Background and Objectives: Hereditary angioedema (HAE) represents a specific form of life-threatening inborn errors of immunity. Current guidelines recommend regular assessment of the disease burden, disease control and quality of life. This study describes the profile of HAE patients in Slovakia, disease control, quality of life, states of anxiety and depression, and socioeconomic situation. Materials and Methods: We used a set of standardized questionnaires-AE-QoL, AECT, HADS and Socioeconomic Status Questionnaire, and a non-standardized questionnaire-to describe the characteristics of the population. Results: We collected data on 56.44% (57 out of 101) of HAE adult patients registered in Slovakia. Moderate to severe HAE was present in 61.40% of patients; 73.68% were on long-term prophylactic treatment; and 19.30% received rescue treatment due to an acute HAE attack during the last 4 weeks. Most patients achieved lower AE-QoL scores, indicating a good quality of life. The AECT score indicated well-controlled disease in 91.23% of patients. Anxiety and/or depression scores were higher than normal in 17.54% of patients. Patients with HAE earned less than the average population, but most of them were economically active with relatively low rates of presenteeism and absenteeism. Only a minority of patients used social system benefits. Patients were exclusively cared for by relatives. Conclusions: The QoL scores achieved in all three standardized questionnaires indicate a good quality of life of HAE patients in Slovakia, which is associated with a high and specialized standard of care. Anxiety and/or depression were present in 17.54% of patients. Direct patients costs and social care costs are low, but there is an indirect socioeconomic burden on patients and their families.
Current guidelines recommend consideration of germline genetic testing for patients with uterine serous carcinoma (USC) but real-world data are limited on completion rates of testing and pathogenic variant (PV) identification. This study aimed to evaluate the rate of genetic testing referral and completion in a cohort of patients with USC, determine the prevalence of clinically meaningful PVs found on testing and explore factors associated with genetics referral and testing completion. We retrospectively examined the medical records of all individuals diagnosed with USC between 2019 and 2024 seen at a single academic cancer centre. Outcomes of interest included referral for germline genetic testing, completion of testing and testing results. Of 131 individuals included, 5 (3.8%) had prior genetic testing and only 45 (34.4%) were recommended to undergo genetic testing or referred to cancer genetics. Younger individuals and those with a personal history of cancer other than USC or family history of breast or ovarian cancer were more likely to be referred. Nine (26.5%) of 34 individuals who completed germline testing had a PV identified in a cancer-related gene, including BRCA1, BRCA2, BRIP1, CHEK2, MSH6, PMS2 and ATM. Only a personal history of cancer other than USC was independently associated with the discovery of a PV on germline genetic testing. In those without a prior personal history of cancer, the PV prevalence was 5.6%. Given the high prevalence of PVs in this population, germline genetic testing for all patients diagnosed with USC can provide clinically meaningful benefit but is currently underused in practice.
Laryngeal squamous cell carcinoma (LSCC) is one of the most common types of head and neck cancer, posing a significant threat to public health. The spindle and kinetochore-associated complex subunit 3 (SKA3), a microtubule-binding subcomplex of the outer kinetochore, participates in cancer progression. However, its role in the progression of LSCC remains unclear. This study aimed to investigate the regulatory effects of SKA3 on LSCC progression and its underlying mechanism. In this study, the expression levels of SKA3 and aldo-keto reductase family 1 member C1 (AKR1C1) mRNA were assessed by quantitative real-time PCR. Protein expression was evaluated using western blotting. Cell proliferation was analyzed using the cell counting kit-8 assay, while apoptosis was assessed by flow cytometry. Cell migration and invasion were measured via Transwell assays. The levels of Fe2+ and glutathione were analyzed with colorimetric assays, while reactive oxygen species (ROS) levels were determined by flow cytometry. Chromatin immunoprecipitation and dual-luciferase reporter assays were employed to explore the interaction between SOX9 and SKA3. The impact of SKA3 silencing and AKR1C1 overexpression on tumor formation was investigated using a xenograft mouse model. The results showed that SKA3 expression was elevated in LSCC tissues and cells when compared with corresponding normal tissues and human nasopharyngeal epithelial cells. Silencing SKA3 suppressed LSCC cell proliferation, migration, and invasion, while promoting apoptosis and ferroptosis. SKA3 upregulated AKR1C1, a key ferroptosis-related gene, in TU177 and AMC-HN-8 cells. Overexpression of AKR1C1 mitigated the effects of SKA3 silencing on the malignant phenotypes of these cells. SOX9 was identified as a transcriptional activator of SKA3 in TU177 and AMC-HN-8 cells, and AKR1C1 overexpression reversed the inhibitory effect of SKA3 silencing on tumor growth in vivo. Thus, SKA3 played a pivotal role in the progression of LSCC through the SOX9/SKA3/AKR1C1 axis, suggesting that targeting SKA3 might have significant clinical implications for the treatment of LSCC.
Focal cortical dysplasia (FCD) is a leading cause of drug-resistant epilepsy, whereas its molecular and cellular mechanisms remain poorly understood. This study aimed to characterize the cellular heterogeneity of FCD and investigate the function of ferroptosis in FCD pathogenesis. Single-nucleus RNA sequencing was carried out on epileptogenic cortical tissues from 18 patients with FCD and 6 perilesional control samples with normal histology. Data were analysed using uniform manifold approximation and projection for dimensionality reduction and visualization. Differentially expressed genes (DEGs) were identified and subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. UCell scoring and gene set enrichment analysis (GSEA) were applied to assess pathway activity. Expression levels of ferroptosis-related genes (FRGs) were validated by immunofluorescence, and biochemical assays quantified the levels of superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA) and lipid peroxides (LPO). A total of 170 747 nuclei were profiled, resolving five major cell types, including inhibitory neurons, excitatory neurons, astrocytes, microglia and oligodendrocytes. DEGs across these populations were significantly enriched in ferroptosis and oxidative stress-associated pathways. UCell and GSEA highlighted remarkable alterations in ferroptosis, apoptosis and oxidative stress, particularly in inhibitory neurons and astrocytes. Immunofluorescence confirmed upregulation of key FRGs, including ferritin light chain, ferritin heavy chain 1, poly rC binding protein 1, microtubule-associated protein 1 light chain 3B and prion protein-encoding gene, in FCD tissues. Concordantly, biochemical assays demonstrated reduced SOD and GSH levels, alongside elevated MDA and LPO levels, confirming the transcriptional and histological findings. The results indicated that ferroptosis may play a notable role or act as a concurrent mechanism in the pathogenesis of FCD, potentially contributing to the neuronal and glial dysfunction and epileptogenesis. Integrating transcriptomic, histological and biochemical data, this study demonstrated that targeting ferroptosis-related pathways may hold promise as a potential therapeutic strategy for FCD, providing new insights into the molecular mechanisms underlying this condition. This study pioneers the first single-nucleus transcriptomic atlas for Focal Cortical Dysplasia (FCD) types I and II, deciphering the cellular heterogeneity across five major brain cell types within the epileptogenic cortex. Through integrated multi-omics analysis, it reveals for the first time a significant association between the ferroptosis pathway and FCD pathogenesis. We identify and validate ferroptosis-related genes (e.g., FTH1, FTL, PCBP1) as potential biomarkers and therapeutic targets, supported by congruent biochemical evidence of oxidative stress in this drug-resistant epilepsy.
This article presents a case of recurrent autoimmune hemolytic anemia in a child with a gain-of-function (GOF) mutation of the TLR7. This patient's condition contrasts with the six previously documented cases of GOF mutations in the TLR7, thereby expanding the phenotypic spectrum of such mutations and enhancing clinical comprehension of childhood systemic lupus erythematosus (cSLE). The article discusses the mechanisms by which TLR7 GOF mutations can result in autoimmune hemolytic anemia, explores the influence of cytomegalovirus (CMV) infection on the disease's development and progression, and emphasizes the therapeutic potential of hematopoietic stem cell transplantation for cases of TLR7 GOF mutations.
Diabetic retinopathy (DR) is a common comorbidity of diabetes involving the formation of abnormal vascular structures in the retina. Tissue inhibitor of metalloproteinases 2 (TIMP2), initially identified as a key mediator of extracellular matrix turnover, is pivotal for inflammatory processes and tissue homeostasis. The current study examined the influence of TIMP2 gene variations on the risk for DR. We investigated the association of TIMP2 gene variations with DR by analyzing four single-nucleotide polymorphisms (SNPs) of the TIMP2 gene (rs16971783, rs2889529, rs7220980, and rs8068674) in a cohort of 672 patients with DR and 919 diabetic controls with normal ophthalmoscopic findings. Our results showed that rs16971783 of TIMP2 gene was associated with a higher risk for DR (TA vs. TT, AOR=1.445, p=0.028; TA+AA vs. TT, AOR=1.179, p=0.046). We further demonstrated that the association of rs16971783 with DR was exclusively observed in diabetic individuals with proliferative DR (TA vs. TT, AOR=1.827, p=0.035; TA+AA vs. TT, AOR=1.351, p=0.027), whereas not detected among those who suffered from non-proliferative DR. In addition, preliminary exploration of gene expression data from public resources reveald that rs16971783 regulated TIMP2 gene expression in various human tissues. Allele-specific expression of TIMP2 gene might contribute to the progression of DR.
The prognosis of lung adenocarcinoma (LUAD) is traditionally evaluated via tumor-node-metastasis (TNM) staging, which does not account for the patient's immune status. This protocol integrates genomic profiling and immune microenvironment analysis to facilitate a more comprehensive postoperative prognostic evaluation. The method involves a retrospective analysis of paraffin-embedded tumor tissues using two primary techniques. First, next-generation sequencing (NGS) is performed with a customized 37-gene panel to identify mutations in driver genes and variants of uncertain significance. Second, multiplex immunofluorescence (mIF) is utilized to target markers including HLA-DR, CD68, CD163, CD206, PD-L1, and PanCK. This enables the quantification of spatial distribution and density for specific immune cell subpopulations across various tumor regions. This integrated approach enables the simultaneous assessment of genomic heterogeneity and tumor-infiltrating immune cell characteristics. The resulting data identifies specific combinations of mutational profiles-such as EGFR status-and immune cell densities. These integrated combinations enable the study of their collective impact on patient survival, offering a promising approach for the development of future lung cancer prognostic models. This protocol demonstrates a robust method for characterizing the complex biological features of the LUAD tumor microenvironment.
Tuberous sclerosis complex (TSC) is a rare genetic disorder caused by pathogenic variants in the TSC1 or TSC2 genes. Apart from multisystem physical manifestations, most individuals with TSC experience TSC-associated neuropsychiatric disorders (TAND). Little is known about how TAND severity changes over time and what factors may predict these changes. Preliminary data suggest the presence of differential TAND severity trajectories. Caregiver well-being may act as a mediator of TAND severity, and a well-being intervention designed for caregivers of children with developmental disabilities may improve caregiver well-being. The study aims are to (1) examine longitudinal trajectories of TAND severity in a large sample of individuals with TSC and to examine potential predictors of differential trajectories, (2) evaluate the association between caregiver well-being characteristics, TAND severity, and severity trajectories, and (3) adapt and evaluate the feasibility, acceptability, and potential efficacy of a brief, online group-based well-being intervention for family caregivers. For the first 2 aims, 500 individuals with TSC or their caregivers will be recruited in an accelerated longitudinal design to document TAND severity at 5 time points over 12 months via a web-based app. At each time point, participants will complete demographic, TSC characteristics, intervention, and well-being questionnaires. Data will be analyzed using latent class mixed and multinomial regression modeling (aim 1) and structural equation and mediation modeling (aim 2). Participatory methods will be used to adapt an existing caregiver well-being intervention for the TSC community (aim 3). Thirty caregivers will be invited to participate in the adapted group-based online well-being intervention. This study was funded from July 2024 (HT94252410790 and HT94252410791), and ethics approvals were obtained from the University of Cape Town (July 2024), Vrije Universiteit Brussel (November 2024), and the Department of Defense Office of Human Research Oversight (December 2024). The TAND Toolkit app was adapted for longitudinal data collection (aims 1 and 2). Recruitment started in December 2025 and will continue until 500 participants are enrolled (anticipated December 2026). Primary outputs are expected by July 2028. For aim 3, experiential and adaptation workshops were completed in June 2025, the pilot intervention was delivered in November 2025, and data collection will continue till May 2026. Outputs are expected by December 2026. Identification of differential longitudinal TAND trajectories and their correlates will stimulate research in TSC and generate evidence for the self-report quantified TAND checklist as a clinical outcome measure. Understanding the association between caregiver well-being and TAND severity will provide support for targeted well-being interventions. A successful pilot trial will provide preliminary data for larger-scale clinical trials, with the potential to support caregivers and improve TAND outcomes. Together, the findings from the study will help close the gap in interventions for TAND. ClinicalTrials.gov NCT06879665; https://clinicaltrials.gov/study/NCT06879665. DERR1-10.2196/91726.
The high heterogeneity of lung adenocarcinoma (LUAD) is largely due to its complex tumor immune microenvironment (TIME). Cancer-associated fibroblasts (CAFs) are a core matrix component of TIME. However, their functional heterogeneity and the specific molecular mechanisms driving tumor progression have not been fully elucidated. In addition, the role of nuclear receptor NR2F2 in tumor development is still controversial. This study integrated scRNA-seq data from the GEO database with RNA-seq data from TCGA and GEO and then performed multiple levels of validation through in vitro experiments. We adopted a systematic computational biology strategy and analyzed the cellular composition, interaction networks and functional states of cancer-associated fibroblasts (CAFs) in lung adenocarcinoma using Seurat, CellChat, and AUCell. According to the marker genes of key CAF subgroup, prognostic risk models were constructed through LASSO-Cox regression and validated in an independent cohort (GSE72094). Afterwards, we carried out in vitro experiments and validated the biological role of NR2F2 through a coculture system. Functional validation was conducted through siRNA knockdown, plasmid overexpression, CCK-8 assay, EdU labeling, and Transwell experiments. We noticed the CAF - 2 subgroup, characterized by the highest level of TGF - β signaling activation, sends various signals to different cell types. We constructed and verified a consistent prognostic signature made of 16 genes using the LASSO-Cox method. This model can effectively assess the risk of LUAD patients. The prognosis in high-risk group is worse. And we also do some analysis to find out that risk score is highly associated with immunosuppressive TME and high expressions of PD - L1. We have found in our further study that the expression of NR2F2 in CAF is associated with the promoting of matrix remodeling and metabolic reprogramming. From the coculture system and in vitro functional experiments, overexpression of NR2F2 in CAFs enhanced tumor cell proliferation and invasion, whereas knockdown of NR2F2 attenuated these malignant phenotypes. Using single-cell RNA sequencing data, we identified a CAF subgroup with the most active TGF-β signaling. Based on the marker genes of the subgroup, we constructed and validated an effective prognostic model, then we further screened and confirmed NR2F2 as a major pro-tumorigenic regulator from this feature gene set through single cell and transcriptome data as well as in vitro experiments. NR2F2 promotes malignant remodeling of TIME by synergistically enhancing TGF-β signaling and EMT processes. Our study provides not only a solid theoretical foundation but also a therapeutic target to explore new therapeutic options targeting the CAFs-TGF-β-EMT axis.
Intervertebral disk degeneration (IDD) is a degenerative disease mainly characterized by intervertebral disk tissue senescence and collagen loss. The role of hsa_circ_0036763 in IDD remains incompletely understood. The clinical value of hsa_circ_0036763 was explored by retrospectively analyzing the serum samples of 120 IDD patients through ROC curve, Kaplan-Meier curve, and Cox proportional hazards analysis. The severity of IDD was distinguished through the modified Pfirrmann grading system. The downstream regulatory mechanism (miR-4741/RGSL1) of hsa_circ_0036763 was mined through the miRDB and TargetScan databases, and their targeting relationships were demonstrated by the dual-luciferase reporter and RNA pull-down assays. The IL-1β-induced senescent nucleus pulposus cells (NPCs) were used to evaluate the potential role of hsa_circ_0036763/miR-4741/RGSL1 axis in IDD progression. Serum hsa_circ_0036763 expression was negatively correlated with the modified Pfirrmann grade of IDD patients (r = -0.675). Its low expression predicted a higher risk of IDD recurrence (HR = 0.252, p = 0.002). Hsa_circ_0036763 sponged miR-4741, thereby relieving its inhibition on RGSL1 expression. Exogenous overexpression of hsa_circ_0036763 alleviated the senescence, collagen loss, and oxidative stress in IL-1β-induced NPCs, which were reversed by co-transfection of miR-4741 mimics and silencing of RGSL1. Hsa_circ_0036763 may serve as a prognostic marker for IDD and participates in IDD-related NPC degeneration by regulating miR-4741/RGSL1.
During the COVID-19 pandemic, international border restrictions, along with traveler screening and quarantine, were implemented to limit virus spread. This study analyzes the epidemiological and genomic profiles of SARS-CoV-2 infections imported into Kinshasa (DRC) during the restrictions period in 2021. As part of the national response to the pandemic, self-reported demographic and clinical data were collected from travelers entering the DRC via N'djili-Kinshasa International Airport. SARS-CoV-2 infection was diagnosed using RT-PCR, and positive samples were subjected to whole genome sequencing (WGS) to determine variant types and viral lineages. The impact of the virus's genomic profile on the clinical presentation of travelers and on the COVID-19 epidemiology in the DRC was then assessed. Of 102,810 included travelers, 1037 (1.0%) tested positive for SARS-CoV-2 and reported significantly more nausea, diarrhea, and weight loss than uninfected travelers (p < 0.001). SARS-Cov-2-infected travelers were predominantly under 43 years old (p < 0.001) and primarily from France (24.8%) and Belgium (19.5%). Of the 105 WGS analyzed, 86 (81.9%) were variants of concern (VOCs), 14 (13.3%) were variants under monitoring (VUM), and the main genomic lineages identified were Delta-B.1.617.2 (24.8%), Alpha-B.1.1.7 (10.5%), Delta-AY.122 (7.6%), and B.1.620 (5.7%). The Delta-VOC was the most prevalent among positive travelers (61/86) and appeared to cause more symptomatic infections than non-Delta variants, although one-third of positive travelers reported no symptoms. SARS-CoV-2 importation into Kinshasa (DRC) mirrored global variant circulation patterns at the study's time. This genomic landscape was consistent with in-country clinical observations, emphasizing the importance of robust border surveillance and adaptive public health strategies during pandemics.
Background/Objectives: Early-onset high myopia (eoHM), defined as high myopia manifesting before 10 years of age, is largely attributed to genetic defects. This study aimed to investigate the genetic underpinnings of eoHM in a cohort of Chinese patients. Methods: We recruited 64 Chinese patients with eoHM. Comprehensive clinical evaluations were performed, and whole exome sequencing (WES) was conducted to identify potential pathogenic variants. The genetic findings were analyzed and correlated with the clinical phenotypes. Results: A total of 64 unrelated Chinese patients with suspected early-onset high myopia were initially recruited. Following whole exome sequencing (WES) and variant annotation, final 37 patients with variants in known myopia-associated genes were included in the analytical cohort. The mean age of onset for the cohort was 5 years (IQR, 4-7), with a mean spherical equivalent refraction of -7 D (IQR, (-8)-(-6)). Genetic analysis revealed variants in 28 known myopia-associated genes. We identified pathogenic or likely pathogenic variants in 11 of the 37 patients (29.7%, 95%CI: 0.1737-0.4590), while the overall diagnostic yield was 17.2% (11/64, 95%CI: 0.0970-0.2839) in initial 64 recruited patients. These genes included seven well-established eoHM-related genes, such as ARR3, CACNA1F, P4HA2, TRPM1, COL11A1, COL2A1, and PAX6. Additionally, variants of uncertain significance (VUS) in seven other candidate genes were detected in patients with eoHM. Conclusions: Our findings expand the genetic spectrum of eoHM and reinforce the critical role of genetic testing in its etiological diagnosis and clinical management. Observed patterns of genotype-phenotype associations are descriptive and should be considered hypothesis-generating, requiring validation in larger cohorts. Additionally, we identify several candidate genes that may serve as prospective biomarkers, though these findings require validation in larger cohorts and functional studies.
Autophagy plays a crucial role in maintaining cellular homeostasis and has been implicated in the pathogenesis of knee osteoarthritis (OA). However, data on radiographic stage-dependent transcriptional variation of autophagy-related genes in patients with knee OA, particularly using peripheral blood samples, remain limited. The aim of this study was to evaluate whether disease severity was associated with stage-dependent changes in the expression of selected autophagy-related genes within a patient cohort. A total of 200 patients diagnosed with knee OA were included in the study. Disease severity was classified according to the Kellgren-Lawrence radiographic grading system. Peripheral blood samples were collected, and the expression levels of selected autophagy-related genes were analyzed using quantitative real-time polymerase chain reaction [autophagy-related 5 (ATG5), ATG7, unc-51-like kinase 1 (ULK1), microtubule-associated protein 1 light chain 3 beta (LC3B), WD repeat domain phosphoinositide-interacting protein 1 (WIPI1), neighbor of BRCA1 gene 1 (NBR1), forkhead box O3 (FOXO3), transcription factor EB (TFEB)]. Relative gene expression was calculated using the ΔCt method, and comparisons were performed across radiographic stages. Associations between gene expression levels and systemic inflammatory markers were also assessed. Significant stage-dependent differences were observed in the expression of ULK1, TFEB, WIPI1, and NBR1 (p<0.05), with higher ΔCt values (reduced relative expression) in advanced radiographic stages compared with early-stage disease. In contrast, ATG5, ATG7, LC3B, and FOXO3 expression remained stable across radiographic stages. Furthermore, no significant associations were observed between expression of autophagy-related genes and systemic inflammatory status, as assessed by C-reactive protein levels. In patients with knee OA, regulatory and early autophagy-related genes exhibit radiographic stage-associated transcriptional alterations in peripheral blood, while expression of core autophagy machinery genes remain relatively stable. These findings suggest that disease severity is associated with selective transcriptional changes in autophagy-related pathways within the OA patient population and support further investigation of stage-dependent molecular patterns in knee OA.
Lung cancer remains a major global public health challenge, with lung adenocarcinoma being the most prevalent histologic subtype. Rosuvastatin, a widely used lipid-lowering agent, has recently attracted attention for its potential antitumor properties. This study investigates the underlying mechanisms and therapeutic potential of rosuvastatin in lung cancer. The effects of rosuvastatin were evaluated in lung adenocarcinoma cell lines using Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU) incorporation, Transwell migration and invasion assays, wound-healing assays, and flow cytometry for apoptosis analysis. RNA sequencing identified cell-cycle signaling pathways as the primary targets of rosuvastatin. Analysis of survival curves and differential gene expression between tumor and adjacent non-tumor tissues using public databases, including the Human Protein Atlas, Gene Expression Profiling Interactive Analysis (GEPIA), and Tumor Immune Estimation Resource (TIMER), suggested that polo-like kinase 1 (PLK1) may be a key target mediating the antitumor effects of rosuvastatin. Western blotting and quantitative reverse transcription polymerase chain reaction (qRT-PCR) were used to confirm the differential expression of PLK1 and related cell-cycle proteins in lung adenocarcinoma cells following treatment with different doses of rosuvastatin. Furthermore, rescue experiments with PLK1 knockdown were performed to verify its role in the mechanism of rosuvastatin. A subcutaneous mouse xenograft model was established in vivo to assess the antitumor activity of rosuvastatin via PLK1 inhibition. Rosuvastatin exerted significant antitumor effects against lung adenocarcinoma both in vitro and in vivo. Mechanistic studies indicated that its anticancer activity is mainly mediated by downregulating PLK1 expression. By suppressing PLK1 expression, rosuvastatin inhibited cancer cell proliferation, migration, and invasion. These findings support the potential of rosuvastatin as a therapeutic agent for lung cancer, although further studies are needed to confirm its clinical utility.
A small subset of isocitrate dehydrogenase-wild-type (IDH-wt) glioblastomas (GBMs) initially present as nonenhancing, T2 FLAIR hyperintense cortical/superficial lesions on MRI, potentially leading to misdiagnosis on the initial imaging and hence delayed treatment. This study aimed to characterize the clinical and MRI features of nonenhancing IDH-wt GBMs to help radiologists in differentiating them from nonmalignant mimic diagnoses (eg, encephalitis). Additionally, the histologic, genomic, and survival profiles of nonenhancing GBMs were compared with those of enhancing GBMs. Clinical and MRI features from 32 patients, each with nonenhancing and enhancing GBMs, and 16 patients with nonmalignant mimic differential diagnoses from a single institution and publicly available data set were retrospectively analyzed. Imaging features were reviewed using the Visually Accessible Rembrandt Images features and the split ADC sign. χ2 tests and a binary logistic regression model were used to compare nonenhancing IDH-wt GBMs with nonmalignant mimics. Histopathologic and genomic analyses were performed on institutional cases. Overall survival between nonenhancing and enhancing GBMs was compared using Kaplan-Meier analysis. No significant difference in age, clinical presentation, or duration of symptoms was found between nonenhancing GBMs and nonmalignant mimics. Imaging features favoring nonenhancing GBMs included a greater proportion of non-contrast-enhancing tumor (OR, 7.4), larger anterior-posterior tumor dimension (OR, 8.4), restricted diffusion (OR, 3.6), and eloquent brain involvement (OR, 3.0) while features favoring mimics included greater edema (OR, 0.07), infiltrative T1 FLAIR ratio (OR, 0.68), hemorrhage (OR, 0.76), satellite lesions (OR, 0.84), and the split ADC sign (OR, 0.89). The logistic regression model achieved a mean area under the receiver operator characteristic curve of 0.89 (SD, 0.20) (accuracy 0.84, sensitivity 0.91, specificity 0.70, and precision 0.88). Twelve of 18 nonenhancing GBMs lacked histologic evidence of necrosis or microvascular proliferation ("molecular GBMs"). Genomic profiles were similar between nonenhancing and enhancing GBMs. Median overall survival was nonsignificantly longer in nonenhancing GBMs compared with enhancing GBMs (39 versus 21 months, P = .078). Nonenhancing GBMs demonstrate distinct MRI features that must be recognized for early diagnosis and differentiation from nonmalignant mimics. Nonenhancing GBMs demonstrated longer overall survival compared with enhancing GBMs, though they were not statistically significant.
Oral squamous cell carcinoma (OSCC) is marked by frequent recurrence rates and an unclear etiology, underscoring the critical need for early detection to improve therapeutic outcomes and reduce healthcare costs. MicroRNAs (miRNAs) have emerged as key regulators of oral carcinogenesis by modulating gene expression at the posttranscriptional level and influencing various aspects of cellular physiology. This study aimed to comprehensively evaluate the prognostic significance of miR-1304 and miR-4652 expression levels in patients with OSCC, and to explore their potential as predictive biomarkers for disease progression and patient survival. TargetScan was used to predict potential gene interactions of the microRNAs. Subsequently, the expression levels of C-Myc and the microRNAs miR-1304-3p and miR-4652-5p were evaluated in 30 pairs of OSCC and adjacent normal tissue samples. qRT-PCR analyses were performed to compare the expression of these molecules between tumor and normal tissues. Additionally, receiver operating characteristic (ROC) curves were generated to assess the potential diagnostic value of these microRNAs in OSCC. The expression levels of miR-1304, miR-4652, and C-Myc were significantly higher in OSCC tissues compared to their matched adjacent non-tumor tissues (p < 0.0001). Notably, high C-Myc expression was significantly correlated with both tumor grade (p = 0.003) and tumor stage (p = 0.005). ROC curve analysis demonstrated that the areas under the curve (AUCs) for C-Myc, hsa-miR-1304, and hsa-miR-4652 were 0.99, 0.99, and 0.95, respectively (p < 0.0001), indicating strong diagnostic potential. These findings suggest that the upregulation of miR-1304 and miR-4652 could be used as biomarkers in OSCC. However, more studies with large samples are necessary.
Carbohydrate Response Element Binding Protein (ChREBP) is a transcription factor known to regulate glucose metabolism and other metabolic processes in various tissues, but its role in lung adenocarcinoma (LUAD) remains poorly understood. In this study, we investigated ChREBP expression and its role in regulating gene expression in LUAD cell lines. Using RT-qPCR, we assessed the expression of ChREBP-α and ChREBP-β isoforms in NCI-H1975, NCI-H1650, and NCI-H2228 LUAD cell lines. The NCI-H1975 cells exhibited the highest levels of both ChREBP isoforms, with a particularly pronounced expression of ChREBP-β. To explore the regulatory role of ChREBP, we generated NCI-H1975 cells with inducible expression of a dominant-negative mutant of human ChREBP (dnChREBP). Overexpression of dnChREBP led to a significant reduction in colony formation and impaired cell migration. Transcriptome analysis revealed 57 upregulated genes and 593 downregulated genes in dnChREBP-expressing cells compared to control cells. Functional annotation and gene set enrichment analysis revealed that the enriched genes were associated with cancer-related processes, including cell proliferation and epithelial-to-mesenchymal transition (EMT). Gene network analysis highlighted 17 downregulated hub genes, with 8 of these genes being associated with EMT. Interestingly, ChREBP and its transcriptionally regulated genes, including 4 top downregulated genes, 5 top upregulated genes, and 5 hub genes identified in NCI-H1975 cells overexpressing dnChREBP, showed significant prognostic value, as their expression levels correlated with overall survival in LUAD patients. Our findings suggest that ChREBP regulates distinct transcriptional programs in LUAD cells and ChREBP and its regulatory network may play a potential role in LUAD progression and patient outcomes.
Chronic stress resulted in poor prognosis of cancer patients in the clinic. This study aimed to explore the mechanism by which chronic stress promotes the progression of lung adenocarcinoma (LUAD) through circ_RPPH1/miR-326 axis. Chronic stress-induced LUAD in vitro and in vivo models were established in A549 cells and C57BL/6 male mice. Sucrose preference test (SPT) and forced-swimming test (FST) were used for in vivo model evaluation. qRT-PCR and western blot were used to detect mRNA and protein levels. Cell proliferation, migration and invasion were also evaluated. Luciferase reporter assay was for target gene verification. In A549 cells, acetylcholine (ACh)-induced chronic stress contributed to the upregulation of circ_RPPH1. circ_RPPH1 knockdown remitted the carcinogenic effect of chronic stress on A549 cells. circ_RPPH1 serves as a sponger of miR-326, and miR-326 downregulation neutralized the beneficial role against tumor cell function and EMT in vitro. In vivo, circ_RPPH1 knockdown reduced the tumor volume and EMT-related protein levels of tumor-bearing mice under chronic stress treatment, while miR-326 antagomir co-transfection neutralized the effect. LARP1 might be the target gene of circ_RPPH1/miR-326 axis in CUMS mice. circ_RPPH1/miR-326 axis was involved in chronic stress-promoted progression and metastasis of LUAD.
To regulate immune and inflammatory responses, suppressor of cytokine signalling (SOCS) proteins bind to multiple signalling components downstream of cytokine receptors, such as Janus kinase (JAK) and signal transducers and activators of transcription (STAT). Dysfunctional SOCS proteins in immune and tissue-resident cells may contribute to chronic inflammation. Abnormal expression of SOCS proteins, including SOCS1, SOCS2, SOCS3, SOCS5, SOCS6, and SOCS7, has been reported in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), playing a vital role in disease pathogenesis. The expression of SOCS1 and SOCS3 varies across different cell types and stages of the disease. Genetic polymorphisms, epigenetic modifications, microRNAs, cytokines, hormones, therapeutic agents, and gender factors can influence SOCS1 and SOCS3 expression in MS patients and EAE mice. The functional impact of SOCS1 and SOCS3 is cell-type specific, with distinct roles in T cell subsets, microglia/macrophages, dendritic cells, astrocytes, and oligodendrocytes. In particular, SOCS1 and SOCS3 affect T cell subset differentiation, Th17/Treg cell balance, microglial/macrophage polarization, dendritic cell functions, as well as oligodendrocyte survival and activity. Therapeutic approaches targeting SOCS molecules, including SOCS1 mimetic peptides, have demonstrated promise in EAE models. This review provides a comprehensive explanation regarding the expression patterns of SOCS molecules in MS patients and EAE model, factors affecting their expression and their mechanistic role in disease immunopathogenesis, as well as highlights their potential as a therapeutic target for MS.
Lung adenocarcinoma is the most common subtype of lung cancer and the leading cause of cancer-related mortality worldwide. Ferroptosis, a regulated form of cell death characterized by iron-dependent lipid peroxidation, has emerged as a promising therapeutic target for lung adenocarcinoma. However, the molecular mechanisms that control ferroptosis sensitivity remain unclear. In this study, we identified ubiquitin-specific protease 45 (USP45) as a critical suppressor of ferroptosis in lung adenocarcinoma cells. Systematic screening of ubiquitin-specific proteases revealed that USP45 robustly enhanced glutathione peroxidase 4 (GPX4) protein expression. Bioinformatics analysis indicates that USP45 is significantly upregulated in lung adenocarcinoma patient datasets from the GEO and TCGA databases. Immunohistochemical results from the HPA database further corroborate this finding. Concurrently, elevated USP45 expression in lung adenocarcinoma patients frequently portends an unfavorable prognosis. Functional assays showed that USP45 depletion sensitized lung adenocarcinoma cells to erastin-induced ferroptosis, leading to impaired viability, colony formation, survival, migration, and invasion, whereas USP45 overexpression conferred resistance to ferroptotic stress and rescued the malignant phenotypes. Mechanistically, USP45 interacts with GPX4 and removes its ubiquitin chains, thereby stabilizing the GPX4 protein. Overexpression of GPX4 rescued ferroptosis sensitivity in USP45-deficient lung adenocarcinoma cells, whereas GPX4 depletion abrogated the protective effect of USP45 overexpression, establishing GPX4 as a functional mediator of USP45 activity. Collectively, these findings reveal a previously unknown USP45-GPX4 axis that promotes ferroptosis resistance and tumor progression in lung adenocarcinoma.