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Long non-coding RNAs (lncRNAs) are well known for their oncogenic or anti-oncogenic roles in cancer development. AGAP2-AS1, a new lncRNA, has been extensively demonstrated as an oncogenic lncRNA in various cancers. Abundant experimental results have proved the aberrantly high level of AGAP2-AS1 in a great number of malignancies, such as glioma, colorectal, lung, ovarian, prostate, breast, cholangiocarcinoma, bladder, colon and pancreatic cancers. Importantly, the biological functions of AGAP2-AS1 have been extensively demonstrated. It could promote the proliferation, migration and invasion of cancer cells. Simultaneously, the clinical significances of AGAP2-AS1 were also illustrated. AGAP2-AS1 was exceptionally overexpressed in various cancer tissues. Clinical studies disclosed that the abnormal overexpression of AGAP2-AS1 was tightly connected with overall survival (OS), lymph nodes metastasis (LNM), clinical stage, tumor infiltration, high histological grade (HG), serous subtype and PFI times. However, to date, the biological actions and clinical significances of AGAP2-AS1 have not been systematically reviewed in human cancers. In the present review, the authors overviewed the biological actions, potential mechanisms and clinical features of AGAP2-AS1 according to the previous studies. In summary, AGAP2-AS1, as a vital oncogenic gene, is a promising biomarker and potential target for carcinoma prognosis and therapy.
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Regulación Neoplásica de la Expresión Génica , Neoplasias , ARN Largo no Codificante , ARN Largo no Codificante/genética , Humanos , Neoplasias/genética , Neoplasias/patología , Neoplasias/metabolismo , Biomarcadores de Tumor/genética , Pronóstico , Proliferación Celular/genética , Movimiento Celular/genéticaRESUMEN
Background: Glioblastoma multiforme (GBM) is the most common malignant form of glioma, but the molecular mechanisms underlying the progression of GBM in hypoxic microenvironment remain elusive. This study aims to explore the pathological functions of hypoxia-responsive genes on GBM progression and its downstream signaling pathways. Methods: RNA-seq was performed in normoxic and hypoxic U87 cells to identify the differentially expressed genes (DEGs) under hypoxia. The mRNA expression levels of hypoxia-responsive gene F3 in glioma clinical samples were analyzed according to the transcriptional information from CGGA, TCGA and Rembrandt databases. EdU, transwell and wound-healing assays were conducted to evaluate the pathological functions of F3 on GBM proliferation and migration under hypoxia. RNA-seq and gene set enrichment analysis were conducted to analyze the enriched pathways in LN229 cells overexpressed F3 compared to controls. GBM cells were treated with NF-κB inhibitor PDTC, and cell experiments were performed to evaluate the effects of PDTC on OE-F3-LN229 and OE-F3-U87 cells. Western blot was performed to validate the downstream pathways. Results: F3 was identified as a hypoxia responsive gene in GBM cells. The mRNA expression level of F3 was negatively correlated with the overall survival of glioma patients, and significantly increased in grade IV and GBM than lower grade or other histology of glioma. Overexpression of F3 enhanced the proliferation and migration of hypoxic U87 and LN229 cells, while knockdown inhibited them. In OE-F3-LN229 cells, the NF-κB pathway was activated, with an increased level of phosphorylated p65. PDTC treatment effectively rescued the enhanced proliferation and migration of OE-F3-LN229 cells under hypoxia, indicating that the effect of F3 on GBM progression is probably dependent on the NF-κB pathway. Conclusion: Hypoxia-induced F3 activates NF-κB pathway through upregulation of the phosphorylated p65, thus promoting the proliferation and migration of GBM cells under hypoxia, which might be a potential therapeutic target for GBM treatment.
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ETHNOPHARMACOLOGICAL RELEVANCE: Qinghao-Biejia herb pair (QB) is the core herb pair of "Jieduquyuziyin prescription" and is one of the commonly used herb pairs for the clinical treatment of systemic lupus erythematosus (SLE). Previous studies have shown that QB reduces the expression of inflammatory cytokines like IL-6 and TNF-α in the serum and kidney of MRL/lpr mice. Additionally, it inhibits the expression of TLR4 and MyD88 in the kidney and aorta and reduces the deposition of renal complement C3 and aortic plaque after treatment. These findings suggest that QB has a preventive and therapeutic effect on lupus rats. AIM OF THE STUDY: This study sought to investigate the mechanisms underlying the anti-SLE combined with atherosclerosis activity of the Qinghao-Biejia herb pair. MATERIALS AND METHODS: Drug targets for QB were identified using the HERB database, while targets associated with SLE and atherosclerosis were retrieved from the GeneCards database. The intersection of these drug and disease targets was then analyzed using a protein-protein interaction (PPI) network with GO and KEGG pathway enrichment analysis. In vivo, apolipoprotein E-deficient (ApoE-/-) mice were induced to develop SLE-AS by intraperitoneal injection of pristane and continued feeding of a high-fat diet. The changes in relevant indexes were observed after 12 weeks of gavage treatment with hydroxychloroquine, QB, Q (Qinghao alone), and B (Biejia alone). Bone marrow-derived macrophages from ApoE-/- mice and Raw 264.7 macrophages were used to explore the mechanisms of QB treatment. RESULTS: The levels of inflammatory cytokines in serum and pathological liver changes in mice were improved to varying degrees in the treatment groups. Additionally, there was a reduction in aortic atheromatous plaque formation and some improvement in cholesterol efflux. Furthermore, QB suppressed the expression of inflammatory cytokines in M1 macrophages, suggesting a role in regulating macrophage polarization. CONCLUSION: QB demonstrates clear efficacy for treating SLE-AS, and its therapeutic mechanism may involve the regulation of macrophage phenotypes by promoting cholesterol efflux.
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Transportador 1 de Casete de Unión a ATP , Aterosclerosis , Colesterol , Medicamentos Herbarios Chinos , Lupus Eritematoso Sistémico , Macrófagos , Animales , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Aterosclerosis/tratamiento farmacológico , Ratones , Lupus Eritematoso Sistémico/tratamiento farmacológico , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Transportador 1 de Casete de Unión a ATP/metabolismo , Colesterol/sangre , Colesterol/metabolismo , Células RAW 264.7 , Ratones Endogámicos C57BL , Femenino , Ratones Endogámicos MRL lpr , Ratones Noqueados para ApoERESUMEN
Vertebrate radial glia progenitors (RGPs), the principal neural stem cells, balance self-renewal and differentiation through asymmetric cell division (ACD), during which unequal inheritance of centrosomes is observed. Mechanistically, how centrosome asymmetry leads to distinct daughter cell fate remains largely unknown. Here we find that the centrosome protein Pericentriolar Material 1 (Pcm1), asymmetrically distributed at the centrosomes, regulates polarized endosome dynamics and RGP fate. In vivo time-lapse imaging and nanoscale-resolution expansion microscopy of zebrafish embryonic RGPs detect Pcm1 on Notch ligand-containing endosomes, in a complex with the polarity regulator Par-3 and dynein motor. Loss of pcm1 disrupts endosome dynamics, with clonal analysis uncovering increased neuronal production at the expense of progenitors. Pcm1 facilitates an exchange of Rab5b (early) for Rab11a (recycling) endosome markers and promotes the formation of Par-3 and dynein macromolecular complexes on recycling endosomes. Finally, in human-induced pluripotent stem cell-derived brain organoids, PCM1 shows asymmetry and co-localization with PARD3 and RAB11A in mitotic neural progenitors. Our data reveal a new mechanism by which centrosome asymmetry is conveyed by Pcm1 to polarize endosome dynamics and Notch signaling in regulating ACD and progenitor fate.
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Background: Predicting the response to neoadjuvant chemoradiotherapy (nCRT) before initiating treatment is essential for tailoring therapeutic strategies and monitoring prognosis in locally advanced rectal cancer (LARC). In this study, we aimed to develop and validate radiomic-based models to predict clinical and pathological complete responses (cCR and pCR, respectively) by incorporating the Shapley Additive exPlanations (SHAP) method for model interpretation. Methods: A total of 285 patients with complete pretreatment clinical characteristics and T1-weighted (T1W) and T2-weighted (T2W) magnetic resonance imaging (MRI) at 3 centers were retrospectively recruited. The features of tumor lesions were extracted by PyRadiomics and selected using least absolute shrinkage and selection operator (LASSO) algorithm. The selected features were used to build multilayer perceptron (MLP) models alone or combined with clinical features. Area under the receiver operating characteristic curve (AUC), decision curve, and calibration curve were applied to evaluate performance of models. The SHAP method was adopted to explain the prediction models. Results: The radiomic-based models all showed better performances than clinical models. The clinical-radiomic models showed the best differentiation on cCR and pCR with mean AUCs of 0.718 and 0.810 in the validation set, respectively. The decision curves of the clinical-radiomic models showed its values in clinical application. The SHAP method powerfully interpreted the prediction models both at a holistic and individual levels. Conclusions: Our study highlights that the radiomic-based prediction models have more excellent abilities than clinical models and can effectively predict treatment response and optimize therapeutic strategies for patients with LARCs.
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INTRODUCTION: Anal mucinous adenocarcinoma (AMAC) is an extremely rare form of anal cancer. Our objective was to examine the incidence, management, and prognostic factors of AMAC. METHODS: We analyzed age-adjusted incidence (AAI) rates over time and compared the prognosis of AMAC with anal squamous cell carcinoma (ASCC) and adenocarcinoma (AAC) using propensity score matching and Kaplan-Meier analysis. Patients were classified based on summary stage and treatments to determine cancer-specific survival. RESULTS: AAI of AMAC fluctuated within a narrow range (0.082-0.237 per million person-years) from 2000 to 2018. AMAC had a slight non-significant trend of worse prognosis than ASCC (p = 0.348) and a better prognosis than AAC (p < 0.01). Females made up a larger proportion of patients diagnosed with the distant disease (p < 0.05) and unmarried (p < 0.05) and somewhat less probably to need surgical removal (p < 0.01) and radiotherapy (p < 0.01). Elderly patients have lower rates of survival (p < 0.05). Localized stage was associated with better prognosis (p < 0.05). Surgery was associated with a tendency toward better survival (p = 0.095). CONCLUSIONS: AMAC exhibits a low incidence yet favorable prognosis compared to typical AAC and slightly worse compared to ASCC. Elderly age is associated with poorer prognosis, while localized stage indicates better prognosis. Surgery demonstrates a trend toward improved survival.
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OBJECTIVES: The translocation of intestinal flora has been linked to the colonization of diverse and heavy lower respiratory flora in patients with septic ARDS, and is considered a critical prognostic factor for patients. METHODS: On the first and third days of ICU admission, BALF, throat swab, and anal swab were collected, resulting in a total of 288 samples. These samples were analyzed using 16S rRNA analysis and the traceability analysis of new generation technology. RESULTS: On the first day, among the top five microbiota species in abundance, four species were found to be identical in BALF and throat samples. Similarly, on the third day, three microbiota species were found to be identical in abundance in both BALF and throat samples. On the first day, 85.16% of microorganisms originated from the throat, 5.79% from the intestines, and 9.05% were unknown. On the third day, 83.52% of microorganisms came from the throat, 4.67% from the intestines, and 11.81% were unknown. Additionally, when regrouping the 46 patients, the results revealed a significant predominance of throat microorganisms in BALF on both the first and third day. Furthermore, as the disease progressed, the proportion of intestinal flora in BALF increased in patients with enterogenic ARDS. CONCLUSIONS: In patients with septic ARDS, the main source of lung microbiota is primarily from the throat. Furthermore, the dynamic trend of the microbiota on the first and third day is essentially consistent.It is important to note that the origin of the intestinal flora does not exclude the possibility of its origin from the throat.
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Bacterias , Líquido del Lavado Bronquioalveolar , Microbiota , Faringe , ARN Ribosómico 16S , Síndrome de Dificultad Respiratoria , Sepsis , Humanos , Masculino , Femenino , Síndrome de Dificultad Respiratoria/microbiología , Persona de Mediana Edad , Faringe/microbiología , ARN Ribosómico 16S/genética , Líquido del Lavado Bronquioalveolar/microbiología , Anciano , Sepsis/microbiología , Bacterias/clasificación , Bacterias/aislamiento & purificación , Bacterias/genética , Alveolos Pulmonares/microbiología , Adulto , Unidades de Cuidados Intensivos , Microbioma GastrointestinalRESUMEN
Microcystin-leucine arginine (MC-LR) is a common cyantotoxin produced by hazardous cyanobacterial blooms, and eutrophication is increasing the contamination level of MC-LR in drinking water supplies and aquatic foods. MC-LR has been linked to colorectal cancer (CRC) progression associated with tumor microenvironment, however, the underlying mechanism is not clearly understood. In present study, by using GEO, KEGG, GESA and ImmPort database, MC-LR related differentially expressed genes (DEGs) and pathway- and gene set-enrichment analysis were performed. Of the three identified DEGs (CXCL1, GUCA2A and GDF15), CXCL1 was shown a positive association with tumor infiltration, and was validated to have a dominantly higher upregulation in MC-LR-treated tumor-associated macrophages (TAMs) rather than in MC-LR-treated CRC cells. Both CRC cell/macrophage co-culture and xenograft mouse models indicated that MC-LR stimulated TAMs to secrete CXCL1 resulting in promoted proliferation, migration, and invasion capability of CRC cells. Furtherly, IP-MS assay found that interaction between TAMs-derived CXCL1 and CRC cell-derived IGHG1 may enhance CRC cell proliferation and migration after MC-LR treatment, and this effect can be attenuated by silencing IGHG1 in CRC cell. In addition, molecular docking analysis, co-immunoprecipitation and immunofluorescence further proved the interactions between CXCL1 and IGHG1. In conclusion, CXCL1 secreted by TAMs can trigger IGHG1 expression in CRC cells, which provides a new clue in elucidating the mechanism of MC-LR-mediated CRC progression.
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Quimiocina CXCL1 , Neoplasias Colorrectales , Transducción de Señal , Macrófagos Asociados a Tumores , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/genética , Humanos , Animales , Quimiocina CXCL1/genética , Quimiocina CXCL1/metabolismo , Ratones , Macrófagos Asociados a Tumores/metabolismo , Microcistinas/toxicidad , Toxinas Marinas , Línea Celular Tumoral , Progresión de la Enfermedad , Proliferación Celular/efectos de los fármacos , Microambiente TumoralRESUMEN
Higher plants survive terrestrial water deficiency and fluctuation by arresting cellular activities (dehydration) and resuscitating processes (rehydration). However, how plants monitor water availability during rehydration is unknown. Although increases in hypo-osmolarity-induced cytosolic Ca2+ concentration (HOSCA) have long been postulated to be the mechanism for sensing hypo-osmolarity in rehydration1,2, the molecular basis remains unknown. Because osmolarity triggers membrane tension and the osmosensing specificity of osmosensing channels can only be determined in vivo3-5, these channels have been classified as a subtype of mechanosensors. Here we identify bona fide cell surface hypo-osmosensors in Arabidopsis and find that pollen Ca2+ spiking is controlled directly by water through these hypo-osmosensors-that is, Ca2+ spiking is the second messenger for water status. We developed a functional expression screen in Escherichia coli for hypo-osmosensitive channels and identified OSCA2.1, a member of the hyperosmolarity-gated calcium-permeable channel (OSCA) family of proteins6. We screened single and high-order OSCA mutants, and observed that the osca2.1/osca2.2 double-knockout mutant was impaired in pollen germination and HOSCA. OSCA2.1 and OSCA2.2 function as hypo-osmosensitive Ca2+-permeable channels in planta and in HEK293 cells. Decreasing osmolarity of the medium enhanced pollen Ca2+ oscillations, which were mediated by OSCA2.1 and OSCA2.2 and required for germination. OSCA2.1 and OSCA2.2 convert extracellular water status into Ca2+ spiking in pollen and may serve as essential hypo-osmosensors for tracking rehydration in plants.
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Arabidopsis , Señalización del Calcio , Calcio , Germinación , Concentración Osmolar , Polen , Arabidopsis/metabolismo , Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Calcio/metabolismo , Canales de Calcio/genética , Canales de Calcio/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Germinación/genética , Mutación , Polen/genética , Polen/metabolismo , Agua/metabolismo , Células HEK293 , Humanos , DeshidrataciónRESUMEN
Choroidal neovascularization (CNV), characterized as a prominent feature of wet age-related macular degeneration (AMD), is a primary contributor to visual impairment and severe vision loss globally, while the prevailing treatments are often unsatisfactory. The development of conventional treatment strategies has largely been based on the understanding that the angiogenic switch of endothelial cells is dictated by angiogenic growth factors alone. Even though treatments targeting vascular endothelial growth factor (VEGF), like Ranibizumab, are widely administered, more than half of the patients still exhibit inadequate or null responses, emphasizing the imperative need for solutions to this problem. Here, aiming to explore therapeutic strategies from a novel perspective of endothelial cell metabolism, a biocompatible nanomedicine delivery system is constructed by loading RGD peptide-modified liposomes with 2-deoxy-D-glucose (RGD@LP-2-DG). RGD@LP-2-DG displayed good targeting performance towards endothelial cells and excellent in vitro and in vivo inhibitory effects on neovascularization were demonstrated. Moreover, our mechanistic studies revealed that 2-DG interfered with N-glycosylation, leading to the inhibition of vascular endothelial growth factor receptor 2 (VEGFR2) and its downstream signaling. Notably, the remarkable inhibitory effect on neovascularization and biocompatibility of RGD@LP-2-DG render it a highly promising and clinically translatable therapeutic candidate for the treatment of wet AMD and other angiogenic diseases, particularly in patients who are unresponsive to currently available treatments.
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Neovascularización Coroidal , Desoxiglucosa , Liposomas , Nanomedicina , Oligopéptidos , Receptor 2 de Factores de Crecimiento Endotelial Vascular , Degeneración Macular Húmeda , Oligopéptidos/química , Animales , Humanos , Nanomedicina/métodos , Neovascularización Coroidal/tratamiento farmacológico , Neovascularización Coroidal/patología , Neovascularización Coroidal/metabolismo , Degeneración Macular Húmeda/tratamiento farmacológico , Degeneración Macular Húmeda/metabolismo , Desoxiglucosa/farmacología , Desoxiglucosa/administración & dosificación , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismoRESUMEN
BACKGROUND AND PURPOSE: This study aimed to investigate the clinical efficacy and safety of telitacicept in patients with generalized myasthenia gravis (gMG) who tested positive for acetylcholine receptor antibodies or muscle-specific kinase antibodies and were receiving standard-of-care therapy. METHODS: Patients meeting the eligibility criteria were randomly assigned to receive telitacicept subcutaneously once a week for 24 weeks in addition to standard-of-care treatment. The primary efficacy endpoint was the mean change in the quantitative myasthenia gravis (QMG) score from baseline to week 24. Secondary efficacy endpoints included mean change in QMG score from baseline to week 12 and gMG clinical absolute score from baseline to week 24. Additionally, safety, tolerability and pharmacodynamics were assessed. RESULTS: Twenty-nine of the 41 patients screened were randomly selected and enrolled. The mean (± standard deviation [SD]) reduction in QMG score from baseline to week 24 was 7.7 (± 5.34) and 9.6 (± 4.29) in the 160 mg and 240 mg groups, respectively. At week 12, mean reductions in QMG scores for these two groups were 5.8 (± 5.85) and 9.5 (± 5.03), respectively, indicating rapid clinical improvement. Safety analysis revealed no adverse events leading to discontinuation or mortalities. All patients showed consistent reductions in serum immunoglobulin (Ig) A, IgG and IgM levels throughout the study. CONCLUSION: Telitacicept demonstrated safety, good tolerability and reduced clinical severity throughout the study period. Further validation of the clinical efficacy of telitacicept in gMG will be conducted in an upcoming phase 3 clinical trial.
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Miastenia Gravis , Humanos , Miastenia Gravis/tratamiento farmacológico , Femenino , Masculino , Persona de Mediana Edad , Adulto , Anciano , Resultado del Tratamiento , Receptores Colinérgicos/inmunologíaRESUMEN
PANoptosis is a newly described inflammatory programmed cell death, that highlights coordination between pyroptosis, apoptosis and necroptosis. However, the functions of PANoptosis-related genes in glioma progression still remain to be explored. This study aims to identify PANoptosis-related predictors that may be utilized for prognosis prediction and development of new therapeutic targets. Firstly, bulk and single-cell RNA-seq (scRNA-seq) data of glioma patients were extracted from TCGA, CGGA and GEO database. Genetic analysis indicates a considerably high mutation frequency of PANoptosis-related genes (PANRGs) in glioma. Consensus clustering was applied to reveal different subtypes of glioma based on PANRGs. Two PANoptosis subtypes with distinct prognostic and TME characteristics were identified. Then, with LASSO-Cox regression analysis, four PANoptosis-related predictors (MYBL2, TUBA1C, C21orf62 and KCNIP2) were determined from bulk and scRNA-seq analysis. Predictive PANRG score model was established with these predictors and its correlation with tumor microenvironment (TME) was investigated. The results showed that patients with low PANRG score, had higher infiltration of anti-tumor immune cells, higher MSI score and lower TIDE score, which are more likely to benefit from immunotherapy. Further analysis identified 16 potential drugs associated with PANoptosis-related predictors. Moreover, the expression levels of four PANoptosis-related predictors were examined in clinical samples and the results were consistent with those analyzed in the database. Besides, we also confirmed the biological functions of two oncogenic predictors (MYBL2 and TUBA1C) by cell experiments, which revealed that knockdown of MYBL2 or TUBA1C could significantly inhibit the proliferation and migration of glioma cells. These findings highlight the prognostic value and biological functions of PANRGs in glioma, which may provide valuable insights for individualized treatment.
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Several types of non-coding RNAs such as circRNAs, lncRNAs, and miRNAs have been identified to regulate mRNAs through the mechanism known as the competitive endogenous RNA (ceRNA) network. To explore the role of the ceRNA regulatory network in the immune microenvironment of bladder cancer, whole-transcriptome sequencing of bladder tumor and its peritumoral tissues from 38 bladder cancer patients, with a total of 63 samples, was performed to screen differentially expressed circ-, lnc-, mi-, and mRNAs to construct a circ/lnc-mi-mRNA regulatory network with pruning algorithms. We excavated a key immune-related gene BDNF to build the final ceRNA network as hsa-miR-107 sponged by hsa-circ-000211, AC108488.1, and LINC00163. Finally, a meta-analysis of 7 public datasets demonstrated that low expression of BDNF and high expression of hsa-miR-107 were associated with longer survival. Our study identified a ceRNA regulatory network as a potentially new prognostic marker and molecular therapeutic target of bladder cancer.
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Cuproptosis and ferroptosis represent copper- and iron-dependent forms of cell death, respectively, and both are known to play pivotal roles in head and neck squamous cell carcinoma (HNSCC). However, few studies have explored the prognostic signatures related to cuproptosis and ferroptosis in HNSCC. Our objective was to construct a prognostic model based on genes associated with cuproptosis and ferroptosis. We randomly assigned 502 HSNCC samples from The Cancer Genome Atlas (TCGA) into training and testing sets. Pearson correlation analysis was utilized to identify cuproptosis-associated ferroptosis genes in the training set. Cox proportional hazards (COX) regression and least absolute shrinkage operator (LASSO) were employed to construct the prognostic model. The performance of the prognostic model was internally validated using single-factor COX regression, multifactor COX regression, Kaplan-Meier analysis, principal component analysis (PCA), and receiver operating curve (ROC) analysis. Additionally, we obtained 97 samples from the Gene Expression Omnibus (GEO) database for external validation. The constructed model, based on 12 cuproptosis-associated ferroptosis genes, proved to be an independent predictor of HNSCC prognosis. Among these genes, the increased expression of aurora kinase A (AURKA) has been implicated in various cancers. To further investigate, we employed small interfering RNAs (siRNAs) to knock down AURKA expression and conducted functional experiments. The results demonstrated that AURKA knockdown significantly inhibited the proliferation and migration of HNSCC cells (Cal27 and CNE2). Therefore, AURKA may serve as a potential biomarker in HNSCC.
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Aurora Quinasa A , Biomarcadores de Tumor , Ferroptosis , Neoplasias de Cabeza y Cuello , Carcinoma de Células Escamosas de Cabeza y Cuello , Humanos , Ferroptosis/genética , Aurora Quinasa A/metabolismo , Aurora Quinasa A/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/metabolismo , Pronóstico , Regulación Neoplásica de la Expresión Génica , Línea Celular Tumoral , Masculino , Femenino , Estimación de Kaplan-Meier , Proliferación Celular/genéticaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Liujunzi formula has been used to treat liver cancer in China for many years, but its underlying mechanism remains unclear. We previously found that decreased expression of miR-122-3p was associated with liver cancer. In this study, we aimed to explore the target of miR-122-3p and the effect of the Liujunzi formula on miR-122-3p and its downstream events in liver cancer. MATERIAL AND METHODS: Bioinformatics pinpointed potential targets of miR-122-3p. The actual target was confirmed by miRNA mimic/inhibitor transfections and a dual-luciferase reporter assay. RNA-seq looked at downstream genes impacted by this target. Flow cytometry checked for changes in T cell apoptosis levels after exposing them to liver cancer cells. Gene expression was measured by RT-qPCR, western blotting, and immunofluorescence staining. RESULTS: Cell experiments found the Liujunzi extract (LJZ) upregulated miR-122-3p and in a dose-dependent manner. Bioinformatics analysis found UBE2I was a potential target of miR-122-3p, which was validated through experiments using miRNA mimics/inhibitors and a dual-luciferase reporter assay. RNA-seq data implicated the NF-κB pathway as being downstream of the miR-122-3p/UBE2I axis, further confirmed by forcing overexpression of UBE2I. Bioinformatic evidence suggested a link between UBE2I and T cell infiltration in liver cancer. Given that the NF-κB pathway drives PD-L1 expression, which can inhibit T cell infiltration, we investigated whether PD-L1 is a downstream effector of miR-122-3p/UBE2I. This was corroborated through mining public databases, UBE2I overexpression studies, and tumor-T cell co-culture assays. In addition, we also confirmed that LJZ downregulates UBE2I and NF-κB/PD-L1 pathways through miR-122-3p. LJZ also suppressed SUMOylation in liver cancer cells and protected PD-1+ T cells from apoptosis induced by co-culture with tumor cells. Strikingly, a miR-122-3p inhibitor abrogated LJZ's effects on UBE2I and PD-L1, and UBE2I overexpression rescued the LJZ-mediated effects on NF-κB and PD-L1. CONCLUSIONS: miR-122-3p targets UBE2I, thereby suppressing the NF-κB signaling cascade and downregulating PD-L1 expression, which potentiates anti-tumor immune responses. LJZ bolsters anti-tumor immunity by modulating the miR-122-3p/UBE2I/NF-κB/PD-L1 axis in liver cancer cells.
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Medicamentos Herbarios Chinos , Neoplasias Hepáticas , MicroARNs , Enzimas Ubiquitina-Conjugadoras , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Humanos , Enzimas Ubiquitina-Conjugadoras/genética , Enzimas Ubiquitina-Conjugadoras/metabolismo , Medicamentos Herbarios Chinos/farmacología , Apoptosis/efectos de los fármacos , FN-kappa B/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Células Hep G2 , Tolerancia Inmunológica/efectos de los fármacosRESUMEN
The external spatiotemporal evolution and intrinsic impact mechanisms of ecosystem service value are of great significance for understanding regional ecosystem issues and enhancing human ecological well-being. Based on grid data, this study used the equivalent factor method and NDVI to measure the ecosystem service value of the Yellow River Basin, analyzed the spatial-temporal evolution of urban ecosystem service value along the basin, and established a GWR model to explore the spatial heterogeneity of each influencing factor on the basis of determining the main influencing factors via geographic detector. The results showed that:â The ecosystem service value of the Yellow River Basin increased first, then decreased, and finally increased from 2000 to 2020, showing a spatial distribution pattern of "the south was higher than the north;" "the lower reaches were lower, and the upper and middle reaches were higher;" and the regulation service contributed the most to the ecosystem service value of the basin. â¡ The results of geographical exploration showed that the degree of influence of various factors was different. Social factors played the strongest role in explaining the ecosystem service value of the Yellow River Basin, followed by economic factors, and natural factors played the weakest role. The high value areas in the upper reaches were mainly related to rivers and lakes, and the high value areas in the middle reaches were mainly related to mountains. ⢠The results of the GWR model showed that population density and land reclamation rate were negatively correlated with ecosystem service value, whereas average annual precipitation was positively correlated, and the effects increased from east to west. The GDP per unit area was negatively correlated with the overall ecosystem service value but positively correlated in the upstream region.
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Early diagnosis plays a pivotal role in handling the global health challenge posed by liver diseases. However, early-stage lesions are typically quite small, presenting significant difficulties due to insufficient regions for developing effective features, indistinguishable boundaries of small lesions, and a lack of tiny liver lesion masks. To address these issues, we approach the solution in two-fold: an efficient model and a high-quality dataset. The model is built upon the advantages of path signature and camouflaged object detection. The path signature narrows down the ambiguous boundaries between lesions and other tissues while the camouflaged object detection achieves high accuracy in detecting inconspicuous lesions. The two are seamlessly integrated to ensure high accuracy and fidelity. For the dataset, we collect more than ten thousand liver images with over four thousand lesions, approximately half of which are small. Experiments on both an established dataset and our newly constructed one show that the proposed model outperforms state-of-the-art semantic segmentation and camouflaged object detection models, particularly in detecting small lesions. Moreover, the decisive and faithful salience maps generated by the model at the boundary regions demonstrate its strong robustness.
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Interpretación de Imagen Asistida por Computador , Hígado , Humanos , Hígado/diagnóstico por imagen , Hígado/patología , Interpretación de Imagen Asistida por Computador/métodos , Algoritmos , Neoplasias Hepáticas/diagnóstico por imagen , Bases de Datos Factuales , Imagen por Resonancia Magnética/métodosRESUMEN
BACKGROUND: As the most common subtype of adult muscular dystrophy worldwide, large cohort reports on myotonic dystrophy type I (DM1) in China are still lacking. This study aims to analyze the genetic and clinical characteristics of Chinese Han DM1 patients. METHODS: Based on the multicenter collaborating effort of the Pan-Yangtze River Delta Alliance for Neuromuscular Disorders, patients with suspected clinical diagnoses of DM1 were genetically confirmed from January 2020 to April 2023. Peak CTG repeats in the DMPK gene were analyzed using triplet repeat-primed PCR (TP-PCR) and flanking PCR. Time-to-event analysis of onset age in females and males was performed. Additionally, detailed clinical features and longitudinal changes from the disease onset in 64 DM1 patients were retrospectively collected and analyzed. The Epworth Sleepiness Scale and Fatigue Severity Scale were used to quantify the severity of daytime sleepiness and fatigue. RESULTS: Among the 211 genetically confirmed DM1 patients, the mean age at diagnosis was 40.9 ± 12.2 (range: 12-74) with a male-to-female ratio of 124:87. The average size of CTG repeats was 511.3 (range: 92-1945). Among the DM1 patients with comprehensive clinical data (n = 64, mean age 41.0 ± 12.0), the age at onset was significantly earlier in males than in females (4.8 years earlier, p = 0.026). Muscle weakness (92.2%), myotonia (85.9%), and fatigue (73.4%) were the most prevalent clinical features. The predominant involved muscles at onset are hands (weakness or myotonia) (52.6%) and legs (walking disability) (42.1%). Of them, 70.3% of patients had daytime sleepiness, 14.1% had cataract surgery, 7.8% used wheelchairs, 4.7% required ventilatory support, and 1.6% required gastric tubes. Regarding the comorbidities, 4.7% of patients had tumors, 17.2% had diabetes, 23.4% had dyspnea, 28.1% had intermittent insomnia, 43.8% experienced dysphagia, and 25% exhibited cognitive impairment. Chinese patients exhibited smaller size of CTG repeats (468 ± 139) than those reported in Italy (613 ± 623), the US (629 ± 386), and Japan (625 [302, 1047]), and milder phenotypes with less multisystem involvement. CONCLUSION: The Chinese Han DM1 patients presented milder phenotypes compared to their Caucasian and Japanese counterparts. A male predominance and an early age of onset were identified in male Chinese Han DM1 patients.
Asunto(s)
Trastornos de Somnolencia Excesiva , Miotonía , Distrofia Miotónica , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos de Somnolencia Excesiva/diagnóstico , Fatiga , Distrofia Miotónica/genética , Distrofia Miotónica/diagnóstico , Estudios Retrospectivos , Niño , Adolescente , Adulto Joven , Anciano , Estudios Multicéntricos como Asunto , Estudios de CohortesRESUMEN
Cerebral cavernous malformation (CCM) is a polygenic disease with intricate genetic interactions contributing to quantitative pathogenesis across multiple factors. The principal pathogenic genes of CCM, specifically KRIT1, CCM2, and PDCD10, have been reported, accompanied by a growing wealth of genetic data related to mutations. Furthermore, numerous other molecules associated with CCM have been unearthed. However, tackling such massive volumes of unstructured data remains challenging until the advent of advanced large language models. In this study, we developed an automated analytical pipeline specialized in single nucleotide variants (SNVs) related biomedical text analysis called BRLM. To facilitate this, BioBERT was employed to vectorize the rich information of SNVs, while a deep residue network was used to discriminate the classes of the SNVs. BRLM was initially constructed on mutations from 12 different types of TCGA cancers, achieving an accuracy exceeding 99%. It was further examined for CCM mutations in familial sequencing data analysis, highlighting an upstream master regulator gene fibroblast growth factor 1 (FGF1). With multi-omics characterization and validation in biological function, FGF1 demonstrated to play a significant role in the development of CCMs, which proved the effectiveness of our model. The BRLM web server is available at http://1.117.230.196.
RESUMEN
OBJECTIVES: We initially explored the link between the differentially expressed long non-coding RNAs (lncRNAs) and the number of regulatory T (Treg) cells by detecting the lncRNA expression profiles in patients with systemic lupus erythematosus (SLE), then analyzed the correlation between Treg-related lncRNAs and the clinical features of SLE patients, predicting the mechanism by which lncRNAs regulate the differentiation and development of Treg cells, and provided new ideas for the treatment of SLE. METHODS: Peripheral blood of 9 active SLE patients were collected and mononuclear cells (PBMCs) were extracted; the lncRNA expression profiles of PBMCs were analyzed by whole transcriptome sequencing. Nine healthy people were used as controls to screen the differentially expressed lncRNAs, to analyze the correlation between lncRNAs and Treg cell number. Pearson test was used to analyze the correlation between lncRNAs and the number of Treg cell, and the correlation between Treg-associated lncRNA and SLEDAI score, ESR, C3, and C4 in SLE patients. The targeted genes of Treg-associated lncRNAs were predicted with miRcode and Targetscan databases and coexpression network. RESULTS: There were 240 differentially expressed lncRNAs in SLE patients compared with healthy controls, including 134 highly expressed lncRNAs (p < 0.05) and 106 lowly expressed lncRNAs (p < 0.05). The expression of ANKRD44-AS1 (r = 0.7417, p = 0.0222), LINC00200 (r = 0.6960, p = 0.0373), AP001363.2 (r = 0.7766, p = 0.0138), and LINC02824 (r = 0.7893, p = 0.0114) were positively correlated with the number of Treg cell, and the expression of AP000640.1 (r = - 0.7225, p = 0.0279), AC124248.1 (r = - 0.7653, p = 0.0163), LINC00482 (r = - 0.8317, p = 0.0054), and MIR503HG (r = - 0.7617, p < 0.05) were negatively correlated with the number of Treg cell. Among these Treg-associated lncRNAs, the expression of LINC00482 (r = - 0.7348, p < 0.05) and MIR503 HG (r = - 0.7617, p < 0.05) were negatively correlated with C3. LINC00200, ANKRD44 - AS1, and AP000640.1 related to Treg cells regulate the expression of signal transducer and activator of transcription 5 (STAT5), phospholipase D1 (PLD1), homeodomain-only protein X (HOPX), and runt-related transcription factor 3 (RUNX3) through competitive binding of miRNA or trans-regulatory mechanism, thereby regulating the differentiation and development of Treg cell. CONCLUSIONS: The lncRNA expression profiles were changed in SLE patients, the differentially expressed lncRNAs were associated with abnormal number and function of Treg cells in SLE, and Treg-associated lncRNAs were associated with SLE-disease activity, which may affect the expression of STAT5, PLD1, HOPX, RUNX3 and regulate Treg cell function and participate in the pathogenesis and progression of SLE by competitively binding to miRNAs or trans-regulatory mechanism. Key points ⢠Systemic lupus erythematosus (SLE) is an autoimmune disease involving multiple organs and systems. lncRNAs may affect Treg cells function by regulating genes expression, which may be an important pathogenesis of SLE. ⢠This study, taking SLE as an example, preliminarily analyzed the correlation between lncRNA and Treg cells in SLE patients, analyzed the correlation between Treg-related lncRNA and the clinical characteristics of SLE, and speculated that lncRNA could regulate the differentiation and development of Treg cells through competitive combination with miRNA or trans-regulatory mechanisms. ⢠It is possible to target epigenetic therapy for SLE.