Proliferative retinopathy (PR), a leading cause of visual impairment, is characterized by pathological retinal neovascularization. As an important methyltransferase, methyltransferase-like 14 (METTL14) plays a key role in the N6-methyladenosine (m6A) modification, which is the most widespread modification in mRNA and has been defined as a critical regulator in retinal diseases. This study aims to clarify the mechanisms by which METTL14 regulates pathological retinal neovascularization in PR. The m6A levels were determined by m6A RNA colorimetric quantification in mice retinas and endothelial cells. The METTL14 levels in mice retinas and endothelial cells were detected by qPCR, western blotting and immunofluorescence assays. Retinal flat mounts from the oxygen-induced retinopathy (OIR) mice were used to assess the effects of METTL14 on retinal neovascularization. The effects of METTL14 on angiogenic functions of endothelial cells were measured by cell counting kit-8 (CCK-8), wound healing and tube formation assays. Mechanistically, we used the sequence-based RNA adenosine methylation site predictor (SRAMP) system to predict the target genes of METTL14 and performed qPCR, western blotting and RNA immunoprecipitation assays to validate their interactions. Statistical analyses were performed using Student’s t test or one-way ANOVA. The levels of m6A and METTL14 were reduced in the retinas of OIR mice and in cobalt chloride (CoCl2)-induced endothelial cells. METTL14 overexpression increased the m6A levels in mice retinas and endothelial cells. METTL14 overexpression in the OIR mice decreased the retinal neovascularization and vaso-obliteration. In CoCl2-induced endothelial cells, METTL14 overexpression enhanced cells viability and reduced cells migration and tube formation. Mechanistically, METTL14 bound to hypoxia-inducible factor 1-alpha (HIF-1α) and suppressed HIF-1α levels. This study suggests that METTL14-mediated m6A modification is a pivotal step in regulating the pathogenesis of retinal neovascularization. Therefore, METTL14 might be introduced as a promising therapeutic strategy for the management of PR. However, our findings are limited by the types of clinical samples, and further validation in larger clinical cohorts is required.

Background: DNA Ligase 4 (LIG4) catalyzes the final ligation step during V(D)J recombination. Biallelic pathogenic variants in LIG4 cause severe combined immunodeficiency (SCID), a life-threatening immunodeficiency characterized by the lack of mature T and B cells. Case Presentation: An 18-year-old male exhibited widespread verrucous and keratotic cutaneous lesions across the face, neck, and extremities. The proband manifested early-onset short stature, chronic malnutrition, recurrent pulmonary infections with bronchiectasis, chronic diarrhea, and bilateral tenosynovitis. Immunophenotyping revealed persistent panhypogammaglobulinemia, absent B cells, reduced T and natural killer (NK) cells, and nearly undetectable naïve T cells. Both α-HPV and β-HPV were detected in the cutaneous lesions. Compound heterozygous LIG4 variants (hg19, NM206937.2, c.833G > T; p.Arg278Leu inherited from the mother; c.833G > A; p.Arg278 His inherited from the father) were identified. Conclusions: This study reports a proband with LIG4 syndrome presenting with rare phenotypes of multiple viral warts and combined lymphopenia of T, B, and NK cells. This proband harbors compound heterozygous variants at the same codon (c.833G), which not only confirm the clinical diagnosis but also enrich the known phenotypic spectrum of LIG4 syndrome.

Inborn errors of immunity (IEI) are a group of complex diseases characterized by reduced immunity and increased susceptibility to external pathogens, autoinflammation, autoimmune conditions, and/or malignancy. The IKAROS zinc-finger (IKZF) family is a group of C2H2 zinc-finger transcription factors that includes IKAROS (IKZF1), HELIOS (IKZF2), AIOLOS (IKZF3), EOS (IKZF4), and PEGASUS (IKZF5). Variants in IKZF have been reported to cause human IEI except IKZF4. This research aimed to identify the pathogenicity and underlying mechanisms of IKZF4 as a novel candidate gene for IEI. Here, we used whole-exome sequencing to identify candidate variants of IEI. Western blotting, quantitative polymerase chain reaction, immune staining, co-immunoprecipitation, flow cytometry, Luminex assays, and single-cell RNA sequencing were used to explore the phenotypes and functional effects in cell and mouse models. An 11-month-old patient presented with repeated fever and convulsions accompanied by persistently reduced immunoglobulin levels and abnormal immune indices, which supported the diagnosis of IEI. A de novo c.1472delG variant (GRCh37/hg19, NM_022465.3) in IKZF4 was selected as the candidate variant for IEI. The c.1472delG variant caused reduced EOS expression and truncated protein (predicted molecular weight 57 kDa), defective pericentromeric heterochromatin targeting, and impaired protein interactions of EOS. A mouse model harboring the corresponding variant in Ikzf4 (Ikzf4+/c.1475delG) showed a proinflammatory switch in regulatory T cells, accompanied by reduced levels of immunoglobulins and a decreased ratio of marginal zone B cells after lipopolysaccharide stimulation, which were potentially caused by the down-regulated transcriptional regulation of EOS on the nuclear factor kappa-B pathway. This research identified IKZF4 as a novel candidate gene for IEI, advancing our knowledge of the IKZF family and the complexity of human IEI.

BackgroundHepatic fibrosis is a key pathological stage in the progression of many chronic liver diseases; timely intervention is critical to preventing cirrhosis and hepatocellular carcinoma. Mitochondria regulate energy metabolism, lipid homeostasis, and redox balance, and their dysfunction is increasingly recognized as a driver of fibrogenesis.ObjectiveTo identify key mitochondria-related genes associated with liver fibrosis and explore their mechanistic roles and therapeutic potential using a multi-omics mining strategy.MethodsFibrosis-related bulk RNA-seq datasets (GSE152329, GSE167216, GSE119953, GSE254610) and scRNA-seq datasets (GSE145086, GSE233084) were retrieved from GEO. WGCNA-derived modules were intersected with DEGs and a mitochondrial gene set to obtain candidate genes. GO and KEGG enrichment analyses were performed with clusterProfiler, and TF activity was inferred with decoupleR. An XGBoost algorithm was utilized to prioritize critical mitochondrial targets. Cell–cell communication was analyzed using CellChat. A CCl4-induced C57BL/6 mouse model was established for HE/Masson staining, Western blotting, and TSA-IF. Crucially, functional validation was performed in human LX-2 hepatic stellate cells via ACOT9 knockdown to assess its regulatory role in fibrogenesis.ResultsBulk RNA-seq and WGCNA identified 38 mitochondria-related DEGs in CCl4-induced fibrosis. Machine learning prioritization highlighted Acot9, Aldh1b1, and Pck2 as key targets. scRNA-seq revealed specific expression patterns (predominantly Aldh1b1 in hepatocytes; Pck2 in cholangiocytes/HSCs; Acot9 in endothelial subsets), and CellChat analysis demonstrated remodeling of TGF-β and COLLAGEN signaling networks. In vivo, ACOT9, ALDH1B1, and PCK2 were upregulated in fibrotic liver tissue, consistent with transcriptomic changes. In the human cirrhosis dataset (GSE254610), ACOT9 was also significantly upregulated, confirming its relevance to advanced human disease. In vitro, silencing ACOT9 in human LX-2 cells significantly downregulated α-SMA, COL1A1, and TGF-β, indicating that ACOT9 functions as an upstream regulator of classical fibrotic markers.ConclusionsAcot9 was identified as a key mitochondrial target associated with liver fibrosis. Its consistent upregulation in fibrotic liver tissue and, notably, the ACOT9-dependent modulation of fibrosis markers in hepatic stellate cells highlight its mechanistic relevance and potential as a therapeutic target for further study.

IRAK4 deficiency is a rare autosomal recessive inborn error of immunity caused by disruption of Toll-like receptor (TLR) signaling, and characterized by recurrent pyogenic bacterial infections and impaired inflammatory responses. Here, we reported an 11-year-old boy presenting with recurrent fever, rare severe brain calcification, and seizures. The persistently elevated C-reactive protein (CRP) levels suggested an underlying defect in innate immune signaling. Genetic analysis identified compound heterozygous variants in IRAK4, including a frameshift variant c.123dupA (p.Pro42Thrfs*4), and a missense variant c.543T>G (p.Asp181Glu). Functional analyses further demonstrated markedly reduced IRAK4 protein expression and impaired TLR-mediated signaling in the patient's peripheral blood and cells transfected with the variant sequences. Consistent with these findings, RNA-sequencing revealed dysregulation of innate immune pathways involved in cytokine and chemokine responses. Together, these results provide converging genetic, structural, and functional evidence supporting the pathogenicity of the identified IRAK4 variants. Our findings expand the variant and phenotype spectrum of IRAK4 deficiency, and underscore the essential role of IRAK4 in regulating innate immune signaling and host defense against bacterial infections.

INTRODUCTION:Risankizumab has demonstrated remarkable efficacy in the treatment of psoriasis; however, its long-term use faces multiple challenges, including high costs, reduced efficacy over time, and potential safety concerns, such as infections and malignancies. Therefore, identifying potential alternative or adjunctive therapies to risankizumab has significant clinical importance. METHODS:We analyzed single-cell RNA sequencing data from mature dendritic cells (mDCs) and CD4⁺ T cells collected before risankizumab treatment and at days 3 and 14 post-treatment. Differential expression, cell communication analysis, pseudotime trajectory analysis, and transcription factor regulatory network analysis were performed. Small-molecule drug prediction was performed using the DsigDB database, and molecular docking was used to evaluate binding interactions between candidate drugs and their targets. RESULTS:We identified 15 key transcription factors (MAFB, IRF3, NFIC, SREBF1, ELF3, DLX5, MEF2A, MXD3, MAFF, MECP2, ERF, KLF9, RARA, KLF5, ZBTB2) that were significantly altered in CD4⁺ T cells during the early phase of risankizumab treatment in psoriasis, along with their downstream differentially expressed genes (including KRT14, S100A9, S100A8, S100A7, KRT6A, GJB2, CALML3, and KRT6B). Based on these core factors, five candidate small-molecule drugs with potential therapeutic value for psoriasis were predicted: alitretinoin, simvastatin, MS-275 (entinostat), colchicine, and (+)-chelidonine. DISCUSSION:This study characterized transcriptional regulation of CD4⁺ T cells and mDCs during early risankizumab treatment in psoriasis, predicting potential therapeutic targets and candidate small-molecule drugs from single-cell regulatory networks. Although promising, these results need further validation in larger cohorts and experimental models. CONCLUSION:These findings offer preliminary clues for future risankizumab-based combination strategies in psoriasis.

BACKGROUND AND OBJECTIVE:Psoriasis is a chronic inflammatory skin disease involving abnormal interactions among inflammation-related cells. Celastrol, a natural compound with broad anti-inflammatory activity, has shown therapeutic potential in psoriasis. However, its mechanism in regulating multicellular interaction networks remains relatively limited. This study aimed to explore how celastrol modulates intercellular interactions in psoriasis. METHODS:Single-cell transcriptomic data from three mouse groups-healthy controls, imiquimod (IMQ)-induced psoriasis-like model, and celastrol-treated-were obtained from the GEO database. CellChat analysis, differential gene expression, GSEA, and transcription factor analyses were conducted. An inflammatory feedback loop mediated by TNC⁺ fibroblasts was proposed based on these results and literature evidence. An IMQ-induced psoriasis-like mouse model was then established in BALB/c mice and treated with different doses of celastrol or methotrexate (MTX). Therapeutic efficacy was assessed by PASI scoring, H&E staining, and ELISA. Immunohistochemistry and immunofluorescence were used to validate the inhibitory effect of celastrol on this loop. Subsequently, functional validation was performed using NIH-3T3 fibroblasts to assess TNC-mediated signaling and its modulation by celastrol. RESULTS:We identified a TNC⁺ fibroblast-driven inflammatory feedback loop in psoriatic skin. These fibroblasts secreted chemokines (Ccl2, Cxcl12) and pro-inflammatory cytokines (Il6, Saa3), interacting with myeloid immune cells to activate the TNF-NF-κB and IL-6-JAK-STAT3 pathways. Both in vitro and in vivo experiments confirmed that celastrol disrupted this loop and alleviated IMQ-induced psoriasis-like skin inflammation by suppressing the expression of multiple key proteins. CONCLUSION:Celastrol alleviates psoriasis by disrupting the TNC⁺ fibroblast-mediated inflammatory feedback loop via multi-target modulation, offering new insights into its therapeutic mechanism and clinical potential.

ABSTRACT Background Human papillomaviruses (HPVs) pose a severe threat to global public health by driving nonmelanoma skin cancer (NMSC) and cervical cancer, with NMSC being one of the most common cancers worldwide. Epidermodysplasia verruciformis (EV) is an inborn error of immunity characterized by an increased susceptibility to persistent infection of cutaneous HPV and a high risk of NMSC. The genetic basis remains unknown in many patients with EV. Methods We collected four unrelated pedigrees with EV. Genetic analysis identified five variants in JAK1 encoding the Janus kinase 1. Ex vivo models and patient-derived tissue were employed to evaluate the functional effects of JAK1 variants and delineate the pathogenic mechanisms. Results We identified different variants in JAK1 in four pedigrees with dominant EV. Genetic analysis revealed five novel variants in JAK1 , three of which resulted in nonsense-mediated mRNA decay (NMD). Functional assays identified a decreased phosphorylation of the signal transducers and activators of transcription (STATs), impaired interferon responses, and defective T cell activation. Immune dysregulation in patients, characterized by a reduced CD4⁺/CD8⁺ T cell ratio, decreased CD8⁺ naïve T cell proportion, and accumulated memory T cells, implies impaired antiviral immunity against HPV. Conclusions Our findings confirm that JAK1 loss-of-function (LOF) variants underlie susceptibility to cutaneous HPV infection. [Funded by the National Natural Science Foundation of China (81788101, 81230015, 82394420, and 82394423), the National Key Research and Development Program of China (2022YFC2703900), the CAMS Innovation Fund for Medical Sciences (2021-I2M-1-018), and the Regione Lombardia, Italy (Innovative Research Project 1137-2010)].

Background and objectivesLactose intolerance and coeliac disease are common clinical nutrient malabsorption disorders, with an unclear pathogenesis and limited therapeutic options. It is widely believed that the gut microbiota plays an important role in many digestive disorders, but its role in lactose intolerance and coeliac disease is not yet clear. This study aimed to investigate the correlation between gut microbiota and lactose intolerance and coeliac disease.Materials and methodsThis study utilized the genome-wide association study database to investigate the association between gut microbiota and lactose intolerance and coeliac disease using Mendelian randomization (MR). The robustness of our findings was confirmed through subsequent analyses including Cochrane’s Q statistic, MR-Egger Intercept Regression, MR-PRESSO Global Test and Leave-one-out methods.ResultsBy employing the inverse variance weighted method, we identified that family Veillonellaceae, genus Oxalobacter and Senegalimassilia were protective against lactose intolerance, whereas genus Anaerotruncus, Eubacterium rectale group and Ruminococcus2 were found to be risk factors for lactose intolerance. Regarding coeliac disease, class Bacilli and Gammaproteobacteria, family FamilyXIII and Veillonellaceae, genus Eisenbergiella, Lachnoclostridium, RuminococcaceaeUCG014 and Ruminococcus2 were identified as protective factors, while class Betaproteobacteria, genus Eubacterium xylanophilum group and Blautia were risk factors. Furthermore, reverse the MR analysis did not reveal any evidence of a causal relationship between lactose intolerance or coeliac disease and the bacteria identified in our study.ConclusionThis study provides novel insights into exploring the role of gut microbiota in lactose intolerance and coeliac disease; however, further experiments investigations are required to elucidate the specific underlying mechanisms.

Hereditary bronchiectasis comprises a group of rare monogenic disorders, with cystic fibrosis (CF) and primary ciliary dyskinesia (PCD) representing the major subtypes. Exome sequencing (ES) remains a central modality for molecular diagnosis; however, it leaves more than half of clinically suspected cases unresolved, largely because it cannot reliably detect copy number variations, deep intronic variants, pseudogene-associated variants, and frequent identification of variants of uncertain significance (VUS). This case series describes five hereditary bronchiectasis cases with initial ES-negative results or VUS findings, illustrating the diagnostic utility of targeted genetic approaches. Systematic re-evaluation-including updated bioinformatic pipelines, familial segregation analyses, genome sequencing, RNA sequencing, and functional assays-such as minigene analysis-enabled the reclassification of VUS and the identification of pathogenic variants, leading to definitive diagnoses of PCD or CF in all individuals. Our findings demonstrate that a multimodal strategy integrating ES reanalysis, advanced genomic technologies, and functional validation is critical for resolving previously undiagnosed cases. Furthermore, emerging multiomics integration, artificial intelligence-driven variant interpretation, and global data-sharing frameworks are positioned to further increase diagnostic precision and support the development of targeted therapies for hereditary bronchiectasis.

gutMSNP (https://bio-computing.hrbmu.edu.cn/gutMSNP/home) is a user-friendly database designed to provide a systematic and comprehensive resource for single-nucleotide polymorphisms (SNPs) in the human gut microbiome. Given that even a single SNP in gut microbial genomes can profoundly modulate microbial pathogenicity and thereby impact host health, a large-scale, standardized SNP repository is indispensable for elucidating microbial functions and the molecular mechanisms underpinning microbiota-driven disorders. The current release of gutMSNP includes: (i) 164 015 783 SNPs identified across human gut microbial genomes and categorized into three coverage confidence levels; (ii) 364 species-level and 8251 gene-level microbial records, each exhibiting phenotype-specific SNP distribution patterns; (iii) 8146 representative reference genomes of human gut microbes; and (iv) an online tool for capturing SNPs. The database enables users to search for SNPs in microbial species of interest along with detailed functional and positional annotations, explore phenotype-specific SNP distribution patterns in selected species and their associated genes, download reference genomes for downstream analyses, and detect as well as annotate SNPs in user-uploaded microbial genome files. With its massive SNP dataset, versatile query capabilities, and integrated analytical tools, gutMSNP will serve as a fundamental resource for SNP-based investigations in the human gut microbiome.

Retinal neovascularization (RNV) causes severe visual impairment in neovascular ocular disorders. This study investigated the therapeutic potential and mechanism of saracatinib, a Src kinase inhibitor, in suppressing RNV. Intravitreal saracatinib was administered to oxygen-induced retinopathy (OIR) mice. Retinal tissues were evaluated via immunofluorescence, Real-time quantitative polymerase chain reaction, and Western blotting. In vitro, hypoxic models of human retinal microvascular endothelial cells (HRMECs) and BV2 microglial cells were established to mimic the hypoxic microenvironment of retinopathy. Cell functions were assessed by migration, tube formation, and inflammatory cytokine assays, with molecular analyses of Src-HIF signaling. In the OIR model, saracatinib markedly suppressed subretinal neovascular growth and enhanced retinal perfusion. In endothelial cells (ECs), saracatinib attenuated migration and tube formation, accompanied by downregulation of pro-angiogenic and chemotactic mediators such as VEGFA and MCP-1. In microglial cells, hypoxia-induced inflammatory cytokine expression, including TNF-α and IL-1β, was reduced by saracatinib. Mechanistic analyses further indicated that these protective actions were tightly linked to regulation of the Src-hypoxia-inducible factor (HIF) signaling cascade: in ECs, saracatinib decreased Src phosphorylation, thereby restraining nuclear translocation and protein expression of HIF-1α, along with suppression of HIF-2α. Similarly, in microglia, saracatinib inhibited Src activation and diminished both nuclear translocation and expression of HIF-1α and HIF-2α. Saracatinib mitigates RNV via cell-specific regulation of the Src-HIF axis: targeting HIF-1α in ECs to inhibit angiogenesis and HIF-1α/HIF-2α in microglia to alleviate inflammation. It addresses inflammation-angiogenesis crosstalk, offering a promising alternative or adjunct to anti-VEGF therapies.

Hepatocellular carcinoma (HCC) is among the most prevalent and lethal malignancies worldwide, often emerging from chronic liver diseases such as cirrhosis. Elucidating the molecular mechanisms driving the transition from cirrhosis to HCC is critical for early diagnosis and therapeutic intervention. Using spatial proteomics and bulk RNA-seq, we systematically analyzed protein expression across adjacent non-tumorous, cirrhotic, and HCC tissues. Our findings revealed significant alterations in protein spatial distribution and expression during disease progression, identifying histone H2A as a key player in the cirrhosis-to-HCC transition. The aberrant expression and subcellular localization of H2A suggest its involvement in chromatin remodeling and transcriptional regulation, potentially facilitating oncogenic transformation. These insights enhance our understanding of liver cancer progression and underscore histone H2A as a potential biomarker and therapeutic target for early HCC intervention.

Background The potential of Lenvatinib to synergize with combined radiotherapy and immunotherapy in LUAD remains incompletely characterized.Methods We investigated Lenvatinib’s effects on radiation-induced PD-L1 in LUAD cells and VEGFR2 in HUVECs via Western blot, VEGFA expression via RT-qPCR/ELISA, and angiogenesis via immunofluorescence. LUAD-HUVEC crosstalk was modeled in vitro. In C57BL/6 mice bearing LUAD tumors, we evaluated the efficacy of RT and anti-PD-L1 with or without Lenvatinib, monitoring tumor growth, survival, and profiling the tumor microenvironment by mIHC and flow cytometry.Results Lenvatinib suppressed radiation-induced PD-L1 and VEGFR2 expression, inhibited angiogenesis, and disrupted HUVEC-facilitated LUAD proliferation. The triple-combination (RT + anti-PD-L1 + Lenvatinib) significantly suppressed tumor progression (P < 0.05) and extended median survival (34 vs. 29.5 days, P < 0.05) versus dual therapy. It also enhanced intratumoral CD8+ T-cell infiltration and cytotoxicity, promoted M1-like macrophage polarization, and reduced regulatory T cell frequency and microvessel density.Conclusions Lenvatinib potentiates RT and anti-PD-L1 therapy in LUAD through dual immune-vascular modulation, supporting the clinical translation of this triple-combination strategy.

Studies indicated that some active flavonoids combined with acarbose could reduce the side effects of acarbose and enhance its efficacy. Isorhamnetin-3-O-rutinoside (IOR) is a flavonoid found in many edible herbs. In this work, the synergistic effects of IOR and acarbose on alpha-amylase/alpha-glucosidase (PA/AG) were evaluated using ZIP score analysis. In the presence of IOR, the binding constant Kb values of acarbose with PA/AG were significantly improved, indicating that IOR exhibited synergistic effect with acarbose by increasing its Kb values. Furthermore, in the presence of IOR, acarbose resulted in greater changes in microenvironment and secondary structure of PA/AG. The docking analysis confirmed that IOR and acarbose bound to the different sites of PA/AG. Compared with pure enzyme, the complexes formed by IOR/acarbose with two enzymes were more stable based on dynamics simulations. This study suggested that IOR might be used as a potential synergistic inhibitor of acarbose.

Background/Objectives: As a global chromatin organizer, SATB1 is increasingly implicated in neurodevelopmental disorders (NDDs). This study aims to delineate the clinical and molecular characteristics of a novel de novo SATB1 variant in a patient presenting with epilepsy-dominant NDDs phenotypes. Methods: Triggered by the onset of seizures, trio-based whole-exome sequencing (Trio-WES) was performed to identify the genetic etiology. Subsequent sleep electroencephalogram (EEG) and magnetic resonance imaging (MRI) were then conducted to further characterize the patient's clinical phenotypes. Pathogenicity was assessed through structural modeling and functional characterization. Nonsense-mediated mRNA decay (NMD) status, protein expression profiles, and subcellular localization were determined by reverse-transcription quantitative PCR (RT-qPCR), Western blotting, and immunofluorescence staining. The transcriptional regulatory impacts of the variant were quantified using dual-luciferase reporter system targeting known downstream regulatory elements. Clinical responses to antiepileptic intervention was also monitored. Results: We identified a novel de novo heterozygous pathogenic frameshift variant in SATB1 (NM_002971.5: c.1718_1719insCA; p.Val574Argfs*134) in a patient presenting with early-onset epilepsy, mild intellectual developmental disorder (IDD), speech delay, and dental anomalies. Functional assays demonstrated that the variant-derived transcript escaping NMD, yielding a truncated protein that forms irregular punctate aggregates within nuclei. Dual-luciferase assays revealed significantly increased transcriptional activity, indicating a loss of the protein's innate transcriptional regulatory capacity. Clinically, treatment with sodium valproate (VPA) successfully stabilized seizures of the patient, markedly reducing both frequency and intensity. Conclusions: The study reports a novel SATB1 frameshift variant that exerts pathogenicity significant functional impairment by disrupting protein localization and transcriptional regulation. These findings expand the genetic spectrum of SATB1-related NDDs and underscore the efficacy of targeted antiepileptic management in genetic diseases.

To report a rare case of coexisting lipemia retinalis and proliferative diabetic retinopathy in a young patient, complicated by chylous vitreous hemorrhage. A 22-year-old female with a 10-year history of type 2 diabetes mellitus and hyperlipidemia presented with progressive bilateral vision loss over two weeks. Visual acuity was counting fingers at 20 cm in the right eye and 20/63 in the left eye. Fundus examination revealed creamy-white retinal vessels in both eyes and yellow-white, lipid-rich material in the right vitreous cavity, consistent with lipemia retinalis and vitreous hemorrhage. Laboratory testing demonstrated severe hypertriglyceridemia. After systemic lipid-lowering therapy, the appearance of the retinal vessels returned to normal, but visual impairment persisted. The patient subsequently underwent pars plana vitrectomy in the right eye and received bilateral intravitreal anti-vascular endothelial growth factor injections. At the five-month follow-up, visual acuity improved to 20/20 in the right eye and 20/25 in the left eye. Lipemia retinalis reflects severe disturbances in lipid metabolism. Early metabolic control and individualized ophthalmic management are essential to optimize visual outcomes.

Background and Objectives:Genetic testing has emerged as a transformative tool for the diagnosis and treatment of epilepsy. The aim of this study was to characterize the genetic basis of pediatric epilepsy. Methods:We analyzed a cohort of 1,109 children with epilepsy who underwent whole-exome sequencing. Genetic findings were interpreted based on medical records and genetic testing results. Results:Genetic diagnostic results were found in 405 of 1,109 patients, with a diagnostic yield of 36.5%. The SCN1A (40/1,109, 3.6%) was the most frequently affected gene, followed by the PRRT2 (26/1,109, 2.3%) and SCN2A (10/1,109, 0.9%). In total, 138 genes were identified with 337 total detections. Gene ontology analysis revealed enrichment in ion channel-related genes (30.0%, 101/337), catalytic activity-related genes (19.6%, 66/337), and pathway-related genes (14.5%, 49/337). Multivariate logistic regression showed that younger age at onset (OR = 0.87, 95% CI 0.81-0.94, p < 0.001), developmental delay or intellectual disability (OR = 2.25, 95% CI 1.62-3.12, p < 0.001), and facial dysmorphisms (OR = 2.30, 95% CI 1.06-5.00, p = 0.036) were associated with a higher likelihood of achieving a genetic diagnosis. Negative results were obtained in 51.4% (570/1,109) of patients. Discussion:This single-center study provides a comprehensive overview of the genetic landscape of pediatric epilepsy, enhancing our understanding of the genetic basis and offering insights for clinical diagnosis and genetic counseling. These findings underscore the clinical utility of genetic testing in pediatric epilepsy.

Cellular senescence is a state of cell cycle arrest caused by various types of stress, and it is characterized by morphological changes, metabolic reprogramming, and the release of the senescence-associated secretory phenotype (SASP). In cancer therapy, senescence plays a complex role by inhibiting cancer progression, mediating metabolic imbalance, modulating local immune responses, and restructuring the cancer microenvironment. These mechanisms have been harnessed to develop nano-drug delivery systems (Nano-DDSs)-based combination therapies for cancer. We systematically explain key biological features of cellular senescence and detail recent advances in creating drug delivery systems aimed at targeting cancer senescence through these four mechanisms. Additionally, we discuss the clinical challenges in translating senescence-targeting strategies with Nano-DDSs and propose future directions within an interdisciplinary framework. This review offers valuable insights into designing advanced Nano-DDSs based on the multidimensional regulatory mechanisms of cellular senescence and their application in cancer treatment.