RESUMO
Acute myeloid leukemia (AML) is an aging-related and heterogeneous hematopoietic malignancy. In this study, a total of 1,474 newly diagnosed AML patients with RNA sequencing data were enrolled, and targeted or whole exome sequencing data were obtained in 94% cases. The correlation of aging-related factors including age and clonal hematopoiesis (CH), gender, and genomic/transcriptomic profiles (gene fusions, genetic mutations, and gene expression networks or pathways) was systematically analyzed. Overall, AML patients aged 60 y and older showed an apparently dismal prognosis. Alongside age, the frequency of gene fusions defined in the World Health Organization classification decreased, while the positive rate of gene mutations, especially CH-related ones, increased. Additionally, the number of genetic mutations was higher in gene fusion-negative (GF-) patients than those with GF. Based on the status of CH- and myelodysplastic syndromes (MDS)-related mutations, three mutant subgroups were identified among the GF- AML cohort, namely, CH-AML, CH-MDS-AML, and other GF- AML. Notably, CH-MDS-AML demonstrated a predominance of elderly and male cases, cytopenia, and significantly adverse clinical outcomes. Besides, gene expression networks including HOXA/B, platelet factors, and inflammatory responses were most striking features associated with aging and poor prognosis in AML. Our work has thus unraveled the intricate regulatory circuitry of interactions among different age, gender, and molecular groups of AML.
Assuntos
Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Idoso , Humanos , Masculino , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Envelhecimento/genética , Mutação , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , PrognósticoRESUMO
Atypical acute promyelocytic leukemia (aAPL) presents a complex landscape of retinoic acid receptor (RAR) fusion genes beyond the well-known PML::RARA fusion. Among these, 31 individually rare RARA and RARG fusion genes have been documented, often reported in the canonical X::RAR bipartite fusion form. Intriguingly, some artificially mimicked bipartite X::RAR fusions respond well to all-trans retinoic acid (ATRA) in vitro, contrasting with the ATRA resistance observed in patients. To unravel the underlying mechanisms, we conducted a comprehensive molecular investigation into the fusion transcripts in 27 RARA fusion gene-positive aAPL (RARA-aAPL) and 21 RARG-aAPL cases. Our analysis revealed an unexpected novel form of X::RAR::X or X::RAR::Y-type tripartite fusions in certain RARA- and all RARG-aAPL cases, with shared features and notable differences between these two disease subgroups. In RARA-aAPL cases, the occurrence of RARA 3' splices was associated with their 5' fusion partner genes, mapping across the coding region of helix 11_12 (H11_12) within the ligand-binding domain (LBD), resulting in LBD-H12 or H11_12 truncation. In RARG-aAPL cases, RARG 3' splices were consistently localized to the terminus of exon 9, leading to LBD-H11_12 truncation. Significant differences were also observed between RARA and RARG 5' splice patterns. Our analysis also revealed extensive involvement of transposable elements in constructing RARA and RARG 3' fusions, suggesting transposition mechanisms for fusion gene ontogeny. Both protein structural analysis and experimental results highlighted the pivotal role of LBD-H11_12/H12 truncation in driving ATRA unresponsiveness and leukemogenesis in tripartite fusion-positive aAPL, through a protein allosteric dysfunction mechanism.
RESUMO
The current classification of acute myeloid leukemia (AML) relies largely on genomic alterations. Robust identification of clinically and biologically relevant molecular subtypes from nongenomic high-throughput sequencing data remains challenging. We established the largest multicenter AML cohort (n = 655) in China, with all patients subjected to RNA sequencing (RNA-Seq) and 619 (94.5%) to targeted or whole-exome sequencing (TES/WES). Based on an enhanced consensus clustering, eight stable gene expression subgroups (G1-G8) with unique clinical and biological significance were identified, including two unreported (G5 and G8) and three redefined ones (G4, G6, and G7). Apart from four well-known low-risk subgroups including PML::RARA (G1), CBFB::MYH11 (G2), RUNX1::RUNX1T1 (G3), biallelic CEBPA mutations or -like (G4), four meta-subgroups with poor outcomes were recognized. The G5 (myelodysplasia-related/-like) subgroup enriched clinical, cytogenetic and genetic features mimicking secondary AML, and hotspot mutations of IKZF1 (p.N159S) (n = 7). In contrast, most NPM1 mutations and KMT2A and NUP98 fusions clustered into G6-G8, showing high expression of HOXA/B genes and diverse differentiation stages, from hematopoietic stem/progenitor cell down to monocyte, namely HOX-primitive (G7), HOX-mixed (G8), and HOX-committed (G6). Through constructing prediction models, the eight gene expression subgroups could be reproduced in the Cancer Genome Atlas (TCGA) and Beat AML cohorts. Each subgroup was associated with distinct prognosis and drug sensitivities, supporting the clinical applicability of this transcriptome-based classification of AML. These molecular subgroups illuminate the complex molecular network of AML, which may promote systematic studies of disease pathogenesis and foster the screening of targeted agents based on omics.
Assuntos
Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Humanos , Transcriptoma , Leucemia Mieloide Aguda/genética , Diferenciação Celular/genética , Células-Tronco HematopoéticasRESUMO
To investigate the clinical characteristics and risk factors of specific human leukocyte antigen loss (HLA loss) in relapsed acute myeloid leukaemia (AML)/myelodysplastic syndrome (MDS) patients after allogeneic haematopoietic stem cell transplantation (allo-HSCT), and compare the responses of patients with HLA loss relapse with those without HLA loss (non-HLA loss) to different treatment regimens. Clinical data of traceable patients with AML/MDS after myeloablative allo-HSCT in our centre between January 2010 and June 2021, who experienced disease relapse after the transplantation, were collected. The patients were divided into the HLA loss relapse group and the non-HLA loss relapsed group based on HLA loss gene test findings by next-generation sequencing. The patients' median overall survival (OS) after the relapse were compared, and univariate and multivariate analyses were performed using the Kaplan-Meier survival curve and Cox proportional hazard model to explore the responses to different treatments after relapse. A total of 2359 patients were selected. Retrospective HLA gene loss gene detection was performed for the deoxyribonucleic acid in 179 relapsed patients, including 47 patients in the HLA loss group (27.2%), 126 patients in the non-HLA loss group (72.8%) and 6 patients were excluded due to a lack of confirmed results. There was no significant statistical difference in the baseline characteristics of patients between the two groups, but as to transplantation-related characteristics, the donor-recipient relationship and HLA mismatched loci were statistically different between the two groups (both p < 0.001). Multivariate Cox analysis showed that more HLA mismatched loci ≥3 (HR = 3.66; 95% CI: 1.61-8.31; p = 0.002), time (≤6 months) from HSCT to relapse (HR = 7.92; 95% CI: 3.35-18.74; p < 0.001) and donor chimerism (CD3) in bone marrow at relapse (HR = 1.02; 95% CI: 1.00-1.03; p = 0.036) were independent factors affecting HLA loss relapse. The ratio of negative conversion of FLT3-ITD or CEBPA mutation was significantly lower in patients with post-transplantation HLA loss relapse than in the non-HLA loss group (0.0% vs. 45.5%, p = 0.003; 0.0% vs. 80.0%, p = 0.035), with none of the patients with FLT3-ITD or CEBPA mutation turned negative in the HLA loss group. The number of gene mutations turned negative when relapse in the non-HLA loss group was remarkably higher than that in the HLA loss group (p = 0.001). Using donor lymphocyte infusion (DLI) could not prolong OS for the HLA loss group (p = 0.42). Nevertheless, second transplantation had a significant positive impact on OS in the HLA loss group (p = 0.017), although only five patients in the HLA loss group underwent second transplantation. However, patients in the non-HLA loss group using DLI had a relatively longer OS time than those without DLI (p = 0.017). Second transplantation could also prolong OS in the non-HLA loss group, but the effect was not as significant as in the HLA loss group (p = 0.053). In summary, HLA loss detection is essential for patients with recurrence after transplantation, especially for those with more HLA mismatched loci and non-sibling donor. Furthermore, the detection of HLA loss has a guiding role in choosing subsequent therapy when relapsed, as secondary transplantation is more suitable than DLI for those with HLA loss.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Humanos , Estudos Retrospectivos , Recidiva Local de Neoplasia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/terapia , Antígenos HLA/genética , Fatores de Risco , Antígenos de Histocompatibilidade Classe II , Modelos de Riscos Proporcionais , RecidivaRESUMO
High hyperdiploid karyotype with ≥ 49 chromosomes (which will be referred to as HHK) is rare in acute myeloid leukemia (AML). The European leukemia network (ELN) excluded those harboring only numerical changes (with ≥ 3 chromosome gains) from CK and listed them in the intermediate risk group, while the UK National Cancer Research Institute Adult Leukaemia Working Group classification defined ≥ 4 unrelated chromosome abnormalities as the cutoff for a poorer prognosis. Controversies occurred among studies on the clinical outcome of HHK AML, and their molecular characteristics remained unstudied. We identified 1.31% (133/10,131) HHK cases within our center, among which 48 cases only had numerical changes (NUM), 42 had ELN defined adverse abnormalities (ADV) and 43 had other structural abnormalities (STR). Our study demonstrated that: (1) No statistical significance for overall survival (OS) was observed among three cytogenetic subgroups (NUM, STR and ADV) and HHK AML should be assigned to the adverse cytogenetic risk group. (2) The OS was significantly worse in HHK AML with ≥ 51 chromosomes compared with those with 49-50 chromosomes. (3) The clinical characteristics were similar between NUM and STR group compared to ADV group. The former two groups had higher white blood cell counts and blasts, lower platelet counts, and mutations associated with signaling, while the ADV group exhibited older age, higher chromosome counts, higher percentage of myelodysplastic syndrome (MDS) history, and a dominant TP53 mutation.
Assuntos
Leucemia Mieloide Aguda , Mutação , Proteína Supressora de Tumor p53 , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/diagnóstico , Pessoa de Meia-Idade , Feminino , Masculino , Adulto , Idoso , Proteína Supressora de Tumor p53/genética , China/epidemiologia , Prognóstico , Adolescente , Adulto Jovem , Idoso de 80 Anos ou mais , Aberrações Cromossômicas , Cariótipo , Taxa de Sobrevida , CariotipagemRESUMO
BACKGROUND: Reducing production costs while producing high-quality livestock and poultry products is an ongoing concern in the livestock industry. The addition of oil to livestock and poultry diets can enhance feed palatability and improve growth performance. Emulsifiers can be used as potential feed supplements to improve dietary energy utilization and maintain the efficient productivity of broilers. Therefore, further investigation is warranted to evaluate whether dietary emulsifier supplementation can improve the efficiency of fat utilization in the diet of yellow-feathered broilers. In the present study, the effects of adding emulsifier to the diet on lipid metabolism and the performance of yellow-feathered broilers were tested. A total of 240 yellow-feasted broilers (21-day-old) were randomly divided into 4 groups (6 replicates per group, 10 broilers per replicate, half male and half female within each replicate). The groups were as follows: the control group (fed with basal diet), the group fed with basal diet supplemented with 500 mg/kg emulsifier, the group fed with a reduced oil diet (reduced by 1%) supplemented with 500 mg/kg emulsifier, and the group fed with a reduced oil diet supplemented with 500 mg/kg emulsifier. The trial lasted for 42 days, during which the average daily feed intake, average daily gain, and feed-to-gain ratio were measured. Additionally, the expression levels of lipid metabolism-related genes in the liver, abdominal fat and each intestinal segment were assessed. RESULTS: The results showed that compared with the basal diet group, (1) The average daily gain of the basal diet + 500 mg/kg emulsifier group significantly increased (P < 0.05), and the half-even-chamber rate was significantly increased (P < 0.05); (2) The mRNA expression levels of Cd36, Dgat2, Apob, Fatp4, Fabp2, and Mttp in the small intestine were significantly increased (P < 0.05). (3) Furthermore, liver TG content significantly decreased (P < 0.05), and the mRNA expression level of Fasn in liver was significantly decreased (P < 0.05), while the expression of Apob, Lpl, Cpt-1, and Pparα significantly increased (P < 0.05). (4) The mRNA expression levels of Lpl and Fatp4 in adipose tissue were significantly increased (P < 0.05), while the expression of Atgl was significantly decreased (P < 0.05). (5) Compared with the reduced oil diet group, the half-evading rate and abdominal fat rate of broilers in the reduced oil diet + 500 mg/kg emulsifier group were significantly increased (P < 0.05), and the serum level of LDL-C increased significantly (P < 0.05)0.6) The mRNA expression levels of Cd36, Fatp4, Dgat2, Apob, and Mttp in the small intestine were significantly increased (P < 0.05). 7) The mRNA expression levels of Fasn and Acc were significantly decreased in the liver (P < 0.05), while the mRNA expression levels of Lpin1, Dgat2, Apob, Lpl, Cpt-1, and Pparα were significantly increased (P < 0.05). CONCLUSIONS: These results suggest that dietary emulsifier can enhance the fat utilization efficiency of broilers by increasing the small intestinal fatty acid uptake capacity, inhibiting hepatic fatty acid synthesis and promoting hepatic TG synthesis and transport capacity. This study provides valuable insights for the potential use of emulsifier supplementation to improve the performance of broiler chickens.
Assuntos
Ração Animal , Galinhas , Dieta , Suplementos Nutricionais , Emulsificantes , Metabolismo dos Lipídeos , Animais , Galinhas/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Emulsificantes/farmacologia , Ração Animal/análise , Masculino , Feminino , Dieta/veterinária , Fígado/metabolismo , Fígado/efeitos dos fármacosRESUMO
Acute promyelocytic leukemia (APL) is a unique disease entity in acute myeloid leukemia, characterized by PML-RARA fusion gene, which is generated by chromosomal translocation t(15;17)(q24;q21). We identified TNRC18-RARA as novel RARA fusion in resembling APL. Our study highlights the importance of combining multiple molecular techniques to characterize and optimally manage APL lacking classic t(15;17)(q24;q12)/PML-RARA fusion.
Assuntos
Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 17/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Leucemia Promielocítica Aguda/genética , Proteínas de Fusão Oncogênica/genética , Receptor alfa de Ácido Retinoico/genética , Translocação Genética , Regulação Leucêmica da Expressão Gênica , Humanos , Hibridização in Situ Fluorescente , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/metabolismo , Receptor alfa de Ácido Retinoico/metabolismoRESUMO
Human cytomegalovirus (HCMV) has led to kinds of clinical disorders and great morbidity worldwide, such as sensorineural hearing loss (SNHL), mental retardation, and developmental delays in immunocompromised individuals. Congenital HCMV infection is a leading cause of birth defects, primarily manifesting as neurological disorders. Previous studies reported that HCMV has evolved a variety of mechanisms to evade the immune system, such as dysregulation of miRNAs. However, reports concerning the role of miRNA in HCMV infection in neural cells are limited. Here, we reported that a host microRNA, miR-182, was significantly up-regulated by HCMV infection in U-251MG and NPCs cells. Subsequently, our results of in vitro and in vivo experiments demonstrated that miR-182 was a positive regulator of interferon regulatory factor 7 (IRF7) by directly targeting FOXO3, resulting in the induction of IFN-I response and suppression of HCMV replication in neural cells. Taken together, our findings provide detailed molecular mechanisms of the antiviral function of miR-182 against HCMV infection in neural cells, and suggest an intrinsic anti-HCMV therapeutic target.
Assuntos
Citomegalovirus/imunologia , Citomegalovirus/fisiologia , Proteína Forkhead Box O3/antagonistas & inibidores , Interferon Tipo I/biossíntese , MicroRNAs/genética , Regiões 3' não Traduzidas , Animais , Sequência de Bases , Linhagem Celular , Citomegalovirus/genética , Infecções por Citomegalovirus/genética , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/virologia , Feminino , Proteína Forkhead Box O3/genética , Proteína Forkhead Box O3/imunologia , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/imunologia , Interações entre Hospedeiro e Microrganismos/fisiologia , Humanos , Fator Regulador 7 de Interferon/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , MicroRNAs/antagonistas & inibidores , MicroRNAs/metabolismo , Neurônios/imunologia , Neurônios/virologia , RNA Interferente Pequeno/genética , Receptor de Interferon alfa e beta/antagonistas & inibidores , Receptor de Interferon alfa e beta/genética , Transdução de Sinais , Replicação Viral/genética , Replicação Viral/imunologia , Replicação Viral/fisiologiaRESUMO
BACKGROUND: RUNX1/AML1, which is a Runt family transcription factor critical for normal hematopoiesis, is frequently mutated or translocated in a broad spectrum of hematopoietic malignancies. FINDINGS: We describe here the case of a 54-year-old female developed acute myeloid leukemia with a t(5;21)(q21;q22). Transcriptome sequencing identified the chromodomain-helicase-DNA-binding protein 1 gene, CHD1, as a novel partner gene of RUNX1. Furthermore, the patient was found to harbor FLT3-ITD mutation, which might collaborated with CHD1-RUNX1 in the development of acute myeloid leukemia. CONCLUSIONS: We have identified CHD1 as the RUNX1 fusion partner in acute myeloid leukemia with t(5;21)(q21;q22).
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Cromossomos Humanos Par 21 , Cromossomos Humanos Par 5 , Subunidade alfa 2 de Fator de Ligação ao Core/genética , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Leucemia Mieloide Aguda/genética , Proteínas de Fusão Oncogênica/genética , Transcriptoma , Translocação Genética , Pontos de Quebra do Cromossomo , Feminino , Ordem dos Genes , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Leucemia Mieloide Aguda/diagnóstico , Pessoa de Meia-Idade , Análise de Sequência de DNAAssuntos
Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 8/genética , Leucemia Mieloide Aguda/genética , Proteínas de Fusão Oncogênica/genética , Proteínas/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Translocação Genética , Humanos , Masculino , Pessoa de Meia-IdadeAssuntos
Leucemia Promielocítica Aguda/genética , Proteínas de Fusão Oncogênica/genética , Receptor alfa de Ácido Retinoico/genética , Fator de Transcrição STAT3/genética , Translocação Genética , Adulto , Cromossomos Humanos Par 15 , Cromossomos Humanos Par 17 , Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/patologia , Masculino , Prognóstico , Adulto JovemAssuntos
Leucemia Promielocítica Aguda , Proteínas de Fusão Oncogênica , Receptores do Ácido Retinoico , Fatores de Poliadenilação e Clivagem de mRNA , Feminino , Humanos , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patologia , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Receptores do Ácido Retinoico/genética , Receptores do Ácido Retinoico/metabolismo , Fatores de Poliadenilação e Clivagem de mRNA/genética , Fatores de Poliadenilação e Clivagem de mRNA/metabolismo , Receptor gama de Ácido RetinoicoAssuntos
Cromossomos Humanos Par 12/ultraestrutura , Cromossomos Humanos Par 4/ultraestrutura , Transtornos Mieloproliferativos/genética , Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas c-ets/genética , RNA Longo não Codificante/genética , Proteínas Repressoras/genética , Translocação Genética , Cariótipo Anormal , Idoso , Medula Óssea/patologia , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 4/genética , Diagnóstico Diferencial , Éxons/genética , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Masculino , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/patologia , Variante 6 da Proteína do Fator de Translocação ETSRESUMO
To understand the evolutionary history of Lymantriinae and test the present higher-level classification, we performed the first broad-scale molecular phylogenetic analysis of the subfamily, based on 154 exemplars representing all recognized tribes and drawn from all major biogeographical regions. We used two mitochondrial genes (cytochrome c oxidase subunit I and 16S ribosomal RNA) and six nuclear genes (elongation factor-1α, carbamoylphosphate synthase domain protein, ribosomal protein S5, cytosolic malate dehydrogenase, glyceraldehyde-3-phosphate dehydrogenase and wingless). Data matrices (in total 5424 bp) were analysed by parsimony and model-based evolutionary methods (maximum likelihood and Bayesian inference). Based on the results of the analyses, we present a new phylogenetic classification for Lymantriinae composed of seven well-supported tribes, two of which are proposed here as new: Arctornithini, Leucomini, Lymantriini, Orgyiini, Nygmiini, Daplasini trib. nov. and Locharnini trib. nov. We discuss the internal structure of each of these tribes and address some of the more complex problems with the genus-level classification, particularly within Orgyiini and Nygmiini.
Assuntos
Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/patologia , Proteínas de Fusão Oncogênica/genética , Receptores do Ácido Retinoico/genética , Receptor alfa de Ácido Retinoico/genética , Translocação Genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 17/genética , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Adulto Jovem , Receptor gama de Ácido RetinoicoRESUMO
OBJECTIVE: To investigate the clinical and genetics characteristics of patients with monosomal karyotype acute myeloid leukemia (MK-AML). METHODS: The karyotypes of 3743 patients with newly-diagnosed de novo AML were analyzed, which had identified 153 cases with MK-AML, for whom the clinical and genetics characteristics were analyzed. RESULTS: There were 2056 patients (54.9%) among all patients. A total of 153 patients fulfilling the criteria for MK-AML were identified, which comprised 93 males and 60 females, with a median age of 54. The median white blood cell count on presentation was 4.4×10 (9)/L. One hundred and forty-five cases (94.8%) have fulfilled the criteria for complex karyotype (≥ 3 chromosomal abnormalities). Although the monosomy could be found with all autosomes, chromosome 7 has been most frequently involved (38.56%, 59/153). CONCLUSION: MK-AML is a distinct cytogenetic subtype of AML. Monosomy 7 is frequently detected among MK-AML patients. The monosomal karyotype is common among elder patients with AML.
Assuntos
Leucemia Mieloide Aguda/genética , Monossomia , Adulto , Idoso , Cromossomos Humanos Par 7/genética , Feminino , Humanos , Cariótipo , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND AND PURPOSE: The pathophysiological features of acute ischemic stroke (AIS) often involve dysfunction of the blood-brain barrier (BBB), characterized by the degradation of tight junction proteins (Tjs) leading to increased permeability. This dysfunction can exacerbate cerebral injury and contribute to severe complications. The permeability of the BBB fluctuates during different stages of AIS and is influenced by various factors. Developing effective therapies to restore BBB function remains a significant challenge in AIS treatment. High levels of vascular endothelial growth factor (VEGF) in the early stages of AIS have been shown to worsen BBB breakdown and stroke progression. Our study aimed to investigate the protective effects of the VEGF receptor inhibitor Axitinib on BBB dysfunction and cerebral ischemia/reperfusion-induced injury. METHODS: BEnd3 cell exposed to oxygen-glucose deprivation (OGD) model was constructed to estimate pharmacological activity of Axitinib (400 ng/ml) on anti-apoptosis and pathological barrier function recovery. In vivo, rats were subjected to a 1 h transient middle cerebral artery occlusion and 23 h reperfusion (tMCAO/R) to investigate the permeability of BBB and cerebral tissue damage. Axitinib was administered through the tail vein at the beginning of reperfusion. BBB integrity was assessed by Evans blue leakage and the expression levels of Tjs claudin-5 and occludin. RESULTS: Our research revealed that co-incubation with Axitinib enhanced the cell viability of OGD-insulted bEnd3 cells, decreased LDH leakage rate, and suppressed the expression of apoptosis-related proteins cytochrome C and Bax. Axitinib also mitigated the damage to Tjs and facilitated the restoration of transepithelial electrical resistance in OGD-insulted bEnd.3 cells. In vivo, Axitinib administration reduced intracerebral Evans blue leakage and up-regulated the expression of Tjs in the penumbra brain tissue in tMCAO/R rats. Notably, 10 mg/kg Axitinib exerted a significant anti-ischemic effect by decreasing cerebral infarct volume and brain edema volume, improving neurological function, and reducing pro-inflammatory cytokines IL-6 and TNF-α in the brain. CONCLUSIONS: Our study highlights Axitinib as a potent protectant of blood-brain barrier function, capable of promoting pathological blood-brain barrier recovery through VEGF inhibition and increased expression of tight junction proteins in AIS. This suggests that VEGF antagonism within the first 24 h post-stroke could be a novel therapeutic approach to enhance blood-brain barrier function and mitigate ischemia-reperfusion injury.
Assuntos
Axitinibe , Barreira Hematoencefálica , AVC Isquêmico , Ratos Sprague-Dawley , Traumatismo por Reperfusão , Animais , Axitinibe/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Ratos , Masculino , AVC Isquêmico/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Camundongos , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/tratamento farmacológicoRESUMO
Objectives: To investigate the risk factors of pulmonary infection in patients with severe myelitis and construct a prediction model. Methods: The clinical data of 177 patients with severe myelitis at admission from the First Affiliated Hospital of Zhengzhou University from January 2020 to December 2022 were retrospectively analyzed. The predicting factors associated with pulmonary infection were screened by multivariate logistic regression analysis, and the nomogram model was constructed, and the predictive efficiency of the model was evaluated, which was verified by calibration curve, Hosmer-Lemeshow goodness-of-fit test and decision curve analysis. Results: Of the 177 patients with severe myelitis, 38 (21.5%) had pulmonary infection. Multivariate logistic regression analysis showed that neutrophil percentage to albumin ratio (NPAR) (OR = 6.865, 95%CI:1.746-26.993, p = 0.006) and high cervical cord lesion (OR = 2.788, 95%CI:1.229-6.323, p = 0.014) were independent risk factors for pulmonary infection, and the combined nomogram could easily predict the occurrence of pulmonary infection, with a C-index of 0.766 (95% CI: 0.678-0.854). The calibration curve, Hosmer-Lemeshow goodness-of-fit test (χ2 = 9.539, p = 0.299) and decision curve analysis showed that the model had good consistency and clinical applicability. Conclusion: The nomogram model constructed based on NPAR combined with high cervical cord lesion at admission has good clinical application value in predicting pulmonary infection in patients with severe myelitis, which is conducive to clinicians' evaluation of patients.
RESUMO
BACKGROUND: Lup-20(29)-en-3H-ol (Lupeol), a dietary triterpene, has been shown to possess multiple pharmacological activities including anti-tumor effects METHODS: In the current study, we noted that low doses of lupeol (<40 µM) promoted the growth of hepatocellular carcinoma (HCC) cells with a significant activation of the PI3-kinase/Akt signaling pathway. We further investigated the combined anti-tumor effect of lupeol and S14161, a newly identified PI3-Kinase inhibitor in vitro and in vivo RESULTS: The results demonstrated that lupeol and S14161 could exert a synergistic antitumor effect resulting in chemo-sensitization of HCC to low doses of lupeol. Using an in vivo HCC model, we further demonstrated that lupeol and S14161 synergistically inhibited tumor growth without any adverse effects on body weight CONCLUSION: Our studies showed that the activation of PI3-kinase/Akt pathway resulted in the tumor-promoting effect with low doses of lupeol. Combining PI3-kinase inhibitor with lupeol could synergistically augment the anti-tumor effect of lupeol and might be an applicable strategy for HCC therapy.