RESUMO
Objective: This study aimed to evaluate the risk of adverse events (AEs) in breast cancer patients treated with pembrolizumab combined with paclitaxel versus those receiving pembrolizumab or paclitaxel monotherapy, using the FDA Adverse Event Reporting System (FAERS) database. Methods: Data were extracted from the FAERS database for breast cancer patients treated with pembrolizumab combined with paclitaxel or with pembrolizumab or paclitaxel monotherapy from Q1 2016 to Q2 2023. Disproportionation analysis was performed by calculating the reporting odds ratio (ROR) with corresponding 95% confidence interval (95% CI), the information component (IC), and the lower bound of the information component 95% confidence interval (IC025) to identify potential safety signals. Results: No significant difference in AEs was observed between the combined treatment group and the pembrolizumab monotherapy group. However, the combined treatment group exhibited a substantial increase in AE risk compared to the paclitaxel monotherapy group. The most significant increases in AE risk were adrenal insufficiency (ROR = 189.94, 95% CI 25.41-1419.7, IC = 3.37, IC025 = 1.59), hypophysitis (ROR = 99.46, 95% CI 12.72-777.4, IC = 3.31, IC025 = 1.44), and myocarditis (ROR = 69.5, 95% CI 8.55-565.23, IC = 3.25, IC025 = 1.33). The time-to-event for combined treatment was 35 (34-70) days, for pembrolizumab was 43 (35-90) days, and for paclitaxel was 42 (37-76) days. The combination therapy group demonstrated significantly shorter intervals to the onset of adrenal insufficiency (p = 0.008), myocarditis (p < 0.001), and immune-related enterocolitis (p = 0.009). Conclusion: Analysis of the FAERS database indicates that combination therapy significantly elevates the risk of adrenal insufficiency, myocarditis, hypophysitis, and immune-related enterocolitis compared to paclitaxel monotherapy. These findings provide critical insights for clinicians in predicting and managing potential AEs associated with this treatment regimen.
RESUMO
Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder associated with insulin resistance (IR) and hyperandrogenaemia (HA). Metabolic inflammation (MI), characterized by a chronic low-grade inflammatory state, is intimately linked with chronic metabolic diseases such as IR and diabetes and is also considered an essential factor in the development of PCOS. Insulin-like growth factor 1 (IGF-1) plays an essential role in PCOS pathogenesis through its multiple functions in regulating cell proliferation metabolic processes and reducing inflammatory responses. This review summarizes the molecular mechanisms by which IGF-1, via MI, participates in the onset and progression of PCOS, aiming to provide insights for studies and clinical treatment of PCOS.
Assuntos
Inflamação , Fator de Crescimento Insulin-Like I , Síndrome do Ovário Policístico , Animais , Feminino , Humanos , Inflamação/metabolismo , Inflamação/imunologia , Resistência à Insulina , Fator de Crescimento Insulin-Like I/metabolismo , Síndrome do Ovário Policístico/metabolismo , Síndrome do Ovário Policístico/imunologiaRESUMO
How to effectively improve energy transfer efficiency and luminous intensity inspired us to synthesize a series of SiO2:x%Tb3+@Gd2O3:y%Eu3+ samples, study their luminescence properties and interfacial energy transfer (IET), and compare with SiO2:x%Eu3+@Gd2O3:y%Tb3+. The results show that SiO2:x%Tb3+@Gd2O3:y%Eu3+ can exhibit adjustable multicolor luminescence from red to green at different concentrations of Eu3+ and Tb3+ or under different excitation wavelengths, and there exists efficient IET from Tb3+ to Eu3+ in SiO2:x%Tb3+@Gd2O3:y%Eu3+ and SiO2:x%Eu3+@Gd2O3:y%Tb3+, which improves the energy transfer efficiency and luminous intensity. In addition, the luminescence properties are different between SiO2:3%Tb3+@Gd2O3:3%Eu3+ and SiO2:3%Eu3+@Gd2O3:3%Tb3+, and the energy transfer efficiency of Tb3+ â Eu3+ in SiO2:3%Tb3+@Gd2O3:3%Eu3+ is obviously higher than that in SiO2:3%Eu3+@Gd2O3:3%Tb3+. The present study not only developed a kind of multicolor luminescent phosphor but also offered an important new strategy for improving the energy transfer efficiency and luminescent intensity.
RESUMO
Objective: The aim of this study was to identify the molecular subtypes of breast cancer based on chromatin regulator-related genes. Methods: The RNA sequencing data of The Cancer Genome Atlas-Breast Cancer cohort were obtained from the official website, while the single-cell data were downloaded from the Gene Expression Omnibus database (GSE176078). Validation was performed using the Molecular Taxonomy of Breast Cancer International Consortium dataset. Furthermore, the immune characteristics, tumor stemness, heterogeneity, and clinical characteristics of these molecular subtypes were analyzed. The correlation between chromatin regulators and chemotherapy resistance was examined in vitro using the quantitative real-time polymerase chain reaction (qRT-PCR) and Cell Counting Kit-8 (CCK8) assays. Results: This study identified three stable molecular subtypes with different prognostic and pathological features. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and protein-protein interaction analyses revealed that the differentially expressed genes were associated with disease processes, such as mitotic nuclear division, chromosome segregation, condensed chromosome, and specific chromosome region. The T stage and subtypes were correlated with the clinical features. Tumor heterogeneity (mutant-allele tumor heterogeneity, tumor mutational burden, purity, and homologous recombination deficiency) and tumor stemness (RNA expression-based stemness score, epigenetically regulated RNA expression-based stemness score, DNA methylation-based stemness score, and epigenetically regulated DNA methylation-based stemness score) significantly varied between the three subtypes. Furthermore, Western blotting, qRT-PCR, and CCK8 assays demonstrated that the expression of ASCL1 was positively correlated with chemotherapy resistance in breast cancer. Conclusion: This study identified the subtypes of breast cancer based on chromatin regulators and analyzed their clinical features, gene mutation status, immunophenotype, and drug sensitivity. The results of this study provide effective strategies for assessing clinical prognosis and developing personalized treatment strategies.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos , Neoplasias da Mama , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias da Mama/genética , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Cromatina/genética , Prognóstico , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Perfilação da Expressão GênicaRESUMO
BACKGROUND: Plasma cell-free DNA (cfDNA) fragmentomics has demonstrated significant differentiation power between cancer patients and healthy individuals, but little is known in pancreatic and biliary tract cancers. The aim of this study is to characterize the cfDNA fragmentomics in biliopancreatic cancers and develop an accurate method for cancer detection. METHODS: One hundred forty-seven patients with biliopancreatic cancers and 71 non-cancer volunteers were enrolled, including 55 patients with cholangiocarcinoma, 30 with gallbladder cancer, and 62 with pancreatic cancer. Low-coverage whole-genome sequencing (median coverage: 2.9 ×) was performed on plasma cfDNA. Three cfDNA fragmentomic features, including fragment size, end motif and nucleosome footprint, were subjected to construct a stacked machine learning model for cancer detection. Integration of carbohydrate antigen 19-9 (CA19-9) was explored to improve model performance. RESULTS: The stacked model presented robust performance for cancer detection (area under curve (AUC) of 0.978 in the training cohort, and AUC of 0.941 in the validation cohort), and remained consistent even when using extremely low-coverage sequencing depth of 0.5 × (AUC: 0.905). Besides, our method could also help differentiate biliopancreatic cancer subtypes. By integrating the stacked model and CA19-9 to generate the final detection model, a high accuracy in distinguishing biliopancreatic cancers from non-cancer samples with an AUC of 0.995 was achieved. CONCLUSIONS: Our model demonstrated ultrasensitivity of plasma cfDNA fragementomics in detecting biliopancreatic cancers, fulfilling the unmet accuracy of widely-used serum biomarker CA19-9, and provided an affordable way for accurate noninvasive biliopancreatic cancer screening in clinical practice.
Assuntos
Neoplasias do Sistema Biliar , Ácidos Nucleicos Livres , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/sangue , Neoplasias do Sistema Biliar/genética , Neoplasias do Sistema Biliar/diagnóstico , Neoplasias do Sistema Biliar/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Biomarcadores Tumorais/sangue , AdultoRESUMO
BACKGROUND: Ciliary body tumor is extremely rare and treatment is challenging. The aim of this study is to present our experience in treating this rare entity, especially large tumors with more than 5 clock hours of involvement, and to evaluate the surgical outcomes and complications of local resection via partial lamellar sclerouvectomy in four cases of ciliary body tumors in China. METHODS: Four patients with ciliary body tumors underwent partial lamellar sclerouvectomy between October 2019 and April 2023 in Shanghai General Hospital, China. Tumor features, histopathologic findings, complications, visual acuity, and surgical outcomes were reviewed at a mean follow-up of 20.8 months. RESULTS: Four patients with a mean age of 31.8 years were included in this study. The histopathological diagnosis was adenoma of non-pigmented ciliary epithelium (ANPCE), schwannoma, and multiple ciliary body pigment epithelial cysts. The mean largest tumor base diameter was 6.00 mm (range: 2.00-10.00) and the mean tumor thickness was 3.50 mm (range: 2.00-5.00). Preoperative complications included cataract in 3 (75%) eyes, lens dislocation in 2 (50%), and secondary glaucoma in 1 (25%). Temporary ocular hypotonia was observed in one case and no other postoperative complications were observed. At a mean follow-up of 20.8 months, the best corrected visual acuity increased in 3 eyes and was stable in 1 eye. Tumor recurrence was absent in all eyes. All patients were alive at the end of follow-up. CONCLUSIONS: Local tumor resection via PLSU is useful in the treatment of ciliary body tumors, including large tumors occupying more than five clock hours of pars plicata. Surgery-related complications were manageable with adequate preoperative assessment and careful operation during surgery.
Assuntos
Corpo Ciliar , Esclera , Neoplasias Uveais , Acuidade Visual , Adulto , Humanos , Corpo Ciliar/cirurgia , Corpo Ciliar/patologia , Seguimentos , Procedimentos Cirúrgicos Oftalmológicos/métodos , Estudos Retrospectivos , Esclera/cirurgia , Esclera/patologia , Neoplasias Uveais/cirurgia , Neoplasias Uveais/diagnóstico , Acuidade Visual/fisiologiaRESUMO
OBJECTIVE: To explore the relationships between S100A7 and the immune characteristics, tumor heterogeneity, and tumor stemness pan-cancer as well as the effect of S100A7 on chemotherapy sensitivity in breast cancer. METHODS: TCGA-BRCA and TCGA-PANCANCER RNA-seq data and clinical follow-up survival data were collected from the University of California Santa Cruz database. Survival analyses were performed to explore the relationship between S100A7 expression and pan-cancer prognosis. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, and Gene Set Enrichment Analysis (GSEA) were used to identify the potential pathways related to the differentially expressed genes in breast cancer. Spearman's and Wilcoxon's tests were used to investigate the relationships between S100A7 expression and immune characteristics, methylation, tumor heterogeneity, and tumor stemness. The potential functions of S100A7 and its influence on chemotherapy sensitivity in breast cancer were elucidated using reverse transcription-quantitative PCR, Cell Counting Kit-8 (CCK-8) assay, Transwell assay, and wound healing assay. RESULTS: S100A7 was highly expressed in most types of tumors and was associated with poor prognosis. S100A7 was closely associated with immunomodulators, immune checkpoint and immune cell infiltration. Further, S100A7 was related to tumor mutational burden, tumor heterogeneity, methylation and tumor stemness in breast cancer. High S100A7 expression was associated with the invasiveness, migration, proliferation and chemotherapy resistance of breast cancer cells in vitro experiments. CONCLUSION: High S100A7 expression was related with poor prognosis and chemotherapy resistance in breast cancer, making it a potential immune and chemotherapy resistance biomarker.
Assuntos
Neoplasias Mamárias Animais , Animais , Adjuvantes Imunológicos , Bioensaio , Metilação , Processamento de Proteína Pós-Traducional , HumanosAssuntos
Neoplasias dos Ductos Biliares , Carcinoma Hepatocelular , Colangiocarcinoma , Neoplasias Hepáticas , Humanos , Neoplasias dos Ductos Biliares/patologia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/diagnóstico , Colangiocarcinoma/patologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/diagnóstico , Melanócitos/patologia , Neoplasias Primárias Múltiplas/patologiaRESUMO
Heart failure (HF) is a complex chronic condition characterized by structural and functional impairments. The differentiation of endothelial cells into myofibroblasts (EndoMT) in response to cardiac fibrosis is controversial, and the relative contribution of endothelial plasticity remains to be explored. Single-cell RNA sequencing was used to identify endothelial cells undergoing fibrotic differentiation within 2 weeks of transverse aortic constriction (TAC). This subset of endothelial cells transiently expressed fibrotic genes but had low expression of alpha-smooth muscle actin, indicating a non-canonical EndoMT, which we named a transient fibrotic-like phenotype (EndoFP). The role of EndoFP in pathological cardiac remodeling may be correlated with increased levels of osteopontin. Cardiomyocytes and fibroblasts co-cultured with EndoFP exhibited heightened pro-hypertrophic and pro-fibrotic effects. Mechanistically, we found that the upregulated expression of insulin-like growth factor-binding protein 5 may be a key mediator of EndoFP-induced cardiac dysfunction. Furthermore, our findings suggested that Rab5a is a novel regulatory gene involved in the EndoFP process. Our study suggests that the specific endothelial subset identified in TAC-induced pressure overload plays a critical role in the cellular interactions that lead to cardiac fibrosis and hypertrophy. Additionally, our findings provide insight into the mechanisms underlying EndoFP, making it a potential therapeutic target for early heart failure.
Assuntos
Cardiomiopatias , Cardiopatias , Insuficiência Cardíaca , Animais , Camundongos , Miócitos Cardíacos , Células Endoteliais/patologia , Cardiopatias/metabolismo , Insuficiência Cardíaca/patologia , Cardiomiopatias/metabolismo , Fibrose , Fibroblastos/metabolismo , Remodelação Ventricular , Camundongos Endogâmicos C57BLRESUMO
Tumorigenesis entails circumventing cell-intrinsic regulatory mechanisms while avoiding extrinsic immune surveillance and other host defence systems. Nevertheless, how tumour cells' ability to eliminate misfolded proteins affects immune surveillance remains poorly understood. In this study, we find that overexpression of murine tripartite motif-containing protein 30a (TRIM30a) sensitises tumour cells to natural killer (NK) cells-mediated cytolysis. TRIM30a has no effect on tumour cell proliferation or apoptosis in vitro. However, TRIM30a-overexpressing tumour cells grow substantially slower than control tumour cells in immune-competent mice but not in NK cell-depleted mice. [Correction added on 04 October 2023, after first online publication: 'NK-depleted' has been changed to 'NK cell-depleted' in the preceding sentence.] Mechanistically, TRIM30a overexpression impedes the clearance of misfolded proteins and increases the production of reactive oxygen species induced by proteotoxic stress, implying that TRIM30a impairs protein quality control (PQC) systems in tumour cells. Furthermore, TRIM30a reduces expression of genes encoding proteasome subunits and antioxidant proteins. Our study demonstrates that TRIM30a is a potential tumour suppressor and immune modulator that promotes tumour cytolysis by NK cells, and suggests that an enhanced PQC and antioxidant capacity is an integral part of the immune escape mechanism during tumorigenesis.
Assuntos
Antioxidantes , Neoplasias , Animais , Camundongos , Antioxidantes/metabolismo , Carcinogênese/metabolismo , Células Matadoras Naturais , Espécies Reativas de Oxigênio/metabolismoRESUMO
Current treatment approaches for renal cell carcinoma (RCC) face challenges in achieving durable tumor responses due to tumor heterogeneity and drug resistance. Combination therapies that leverage tumor molecular profiles could offer an avenue for enhancing treatment efficacy and addressing the limitations of current therapies. To identify effective strategies for treating RCC, we selected ten drugs guided by tumor biology to test in six RCC patient-derived xenograft (PDX) models. The multitargeted tyrosine kinase inhibitor (TKI) cabozantinib and mTORC1/2 inhibitor sapanisertib emerged as the most effective drugs, particularly when combined. The combination demonstrated favorable tolerability and inhibited tumor growth or induced tumor regression in all models, including two from patients who experienced treatment failure with FDA-approved TKI and immunotherapy combinations. In cabozantinib-treated samples, imaging analysis revealed a significant reduction in vascular density, and single-nucleus RNA sequencing (snRNA-seq) analysis indicated a decreased proportion of endothelial cells in the tumors. SnRNA-seq data further identified a tumor subpopulation enriched with cell-cycle activity that exhibited heightened sensitivity to the cabozantinib and sapanisertib combination. Conversely, activation of the epithelial-mesenchymal transition pathway, detected at the protein level, was associated with drug resistance in residual tumors following combination treatment. The combination effectively restrained ERK phosphorylation and reduced expression of ERK downstream transcription factors and their target genes implicated in cell-cycle control and apoptosis. This study highlights the potential of the cabozantinib plus sapanisertib combination as a promising treatment approach for patients with RCC, particularly those whose tumors progressed on immune checkpoint inhibitors and other TKIs. SIGNIFICANCE: The molecular-guided therapeutic strategy of combining cabozantinib and sapanisertib restrains ERK activity to effectively suppress growth of renal cell carcinomas, including those unresponsive to immune checkpoint inhibitors.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Sistema de Sinalização das MAP Quinases , Inibidores de Checkpoint Imunológico/uso terapêutico , Alvo Mecanístico do Complexo 1 de Rapamicina , Células Endoteliais/patologia , Inibidores de Proteínas Quinases/efeitos adversos , Anilidas/farmacologia , Anilidas/uso terapêutico , RNA Nuclear Pequeno/uso terapêuticoRESUMO
The Middle East holds a critical strategic position in global politics, economy, and military affairs, serving as a pivotal hub for the advancement of the Belt and Road Initiative (BRI) through both land and sea routes. Since the proposal of BRI, China's cooperation with Middle Eastern countries has steadily deepened. Consequently, examining the evolution of China's interaction with Middle Eastern nations over the past decade is of paramount significance for future development. This study utilizes the GDELT database to construct formulas for measuring event impact and bilateral relationship intensity. It analyzes the temporal development and spatial patterns of China's interaction with Middle Eastern countries while also examining the types of interactive relationships between China and individual countries in the Middle East under the principle of reciprocity. The findings indicate that the overall interaction between China and Middle Eastern countries remains stable. Cooperative relationships have transitioned from a "single cooperation" approach to a "dual cooperation" model involving Iran and Saudi Arabia. Moreover, the development trajectory has shifted from an imbalanced "north-high, south-low" pattern towards equilibrium, resulting in a general decline in conflict relations and a decrease in inter-country disparities. The prevalent type of interaction between countries is characterized by balance.
RESUMO
BACKGROUND: Metaplastic breast cancer(MBC) is a specific pathological type of invasive breast cancer. There are few studies related to MBC due to its rarity. This study aimed to analyse the differences in clinicopathological characteristics and prognosis between Metaplastic breast cancer and triple-negative invasive ductal carcinoma (TN-IDC). METHODS: We retrospectively compared the clinicopathological characteristics of patients diagnosed with MBC and TN-IDC at the Fourth Hospital of Hebei Medical University between 2011 and 2020 in a 1:2 ratio. The log-rank test was used to compare the two groups' disease-free survival (DFS) and overall survival (OS). For MBCs, we performed univariate and multivariate analyses using the Cox proportional hazards model to determine the characteristics that impacted OS and DFS. RESULTS: A total of 81 patients with MBC and 162 patients with TN-IDC were included in this study. At initial diagnosis, MBC patients had larger tumour diameters(P = 0.03) and fewer positive lymph nodes (P = 0.04). Patients with MBC were more likely to have organ metastases after surgery (P = 0.03). Despite receiving the same treatment, MBC patients had worse DFS (HR = 1.66, 95%CI 0.90-3.08, P = 0.11) and OS (HR = 1.98, 95% CI 1.03-3.81, P = 0.04), and OS was statistically significant. Positive lymph nodes at initial diagnosis were associated with worse DFS (HR = 3.98, 95%CI 1.05-15.12, P = 0.04) and OS (HR = 3.70, 95%CI 1.03-13.34, P = 0.04) for patients with MBC. The efficacy of platinum-based agents is insensitive for MBC patients receiving chemotherapy. In addition, patients treated with preoperative chemotherapy had worse DFS compared to patients treated with postoperative chemotherapy (HR = 3.51, 95%CI 1.05-11.75, P = 0.04). CONCLUSIONS: The clinicopathological characteristics and prognosis of MBC and TN-IDC differ in many ways. Further studies are required to determine suitable treatment guidelines for patients with MBC.
Assuntos
Neoplasias da Mama , Carcinoma Ductal de Mama , Humanos , Feminino , Estudos Retrospectivos , Carcinoma Ductal de Mama/terapia , Prognóstico , Intervalo Livre de DoençaRESUMO
This study analysed the data from the NHANES (1999-2018) to examine how different sources of carbohydrate intake affected the all-cause and cardiovascular mortality of 11,302 chronic kidney disease (CKD) patients. The data were adjusted for other factors using various methods. The results showed that CKD patients (stages 1-2 and 3-5) who consumed more carbohydrates from whole grains, fruits, vegetables and less carbohydrates from fruit juice or sauces had lower mortality rates. Replacing fat intake with carbohydrates from whole grains (HR = 0.86[0.78-0.95]), fruits (raw) (HR = 0.79[0.70-0.88]) and non-starchy vegetables (HR = 0.82[0.70-0.96]), but not protein intake, was linked to lower all-cause mortality. The fibre content in carbohydrates might partly account for the benefits of selected carbohydrate intake. This study provided practical recommendations for optimising the carbohydrate sources in CKD patients.
Assuntos
Doenças Cardiovasculares , Insuficiência Renal Crônica , Humanos , Inquéritos Nutricionais , Verduras , Insuficiência Renal Crônica/complicações , Doenças Cardiovasculares/etiologia , CarboidratosRESUMO
Aggregation of tau into filamentous inclusions underlies Alzheimer's disease (AD) and numerous other neurodegenerative tauopathies. The pathogenesis of tauopathies remains unclear, which impedes the development of disease-modifying treatments. Here, by systematically analyzing human tripartite motif (TRIM) proteins, we identified a few TRIMs that could potently inhibit tau aggregation. Among them, TRIM11 was markedly down-regulated in AD brains. TRIM11 promoted the proteasomal degradation of mutant tau as well as superfluous normal tau. It also enhanced tau solubility by acting as both a molecular chaperone to prevent tau misfolding and a disaggregase to dissolve preformed tau fibrils. TRIM11 maintained the connectivity and viability of neurons. Intracranial delivery of TRIM11 through adeno-associated viruses ameliorated pathology, neuroinflammation, and cognitive impairments in multiple animal models of tauopathies. These results suggest that TRIM11 down-regulation contributes to the pathogenesis of tauopathies and that restoring TRIM11 expression may represent an effective therapeutic strategy.
Assuntos
Agregação Patológica de Proteínas , Tauopatias , Animais , Humanos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Neurônios/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismo , Tauopatias/genética , Tauopatias/metabolismo , Proteínas com Motivo Tripartido/genética , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismoRESUMO
PURPOSE: To explore the relationship between C2 slope with sagittal parameters and clinical function of degenerative cervical kyphosis (DCK). METHODS: A retrospective analysis of 127 patients with degenerative cervical spondylosis treated in our spinal deformity center from January 2019 to June 2022. Patients were categorized into two groups and compared based on C2-7 angle (C2-7 ≥ 5° as kyphosis group, C2-7 < 5° as lordosis group). Pearson correlation or Spearman correlation was used to analyze the relationship between C2S and conventional radiological parameters and health -related quality-of-life (HRQOL) outcomes as measured by the EuroQol 5 dimension questionnaire (EQ5D), NRS, and the neck disability index (NDI). The cutoff value of C2S was determined by a receiver operating characteristic (ROC) curve. RESULTS: There were 127 patients who met inclusion criteria (79 men and 48 women). Average 56.00 ± 10.27 years old (range 31-81 years old). C2S of kyphosis group is higher than non-kyphosis group. Aggravating cervical kyphosis increases cSVA positively. For all patients, C2S demonstrated a significant correlation with the O-C2 angle, C2-7 angle, cSVA, and TS-CL (p < 0.05). NRS, NDI and EQ5D-VAS scores revealed a significant correlation with C2S and cSVA (p < 0.01). For the subgroup of patients presenting with DCK, ROC curves demonstrated the cutoff values of C2S as 26.3°, and 30.5°, according to a cSVA of 40 mm, and severe disability expressed by NDI, respectively. CONCLUSION: On the basis of retaining the consistency of cranio-cervical and cervico-thoracic structure, C2S can better analyze the sagittal alignment of DCK patients than TS-CL and has good practicability in clinical application and HRQOL evaluation.
Assuntos
Cifose , Lordose , Masculino , Humanos , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Idoso de 80 Anos ou mais , Estudos Retrospectivos , Vértebras Cervicais/diagnóstico por imagem , Cifose/diagnóstico por imagem , Lordose/diagnóstico por imagem , PescoçoRESUMO
BACKGROUND: The relationship between dietary total antioxidant capacity (DTAC) and death risk among CKD populations remains unclear. METHODS: Based on vitamin C equivalent antioxidant capacity (VCEAC) and the component dietary antioxidant index (CDAI) indices, we analyzed two cohorts to investigate the association of DTAC with all-cause and CVD mortality in CKD patients using data from National Health and Nutrition Examination Survey (2007-2018). VCEAC (n = 6330) and CDAI (n = 6300) cohorts with mortality follow-up data available through 2018 were included. Cox models with restricted cubic splines was used to model the nonlinear association between VCEAC/CDAI and outcomes in CKD patients. RESULTS: Our results showed L-shaped associations of DTAC with all-cause mortality among individuals with CKD stages 1-2 in both cohorts. Compared to the lowest quartile, higher dietary total antioxidant intake was associated with lower all-cause mortality risks among CKD stages 1-2 after adjustment for covariates, with HRs (95%CI) of 1.00, 0.91 (0.71,1.17), 0.69 (0.53,0.90), and 0.70 (0.54,0.91) in VCEAC, and similar respective estimate trends in CDAI. After sensitivity and subgroup analyses, there were no benefits for patients with stage 3-5 CKD or albuminuria. Mediation analysis revealed that the proportions mediated in both cohorts were less consistent. CONCLUSIONS: Moderate dietary total antioxidants intake has potential benefits for early-stage CKD patients. However, further evidence is needed to confirm whether patients with worsening CKD can benefit in the long term.
Assuntos
Antioxidantes , Doenças Cardiovasculares , Insuficiência Renal Crônica , Antioxidantes/administração & dosagem , Doenças Cardiovasculares/mortalidade , Insuficiência Renal Crônica/mortalidade , Estudos Retrospectivos , Ácido Ascórbico/administração & dosagem , Inquéritos Nutricionais , MortalidadeRESUMO
Uveitis is a major cause of vision impairment worldwide. Current treatments have limited effectiveness but severe complications. Mannose binding lectin (MBL) is an important protein of the innate immune system that binds to TLR4 and suppresses LPS-induced inflammatory cytokine secretion. MBL-mediated inhibition of inflammation via the TLR4 pathway and MBL-derived peptides might be a potential therapeutics. In this study, we designed a novel MBL-derived peptide, WP-17, targeting TLR4. Bioinformatics analysis was conducted for the sequence, structure and biological properties of WP-17. The binding of WP-17 to THP-1 cells was analyzed using flow cytometry. Signaling molecules were analyzed by western blotting, and activation of NF-κB was measured by immunofluorescence-histochemical analysis. Effects of WP-17 were studied in vitro using LPS-stimulated THP-1 cells and in vivo in endotoxin-induced uveitis (EIU). Our results showed that WP-17 could bind to TLR4 expressed on macrophages, thus downregulating the expression levels of MyD88, IRAK-4, and TRAF-6, and inhibiting the downstream NF-kB signaling pathway and LPS-induced expression of TNF-α and IL-6 in THP-1 cells. Moreover, in EIU rats, intravitreal pretreatment with WP-17 demonstrated significant inhibitory effects on ocular inflammation, attenuating the clinical and histopathological manifestations of uveitis, reducing protein leakage and cell infiltration into the aqueous humor, and suppressing TNF-α and IL-6 production in ocular tissues. In summary, our study provides the first evidence of a novel MBL-derived peptide that suppressed activation of the NF-кB pathway by targeting TLR4. The peptide effectively inhibited rat uveitis and may be a promising candidate for the management of ocular inflammatory diseases.
Assuntos
NF-kappa B , Uveíte , Ratos , Animais , NF-kappa B/metabolismo , Lipopolissacarídeos/farmacologia , Lipopolissacarídeos/metabolismo , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Transdução de Sinais , Inflamação/tratamento farmacológico , Inflamação/patologia , Uveíte/induzido quimicamente , Uveíte/tratamento farmacológico , Uveíte/patologia , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Lectinas de Ligação a Manose/metabolismo , Lectinas de Ligação a Manose/farmacologia , Lectinas de Ligação a Manose/uso terapêuticoRESUMO
The phytohormone auxin plays crucial roles in nearly every aspect of plant growth and development. Auxin signaling is activated through the phytohormone-induced proteasomal degradation of the Auxin/INDOLE-3-ACETIC ACID (Aux/IAA) family of transcriptional repressors. Notably, many auxin-modulated physiological processes are also regulated by nitric oxide (NO) that executes its biological effects predominantly through protein S-nitrosylation at specific cysteine residues. However, little is known about the molecular mechanisms in regulating the interactive NO and auxin networks. Here, we show that NO represses auxin signaling by inhibiting IAA17 protein degradation. NO induces the S-nitrosylation of Cys-70 located in the intrinsically disordered region of IAA17, which inhibits the TIR1-IAA17 interaction and consequently the proteasomal degradation of IAA17. The accumulation of a higher level of IAA17 attenuates auxin response. Moreover, an IAA17C70W nitrosomimetic mutation renders the accumulation of a higher level of the mutated protein, thereby causing partial resistance to auxin and defective lateral root development. Taken together, these results suggest that S-nitrosylation of IAA17 at Cys-70 inhibits its interaction with TIR1, thereby negatively regulating auxin signaling. This study provides unique molecular insights into the redox-based auxin signaling in regulating plant growth and development.