Search Results (756)

Alterations in gene expression induced by ionizing radiation (IR) were commonly explained by transcriptional activation. However, the weak correlation between mRNA and protein levels following IR indicates the significant role for post-transcriptional regulation. microRNAs (miRNAs) bound to AGO2 play a significant role in post-transcriptional regulation; however, their role in radiation response is not clear. miRNA sequencing was performed to analyze the miRNAome of glioma cells. The effect of IR on Let-7 miRNAs and their association with AGO2 was examined using RT-qPCR and RNA immunoprecipitation (RIP) assays. Clonogenic assays were performed to measure radiosensitivity following Let-7a overexpression or knockdown. DNA damage (γH2AX foci) and cell cycle distribution were analyzed by immunofluorescence and flow cytometry. Let-7 miRNA regulatory networks were identified through target prediction and pathway enrichment analysis. AGO2-Let-7 binding decreased post IR, indicating impaired RISC loading. Let-7 overexpression increased radiosensitivity, DNA damage and G2/M cell cycle arrest in glioma and other cells (HeLa and MDA-MB-231). Let-7 miRNAs mainly targeted cell cycle and DNA damage response (DDR) pathways. Our study showed radiation impairs AGO2-miRNA binding, while restoring Let-7-AGO2 interaction enhances radiosensitivity by modulating DNA repair and cell cycle checkpoint activation. Targeting AGO2-miRNA dynamics represents a promising approach to improve radiotherapy outcomes. Full article

Acute pulmonary embolism (APE) represents a significant cause of morbidity and mortality worldwide, requiring rapid and precise diagnosis and effective therapy strategies. Computed Tomography Pulmonary Angiography (CTPA) is currently the gold standard technique for diagnosing PE; however, it presents some disadvantages, including limited sensitivity in detecting sub-segmental emboli and contrast-related risks. Recent advancements in imaging technologies, including Dual-Energy Computed Tomography (DECT) and Photon Counting (PC), offer improved sensitivity and specificity for APE and perfusion abnormalities detection. Digital Dynamic Radiography (DDR) perfusion imaging represents a novel imaging that allows pulmonary perfusion assessment without contrast medium administration, able to detect anomalies at the patient’s bedside, representing a promising advancement, particularly for critically ill or contrast-allergic patients. In parallel, interventional radiology has become integral to APE management, particularly for high-risk and intermediate–high-risk patients, with evolving intravascular treatment techniques such as catheter-directed thrombolysis, mechanical thrombectomy, and thrombus aspiration. This narrative review provides an overview of the latest developments in APE diagnostic imaging and interventional radiology, contextualizing them within current guideline recommendations for endovascular treatment. Full article

The rapid advancement of artificial intelligence has fundamentally transformed how knowledge is created, disseminated, and applied in problem-solving, presenting new challenges for educational models. This study introduces Intelligent Problem-Solving Learning (IPSL)—a capability-based instructional design framework aimed at cultivating learners’ adaptability, creativity, and meta-learning in AI-enhanced environments. Grounded in connectivism, extended mind theory, and the concept of augmented intelligence, IPSL places human–AI collaboration at the core of instructional design. Using a design and development research (DDR) methodology, the study constructs a conceptual model comprising three main categories and eight subcategories, supported by eighteen instructional design principles. The model’s clarity, theoretical coherence, and educational relevance were validated through two rounds of expert review using the Content Validity Index (CVI) and Inter-Rater Agreement (IRA). IPSL emphasizes differentiated task roles—those exclusive to humans, suitable for human–AI collaboration, or fully delegable to AI—alongside meta-learning strategies that empower learners to navigate complex and unpredictable problems. This framework offers both theoretical and practical guidance for building future-oriented education systems, positioning AI as a learning partner while upholding essential human qualities such as ethical judgment, creativity, and agency. It equips educators with actionable principles to harmonize technological integration with human-centered learning in an age of rapid transformation. Full article

Background: Clear cell renal cell carcinoma with rhabdoid features (ccRCC-R) is a highly aggressive variant of renal cell carcinoma that carries a poor prognosis and limited treatment options. Methods: To better define the clinicopathologic and molecular landscape of ccRCC-R, we conducted an integrated clinicopathologic and molecular study of 17 tumors of ccRCC-R, utilizing comprehensive histomorphologic evaluation, immunohistochemistry, and targeted next-generation sequencing (NGS). Results: Histologically, all tumors demonstrated classic clear cell renal cell carcinoma morphology with focal to extensive rhabdoid differentiation, characterized by eccentrically located nuclei, prominent nucleoli, abundant eosinophilic cytoplasm, and paranuclear intracytoplasmic inclusion. Architectural alterations, including solid/sheet-like, alveolar/trabecular, and pseudopapillary growth patterns, were frequently observed. Immunohistochemically, tumors commonly exhibited loss of PAX8 and Claudin4 expression, preserved cytokeratin AE1/AE3 staining, and diffuse membranous CAIX expression. Frequent loss of SMARCA2 with retained SMARCA4 supported aberrations in chromatin remodeling. Unsupervised hierarchical clustering based on pathway-specific somatic mutations identified four distinct molecular subgroups defined by recurrent alterations in (1) DNA damage repair (DDR) genes, (2) chromatin remodeling genes, (3) PI3K/AKT/mTOR signaling components, and (4) MAPK pathway genes. Clinicopathologic correlation revealed that each subgroup was associated with unique biological characteristics and suggested distinct therapeutic vulnerabilities. Conclusions: Our findings underscore the molecular heterogeneity of ccRCC-R and support the utility of pathway-based stratification for guiding precision oncology approaches and biomarker-informed clinical trial design. Full article

Background/Objectives: Current bone-based landmark approaches have shown variable accuracy and poor reproducibility. We validated a two-point “tuberculum sellae–anterior clinoid process” (TS–ACP) line traced on routine 3D-computed tomography angiography (CTA) for predicting distal dural ring (DDR) position and quantified the interobserver agreement. Methods: We retrospectively reviewed data from 85 patients (87 aneurysms) who were treated via clipping between June 2012 and December 2024. Two blinded neurosurgeons classified each aneurysm as extradural, intradural, or straddling the TS–ACP line. The intraoperative DDR inspection served as the reference standard. Diagnostic accuracy, χ² statistics, and Cohen’s κ were calculated. Results: The TS–ACP line landmarks were identifiable in all cases. The TS–ACP line classification correlated strongly with operative findings (χ² = 138.3, p = 6.4 × 10⁻²⁹). The overall accuracy was 89.7% (78/87), and sensitivity and specificity for identifying intradural aneurysms were 94% and 82%, respectively. The interobserver agreement was substantial (κ = 0.78). Nine aneurysms were misclassified, including four cavernous-sinus lesions that partially crossed the DDR. Retrospective fusion using constructive interference in steady-state magnetic resonance imaging corrected these errors. Conclusions: The TS–ACP line represents a rapid, reproducible tool that reliably localizes the DDR on standard 3D-CTA, showing higher accuracy than previously reported single-landmark techniques. Its high accuracy and substantial inter-observer concordance support incorporation into routine preoperative assessments. Because the method depends on only two easily detectable bony points, it is well-suited for automated implementation, offering a practical pathway toward artificial intelligence-assisted stratification of paraclinoid aneurysms. Full article

Vitiligo is a chronic autoimmune dermatosis defined by selective melanocyte depletion and patchy depigmentation. IFN–γ-driven recruitment of autoreactive CD8⁺ T cells and induction of melanocyte apoptosis are central to its pathogenesis. Current therapies—including UVB phototherapy, tacrolimus, vitamin D3 analogs, and surgical methods—show limited and inconsistent efficacy. Emerging treatments like JAK inhibitors and WNT activators offer potential but require further validation. Translational progress is hindered by a lack of scalable human models. Here, we describe a tunable in vitro vitiligo platform in which human iPSC-derived melanocytes (iMc) are co-cultured with keratinocytes on Matrigel and exposed to precise graded IFN-γ concentrations. Our data revealed dose-dependent decreases in iMc survival and dendritic structure, faithfully mirroring derived melanocyte pathology. Leveraging this platform, we first evaluated the short-term efficacy of the ROCK inhibitor Y27632 under early-stage patient IFN-γ concentrations representative of patient lesional thresholds. At three days, Y27632 significantly upregulated adhesion molecules E-cadherin and DDR1, and two central factors—ET1 and bFGF. Importantly, ROCK inhibition reversed dendritic retraction and improved overall viability of iMc-keratinocytes. These findings position ROCK blockade as a promising adjunctive strategy and establish a pre-clinical platform for evaluating combination therapies for durable pigment restoration. Full article

Accurate segmentation of retinal lesions is critical for the diagnosis and management of ophthalmic diseases, but pixel-level annotation is labor-intensive and demanding in clinical scenarios. To address this, we introduce a promptable segmentation approach based on prototype learning that enables precise retinal lesion segmentation from low-cost, coarse annotations. Our framework treats clinician-provided coarse masks (such as ellipses) as prompts to guide the extraction and refinement of lesion and background feature prototypes. A lightweight U-Net backbone fuses image content with spatial priors, while a superpixel-guided prototype weighting module is employed to mitigate background interference within coarse prompts. We simulate coarse prompts from fine-grained masks to train the model, and extensively validate our method across three datasets (IDRiD, DDR, and a private clinical set) with a range of annotation coarseness levels. Experimental results demonstrate that our prototype-based model significantly outperforms fully supervised and non-prototypical promptable baselines, achieving more accurate and robust segmentation, particularly for challenging and variable lesions. The approach exhibits excellent adaptability to unseen data distributions and lesion types, maintaining stable performance even under highly coarse prompts. This work highlights the potential of prompt-driven, prototype-based solutions for efficient and reliable medical image segmentation in practical clinical settings. Full article

With advancements in remote sensing technology and very-large-scale integration (VLSI) circuit technology, the Earth observation capabilities of spaceborne synthetic aperture radar (SAR) have continuously improved, leading to significantly increased performance demands for on-board SAR real-time imaging processors. Currently, the low data access efficiency of traditional direct memory access (DMA) engines remains a critical technical bottleneck limiting the real-time processing performance of SAR imaging systems. To address this limitation, this paper proposes a dedicated instruction set for spaceborne SAR data transfer control, leveraging the memory access characteristics of DDR4 SDRAM and common data read/write address jump patterns during on-board SAR real-time imaging processing. This instruction set can significantly reduce the number of instructions required in DMA engine data access operations and optimize data access logic patterns. While effectively reducing memory resource usage, it also substantially enhances the data access efficiency of DMA engines. Based on the proposed dedicated instruction set, we designed a DMA engine optimized for efficient data access in on-board SAR real-time imaging processing scenarios. Module-level performance tests were conducted on this engine, and full-process imaging experiments were performed using an FPGA-based SAR imaging system. Experimental results demonstrate that, under spaceborne SAR imaging processing conditions, the proposed DMA engine achieves a receive data bandwidth of 2.385 GB/s and a transmit data bandwidth of 2.649 GB/s at a 200 MHz clock frequency, indicating excellent memory access bandwidth and efficiency. Furthermore, tests show that the complete SAR imaging system incorporating this DMA engine processes a 16 k × 16 k SAR image using the Chirp Scaling (CS) algorithm in 1.2325 s, representing a significant improvement in timeliness compared to existing solutions. Full article

Discoidin domain receptor 1 (DDR1), a collagen-binding receptor tyrosine kinase, plays a key role in extracellular matrix remodeling, tumor progression, and immune evasion. However, DDR1’s comprehensive role across diverse cancers and its therapeutic potential in immune-resistant tumors remain poorly defined. We performed a pan-cancer analysis integrating bulk transcriptomic datasets, single-cell RNA sequencing, and pathway enrichment to evaluate DDR1 expression, genetic alterations, and its associations with immune cell infiltration and clinical outcomes. DDR1 was consistently overexpressed in 21 cancer types, correlating with poor prognosis and reduced immune cell infiltration. Mechanistically, DDR1 promoted collagen remodeling, immune exclusion, and upregulated immunosuppressive pathways. Single-cell analysis in pancreatic ductal adenocarcinoma (PDAC) revealed DDR1-high ductal cells associated with reduced cytotoxic T cell infiltration and increased regulatory T cell populations. Therapeutic blockade of DDR1 in an immunocompetent KPC mouse model of PDAC disrupted collagen architecture, enhanced CD8⁺ T cell infiltration, and improved responses to chemotherapy, highlighting a direct link between DDR1 inhibition and immune reactivation. These findings establish DDR1 as a key mediator of collagen-driven immune resistance and a promising therapeutic target for overcoming immune exclusion, especially in PDAC and other collagen-rich solid tumors. Full article

Prostate cancer accounts for approximately 1.5 million new diagnoses and 400,000 deaths every year worldwide, and demographic projections indicate a near-doubling of both figures by 2040. Despite existing treatments, 10–20% of patients eventually progress to metastatic castration-resistant disease (mCRPC). The median overall survival (OS) after progression to mCPRC drops to 24 months, and efficacy drops severely after each additional line of treatment. Omics platforms have reached advanced levels and enable the acquisition of high-resolution large datasets that can provide insights into the molecular mechanisms underlying PCa pathology. Genomics, especially DDR (DNA damage response) gene alterations, detected via tissue and/or circulating tumor DNA, efficiently guides therapy in advanced prostate cancer. Given recent developments, we have performed a comprehensive literature search to cover recent research and clinical trial reports (over the last five years) that integrate omics along three converging trajectories in therapeutic development: (i) predicting response to approved agents with demonstrated survival benefits, (ii) stratifying patients to receive therapies in clinical trials, (iii) guiding drug development as part of drug repurposing frameworks. Collectively, this review is intended to serve as a comprehensive resource of recent advancements in omics-guided therapies for advanced prostate cancer, a clinical setting with existing clinical needs and poor outcomes. Full article

Cells are assaulted daily by stresses that jeopardize genome integrity. Primary human cells adapt their response to the intensity of replication stress (RS) in a diphasic manner: below a stress threshold, the canonical DNA damage response (cDDR) is not activated, but a noncanonical cellular response, low-level stress-DDR (LoL-DDR), has recently been described. LoL-DDR prevents the accumulation of premutagenic oxidized bases (8-oxoguanine) through the production of ROS in an adaptive way. The production of RS-induced ROS (RIR) is tightly controlled: RIR are excluded from the nucleus and are produced by the NADPH oxidases DUOX1/DUOX2, which are controlled by NF-κB and PARP1; then, RIR activate the FOXO1-detoxifying pathway. Increasing the intensity of RS suppresses RIR via p53 and ATM. Notably, LoL-DDR is dysregulated in cancer cell lines, in which RIR are not produced by NADPH oxidases, are not detoxified under high-level stress, and favor the accumulation of 8-oxoguanine. LoL-DDR dysregulation occurred at an early stage of cancer progression in an in vitro model. Since, conversely, ROS trigger RS, this establishes a vicious cycle that continuously jeopardizes genome integrity, fueling tumorigenesis. These data reveal a novel type of ROS-controlled DNA damage response and demonstrate the fine-tuning of the cellular response to stress. The effects on genomic stability and carcinogenesis are discussed here. Full article

This study focuses on the evaluation of electrical stress limit capability for 3D-packaged memory (256 M × 72-bit DDR3 SDRAM) (Shanghai Fudan Microelectronics Group Co., Ltd., Shanghai, China). Guided by Reliability Enhancement Theory, this study presents a meticulously designed comprehensive test profile that incorporates critical stress parameters, including supply voltage, input clock frequency, electrostatic discharge (ESD) sensitivity, and electrical endurance. Explicit criteria for stress selection, upper/lower bounds, step increments, and duration are established. A dedicated test platform is constructed, integrating automated test equipment (ATE) and ESD sensitivity analyzers with detailed specifications on device selection criteria and operational principles. The functional performance testing methodology is systematically investigated, covering test platform configuration, initialization protocols, parametric testing procedures, functional verification, and acceptance criteria. Extreme-condition experiments—including supply voltage margining, input clock frequency tolerance, ESD sensitivity characterization, and accelerated electrical endurance testing—are conducted to quantify operational and destructive limits. The findings provide critical theoretical insights and practical guidelines for the design optimization, quality control, and reliability enhancement of 3D-packaged memory devices. Full article

DNA damage repair is a hallmark of any cancer growth, eventually leading to drug resistance and death. The poly ADP-ribose polymerase (PARP) enzyme is vital in repairing damaged DNA in normal and cancer cells with mutated DNA damage response (DDR) genes. Inhibitors of the PARP enzyme aid in chemotherapy, as shown by drug combinations such as Olaparib and Irinotecan in breast cancer treatment. However, the effect of Olaparib in colon cancer has not been studied extensively. Synthetic drugs have a significant limitation in cancer treatment due to drug resistance, leading to colon cancer relapse. Bioavailability of Olaparib and other PARP inhibitors is limited due to their hydrophobicity, which poses a significant challenge. These limitations and challenges can be addressed by encapsulating Olaparib in nanoparticles that could possibly increase the bioavailability of the drug at the site of action. New age nanoparticles, such as hybrid nanoparticles, provide superior quality in terms of design and circulatory time of the drug in the plasma. The side effects of Olaparib as a chemotherapeutic pave the way for exploring phytochemicals that may have similar effects. The combined impact of Olaparib and phytochemicals such as genistein, resveratrol and others in nano-encapsulated form can be explored in the treatment of colon cancer. Full article

Purpose: Neuroendocrine carcinomas (NECs) are aggressive tumors treated with cisplatin-based chemotherapy, though responses vary. As DNA damage response (DDR) pathways influence cisplatin sensitivity, this single-center retrospective study evaluates the efficacy of first-line cisplatin in recurrent or metastatic NEC based on DDR mutation status. Materials and Methods: This study analyzed patients with grade 3 recurrent or metastatic NEC treated with first-line etoposide plus cisplatin at Samsung Medical Center between January 2019 and September 2023. All patients underwent next-generation sequencing to determine DDR mutation status, defined by pathogenic alterations in major DNA repair pathways. Clinical outcomes were assessed per RECIST v1.1. Survival analyses were conducted using Kaplan–Meier methods and Cox regression models, with significance set at p ≤ 0.05. Results: A total of 40 patients with NEC were included in this study. There were 16 patients with DDR wild-type (WT) and 24 patients with DDR mutant type (MT). The most common primary tumor sites were the pancreas (25.0%), stomach (20.0%), and gallbladder/duct (12.5%). Among 40 patients, those with DDR mutations (n = 24) showed significantly higher objective response (58.3% vs. 12.5%) and disease control rates (91.7% vs. 50.0%) compared to patients with DDR WT (n = 16). The median progression-free survival (PFS) showed the favorable trend in the DDR mutant group (8.0 vs. 4.3 months; p = 0.15), with similar trends observed across homologous recombination repair (HRR), Fanconi anemia (FA), and mismatch repair (MMR) subgroups. Conclusions: This study revealed that patients with DDR mutations had significantly higher response to first-line etoposide–cisplatin, suggesting DDR mutation status as a potential predictive marker to guide treatment and improve outcomes in recurrent or metastatic NEC. Full article

The pyrrolo[2,3-d]pyrimidine (7-deazapurine) scaffold is a unique heterocyclic system included in the composition of most nucleotides. In this study, series of the pyrrolo[2,3-d]pyrimidine-imines and 3-halo-substituted pyrrolo[2,3-d]pyrimidines were designed and prepared in high yields. Condensed pyrimidines are obtained via carbonyl-amine condensation and carbon-halogen bond formation. Pyrrolo[2,3-d]pyrimidine-imines containing a bromine substituent at position C-4 of the phenyl ring and azepine side-ring exhibited superior antitumor activity on the colon cancer HT-29 cell line; IC₅₀ values were 4.55 and 4.01 µM, respectively. These results revealed an interesting pattern, where condensed pyrimidinones containing an azepine ring demonstrated selective antitumor activity on the colon cancer cell line HT-29. In addition, the molecular docking results suggest that compound 8g provided a thorough understanding of its interactions with the DDR2 active site. This could pave the way for further development and optimization of DDR-targeting drugs, contributing to advancements in cancer therapeutics. This lead compound may serve as design templates for further studies. Full article