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PURPOSE: Next-generation sequencing (NGS) has enabled the detection of concomitant driver alterations in non-small cell lung cancer (NSCLC). However, the magnitude and clinical relevance of concomitant drivers remain to be explored. METHODS: We profiled concomitant driver alterations of EGFR+ NSCLC by using targeted NGS. The associated genomic and clinical features were analyzed and validated in an independent The Cancer Genome Atlas cohort of patients with EGFR+ NSCLC. RESULTS: Out of the total patient population, 334 patients had EGFR mutations along with concomitant driver mutations, comprising 3.09% of the entire cohort. The most frequent co-occurring mutations with sensitizing EGFR mutations include KRAS at 53.9%, followed by ERBB2 at 24.3%, MET at 16.5%, and BRAF at 3.3%. KRAS mutations in concomitant drivers were frequently hyperexchange mutations (25.6% v 8.2%, P < .001), compared with KRAS single drivers. EGFR/ERBB2 drivers exhibited a higher incidence of ERBB2 amplification (40.7% v 16.5%, P < .001) and p.S310F/Y mutations (44.4% v 4.3%, P < .001) compared with ERBB2 alone. EGFR/MET drivers had a higher frequency of MET amplification (71.4% v 43.3%) than MET single drivers. At the genomic level, the median number of additional concurrent mutations was four, with TSC2 (4%), CD274 (1%), and TP53 (63%) being the most frequently coaltered genes in concomitant driver tumors. Interestingly, clonality analysis indicated that EGFR mutations were more likely to occur as clonal events, whereas the codrivers were more often subclonal. Patients with concomitant drivers or with concomitant MET amplification exhibited worse prognosis. CONCLUSION: These findings might aid in the selection of effective therapeutic regimens and facilitate the development of combination therapies.
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Carcinoma Pulmonar de Células não Pequenas , Receptores ErbB , Neoplasias Pulmonares , Mutação , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Receptores ErbB/genética , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Idoso de 80 Anos ou mais , Sequenciamento de Nucleotídeos em Larga EscalaRESUMO
OBJECTIVE: The International Federation of Gynecology and Obstetrics (FIGO) 2023 staging system for endometrial cancer (EC) was released with incorporating histology, lympho-vascular space invasion, and molecular classification together. Our objective is to further explore the clinical utility and prognostic significance of the 2023 FIGO staging system in China. METHODS: A retrospective analysis was conducted for patients who received standard surgeries and underwent genetic testing using multigene next-generation sequencing (NGS) panels between December 2018 and December 2023 at Fudan University Shanghai Cancer Center, Shanghai, China. The genomic and clinical data of all patients were analyzed, and stages were determined by both the 2009 and 2023 FIGO staging systems. Kaplan-Meier estimators and Cox proportional hazards models were used for survival analysis. RESULTS: A total of 547 patients were enrolled in the study. After the restaged by the FIGO 2023 staging system, stage shifts occurred in 147/547 (26.9%) patients. In patients with early stages in FIGO 2009 (stage I-II), 63 cases were rearranged to IAmPOLEmut and 53 cases to IICmp53abn due to the molecular classification of POLEmut and p53abn. Altogether 345 cases were in stage I, 107 cases in stage II, 69 cases in stage III, and 26 cases in stage IV according to the FIGO 2023 staging criteria. For stage I diseases, the 3-year PFS rate was 92.7% and 95.3% in 2009 and 2023 FIGO staging systems, respectively. The 3-year PFS of stage II in 2023 FIGO was lower than that of FIGO 2009 (3-year PFS: 85.0% versus 90.9%), especially in substage IIC and IICmp53abn. Three cases (12%) of stage IIIA in FIGO 2009 were shifted to stage IA3 FIGO 2023, with 3-year PFS rates of 90.9% versus 100%, respectively. In NGS analysis, the most prevalent gene alterations were observed in PTEN and PIK3CA. CONCLUSION: The FIGO 2023 staging system was proved to be a good predictor of survival for EC patients with enhanced precision compared to FIGO 2009. Predominant stage shifts were observed in early-stage diseases. Distinct gene alterations of different subtypes may help to explore more accurate target therapies.
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Neoplasias do Endométrio , Estadiamento de Neoplasias , Humanos , Feminino , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/mortalidade , Pessoa de Meia-Idade , Estudos Retrospectivos , China/epidemiologia , Idoso , Adulto , Sequenciamento de Nucleotídeos em Larga Escala , Prognóstico , Idoso de 80 Anos ou mais , Estimativa de Kaplan-Meier , Mutação , População do Leste AsiáticoRESUMO
Background: The interactions between fibroblasts and bronchial epithelial cells play important roles in the development of chronic obstructive pulmonary disease (COPD). Interleukin (IL)-17A triggers the activation of fibroblasts and secretion of inflammatory mediators, which promotes epithelial mesenchymal transition (EMT) in bronchial epithelial cells. Fibroblasts secrete C-X-C motif chemokine ligand 12 (CXCL12), which specifically binds to its receptor, C-X-C motif chemokine receptor 4 (CXCR4) to mediate inflammatory responses. This study aims to investigate IL-17A- and CXCL12-induced airway remodeling. Methods: Primary lung fibroblasts were isolated from human and murine lung tissue for the in vitro experiments, and a mouse model of cigarette smoke (CS)-induced COPD was established for the in vivo experiments. The results were analyzed using one-way ANOVA and Tukey's test or Bonferroni's test for post-hoc test. A p-value < 0.05 was considered statistically significant. Results: Through in vitro experiments, we found that IL-17A-activated primary lung fibroblasts secreted CXCL12 and stimulated EMT in bronchial epithelial cells. However, these effects could be blocked by neutralizing IL-17A or CXCL12. In vivo, an anti-IL-17A antibody or a CXCR4 antagonist (AMD3100) could reverse the degree of EMT in lungs of the COPD mouse model. The IL-17A-induced EMT and increased CXCL12 expression occurred via extracellular signal-regulated kinase (ERK)/phosphorylated (p-)ERK pathways. Conclusion: This study showed that exposure of mice to CS and IL-17A stimulation upregulated CXCL12 expression and induced EMT by activating the ERK signaling pathway. These data offer a novel perspective regarding the molecular mechanism of CXCL12/CXCR4 signaling in IL-17A-induced EMT related to airway remodeling.
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Chloroplast capture, a phenomenon that can occur through interspecific hybridization and introgression, is frequently invoked to explain cytonuclear discordance in plants. However, relatively few studies have documented the mechanisms of cytonuclear coevolution and its potential for driving species differentiation and possible functional differences in the context of chloroplast capture. To address this crucial question, we chose the Aquilegia genus, which is known for having minimal sterility among species, and inferred that A. amurensis captured the plastome of A. parviflora based on cytonuclear discordance and gene flow between the two species. We focused on the introgression region and its differentiation from corresponding regions in closely related species, especially its composition in a chloroplast capture scenario. We found that nuclear genes encoding cytonuclear enzyme complexes (CECs; i.e., organelle-targeted genes) of chloroplast donor species were selectively retained and displaced the original CEC genes in chloroplast-receiving species due to cytonuclear interactions during introgression. Notably, the intrinsic correlation of CEC introgression was a greater degree of evolutionary distance for these CECs between A. amurensis and A. parviflora. Terpene synthase activity genes (GO: 0010333) were overrepresented among the introgressed genes, and more than 30% of these genes were CEC genes. These findings support our observations that floral terpene release pattern is similar between A. amurensis and A. parviflora compared with A. japonica. Our study clarifies the mechanisms of cytonuclear coevolution, species differentiation and functional differences in the context of chloroplast capture and highlights the potential role of chloroplast capture in adaptation.
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BACKGROUND: Cancer-associated fibroblasts (CAFs) and their secretion, C-X-C motif chemokine ligand 12 (CXCL12), play an important role in the development of lung adenocarcinoma (LUAD). Interleukin 17A (IL-17A) is also crucial in regulating tumor progression. Herein, we explored the specific relationships between these two factors and their mechanisms in the progression of LUAD. METHODS: Immunohistochemistry was utilized to assess the differential expression levels of IL-17A and CXCL12 in tumor versus normal tissues of LUAD patients, followed by gene correlation analysis. Cell counting kit-8 (CCK8), wound-healing and transwell assays were performed to investigate the effect of IL-17A on the function of LUAD cells. qPCR, immunofluorescence, immunohistochemistry and western blot analyses were conducted to elucidate the potential mechanism by which IL-17A facilitates the development of LUAD via CXCL12. Male BALB-C nude mice were used to explore the role of IL-17A in subcutaneous LUAD mouse models. RESULTS: Elevated expression levels of IL-17A and CXCL12 were observed in LUAD tissues, exhibiting a positive correlation. Further studies revealed that IL-17A could stimulate CAFs to enhance the release of CXCL12, thereby facilitating the growth, proliferation, and metastasis of LUAD. The binding of CXCL12 to its specific receptor influences the activation of the Wnt/ß-Catenin pathway, which in turn affects the progression of LUAD. In vivo experiments have demonstrated that IL-17A enhances the growth of LUAD tumors by facilitating the secretion of CXCL12. Conversely, inhibiting CXCL12 has been demonstrated to impede tumor growth. CONCLUSIONS: We discovered that IL-17A promotes the release of CAFs-derived CXCL12, which in turn facilitates the development of LUAD via the Wnt/ß-Catenin signaling pathway.
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Adenocarcinoma de Pulmão , Fibroblastos Associados a Câncer , Quimiocina CXCL12 , Progressão da Doença , Interleucina-17 , Neoplasias Pulmonares , Camundongos Endogâmicos BALB C , Camundongos Nus , Via de Sinalização Wnt , Interleucina-17/metabolismo , Quimiocina CXCL12/metabolismo , Humanos , Animais , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Camundongos , Masculino , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , beta Catenina/metabolismoRESUMO
PURPOSE: Lung adenocarcinoma (LUAD) is a prevalent malignant tumor worldwide, with high incidence and mortality rates. However, there is still a lack of specific and sensitive biomarkers for its early diagnosis and targeted treatment. Disulfidptosis is a newly identified mode of cell death that is characteristic of disulfide stress. Therefore, exploring the correlation between disulfidptosis-related long non-coding RNAs (DRGs-lncRNAs) and patient prognosis can provide new molecular targets for LUAD patients. METHODS: The study analysed the transcriptome data and clinical data of LUAD patients in The Cancer Genome Atlas (TCGA) database, gene co-expression, and univariate Cox regression methods were used to screen for DRGs-lncRNAs related to prognosis. The risk score model of lncRNA was established by univariate and multivariate Cox regression models. TIMER, CIBERSORT, CIBERSORT-ABS, and other methods were used to analyze immune infiltration and further evaluate immune function analysis, immune checkpoints, and drug sensitivity. Real-time polymerase chain reaction (RT-PCR) was performed to detect the expression of DRGs-lncRNAs in LUAD cell lines. RESULTS: A total of 108 lncRNAs significantly associated with disulfidptosis were identified. A prognostic model was constructed by screening 10 lncRNAs with independent prognostic significance through single-factor Cox regression analysis, LASSO regression analysis, and multiple-factor Cox regression analysis. Survival analysis of patients through the prognostic model showed that there were obvious survival differences between the high- and low-risk groups. The risk score of the prognostic model can be used as an independent prognostic factor independent of other clinical traits, and the risk score increases with stage. Further analysis showed that the prognostic model was also different from tumor immune cell infiltration, immune function, and immune checkpoint genes in the high- and low-risk groups. Chemotherapy drug susceptibility analysis showed that high-risk patients were more sensitive to Paclitaxel, 5-Fluorouracil, Gefitinib, Docetaxel, Cytarabine, and Cisplatin. Additionally, RT-PCR analysis demonstrated differential expression of DRGs-lncRNAs between LUAD cell lines and the human bronchial epithelial cell line. CONCLUSIONS: The prognostic model of DRGs-lncRNAs constructed in this study has certain accuracy and reliability in predicting the survival prognosis of LUAD patients, and provides clues for the interaction between disulfidptosis and LUAD immunotherapy.
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Adenocarcinoma de Pulmão , Biomarcadores Tumorais , Regulação Neoplásica da Expressão Gênica , Imunoterapia , Neoplasias Pulmonares , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/mortalidade , Adenocarcinoma de Pulmão/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Prognóstico , Biomarcadores Tumorais/genética , Imunoterapia/métodos , Masculino , Feminino , Linhagem Celular Tumoral , Transcriptoma , Pessoa de Meia-IdadeRESUMO
The localized high-concentration electrolyte (LHCE) propels the advanced high-voltage battery system. Sulfone-based LHCE is a transformative direction compatible with high energy density and high safety. In this work, the application of lithium bis(trifluoromethanesulphonyl)imide and lithium bis(fluorosulfonyl)imide (LiFSI) in the LHCE system constructed from sulfolane and 1,1,2,2-tetrafluoroethyl-2,2,3,3-tetrafluoropropyl ether (TTE) is investigated. The addition of diluent causes an increase of contact ion pairs and ionic aggregates in the solvation cluster and an acceptable quantity of free solvent molecules. A small amount of LiFSI as an additive can synergistically decompose with TTE on the cathode and participate in the construction of both electrode interfaces. The designed electrolyte helps the Ni-rich system to cycle firmly at a high voltage of 4.5 V. Even with high mass load and lean electrolyte, it can keep a reversible specific capacity of 91.5% after 50 cycles. The constructed sulfone-based electrolyte system exhibits excellent thermal stability far beyond the commercial electrolytes. Further exploration of in-situ gelation has led to a quick conversion of the designed liquid electrolyte to the gel state, accompanied by preserved stability, which provides a direction for the synergistic development of LHCE with gel electrolytes.
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BACKGROUND: Emerging evidence reveals the key role of ferroptosis in the pathophysiological process of acute kidney injury (AKI). Our study aimed to investigate the potential ferroptosis-related gene in AKI through bioinformatics and experimental validation. METHODS: The AKI single-cell sequencing dataset was retrieved from the GEO database and ferroptosis-related genes were extracted from the GENECARD website. The potential differentially expressed ferroptosis-related genes of AKI were selected. Functional enrichment analysis was performed. Machine learning algorithms were used to identify key ferroptosis-related genes associated with AKI. A multi-factor Cox regression analysis was used to construct a risk score model. The accuracy of the risk score model was validated using receiver operating characteristic (ROC) curve analysis. We extensively explored the immune landscape of AKI using CIBERSORT tool. Finally, expressions of ferroptosis DEGs were validated in vivo and in vitro by Western blot, ICH and transfection experiments. RESULTS: Three hub genes (BAP1, MDM4, SLC2A1) were identified and validated by constructing drug regulatory network and subsequent screening using experimentally determined interactions. The risk mode showed the low-risk group had significantly better prognosis compared to high-risk group. The risk score was independently associated with overall survival. The ROC curve analysis showed that the prognosis model had good predictive ability. Additionally, CIBERSORT immune infiltration analysis suggest that the hub gene may influence cell recruitment and infiltration in AKI. Validation experiments revealed that SLC2A1 functions by regulating ferroptosis. CONCLUSIONS: In summary, our study not only identifies SLC2A1 as diagnostic biomarker for AKI, but also sheds light on the role of it in AKI progression, providing novel insights for the clinical diagnosis and treatment of AKI.
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Injúria Renal Aguda , Ferroptose , Humanos , Prognóstico , Ferroptose/genética , Injúria Renal Aguda/genética , Algoritmos , Biomarcadores , Proteínas Proto-Oncogênicas , Proteínas de Ciclo Celular , Transportador de Glucose Tipo 1RESUMO
BACKGROUND: Aquilegia is a model system for studying the evolution of adaptive radiation. However, very few studies have been conducted on the Aquilegia mitochondrial genome. Since mitochondria play a key role in plant adaptation to abiotic stress, analyzing the mitochondrial genome may provide a new perspective for understanding adaptive evolution. RESULTS: The Aquilegia amurensis mitochondrial genome was characterized by a circular chromosome and two linear chromosomes, with a total length of 538,736 bp; the genes included 33 protein-coding genes, 24 transfer RNA (tRNA) genes and 3 ribosomal RNA (rRNA) genes. We subsequently conducted a phylogenetic analysis based on single nucleotide polymorphisms (SNPs) in the mitochondrial genomes of 18 Aquilegia species, which were roughly divided into two clades: the European-Asian clade and the North American clade. Moreover, the genes mttB and rpl5 were shown to be positively selected in European-Asian species, and they may help European and Asian species adapt to environmental changes. CONCLUSIONS: In this study, we assembled and annotated the first mitochondrial genome of the adaptive evolution model plant Aquilegia. The subsequent analysis provided us with a basis for further molecular studies on Aquilegia mitochondrial genomes and valuable information on adaptive evolution in Aquilegia.
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Aquilegia , Genoma Mitocondrial , Filogenia , Aquilegia/genética , Genoma Mitocondrial/genética , Mitocôndrias/genética , RNA de Transferência/genéticaRESUMO
INTRODUCTION: Mucoepidermoid carcinoma (MEC) of the breast is an extremely rare primary breast tumor. Between 1979 and June 2022, only 50 cases were reported. The pathological morphology and biological behavior of breast MEC remain poorly understood. PATIENT CONCERNS: A 47-year-old female was presented with a 10-day-old left breast mass detected by physical examination. DIAGNOSES: Ultrasonography could not distinguish whether the breast tumor was benign or malignant. After a biopsy of a breast tumor excision specimen, combined with immunohistochemical results, the patient was diagnosed with high-grade mucoepidermoid breast carcinoma. INTERVENTIONS: The patient underwent a modified radical mastectomy for her left breast. OUTCOMES: The patient was still free from local recurrence or metastases at 1-year follow-up. CONCLUSION: A high-grade MEC case without MAML2 rearrangement shows good recovery without complications. The diagnosis was confirmed by histomorphology and immunohistochemical markers. It is sometimes necessary to distinguish it from adenosquamous, adenoid cystic, or mucinous carcinoma. The primary treatment is surgical resection, and the prognosis is closely related to the pathological grade.
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Neoplasias da Mama , Carcinoma Mucoepidermoide , Humanos , Feminino , Pessoa de Meia-Idade , Proteínas de Ligação a DNA/genética , Transativadores , Neoplasias da Mama/genética , Neoplasias da Mama/cirurgia , Carcinoma Mucoepidermoide/diagnóstico , Carcinoma Mucoepidermoide/genética , Carcinoma Mucoepidermoide/cirurgia , Mastectomia , Fatores de TranscriçãoRESUMO
Mung bean (Vigna radiata) stands as a crucial legume crop in Asia, contributing to food security. However, our understanding of the underlying genetic foundation governing domesticated agronomic traits, especially those linked to pod architecture, remains largely unexplored. In this study, we delved into the genomic divergence between wild and domesticated mung bean varieties, leveraging germplasm obtained from diverse sources. Our findings unveiled pronounced variation in promoter regions (35%) between the two mung bean subpopulations, suggesting substantial changes in gene expression patterns during domestication. Leveraging transcriptome analysis using distinct reproductive stage pods and subpopulations, we identified candidate genes responsible for pod and seed architecture development, along with Genome-Wide Association Studies (GWAS) and Quantitative Trait Locus (QTL) analysis. Notably, our research conclusively confirmed PDH1 as a parallel domesticated gene governing pod dehiscence in legumes. This study imparts valuable insights into the genetic underpinnings of domesticated agronomic traits in mung bean, and simultaneously highlighting the parallel domestication of pivotal traits within the realm of legume crops.
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Produtos Agrícolas , Domesticação , Estudo de Associação Genômica Ampla , Locos de Características Quantitativas , Vigna , Vigna/genética , Locos de Características Quantitativas/genética , Produtos Agrícolas/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Sementes/genética , Genoma de Planta/genética , Regulação da Expressão Gênica de Plantas , Genômica , FenótipoRESUMO
BACKGROUND: Lung cancer is a malignant tumor with the highest mortality worldwide. Abnormalities in the ubiquitin proteasome system are considered to be contributed to lung cancer progression with deleterious effects. DDB1 and CUL4 associated factor 13 (DCAF13) is a substrate receptor of the E3 ubiquitin ligase CRL4, but its role in lung cancer remains unknown. In this study, we aimed to investigate the regulatory mechanisms of DCAF13 in lung adenocarcinoma (LUAD). METHODS: So as to investigate the effect of DCAF13 on lung adenocarcinoma cell function using in vivo and in vitro. Mechanistically, we have identified the downstream targets of DCAF13 by using RNA-sequencing, as well as ubiquitination assays, co-immunoprecipitation, immunofluorescence, immunohistochemistry and chromatin immunoprecipitation - qPCR experiments. RESULTS: Our findings reveal that DCAF13 is a carcinogenic factor in LUAD, as it is highly expressed and negatively correlated with clinical outcomes in LUAD patients. Through RNA-sequencing, it has been shown that DCAF13 negatively regulates the p53 signaling pathway and inhibits p53 downstream targets including p21, BAX, FAS, and PIDD1. We also demonstrate that DCAF13 can bind to p53 protein, leading to K48-linked ubiquitination and degradation of p53. Functionally, we have shown that DCAF13 knockdown inhibits cell proliferation and migration. Our results highlight the significant role of DCAF13 in promoting LUAD progression by inhibiting p53 protein stabilization and the p53 signaling pathway. Furthermore, our findings suggest that high DCAF13 expression is a poor prognostic indicator in LUAD, and DCAF13 may be a potential therapeutic target for treating with this aggressive cancer. CONCLUSIONS: The DCAF13 as a novel negative regulator of p53 to promote LUAD progression via facilitating p53 ubiquitination and degradation, suggesting that DCAF13 might be a novel biomarker and therapeutical target for LUAD.
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Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Proteína Supressora de Tumor p53/genética , Fator XIII , Adenocarcinoma de Pulmão/genética , Neoplasias Pulmonares/genética , Ubiquitinação , Proliferação de Células , Transdução de Sinais , RNA , Proteínas de Ligação a RNARESUMO
Circular RNAs (circRNAs) are the non-coding types of RNAs and are thoughts to be linked with human cancer progression. circFOXK2 is believed to be associated with cancers, however, the molecular mechanisms of circFOXK2 in non-small cell lung cancer (NSCLC) are still unclear. Here we firstly reported that circFOXK2 enhances the tumorigenesis of NSCLC through the miR-149-3p/IL-6 axis. The expression of circFOXK2, microRNA-149-3p (miR-149-3p) and IL-6 were assessed by qRT-PCR and western blot. Transwell, colony formation, wound healing, and CCK-8 assays were used to elucidate NSCLC cells' proliferation, migration, and invasion. MiR-149-3p interaction with circFOXK2 was confirmed by dual-luciferase reporter gene assay (DLRGA). Furthermore, the biological effect of circFOXK2 on NSCLC progression was detected by tumor xenograft assay. CircFOXK2 were upregulated in NSCLC tissues and cells, miR-149-3p were downregulated in NSCLC tissues and cells. In addition, circFOXK2 stimulated NSCLC cell proliferation, migration and invasion in vitro. Mechanical analysis indicated that circFOXK2 modulated IL-6 via miR-149-3p sponging. Furthermore, circFOXK2 overexpression promoted tumor growth in vivo. Overall, this research verified that circFOXK2 enhances the tumorigenesis of NSCLC through the miR-149-3p/IL-6 axis.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , MicroRNAs , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , RNA Circular/genética , Neoplasias Pulmonares/patologia , Interleucina-6/genética , MicroRNAs/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Carcinogênese/genética , Regulação Neoplásica da Expressão Gênica , Movimento CelularRESUMO
INTRODUCTION: Whether dexmedetomidine (DEX), an anesthetic adjuvant, can improve renal transplant outcomes is not clear. METHODS: We systematically identified clinical trials in which DEX was administered in renal transplantation (RT). On November 1, 2022, we searched The Cochrane Library, MEDLINE, EMBASE and https://www. CLINICALTRIALS: gov/. The main outcomes were delayed graft function and acute rejection. RESULTS: A total of seven studies were included in the meta-analysis. The results showed that compared with the control, DEX significantly reduced the occurrence of delayed graft function (RR 0.76; 95% CI 0.60-0.98), short-term serum creatinine [postoperative day (POD) 2: (MD -22.82; 95% CI -42.01 - -3.64)] and blood urea nitrogen [POD 2: (MD -2.90; 95% CI -5.10 - -0.70); POD 3: (MD 2.07; 95% CI -4.12 - -0.02)] levels, postoperative morphine consumption (MD -4.27; 95% CI -5.92 - -2.61) and the length of hospital stay (MD -0.85; 95% CI-1.47 - -0.23). However, DEX did not reduce the risk of postoperative acute rejection (RR 0.75; 95% CI 0.45-1.23). The results of the subgroup analysis showed that country type, donor type, and average age had a certain impact on the role of DEX. CONCLUSIONS: DEX may improve the short-term clinical outcome of RT and shorten the length of hospital stay of patients.
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Dexmedetomidina , Transplante de Rim , Humanos , Dexmedetomidina/uso terapêutico , Função Retardada do Enxerto/tratamento farmacológicoRESUMO
OBJECTIVE: This study aimed to prospectively evaluate the efficacy and safety of anlotinib in patients with platinum resistant/refractory ovarian cancer. METHODS: In this prospective, single arm, phase II study, patients with platinum resistant/refractory ovarian cancer received anlotinib (12 mg once daily; days 1-14; 21 days per cycle) until disease progression, unacceptable toxicity, or study withdrawal. The study was conducted between May 2019 and May 2021. The primary endpoint was objective response rate. Secondary endpoints were disease control rate, progression free survival, overall survival, and safety. An exploratory biomarker analysis was performed to evaluate the correlation of baseline TP53 mutation status with outcomes. RESULTS: 33 of 34 enrolled patients received at least one dose of anlotinib. The objective response rate was 31.2% (95% confidence interval (CI) 16.1% to 50.0%), with 2 (6.3%) complete and 8 (25.0%) partial responses. In total, 14 (43.8%) patients achieved stable disease, resulting in a disease control rate of 75.0% (95% CI 56.6% to 88.5%). With a median follow-up of 4.6 months (range 0.5-17.2) at data cut-off (September 16, 2022), median progression free survival was 5.3 months (95% CI 4.04 to 6.56) and median overall survival was not reached. In a subgroup analysis, patients with a TP53 mutation showed a trend towards worse progression free survival than those with the wild-type TP53 (4.4 months vs 8.4 months; hazard ratio 2.48 (95% CI 0.91 to 6.76), p=0.067). Common adverse events were hypertension (42.4%), hand-foot syndrome (27.3%), and fatigue (24.2%). Grade 3 events were reported in 3 (9.1%) patients and no grade 4-5 events or deaths were observed. CONCLUSION: Anlotinib showed antitumor activity with an acceptable safety profile in patients with platinum resistant/refractory ovarian cancer, and it might be a potential treatment in this population.
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Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/patologia , Estudos Prospectivos , Carcinoma Epitelial do Ovário , Indóis/uso terapêuticoRESUMO
Hypertension is a primary modifiable risk factor for cardiovascular diseases, which often induces renal end-organ damage and complicates chronic kidney disease (CKD). In the present study, histological analysis of human kidney samples revealed that hypertension induced mtDNA leakage and promoted the expression of stimulator of interferon genes (STING) in renal epithelial cells. We used angiotensin II (AngII)- and 2K1C-treated mouse kidneys to elucidate the underlying mechanisms. Abnormal renal mtDNA packing caused by AngII promoted STING-dependent production of inflammatory cytokines, macrophage infiltration, and a fibrogenic response. STING knockout significantly decreased nuclear factor-κB activation and immune cell infiltration, attenuating tubule atrophy and extracellular matrix accumulation in vivo and in vitro. These effects delayed CKD progression. Immunoprecipitation assays and liquid chromatography-tandem mass spectrometry showed that STING and ACSL4 were directly combined at the D53 and K412 amino acids of ACSL4. Furthermore, STING induced renal inflammatory response and fibrosis through ACSL4-dependent ferroptosis. Last, inhibition of ACSL4 using small interfering RNA, rosiglitazone, or Fer-1 downregulated AngII-induced mtDNA-STING-dependent renal inflammation. These results suggest that targeting the STING/ACSL4 axis might represent a potential strategy for treating hypertension-associated CKD.
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Increasing evidence and our preliminary work have revealed the significant role of ferroptosis in acute kidney injury (AKI) induced by ischemia/reperfusion (IR). Carnosine (Car), a dipeptide consisting of ß-alanine and L-histidine, has been shown to ameliorate HG-induced tubular epithelial cells inflammation. Whether Car exerts protective effects on AKI, and its molecular mechanism have not been clarified. Our in vivo and in vitro IR-AKI mouse models demonstrated that Car alleviates kidney injury, inflammation and ferroptosis. In hypoxia/reoxygenation (HR) induced human renal tubular epithelial cells (HK2), Car treatment reduced lipid peroxidation and iron accumulation, suppressed oxidative stress, and inhibited ferroptosis. Through cellular thermal shift assay (CETSA) and molecular docking, we identified GPX4 as a potential target that binds with Car. Further study showed that overexpressed GPX4 had a comparable protective effect on HK2 cells under HR conditions, similar to Car. Additionally, our findings demonstrated that Car exhibited similar anti-ferroptosis effects in both folic acid (FA)-induced AKI mouse models and Erastin induced HK2 cells. In conclusion, our results highlight that Car alleviate renal IR injury by inhibiting GPX4-mediated ferroptosis. Car shows promise as a potential therapeutic drug for IR-AKI and other diseases associated with ferroptosis.
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PURPOSE: This study aimed to investigate the prognostic significance of surgery in large-cell neuroendocrine carcinoma (LCNC) patients. METHODS: A total of 453 patients from the Surveillance, Epidemiology, and End Results database diagnosed with stage T1-4N0-2M0 LCNC from 2010 to 2015 were analyzed. The propensity-score matching analysis with a ratio of 1:1 was used to minimize the bias effect of other clinical characteristics, and 77 pairs of patients' data were performed for subsequent statistical analysis. The Cox proportional hazards model, Kaplan-Meier analysis, and Log-rank test were used in the present study. The primary observational endpoint was cancer-specific survival (CSS). RESULTS: The 1-year, 3-year, and 5-year CSS rates were 60.0%, 45.0%, and 42.0% in those 453 LCNC patients. Compared with patients who underwent surgical resection, patients without surgery had a lower 5-year CSS rate (18.0% vs. 52.0%, P < 0.001). After analyses of multivariable Cox regression, chemotherapy, T stage, N stage, and surgery were identified as independent prognostic indicators (all P < 0.05). In the cohort of old patients, the median survival time was longer in cases after surgery than those without surgery (13.0 months vs. NA, P < 0.001). Besides, in patients with different clinical characteristics, the receiving surgery was a protective prognostic factor (all hazard ratio < 1, all P < 0.05). In addition, for the cohort with stage T1-2N0-2M0, patients after the operation had more improved outcomes than patients without surgery (P < 0.001). CONCLUSIONS: We proposed that the surgery could improve the survival outcomes of LCNC patients with stage T1-4N0-2M0. Moreover, old patients could benefit from surgery.
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Carcinoma Neuroendócrino , Neoplasias Pulmonares , Humanos , Estudos Retrospectivos , Carcinoma Neuroendócrino/cirurgia , Carcinoma Neuroendócrino/patologia , Prognóstico , Neoplasias Pulmonares/patologia , Pulmão/patologia , Estadiamento de Neoplasias , Pontuação de PropensãoRESUMO
The effect of polydopamine (PDA) modification on aminated Fe3O4 nanoparticles (Fe3O4-NH2)/graphite oxide (GO)/ß-cyclodextrin polymer cross-linked by citric acid (CDP-CA) composites were studied for the removal of a cationic dye (methylene blue, MB) and an anionic dye (Congo red, CR) from waters. The micro-structural and magnetic characterizations confirmed the successful preparation of Fe3O4-NH2/GO/CDP-CA and PDA/Fe3O4-NH2/GO/CDP-CA composites. The maximum MB and CR adsorption capacities of Fe3O4-NH2/GO/CDP-CA were 75 mg/g and 104 mg/g, respectively, while the corresponding amounts for PDA/Fe3O4-NH2/GO/CDP-CA composite were 195 mg/g and 64 mg/g, respectively. The dye sorption behaviors of these two composites were explained by their corresponding surface-charged properties according to the measured zeta potential results. Moreover, the high saturation magnetizations and the stable dye removal rate in the adsorption-desorption cycles indicated the good recyclability and reusability of the fabricated composites.