war ; armed conflicts ; Nuclear Energy ; Atomic Energy ; Radiation ; Nuclear Weapons

war ; Armed Conflicts ; Nuclear Energy ; Atomic Energy ; Radiation ; Nuclear Weapons

Objective: To perform an in silico bioinformatics analysis to identify differentially expressed microRNAs (miRNAs) implicated in rheumatoid arthritis (RA) pathogenesis and evaluate their potential as biomarkers for assessing therapeutic efficacy and monitoring acupuncture treatment. Methods: miRNA microarray data (CEL and TXT formats) were acquired from human and murine RA models, with the latter undergoing acupuncture treatment. Data were normalized using the robust multi-array average (RMA) method and analyzed for differential expression. Differential expression analysis identified miRNAs through a comparative analysis of RA human tissues, acupuncture-treated murine RA models, and a bibliographic search for miRNAs implicated in RA pathogenesis and acupuncture treatment. Bioinformatics analysis was performed to identify potential target genes for each miRNA and signaling pathways via search tools for the Retrieval of Interacting Genes/Proteins (STRING) and ShinyGO. Gene-drug interaction analysis was performed through Drug-Gene Interaction Database (DGIdb) screening. Interaction networks were constructed with the Cytoscape v3.10.3 software. Results: The hsa-miR-125a-5p and hsa-miR-125b-5p were identified as potential biomarkers associated with RA pathogenesis, presenting 468 and 455 target genes, respectively. These genes were enriched in 20 signaling pathways, including Janus kinasa-signal transducer and activator of transcription (JAK-STAT), mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase-protein kinase B (PI3K-Akt), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway, which have been associated with RA pathogenesis and progression. Drug-gene interaction networks revealed that 22 genes were significantly associated with 58 RA treatment drugs, among which 13 genes interacted with members of the hsa-miR-125 family. Conclusion The hsa-miR-125a-5p and hsa-miR-125b-5p demonstrate critical regulatory role in RA pathogenesis by modulating signaling pathways, including JAK-STAT, MAPK, PI3K-Akt, and NF-κB. Our findings show that the hsa-miR-125a-5p and hsa-miR-125b-5p exhibit differential expression patterns in response to pharmacological intervention in various diseases, including RA management. This suggests their potential roles as biomarkers for monitoring acupuncture treatment. Although existing evidence indicates that acupuncture can modify miRNA expression profiles, rigorous validation through biological models remains essential to confirm these results.

Over the past two decades, marked progress has been made in treating non-small cell lung cancer (NSCLC) patients with EGFR-, ALK-, ROS1- and KRAS^G12C-targeted inhibitors. NSCLC patients very often develop brain metastases. Despite the continuous development of newer and better inhibitors, the survival outcomes of NSCLC patients with brain metastases remain significantly worse than those of patients without. The main challenges in these pharmacotherapies are the development of resistance mutations, and, potentially, the presence of the blood-brain barrier (BBB). The outcomes of clinical studies show the improved efficacy of later-generation targeted inhibitors. The increase in progression free survival (PFS) in patients treated with these later-generation inhibitors is largely attributed to their efficacy against multiple resistance mutations, and possibly due to enhanced brain penetration. This review explores the different aspects hindering the targeted treatment of NSCLC and especially of brain metastases, focusing on recent clinical trials and emerging resistance mutations and the influence of the BBB on the efficacy of EGFR, ALK, ROS1 and KRAS^G12C inhibitors. The role of the ABCB1 and ABCG2 drug transporters in differential efflux of the targeted drugs at the BBB is also discussed, since preclinical studies indicate that they may reduce the efficacy of transported inhibitors.

Human ; Complicity ; Consciousness ; Residence Characteristics

Acoustic Vibration Enhances Osteogenic Differentiation in Dental Mesenchymal Stem Cells Vibration-assisted orthodontic treatment accelerates tooth movement and reduces complications associated with prolonged interventions. While vibration has been shown to enhance osteogenic potential in bone marrow-derived mesenchymal stem cells (MSCs), its effects on dental tissue-derived MSCs remain unclear. This study investigated the impact of acoustic-frequency vibratory stimulation (AFVS) on gingival-tissue-derived MSCs (GT-MSCs) at 20 Hz and 60 Hz under both basal and osteogenic conditions. A custom vibratory platform was developed, and GT-MSCs were assessed for viability, proliferation, and osteogenic differentiation. Resazurin assay, Calcein-AM staining, and vimentin immunohistochemistry were used to evaluate cell viability, proliferation, and morphology, while Alizarin Red staining and calcium accumulation assays measured extracellular matrix mineralization at 7, 14, and 21 days. A Reverse-Transcription Quantitative Polymerase Chain Reaction (RT-qPCR) reaction was performed to quantify osteogenic markers (colagen type I [COL-I], osteopontin [OPN], and alkaline phosphatase [ALP]), and protein expression for COL-I and OPN was confirmed by immunohistochemistry. The results showed that AFVS at 20 Hz and 60 Hz enhanced osteogenic differentiation in GT-MSCs compare with other groups. Extracellular matrix mineralisation increased significantly, with 60 Hz resulting in the highest calcium deposition. Transcript levels of COL-I and OPN were markedly upregulated at 60 Hz, indicating a frequency-dependent response. Cell proliferation was also promoted, with optimal results observed at 60 Hz compare with other groups. These findings highlight the role of mechanical stimulation in enhancing the osteogenic potential of GT-MSCs, suggesting that AFVS is a promising tool for regenerative and orthodontic treatments. This study provides new insights into the frequency-specific effects of vibration, supporting the use of vibration therapy strategies in dental applications.

The reconstruction of craniomaxillofacial bone defects remains clinically challenging.To date,autogenous grafts are considered the gold standard but present critical drawbacks.These shortcomings have driven recent research on craniomaxillofacial bone reconstruction to focus on synthetic grafts with distinct materials and fabrication techniques.Among the various fabrication methods,additive manufacturing(AM)has shown significant clinical potential.AM technologies build three-dimensional(3D)objects with personalized geometry customizable from a computer-aided design.These layer-by-layer 3D biomaterial structures can support bone formation by guiding cell migration/proliferation,osteogenesis,and angiogenesis.Additionally,these structures can be engineered to degrade concomitantly with the new bone tissue formation,making them ideal as synthetic grafts.This review delves into the key advances of bioceramic grafts/scaffolds obtained by 3D printing for personalized craniomaxillofacial bone reconstruction.In this regard,clinically relevant topics such as ceramic-based biomaterials,graft/scaffold characteristics(macro/micro-features),material extrusion-based 3D printing,and the step-by-step workflow to engineer personalized bioceramic grafts are discussed.Importantly,in vitro models are highlighted in conjunction with a thorough examination of the signaling pathways reported when investigating these bioceramics and their effect on cellular response/behavior.Lastly,we summarize the clinical potential and translation opportunities of personalized bioceramics for craniomaxillofacial bone regeneration.

The reconstruction of craniomaxillofacial bone defects remains clinically challenging.To date,autogenous grafts are considered the gold standard but present critical drawbacks.These shortcomings have driven recent research on craniomaxillofacial bone reconstruction to focus on synthetic grafts with distinct materials and fabrication techniques.Among the various fabrication methods,additive manufacturing(AM)has shown significant clinical potential.AM technologies build three-dimensional(3D)objects with personalized geometry customizable from a computer-aided design.These layer-by-layer 3D biomaterial structures can support bone formation by guiding cell migration/proliferation,osteogenesis,and angiogenesis.Additionally,these structures can be engineered to degrade concomitantly with the new bone tissue formation,making them ideal as synthetic grafts.This review delves into the key advances of bioceramic grafts/scaffolds obtained by 3D printing for personalized craniomaxillofacial bone reconstruction.In this regard,clinically relevant topics such as ceramic-based biomaterials,graft/scaffold characteristics(macro/micro-features),material extrusion-based 3D printing,and the step-by-step workflow to engineer personalized bioceramic grafts are discussed.Importantly,in vitro models are highlighted in conjunction with a thorough examination of the signaling pathways reported when investigating these bioceramics and their effect on cellular response/behavior.Lastly,we summarize the clinical potential and translation opportunities of personalized bioceramics for craniomaxillofacial bone regeneration.

The mammalian carboxylesterase 1 (Ces1/CES1) family comprises several enzymes that hydrolyze many xenobiotic chemicals and endogenous lipids. To investigate the pharmacological and physiological roles of Ces1/CES1, we generated Ces1 cluster knockout (Ces1 ^-/- ) mice, and a hepatic human CES1 transgenic model in the Ces1 ^-/- background (TgCES1). Ces1 ^-/- mice displayed profoundly decreased conversion of the anticancer prodrug irinotecan to SN-38 in plasma and tissues. TgCES1 mice exhibited enhanced metabolism of irinotecan to SN-38 in liver and kidney. Ces1 and hCES1 activity increased irinotecan toxicity, likely by enhancing the formation of pharmacodynamically active SN-38. Ces1 ^-/- mice also showed markedly increased capecitabine plasma exposure, which was moderately decreased in TgCES1 mice. Ces1 ^-/- mice were overweight with increased adipose tissue, white adipose tissue inflammation (in males), a higher lipid load in brown adipose tissue, and impaired blood glucose tolerance (in males). These phenotypes were mostly reversed in TgCES1 mice. TgCES1 mice displayed increased triglyceride secretion from liver to plasma, together with higher triglyceride levels in the male liver. These results indicate that the carboxylesterase 1 family plays essential roles in drug and lipid metabolism and detoxification. Ces1 ^-/- and TgCES1 mice will provide excellent tools for further study of the in vivo functions of Ces1/CES1 enzymes.