trajectory, attitude, angular rate, and velocity loops, with prescribed-performance constraints imposed on the attitude response. A predefined-time disturbance observer is introduced to estimate the lumped aerodynamic disturbances, while an auxiliary anti-saturation mechanism compensates for the effect of trailing-edge flap saturation. Lyapunov analysis establishes the practical predefined-time stability of the closed-loop system under bounded disturbances and actuator constraints. Various simulations demonstrate that the proposed architecture improves lateral and vertical tracking while preserving the UAV attitude, and Monte Carlo simulations further confirm the robustness of PTDIAL. Full article

Background: Non-invasive therapies for heart failure represent one of the current major focuses in clinical research. Plant-derived extracellular vesicles (PEVs) have recently emerged as a promising therapeutic modality. Objectives: In this study, we investigated the therapeutic potential of PEVs in heart failure with preserved ejection fraction (HFpEF), focusing on extracellular vesicles derived from Lycium barbarum (Gq-EVs). Methods: We first obtained Gq-EVs with high biological activity and high concentration from Lycium barbarum juice and characterized them by using transmission electron microscopy, nanoparticle tracking analysis, and metabolite composition analysis. Results: Our in vivo findings indicate that nebulized inhalation of Gq-EVs for 7, 14, and 21 days improved abnormal cardiac diastolic function, reduced excessive myocardial hypertrophy, and attenuated inflammatory cell infiltration and collagen deposition in HFpEF mice. Further in vivo and in vitro experiments showed that Gq-EVs can reach injured cardiac tissue, improve mitochondrial function, and are associated with reduced cardiomyocyte apoptosis and amelioration of myocardial hypertrophy, potentially involving TP53-related apoptotic signaling. Conclusions: Overall, nebulized delivery of Gq-EVs may be a relatively non-invasive, well-tolerated, and cost-effective therapeutic strategy for HFpEF, highlighting the potential of PEV-based nanotherapies and offering a sustainable approach for the medical utilization of Lycium barbarum resources. Full article

The valorization of wood derived from thinning operations in tropical plantations represents an alternative to enhance the sustainability and profitability of forest production systems. This study evaluated the hygroscopic, physical, and machining properties of 13-year-old Simarouba amara Aubl. thinning wood obtained from a plantation established in the Peruvian Amazon. Two planting spacings (2 × 2 m and 3 × 3 m) and three longitudinal stem positions (base, middle, and apex) were analyzed using a factorial design and generalized linear mixed models. Planting density and longitudinal position significantly influenced (p < 0.05) most of the evaluated properties. The saturated moisture content increased from 96.17% at the base to 135.42% at the apex, whereas basic density decreased from 0.45 to 0.30 g cm⁻³. Volumetric shrinkage ranged from 10.19% to 14.81%, and the dimensional stability index varied between 1.66 and 1.91. The first principal component (PC1) explained 98.4% of the total variance and clearly differentiated the treatments. The wood exhibited excellent performance in planing and molding, good performance in drilling, and fair performance in turning, indicating strong potential for the manufacture of higher value-added products and for sustainable utilization in tropical plantation forests. Full article

Glioblastoma (GB), the most prevalent and aggressive brain tumor, remains one of the most lethal challenges in modern oncology. Standard therapy remains largely ineffective, mainly due to limited therapeutic penetration across the blood–brain barrier (BBB) and adaptive tumor resistance. Consequently, there is an urgent need for innovative strategies to enhance therapeutic precision and efficacy. To address these limitations, we engineered a targeted peptide-based co-delivery system using the WRAP5 cell-penetrating peptide functionalized with a transferrin receptor (TfR)-targeting T7 peptide (sequence: HAIYPRH), enabling simultaneous delivery of temozolomide (TMZ) and a p53-encoding plasmid DNA. The resulting peptide-based TMZ/p53 nanocomplexes exhibited favorable physicochemical properties, enhanced TfR-mediated cellular uptake, and targeted antitumor activity mediated through p53-induced apoptosis in two-dimensional (2D) U87 MG cell cultures. To better reproduce the structural and cellular complexity of the tumor microenvironment, a three-dimensional U87 MG spheroid model was established and optimized using a Design of Experiments (DoE) approach to improve reproducibility and physiological relevance. The developed WRAP5-based nanocomplexes induced a significant dose-dependent inhibition of growth and morphological alterations in the U87 MG spheroid model, accompanied by deep penetration and cell death throughout the spheroid. Collectively, these findings highlight the potential of this targeted and tailored nanosystem to enhance cellular transfection, enable drug/gene co-delivery, restore p53 function, and promote apoptosis, representing a promising therapeutic strategy for GB treatment. Full article

Oral squamous cell carcinoma (OSCC) is the most common malignancy of the head and neck, with current treatments offering limited improvement in survival outcomes. This has driven interest in natural compounds as potential therapeutic alternatives. Cosmos caudatus (CC), commonly known as “ulam raja,” possesses antioxidant and anticancer properties, but its effects on OSCC remain insufficiently explored. This study aimed to evaluate the cytotoxic effects of CC extract and its impact on TP53/p53 and CD44 expression in an OSCC cell line in vitro. Cells were characterised using immunocytochemistry (ICC) and treated with CC extract (10–80 mg/mL). Cell viability was assessed using the MTT assay, while TP53 and CD44 gene expression were analysed via RT-qPCR. p53 protein levels were quantified using ELISA, and ICC was performed to assess protein expression. Results: CC demonstrated significant cytotoxicity with an IC₅₀ of 58 mg/mL (p < 0.05). Treatment resulted in significant downregulation of TP53/p53 at both gene and protein levels (p < 0.05), alongside increased CD44 mRNA expression but reduced protein staining. CC may therefore have potential as a plant-derived adjunctive therapeutic agent, although further studies are required to elucidate its mechanisms and clinical applicability. Full article

Dynamic comparators are key building blocks in low-power successive-approximation-register (SAR) analog-to-digital converters (ADCs), where energy efficiency, decision speed, and reliable operation under process, voltage, and temperature (PVT) variations are essential design requirements. This paper presents a 0.8 V subthreshold double-tail dynamic comparator incorporating a threshold-controlled latch activation mechanism for differential 10-bit SAR ADC applications. By delaying latch regeneration until sufficient differential voltage amplification is established by the dynamic amplifier stage, the proposed architecture suppresses premature regeneration, reduces kickback-induced disturbances, and improves comparator operation under low-voltage conditions. To comprehensively evaluate robustness under extreme operating conditions, a dedicated Input Test Pattern (ITP)-based validation methodology was developed and applied across 45 PVT corners comprising TT, SS, FF, FS, and SF process conditions, ±10% supply-voltage variation (0.72–0.88 V), and temperatures ranging from 0 °C to 100 °C. The comparator was implemented in a 180 nm CMOS technology and evaluated through schematic and post-layout simulations. Under nominal operating conditions, the proposed comparator resolved a minimum differential input voltage of 0.8 mV while achieving a post-layout regeneration delay of 327 ps, an average power consumption of 41.4 nW, and an energy efficiency of 20.7 fJ/comparison-step. In addition, the proposed architecture achieved a peak-to-peak kickback noise of 197 mV and successfully passed all 45 post-layout PVT corner simulations, demonstrating reliable functionality under wide process, voltage, and temperature variations. These results validate the effectiveness of the proposed threshold-controlled latch activation mechanism and the ITP-based validation methodology, demonstrating that the proposed JRR2 comparator provides an effective balance among low-voltage operation, decision speed, ultra-low-power consumption, energy efficiency, and robustness for differential 10-bit SAR ADC applications. Full article

Background: Pancreatic ductal adenocarcinoma (PDAC) carries a dismal prognosis, and KRAS and TP53 mutational status is increasingly recognized as both prognostic and therapeutically actionable. Because next-generation sequencing has long turnaround times, high costs, and substantial tissue requirements, we aimed to develop and externally validate a deep-learning framework for inferring KRAS and TP53 mutation status directly from routine hematoxylin-and-eosin (H&E) whole-slide images (WSIs) of PDAC. Methods: A training cohort was assembled from TCGA-PAAD (n = 206) and CPTAC-PAAD (n = 147), and an independent external validation cohort (n = 86) was obtained from Osaka Metropolitan University (OMU) Hospital. We benchmarked 28 model configurations per gene, comprising three pathology foundation models (CONCH-v1.5, CTransPath, and Prov-GigaPath) crossed with nine multiple-instance-learning (MIL) aggregators (ABMIL, CLAM-SB, CLAM-MB, DSMIL, TransMIL, MeanMIL, MaxMIL, AEM, and MIL-Dropout), plus a ResNet-50 + MeanMIL baseline. Performance was evaluated by patient-level five-fold cross-validation (AUC, accuracy, precision, sensitivity, and specificity) and external AUC; attention heatmaps were generated for interpretability. Results: For KRAS, CONCH-v1.5 + MeanMIL achieved the best internal AUC of 0.717 and CONCH-v1.5 + ABMIL the best external AUC of 0.705. For TP53, CTransPath + DSMIL achieved the best internal AUC of 0.668 and CTransPath + MeanMIL the best external AUC of 0.744. Conclusions: H&E-based deep learning can infer KRAS and TP53 mutation status in PDAC with moderate but reproducible discrimination, supporting its potential as a low-cost upstream prescreening tool that triages candidates for confirmatory molecular sequencing and genotype-directed targeted therapy. Full article

Chronic lymphocytic leukemia (CLL) is a genetically heterogeneous disease in which TP53 alterations represent major adverse prognostic factors; this study aims to describe the clinical implications of complex TP53 disruption in a rare case context. Molecular and cytogenetic profiling was performed using MLPA for copy number variations and targeted next-generation sequencing for mutation detection, following DNA extraction from peripheral blood and standardized bioinformatic analysis pipelines. The patient exhibited concomitant del(13q14) and del(17p13), alongside two pathogenic TP53 mutations, indicating functional inactivation of p53 and a high-risk genomic profile; despite this, treatment with a Bruton’s tyrosine kinase inhibitor resulted in significant hematological improvement within six months. These findings highlight that adverse TP53 alterations override favorable cytogenetic markers and emphasize the necessity of comprehensive genomic testing to guide prognosis and personalized therapy in CLL. Full article

Addressing critical bottlenecks in traditional hydrogen refueling station operations—specifically supply–demand imbalances and suboptimal scheduling—this paper presents a systematic review of the advancements and practical implementations of intelligent transportation platforms (ITPs). We explore how these platforms catalyze enhancing operational efficiency within the hydrogen ecosystem. This paper first outlines the technical foundations of Vehicle-to-Everything communication, edge computing, and multi-source data fusion, and provides an in-depth analysis of core challenges, such as demand uncertainty and resource scheduling complexity, as well as existing optimization algorithms. Through typical case studies, the significant value of such platforms in breaking down data silos, reducing equipment idle rates, and achieving end-to-end energy efficiency optimization is demonstrated. This study notes that current bottlenecks include fragmented standards, difficulties in implementing algorithms, commercial challenges, and the retrofitting of existing infrastructure. Moving forward, efforts should shift from isolated technological breakthroughs to ecosystem development. This includes improving demand forecasting accuracy in low-penetration regions, implementing lightweight retrofits to revitalize the existing market, establishing cross-domain data collaboration standards, building a trustworthy cross-platform settlement system, and exploring innovative pathways that integrate “hydrogen, carbon, and computing.” Full article

Myelodysplastic syndromes are clonal hematopoietic neoplasms in which ineffective hematopoiesis arises within the context of chronic inflammation and immune dysregulation. Growing evidence indicates that aging-associated inflammaging and inflammation-driven remodeling of the bone marrow microenvironment are not secondary phenomena, but active forces that shape clonal selection, lineage commitment, and disease evolution. This narrative review integrates recent insights from translational immunology, stem cell biology, multi-omics analyses, and clinical studies to examine the reciprocal interplay between inflammation and myelodysplastic syndrome pathogenesis. Chronic inflammatory stress imposes selective pressure on hematopoietic stem cells, favoring the expansion of mutation-bearing clones characteristic of clonal hematopoiesis and overt disease. As inflammation persists, immune dysfunction, together with stromal alterations, progressively reinforce ineffective hematopoiesis and clonal dominance. Genetic lesions, including TP53 and spliceosome mutations, further amplify inflammatory signaling and reshape the marrow niche, conferring clonal fitness and genomic instability. Clinically, readily accessible peripheral blood inflammatory indices reflect these biological processes and correlate with prognosis and therapeutic response. Collectively, these observations position inflammation as a unifying determinant of myelodysplastic syndrome initiation, progression, and treatment sensitivity. Integrating inflammatory signatures with genomic profiling may refine risk stratification and support the development of therapeutic strategies aimed at restoring marrow homeostasis and limiting inflammation-driven clonal evolution. Full article

The oncocytic variant of adrenocortical carcinoma (OACC) represents an exceptional type of adrenal malignancy, with heterogenous presentation. Currently, the genetic and molecular spectrum remains an open matter. A 20-year-old adult was accidentally found with a 7.2 cm adrenal tumor and underwent an open right adrenalectomy with OACC confirmation. Post-adrenalectomy positron emission tomography/computed tomography was negative. Immunohistochemistry was positive for calretin, inhibin, steroidogenic factor 1; Ki67 of 20%. Microsatellite instability was 7.61. Lin–Weiss–Bisceglia score showed 2 major criteria [mitoses 6/50 HPF + positive atypical mitoses], the reticuline algorithm (disrupted reticuline network + mitoses 6/50 HPF) was consistent for a malignant behavior, the Helsinki score was of 48. Next generation sequencing identified a likely pathogenic variant of CEL gene (heterozygote, c.539-2A>G) in peripheral blood and two pathogenic variants in the tumor: exon 48, NF1 gene [c.7159_7164del p.(N2387_F2388del)] and exon 6, TP53 gene [c.596delG p.(G199Efs*48)]. Polycystic ovary syndrome type A has been diagnosed as teenager with no phenotype change before the tumor detection. After surgery, oocyte retrieval and cryopreservation upon ovarian stimulation protocol (OSP) was performed before starting mitotane therapy. To the best of our knowledge, this is a novel genetic configuration in OACC with an impact on prognosis to be determined. Hyperandrogenemia stands on a dual source (potential CEL-driven insulin resistance for the ovary and OACC-originating for the adrenal glands). Also, this is the first case to receive OSP in OACC, noting that a tailored multidisciplinary management is mandatory. Full article

Immune thrombocytopenia (ITP) is a heterogeneous autoimmune disorder characterized by immune-mediated platelet destruction and impaired platelet production. Increasing evidence suggests that systemic inflammation plays a significant role in disease pathogenesis and clinical outcomes. This study aimed to evaluate the prognostic significance of inflammatory indices and their association with complications, mortality, treatment response, and relapse in patients with ITP. In this single-center retrospective study, 166 adult patients diagnosed with primary ITP between January 2015 and December 2024 were analyzed. Demographic, clinical, and laboratory data at diagnosis were collected. Inflammatory indices derived from complete blood count parameters, including neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), were evaluated. Their associations with clinical outcomes were assessed using appropriate statistical methods. During the observation period based on retrospective medical records, complications occurred in 12% of patients, and mortality was observed in 6.6%. Patients with complications had significantly higher D-dimer levels and reduced bone marrow megakaryocyte production. In group comparisons, mortality was significantly associated with advanced age, male sex, and comorbidities. Laboratory findings revealed that lower hemoglobin, lymphocyte count, mean platelet volume, and albumin levels, along with higher PLR, erythrocyte sedimentation rate, bilirubin, and D-dimer levels, were significantly associated with mortality. Inflammatory indices such as NLR and PLR were not associated with complication development, but PLR was significantly associated with mortality. Response to intravenous immunoglobulin (IVIG) therapy was significantly associated with higher total protein, albumin, and fibrinogen levels, and lower erythrocyte sedimentation rate. Relapse was significantly associated in group comparisons with increased inflammatory activity, higher reticulocyte count, and positivity for antinuclear antibodies and Helicobacter pylori antigen. Systemic inflammation and impaired megakaryopoiesis play critical roles in the prognosis of ITP. While conventional inflammatory indices showed limited predictive value for complications, markers such as PLR, D-dimer, and albumin were associated with mortality and clinical outcomes. These findings suggest that readily available laboratory parameters may provide valuable insights for risk stratification and personalized management in patients with ITP. Full article