RESUMO
BACKGROUND: Difficult-to-treat Rheumatoid arthritis (D2T RA) is primarily characterised by failure of at least two different mechanism of action biologic/targeted synthetic disease-modifying antirheumatic drug (DMARDs) with evidence of active/progressive disease. While a variety of drugs have been used in previous studies to treat D2T RA, there has been no systematic summary of these drugs. This study conducted a systematic review of randomized controlled trials aimed at analyzing the efficacy and safety of individual therapeutic agents for the treatment of D2T RA and recommending the optimal therapeutic dose. METHODS: The English databases were searched for studies on the treatment of D2T RA published between the date of the database's establishment and March, 2024. This study uses R 3.1.2 for data analysis, and the rjags package runs JAGS 3.4.0.20. The study fitted a stochastic effects Bayesian network meta-analysis for each outcome measure. RESULT: A total of 42 studies were included in this study. Compared with placebo, the improvement of Disease Activity Score of 28 Joints (DAS28) score is ranked from high to low as tocilizumab, baricitinib and opinercept. The improvement of American College of Rheumatology 50 response (ACR50) score in patients with drug use was ranked from good to poor as follows: olokizumab, tocilizumab, adalimumab, baricitinib, and upadacitinib, and 8 mg/4w tocilizumab demonstrated the best efficacy. Notably, rituximab is generally the safest drug. Janus kinase (JAK) inhibitors and T cell costimulation modulators are effective in D2T RA refractory to biologic DMARDs, while JAK inhibitors and interleukin-6 (IL-6) inhibitors show effectiveness in D2T RA refractory to csDMARDs. CONCLUSION: Tocilizumab and rituximab have better efficacy and safety in the treatment of D2T RA, and the 8 mg/4w dose of tocilizumab may be the first choice for achieving disease remission.
Assuntos
Antirreumáticos , Artrite Reumatoide , Humanos , Antirreumáticos/uso terapêutico , Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Metanálise em Rede , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
BACKGROUND: Aberrant expression of MUC1 correlates with the progression of esophageal squamous cell carcinoma (ESCC), this study aimed to explore the effect of targeting MUC1 by Go-203 on malignant behavior of ESCC and the underlying mechanism. METHODS AND RESULTS: IHC was used to examine the expression of MUC1 and DNAJB6 in ESCC samples. qRT-PCR and western blotting were used to examine the expression of MUC1 and DNAJB6 in ESCC cell lines. CCK8, wound healing, and transwell assays were used to determine the effect of regulating MUC1/DNAJB6 on the proliferation, migration, and invasion of ESCC cells. The effect of overexpressing/targeting MUC1 on the activation of the AKT/HSF-1 pathway was determined by western blotting. A negative correlation was confirmed between the expression of DNAJB6 and MUC1 in ESCC tissue samples by IHC, and high expression of MUC1 and low expression of DNAJB6 correlated with lymph node metastasis in ESCC patients. Overexpressing MUC1 downregulated the expression of DNAJB6, promoted ESCC proliferation, invasion, migration and activated the AKT pathway, while targeting MUC1 suppressed proliferation, invasion, migration, and the AKT pathway and up-regulated DNAJB6 expression in vitro. Moreover, MUC1 increased the phosphorylation of HSF-1 via the AKT pathway, and inhibiting AKT-HSF-1 increased the expression of DNAJB6 in vitro. CONCLUSIONS: This study indicated that MUC1 could promote tumorigenesis and metastasis in ESCC by downregulating DNAJB6 expression through AKT-HSF-1 pathway.
Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/metabolismo , Carcinoma de Células Escamosas do Esôfago/patologia , Neoplasias Esofágicas/metabolismo , Metástase Linfática , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Movimento Celular , Regulação Neoplásica da Expressão Gênica , Proteínas do Tecido Nervoso/metabolismo , Chaperonas Moleculares/metabolismo , Proteínas de Choque Térmico HSP40/genética , Proteínas de Choque Térmico HSP40/metabolismo , Mucina-1/metabolismoRESUMO
BACKGROUND: DnaJ/Hsp40 homolog, subfamily B, member 6 (DNAJB6) is significantly down-regulated in esophageal squamous cell carcinoma (ESCC), while its complicated molecular mechanisms are still unknown. AIMS: To investigate the relationship between DNAJB6 and ESCC. METHODS: The expression of DNAJB6 was detected in ESCC patient by Western blot and immunohistochemistry. To overexpress DNAJB6a by lentivirus infection, colony-forming, CCK-8, transwell, mouse xenograft assays were utilized to verify the proliferous, invasive, and migratory role of DNAJB6a in ESCC cells. The MDA and GSH assays determine whether DNAJB6a participates in cell redox reaction. The variation of AKT and GPX4 was detected by Western blot. RESULTS: The correlation between DNAJB6 level and lymph node metastasis in ESCC patient was negative. Overexpressing DNAJB6a shows tumor-suppressive effects in vitro and in vivo. In addition, DNAJB6a overexpression was accompanied together with a remarkable reduction in the protein levels of GPX4 and phosphorylated AKT (p-AKT). CONCLUSION: DNAJB6 plays an important anti-oncogenic role in ESCC evolvement via ferroptosis.
Assuntos
Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Proteínas de Choque Térmico HSP40/genética , Chaperonas Moleculares/genética , Proteínas do Tecido Nervoso/genética , Animais , Western Blotting , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/metabolismo , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Ferroptose/genética , Glutationa/metabolismo , Proteínas de Choque Térmico HSP40/metabolismo , Humanos , Técnicas In Vitro , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Mitocôndrias/ultraestrutura , Chaperonas Moleculares/metabolismo , Gradação de Tumores , Invasividade Neoplásica , Estadiamento de Neoplasias , Proteínas do Tecido Nervoso/metabolismo , Oxirredução , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Isoformas de Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Esophageal squamous cell carcinoma (ESCC) is one of the most common digestive tumors worldwide. The Mucin 1 (MUC1) heterodimeric protein has been confirmed that is overexpressed in ESCC and induced adverse outcomes. However, the detailed mechanism(s) remained challenging. So, we investigated the relationship between MUC1-C and metabolism in ESCC cells. In the results, TP53-induced glycolysis and apoptosis regulator (TIGAR) was overexpressed and correlative with MUC1-C positively in ESCC tissue. Targeting MUC1-C inhibits AKT-mTORC-S6K1 signaling and blocks TIGAR translation. We found that the inhibitory effect of GO-203 on TIGAR was mediated by inhibition of AKT-mTOR-S6K1 pathway. The findings also demonstrated that the suppressive effect of GO-203 on TIGAR is related to the decrease of glutathione level, the increase of reactive oxygen species and the loss of mitochondrial transmembrane membrane potential. In xenograft tissues, GO-203 inhibited the growth of ESCC cells and lead to the low expression of transmembrane C-terminal subunit (MUC1-C) and TIGAR. This evidence supports the contention that MUC1-C is significant for metabolism in ESCC and indicated that MUC1-C is a potential target for the treatment of ESCC.
Assuntos
Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Mucina-1/efeitos dos fármacos , Peptídeos/farmacologia , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/metabolismo , Feminino , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Mucina-1/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
To identify new bacterial antagonists for cucurbit downy mildew (CDM) caused by Pseudoperonospora cubensis, 163 bacterial isolates were recovered from different microenvironments of field-grown cucumber plants. In the greenhouse, 19 representative isolates were applied to cucumber plants as a foliar spray (FS); 7 isolates achieved the efficacy over 60% against CDM, with 5 (DS22, HS10, DP14, HP4, and DS57) identified as Bacillus pumilus, B. licheniformis, Enterobacter sp., Bacillus sp., and Stenotrophomonas maltophilia, respectively. Strains DP14, DS22, and HS10 were assessed for their biocontrol effect on naturally occurring CDM in 2-year field trials (2010 and 2011), in which their overall efficacy relative to that of propamocarb was 106.25 to 117.17% with foliar spray plus root drench (FS+RD) but only 70.98 to 84.03% with FS. Coincidently, DP14 and HS10 applied as root drench (RD) alone also significantly reduced CDM. Under field conditions, DP14, DS22, and HS10 all successfully colonized cucumber leaves and the rhizosphere, and also significantly increased fruit yield by 37.60 to 51.03%, as well as nutrient levels. Taken together, Enterobacter sp. DP14, B. licheniformis HS10, and B. pumilus DS22 are plant-growth-promoting rhizobacteria effective in controlling CDM in the field, whose efficacy increased with FS+RD compared with FS alone.
Assuntos
Antibiose , Bacillus/fisiologia , Cucumis sativus/microbiologia , Enterobacter/fisiologia , Oomicetos/microbiologia , Doenças das Plantas/prevenção & controle , Bacillus/isolamento & purificação , Cucumis sativus/parasitologia , Enterobacter/isolamento & purificação , Doenças das Plantas/microbiologia , Doenças das Plantas/parasitologia , Folhas de Planta/microbiologia , Folhas de Planta/parasitologiaRESUMO
In this review, we focused on a few obstacles that hinder three-dimensional (3D) bioprinting process in tissue engineering. One of the obstacles is the bioinks used to deliver cells. Hydrogels are the most widely used bioink materials; however, they aremechanically weak in nature and cannot meet the requirements for supporting structures, especially when the tissues, such as cartilage, require extracellular matrix to be mechanically strong. Secondly and more importantly, tissue regeneration is not only about building all the components in a way that mimics the structures of living tissues, but also about how to make the constructs function normally in the long term. One of the key issues is sufficient nutrient and oxygen supply to the engineered living constructs. The other is to coordinate the interplays between cells, bioactive agents and extracellular matrix in a natural way. This article reviews the approaches to improve the mechanical strength of hydrogels and their suitability for 3D bioprinting; moreover, the key issues of multiple cell lines coprinting with multiple growth factors, vascularization within engineered living constructs etc. were also reviewed.
Assuntos
Bioimpressão , Engenharia Tecidual , Animais , Linhagem Celular , Humanos , Hidrogéis , NanopartículasRESUMO
Recent studies have shown that Ku80, a DNA repair protein, was involved in progression of malignant tumors. This study aimed to clarify the clinicopathological significance and prognostic value of Ku80 in pT2N0M0 esophageal squamous cell carcinoma (ESCC). We enrolled 217 patients with pT2N0M0 midthoracic ESCC who had undergone Ivor-Lewis esophagectomy. The expression profile of Ku80 was examined by immunohistochemistry. The results were correlated with the clinicopathological variables, overall survival (OS) and disease-free survival (DFS), in pT2N0M0 ESCC patients. The expression of Ku80 were higher in ESCC tissues than the corresponding health esophageal mucosa (P < 0.001). Clinically, the Ku80 expression levels were significantly related to tumor size (P = 0.018), differentiation degree (P = 0.010), and tumor-node-metastasis (TNM) stage (P = 0.001). Subsequent multivariate analysis demonstrated that tumor size, differentiation degree, TNM stage, and Ku80 expression were independent prognostic factors for the OS and the DFS of pT2N0M0 ESCC patients. Our data indicated that Ku80 expression level associates with key clinicopathological features and is an independent predictor of the OS and the DFS in pT2N0M0 ESCC patients.
Assuntos
Antígenos Nucleares/biossíntese , Biomarcadores Tumorais/biossíntese , Carcinoma de Células Escamosas/genética , Proteínas de Ligação a DNA/biossíntese , Neoplasias Esofágicas/genética , Recidiva Local de Neoplasia/genética , Adulto , Idoso , Antígenos Nucleares/genética , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Proteínas de Ligação a DNA/genética , Intervalo Livre de Doença , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/cirurgia , Carcinoma de Células Escamosas do Esôfago , Esofagectomia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Autoantígeno Ku , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , PrognósticoRESUMO
A novel adsorbent based on iron oxide dispersed over activated carbon (AC) were prepared, and used for phosphate removal from aqueous solutions. The influence of pre-oxidation treatment on the physical, chemical and phosphate adsorption properties of iron-containing AC were determined. Two series of ACs, non-oxidized and oxidized carbon modified by iron (denoted as AC-Fe and AC/O-Fe), resulted in a maximum impregnated iron of 4.03% and 7.56%, respectively. AC/O-Fe showed 34.0%-46.6% higher phosphate removal efficiency than the AC-Fe did. This was first attributed to the moderate pre-oxidation of raw AC by nitric acid, achieved by dosing Fe(II) after a pre-oxidation, to obtain higher iron loading, which is favorable for phosphate adsorption. Additionally, the in-situ formed active site on the surface of carbon, which was derived from the oxidation of Fe(II) by nitric acid dominated the remarkably high efficiency with respect to the removal of phosphate. The activation energy for adsorption was calculated to be 10.53 and 18.88 kJ/mol for AC-Fe and AC/O-Fe, respectively. The results showed that the surface mass transfer and intra-particle diffusion were simultaneously occurring during the process and contribute to the adsorption mechanism.
Assuntos
Carbono/química , Poluentes Químicos da Água/isolamento & purificação , Adsorção , Ferro/química , Nitrogênio , Oxirredução , Fosfatos/isolamento & purificação , Porosidade , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios XRESUMO
PURPOSE: Esophageal squamous cell carcinoma (ESCC) is a dominant pathological type in China. NUPR1 is a complex molecule implicated in various physiological and biological functions whose expression is upregulated in response to stress. Furthermore, autophagy is a vital physiological mechanism in the onset and metastasis of malignancies. This study aims to uncover the influence of NUPR1 on ESCC occurrence and development by regulating autophagy while also exploring its association with the MAPK signaling pathway. METHODS: First, the differences in NUPR1 between ESCC and normal tissues were analyzed through online databases. Subsequently, the pathological tissues of clinical samples were stained and scored using immunohistochemistry. And NUPR1 expression in ESCC cells was investigated, as was the function of NUPR1 in the modulation of ESCC's malignant behavior. Furthermore, a nude mouse ESCC xenograft model was developed. Finally, RNA sequencing was performed on NUPR1-downregulated ESCC cells, which was verified using WB. RESULTS: Our findings initially uncovered differences in the expression of NUPR1 in ESCC and normal tissues. In vitro experiments demonstrated that NUPR1 downregulation significantly inhibited ESCC cell proliferation, invasion, and migration, as well as promoted their apoptosis. Our xenograft model exhibited significant inhibition of ESCC tumors upon NUPR1 downregulation. Subsequently, RNA sequencing uncovered that NUPR1 regulates its malignant biological behavior through MAPK-mTOR signaling pathway. Finally, we found that NUPR1 downregulation can inhibit autophagic flux in ESCC. CONCLUSION: Collectively, our findings show that NUPR1 enhances the progression of ESCC by triggering autophagy and is associated with the MAPK-mTOR signaling pathway.
Assuntos
Autofagia , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Progressão da Doença , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Camundongos Nus , Proteínas de Neoplasias , Serina-Treonina Quinases TOR , Humanos , Autofagia/fisiologia , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/metabolismo , Carcinoma de Células Escamosas do Esôfago/genética , Serina-Treonina Quinases TOR/metabolismo , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Camundongos , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/genética , Sistema de Sinalização das MAP Quinases/fisiologia , Proliferação de Células/fisiologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Transdução de Sinais/fisiologia , Masculino , Feminino , Apoptose/fisiologia , Camundongos Endogâmicos BALB C , Movimento CelularRESUMO
Bacterial wilt caused by Ralstonia solanacearum is a serious threat for agricultural production in China. Eight soil bacterial isolates with activity against R. solanacearum TM15 (biovar 3) were tested in this study for their in vitro activity towards ten genetically diverse R. solanacearum isolates from China. The results indicated that each antagonist showed remarkable differences in its ability to in vitro antagonize the ten different R. solanacearum strains. Strain XY21 (based on 16S rRNA gene sequencing affiliated to Serratia) was selected for further studies based on its in vitro antagonistic activity and its excellent rhizocompetence on tomato plants. Under greenhouse conditions XY21 mediated biocontrol of tomato wilt caused by seven different R. solanacearum strains ranged from 19 to 70 %. The establishment of XY21 and its effects on the bacterial community in the tomato rhizosphere were monitored by denaturing gradient gel electrophoresis of 16S rRNA gene fragments PCR-amplified from total community DNA. A positive correlation of the in vitro antagonistic activities of XY21 and the actual biocontrol efficacies towards seven genetically different R. solanacearum strains was found and further confirmed by the efficacy of XY21 in controlling bacterial wilt under field conditions.
Assuntos
Antibiose , Ralstonia solanacearum/crescimento & desenvolvimento , Ralstonia solanacearum/patogenicidade , Serratia/classificação , Serratia/fisiologia , Microbiologia do Solo , China , DNA Bacteriano/química , DNA Bacteriano/genética , DNA Ribossômico/química , DNA Ribossômico/genética , Solanum lycopersicum/microbiologia , Dados de Sequência Molecular , Controle Biológico de Vetores/métodos , Doenças das Plantas/microbiologia , Doenças das Plantas/prevenção & controle , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Serratia/isolamento & purificaçãoRESUMO
Two kinds of activated carbons modified by Na+ impregnation after pre-treatments involving oxidation by nitric acid or acidification by hydrochloric acid (denoted as AC/N-Na and AC/HCl-Na, respectively), were used as adsorbents to remove NH4(+)-N. The surface features of samples were investigated by BET, SEM, XRD and FT-IR. The adsorption experiments were conducted in equilibrium and kinetic conditions. Influencing factors such as initial solution pH and initial concentration were investigated. A possible mechanism was proposed. Results showed that optimal NH4(+)-N removal efficiency was achieved at a neutral pH condition for the modified ACs. The Langmuir isotherm adsorption equation provided a better fit than other models for the equilibrium study. The adsorption kinetics followed both the pseudo second-order kinetics model and intra-particle kinetic model. Chemical surface analysis indicated that Na+ ions form ionic bonds with available surface functional groups created by pre-treatment, especially oxidation by nitric acid, thus increasing the removal efficiency of the modified ACs for NH4(+)-N. Na(+)-impregnated ACs had a higher removal capability in removing NH4(+)-N than unmodified AC, possibly resulting from higher numbers of surface functional groups and better intra-particle diffusion. The good fit of Langmuir isotherm adsorption to the data indicated the presence of monolayer NH4(+)-N adsorption on the active homogenous sites within the adsorbents. The applicability of pseudo second-order and intra-particle kinetic models revealed the complex nature of the adsorption mechanism. The intra-particle diffusion model revealed that the adsorption process consisted not only of surface adsorption but also intra-particle diffusion.
Assuntos
Compostos de Amônio/química , Carbono/química , Sódio/química , Adsorção , Concentração de Íons de Hidrogênio , Cinética , Microscopia Eletrônica de Varredura , Soluções , Espectroscopia de Infravermelho com Transformada de Fourier , Água/química , Difração de Raios XRESUMO
BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a malignant tumor with a high incidence of lymph node metastasis. This study was undertaken to investigate the expression of CCR7 and VEGF-C in pN0 ESCC and its relationship with lymphatic metastatic recurrence. METHODS: The expression of CCR7 and VEGF-C was examined by RT-PCR and immunohistochemistry. The recurrence rates were calculated by the Kaplan-Meier method and their difference was determined by log rank analysis. Cox regression analysis was performed to determine the independent risk factors. RESULTS: In 99 patients, CCR7 mRNA expression was observed in 42 patients with a 3 year recurrence rate of 57.1%; VEGF-C mRNA expression was observed in 52 patients with a 3 year recurrence rate of 53.8%; and coexpression of CCR7 mRNA and VEGF-C mRNA was observed in 22 patients with a 3 year recurrence of 63.6%. Neither CCR7 mRNA nor VEGF-C mRNA expression was observed in 27 patients with a 3 year recurrence rate of 22.2%. The recurrence rates of patients with positive expression of CCR7 mRNA and/or VEGF-C mRNA were significantly higher than in patients without expression of both CCR7 mRNA and VEGF-C mRNA. We achieved better concordance between RT-PCR and immunohistochemistry detection of both markers. The Cox regression analysis showed tumor T classification, positive expression of CCR7/VEGF-C mRNA, and positive expression of CCR7/VEGF-C protein in tumor tissues to be independent risk factors for 3 year recurrence. CONCLUSIONS: Patients with positive expression of CCR7 and/or VEGF-C have a higher recurrence rate than patients without expression of both CCR7 and VEGF-C. CCR7 and VEGF-C may become molecular indicators of disease in patients vulnerable to lymphatic metastatic recurrence.
Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/metabolismo , Neoplasias Esofágicas/metabolismo , RNA Mensageiro/metabolismo , Receptores CCR7/metabolismo , Fator C de Crescimento do Endotélio Vascular/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/secundário , Carcinoma de Células Escamosas/cirurgia , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/cirurgia , Esofagectomia , Feminino , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Receptores CCR7/genética , Fator C de Crescimento do Endotélio Vascular/genéticaRESUMO
BACKGROUND: Esophageal cancer is one of the most lethal tumors worldwide. The most common histological type in China is esophageal squamous cell carcinoma (ESCC), accounting for 90% of cases. Esophageal cancer occurs at a high incidence in certain areas, among which China has the highest incidence. Although various therapeutic strategies have been used in clinical treatment, the 5-year survival rate is still not satisfactory, as it is only 15-20%. The reason for the poor prognosis of ESCC is that the distant metastasis easily occurs in these tumors. However, the mechanism of metastasis has not been studied clearly. OBJECTIVES: To investigate the function of hypoxia-inducible factor-2α (hif-2α) in ESCC. MATERIAL AND METHODS: Immunohistochemistry and immunofluorescence were used to detect the expression of hif-2α in tissues and cells. Clinicopathological data from 100 ESCC patients were used to investigate the relationship between hif-2α and prognosis. Cell experiments (Cell Counting Kit-8 (CCK-8) assay and transwell migration assays) were utilized to verify the roles of hif-2α on the ESCC cells. Western blotting was used to explore the mechanism of hif-2α in ESCC. Mouse model was used to clarify the effect of hif-2α on ESCC cells in vivo. RESULTS: The hif-2α was overexpressed both in ESCC tissues and cells, and was related with poor prognosis in ESCC patients. The CCK-8 assay evidenced that silencing hif-2α suppressed the proliferation of ESCC cells, while transwell assay - that overexpression of hif-2α promoted the migration of ESCC cells. Western blot assay indicated that hif-2α regulated epithelial-mesenchymal transition (EMT) through Notch pathway in ESCC cells. Mouse model showed that silencing hif-2α significantly suppressed the proliferation of ESCC cells in vivo. CONCLUSIONS: The hif-2α promotes EMT in ESCC through the Notch pathway.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal , Neoplasias Esofágicas/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Hipóxia , CamundongosRESUMO
BACKGROUND: Fibulin-4, namely, EFEMP2, is an essential matricellular protein associated with a variety of malignancies. The aim of this study was to explore the role of fibulin-4 in the progression of esophageal squamous cell carcinoma (ESCC), as well as its effect on ESCC sensitivity to apatinib treatment. METHODS: The expression of fibulin-4 in ESCC tissues and cell lines was detected. Stably transfected ESCC cells were established by transducing lentiviral vectors for silencing or overexpressing the fibulin-4 gene into ESCC cells, and a subcutaneous xenograft tumor model of ESCC in mice was successfully established. IHC, RT-qPCR and western blotting were used to detect the expression of related genes and proteins. The CCK8 assay, EdU cell proliferation assay, wound healing assay, transwell assay and flow cytometry were used to evaluate the proliferation, invasion, migration and apoptosis of ESCC cells. After mice were sacrificed, the transplanted tumors were resected, and their volumes were measured. RESULTS: The expression of fibulin-4 was significantly increased in both ESCC tissues and cell lines, and the high expression was closely related to the poor clinicopathological features. Downregulation of fibulin-4 inhibited the proliferation, invasion and migration of ESCC cells in vitro and in vivo. Meanwhile, fibulin-4 knockdown inhibited autophagy of tumor cells by activating the Akt-mTOR signaling pathway and significantly promoted apatinib-induced apoptosis of ESCC cells. CONCLUSION: Our study showed that fibulin-4 is an oncogene that can promote ESCC progression and inhibit apoptosis. Downregulation of fibulin-4 enhances the sensitivity of ESCC cells to apatinib by inhibiting cellular protective autophagy through activating the Akt-mTOR signaling pathway.
Assuntos
Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Proteínas da Matriz Extracelular , Animais , Apoptose/genética , Autofagia , Proteínas de Ligação ao Cálcio , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células/genética , Regulação para Baixo , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Proteínas da Matriz Extracelular/genética , Humanos , Camundongos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piridinas , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismoRESUMO
Objective: To analyze the 2022 multiple-country monkeypox outbreak and assess its importation risk into China. Methods: Data was from United States Centers for Disease Control and Prevention. We described the global epidemic and calculated concentration index to measure economic-related inequality. Importation risk into China was evaluated and ranked by using risk matrix method and Borda count method, respectively. Results: As of July 29, 2022, of 79 countries or territories, 39 (49.37%, 39/79), 17 (21.52%, 17/79), 6 (7.59%, 6/79), 12 (15.19%, 12/79), and 5 (6.33%, 5/79) country or territories identified cases < 10, 10-, 51-, 101-, and > 1,000. There were economic-related health disparities exist in the distribution of cases (the concentration index = 0.42, P = 0.027), and the inequality disadvantageous to the rich (pro-poor). There were 12 (15.38%, 12/78), 15 (19.23%, 15/78), 6 (7.69%, 6/78), and 45 (57.69%, 45/78) countries or territories with extremely high, high, moderate, and low importation risk. United States and France ranked first with the highest Borda points of 156, and counts of zero. Conclusion: Of 78 countries or territories, the key attention need be paid to the United States and France, relatively. As the epidemic progresses, preparing prevention and control measures to further reduce importation risk was crucial.
Assuntos
Surtos de Doenças , Mpox , Humanos , China/epidemiologia , Surtos de Doenças/prevenção & controle , França , Mpox/epidemiologia , Mpox/prevenção & controle , Medição de RiscoRESUMO
BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors worldwide and is characterized by activation of epithelial-mesenchymal transition (EMT). EPB41L5 is regarded as a key factor in the progression of EMT and metastasis in various kinds of cancers, although the role and mechanism of EPB41L5 in ESCC have not yet been elucidated. In addition, tumor cells can acquire enhanced aggressiveness and a mesenchymal phenotype through phosphorylation of MAPK signaling pathway components. Here, we intend to explore whether EPB41L5 can regulate the EMT process in ESCC and reveal whether the MAPK signaling pathway is involved. METHODS: We compared the expression level of EPB41L5 with the prognostic characteristics of 100 ESCC patients to hypothesize the role of EPB41L5 in the progression of ESCC. Furthermore, in vivo and in vitro experiments were conducted to verify the conclusions from the analysis of clinical specimens and investigate the underlying mechanism by which EPB41L5 contributes to ESCC. RESULTS: We discovered that EPB41L5 was overexpressed in ESCC and that higher EPB41L5 expression was related to higher TNM stage, a higher incidence of lymphatic metastasis and worse prognosis. Moreover, using ESCC cells and nude mouse models, we found that EPB41L5 promoted EMT, proliferation, migration and invasion in ESCC. Mechanistically, activation of phosphorylation in the ERK/p38 MAPK signaling pathway was involved in the EPB41L5-mediated regulation of EMT. CONCLUSION: In conclusion, our findings suggest that EPB41L5 plays a critical role in the regulation of EMT and the progression of ESCC.
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Transição Epitelial-Mesenquimal/fisiologia , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Proteínas de Membrana/metabolismo , Adulto , Idoso , Animais , Progressão da Doença , Feminino , Xenoenxertos , Humanos , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Transdução de Sinais/fisiologiaRESUMO
BACKGROUND: Early-stage lung squamous cell carcinoma (LUSC) progression is accompanied by changes in immune microenvironments and the expression of immune-related genes (IRGs). Identifying innate IRGs associated with prognosis may improve treatment and reveal new immunotherapeutic targets. METHODS: Gene expression profiles and clinical data of early-stage LUSC patients were obtained from the Gene Expression Omnibus and The Cancer Genome Atlas databases and IRGs from the InnateDB database. Univariate and multivariate Cox regression and LASSO regression analyses were performed to identify an innate IRG signature model prognostic in patients with early-stage LUSC. The predictive ability of this model was assessed by time-dependent receiver operator characteristic curve analysis, with the independence of the model-determined risk score assessed by univariate and multivariate Cox regression analyses. Overall survival (OS) in early-stage LUSC patients was assessed using a nomogram and decision curve analysis (DCA). Functional and biological pathways were determined by gene set enrichment analysis, and differences in biological functions and immune microenvironments between the high- and low-risk groups were assessed by ESTIMATE and the CIBERSORT algorithm. RESULTS: A signature involving six IRGs (SREBF2, GP2, BMX, NR1H4, DDX41, and GOPC) was prognostic of OS. Samples were divided into high- and low-risk groups based on median risk scores. OS was significantly shorter in the high-risk than in the low-risk group in the training (P < 0.001), GEO validation (P = 0.00021) and TCGA validation (P = 0.034) cohorts. Multivariate Cox regression analysis showed that risk score was an independent risk factor for OS, with the combination of risk score and T stage being optimally predictive of clinical benefit. GSEA, ESTIMATE, and the CIBERSORT algorithm showed that immune cell infiltration was higher and immune-related pathways were more strongly expressed in the low-risk group. CONCLUSION: A signature that includes these six innate IRGs may predict prognosis in patients with early-stage LUSC.
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BACKGROUND: The efficacy of chemotherapeutic treatment of esophageal squamous cell carcinoma (ESCC) is limited by drug resistance during. This severely compromises the long-term survival rate of patients. Therefore, reversing chemotherapy resistance in ESCC may improve the therapeutic outcome. Here, we investigated the molecular mechanism of MUC1-C, the C-terminal transmembrane subunit of MUC1 (a transmembrane heterodimer protein), and its role in the reversal of cisplatin sensitivity in ESCC cells. METHODS: We assessed the efficacy of GO-203, a cell-penetrating peptide, as a chemotherapeutic target of MUC1-C using cell proliferation, colony-forming, and transwell assays. Apoptosis was analyzed in GO-203-treated cells by flow cytometry. Tumor xenograft assay was performed in nude mice to corroborate our in vitro findings. RESULTS: GO-203 treatment inhibited cell proliferation and restrained the migration and invasion of cisplatin-resistant ESCC. Moreover, targeting MUC1 resulted in enhanced apoptosis in GO-203-treated cells. These in vitro pro-apoptotic and anti-proliferative effects of GO-203 in combination with cisplatin were validated by in vivo models. Significantly smaller tumor volumes were observed in ESCCs-xenografted nude mice treated with GO-203 in combination with cisplatin compared with mice treated with monotherapy or their control counterparts. We found that blocking MUC1-C with GO-203 significantly reversed the cisplatin resistance in ESCC via modulating Akt and ERK pathways. CONCLUSIONS: Our findings suggest that GO-203 may hold potential as an ancillary therapeutic molecule and a chemosensitizer to improve the outcomes of cisplatin-based chemotherapy especially in patients with cisplatin-resistant ESCC.
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Objective: Although epidural analgesia is widely used during labor, its impact on breastfeeding has not yet reached a consensus. This retrospective cohort study was to investigate the association of patient-controlled epidural analgesia (PCEA) during labor with breastfeeding initiation and continuation.Methods: Medical records from 1 February, 2016 to 31 December, 2016 at Guangzhou Women and Children's Medical Center, China were reviewed for women received PCEA or not. Breastfeeding continuation was assessed by a questionnaire at 6 months after hospital discharge.Results: Nine hundred twenty-two women were enrolled in the study, with 527 of these women received PCEA for labor analgesia. The proportion of timely initiation of breastfeeding (within 1 h after birth), and exclusive or partial breastfeeding at any of the evaluation time points (1, 3, and 6 months) between two groups showed no statistically significant difference.Conclusion: Our data do not support an association between the PCEA and discontinuation of breastfeeding within 6 months postpartum.
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Analgesia Epidural , Analgesia Obstétrica , Analgesia Epidural/efeitos adversos , Analgesia Controlada pelo Paciente , Aleitamento Materno , Criança , China/epidemiologia , Feminino , Humanos , Estudos RetrospectivosRESUMO
BACKGROUND: Epidermal growth factor-containing fibulin-like extracellular matrix protein 2 (EFEMP2), also known as fibulin-4, MBP1 and UPH1, is an extracellular matrix protein associated with a variety of tumors. The purpose of this study was to investigate the prognostic value and the function of EFEMP2 in lung cancer. METHODS: The mRNA and protein expression of EFEMP2 in lung normal and cancer tissues, lung cancer cell lines (A549, H460, H1299 and H1650) and normal epithelial cell line BEAS-2B were evaluated by immunohistochemistry, RT-qPCR and Western blotting. The Public databases (Oncomine and Kaplan-Meier plotter) were used to investigate the prognostic value of EFEMP2 in lung cancer. RNA interference (RNAi) and overexpression transfection were performed to detect the effects of EFEMP2 up- or down-regulation on lung normal and cancer cell proliferation, invasion and metastasis in vitro and in vivo. RESULTS: EFEMP2 was lowly expressed in lung cancer tissues and cells, and its low expression was associated with malignant phenotype and poor prognosis of lung cancer. The same conclusion had been drawn from the Public databases. EFEMP2 overexpression significantly inhibited the invasion of lung cancer cells, hampered the process of EMT, and decreased the expression and activity of MMP2 and MMP9, while EFEMP2 knockdown remarkably enhanced the invasion of lung cancer cells, promoted EMT, and increased the expression and activity of MMP2 and MMP9. CONCLUSION: The low expression of EFEMP2 was detected in lung cancer and was positively correlated with the poor prognosis of patients. EFEMP2 was a tumor suppressor gene that inhibited the progress of lung cancer, which suggested a new research objective for the future studies.