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BACKGROUND The Lisfranc ligament is crucial for maintaining the transverse and longitudinal arch of the foot. Owing to the disruption between the medial cuneiform bone and the base of the second metatarsal bone, the currently preferred fixation method remains controversial. Our fixation technique involves screwing one anchor to the medial and intermediate cuneiform bones and using the anchor to carry the ligament to bind the Lisfranc joint and first and second metatarsal joints altogether for elastic fixation. This study evaluated the clinical and functional outcomes of InternalBrace fixation for Lisfranc injury. MATERIAL AND METHODS This retrospective study included 58 patients who underwent InternalBrace fixation for Lisfranc injury between January 2019 and September 2022 by an experienced surgeon. One-way analysis of variance or t test was used. Preoperative classification was performed according to the Myerson classification with imaging data. Postoperative follow-up was performed based on intraoperative blood loss, fracture healing time, visual analog scale (VAS) score, the American Orthopedic Foot and Ankle Society (AOFAS) score, Tegner score, and complications. RESULTS Surgery was completed in all patients, and follow-up was performed. The patients' ages ranged from 19 to 62 years (average: 34.6±9.4 years). The postoperative follow-up time was 12-24 months (average: 16.9±3.0 months). The average time for fracture healing was 12.8±3.0 (10-24) weeks. The VAS, AOFAS, and Tegner scores significantly improved postoperatively (from 5.33±1.0 (3-7) to 1.24±0.57 (0-2); 28.02±6.70 (18-51) to 91.59±4.76 (82-96); and 2.40±0.67 (1-4) to 6.53±0.54 (6-7), respectively), which was statistically significant (P<0.01), and the good rate of AOFAS was 91.4%. The postoperative complications were traumatic arthritis, incision infection, and temporary dorsal foot numbness, which gradually recovered. No other rejection reactions or Lisfranc fracture/dislocations recurrence occurred during the follow-up period. CONCLUSIONS InternalBrace fixation for Lisfranc injury is beneficial for restoring Lisfranc joint stability and function and allows for early and more aggressive rehabilitation for patients, with fewer surgical complications.
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Fixação Interna de Fraturas , Ossos do Metatarso , Humanos , Estudos Retrospectivos , Adulto , Feminino , Masculino , Pessoa de Meia-Idade , Fixação Interna de Fraturas/métodos , Ossos do Metatarso/cirurgia , Ossos do Metatarso/lesões , Adulto Jovem , Traumatismos do Pé/cirurgia , Resultado do Tratamento , Ligamentos Articulares/cirurgia , Ligamentos Articulares/lesõesRESUMO
AIM: Disulfidptosis is a new metabolic-related regulated cell death associated with cancer growth. This study aimed to investigate the molecular mechanisms associated with disulfidptosis in skin cutaneous melanoma (SKCM) and establish a disulfidptosis-related gene signature for prognostic prediction in SKCM. METHODS: Disulfidptosis-associated genes were identified from RNA-seq data of SKCM. A risk score signature was developed and validated through univariate Cox and LASSO analyses. Additionally, the immune microenvironment related to the risk score signature was investigated. Finally, a disulfidptosis-related genes-transcription factor -miRNA network was developed, and the expression levels of five disulfidptosis-related genes were initially verified in SKCM cell lines. RESULTS: A total of 107 disulfidptosis-related differentially expressed genes in SKCM samples were identified. A ten-disulfidptosis-gene signature was established, including BIN2, CCL3L3, CCL8, CD79A, CIITA, CXCR3, DEFB1, GPR171, IL2RB, and SOCS1. The SKCM samples were divided into high- and low-risk groups, of which samples in the low-risk group showed better survival performance. The receiver operating characteristic curve analysis confirmed the good potency of the disulfidptosis-related gene prognostic model. Except for DEFB1, the other nine genes were positively related with T cell CD8+, T cell CD4+ memory activated, T cell gamma delta, NK cell activated, and macrophage M1, and they were all negatively related with NK cell resting, macrophage M0, macrophage M2, and mast cell activated. Finally, we verified downregulated levels of SOCS1 and DEFB1 and upregulated CXCR3, BIN2, and CCL3L3 in A875 and A375. CONCLUSION: We successfully established ten disulfidptosis-related genes' prediction prognostic signatures for SKCM patients.
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Background: Psoriasis is a chronic immune-mediated inflammatory disease. N6-methyladenosine (m6A) is involved in numerous biological processes in both normal and diseased states. Herein, we aimed to explore the potential role of m6A regulators in the diagnosis of psoriasis and predict molecular mechanisms by which m6A regulators impact psoriasis. Methods: GSE30999 (170 human skin tissue samples) and GSE13355 (180 human skin tissue samples) were downloaded as the training analysis dataset and validation dataset respectively. M6A-related genes were obtained from the literature and their expression levels in GSE30999 samples were measured to identify M6A-related DEGs between psoriasis lesions (LS) and non-lesional lesions (NL). We identified m6A-related DEGs using differential expression analysis and assessed their interactions through correlation analysis and network construction. A logistic regression analysis followed by LASSO optimization was employed to select m6A-related DEGs for the construction of a diagnostic model. The performance of the model was validated using support vector machine (SVM) methodology with sigmoid kernel function and extensive cross-validation. Additionally, the correlation between m6A-related DEGs and immune cell infiltration was analyzed, as well as the association of these DEGs with psoriasis subtypes. Functional analysis of the m6A-related DEGs included the construction of regulatory networks involving miRNAs, transcription factors (TFs), and small-molecule drugs. The m6A modification patterns were also explored by examining the gene expression differences between psoriasis subtypes and their enriched biological pathways. Finally, the expression of significant m6A regulators involved in the diagnostic model was examined by RT-qPCR. Results: In this study, ten optimal m6A-related DEGs were identified, including FTO, IGF2BP2, METTL3, YTHDC1, ZC3H13, HNRNPC, IGF2BP3, LRPPRC, YTHDC2, and HNRNPA2B1. A diagnostic model based on these m6A-related DEGs was constructed, demonstrating high diagnostic accuracy with an area under the curve (AUC) in GSE30999 and GSE13355 of 0.974 and 0.730, respectively. Meanwhile, the expression level of m6A regulators verified by RT-qPCR was consistent with the results in GSE30999. The infiltration of activated mast cells and NK cells was significantly associated with all ten m6A-related DEGs in psoriasis. Among them, YTHDC1, HNRNPC, and FTO were targeted by most miRNAs and were regulated by nine related TFs. Therefore, patients may benefit from dorsomorphin and cyclosporine therapy. Between the two subgroups, 1,592 DEGs were identified, including LRPPRC and METTL3. These DEGs were predicted to be involved in neutrophil activation, cytokine-cytokine receptor interactions, and chemokine signaling pathways. Conclusions: A diagnostic model based on ten m6A-related DEGs in patients with psoriasis was constructed, which may provide early diagnostic biomarkers and therapeutic targets for psoriasis.
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Adenina/análogos & derivados , MicroRNAs , Psoríase , Humanos , Psoríase/diagnóstico , Adenosina , Metiltransferases , Proteínas de Ligação a RNA , Dioxigenase FTO Dependente de alfa-CetoglutaratoRESUMO
BACKGROUND Anterior talofibular ligament (ATFL) is the most easily injured or even broken of ankle sprain. Patients who fail to receive conservative treatment, resulting in persistent ankle swelling, painful and functional decline that it is so-called chronic lateral ankle instability (CLAI). It makes sense to investigate all-inside arthroscopic reconstruction of ATFL with InternalBrace™ for CLAI. MATERIAL AND METHODS We included 108 patients who underwent all-inside arthroscopic ATFL reconstruction with InternalBrace™ for CLAI from January 2018 to April 2020 through a retrospective study. Patients age ranged from 19 to 58 years (mean 35.6±8.7 years). Several elements are used to evaluate the clinical consequences of ankle function, including the American Orthopedic Foot and Ankle Society (AOFAS), Japanese Society for Surgery of the Foot Ankle-Hindfoot (JSSF), Kofoed, Tegner scores and complications, and the tilt angle of talus (TT) and the anterior displacement of talus (ADT) with stressing radiographs were taken to measure in follow-ups. RESULTS All 108 patients had all-inside arthroscopic procedures performed smoothly without serious complications. During the follow-up period (26.7±2.6 months on average), no recurrence of ankle instability and other serious complications happened. The AOFAS, JSSF, Kofoed, and Tegner scores significantly increased as time went by postoperatively, which proved statistically significant (P<0.01). Regarding stress-radiographic measurements, TT significantly decreased from (9.5±1.1)° preoperatively to (2.6±0.6)° at the latest follow-up (P<0.01), while ADT significantly decreased from (9.5±1.0) mm preoperatively to (2.6±0.6) mm at the latest examination (P<0.01). CONCLUSIONS All-inside arthroscopic ATFL reconstruction with the InternalBrace™ for CLAI is beneficial for ankle stability, allowing earlier return to activities.
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Instabilidade Articular , Ligamentos Laterais do Tornozelo , Adulto , Tornozelo , Articulação do Tornozelo/cirurgia , Artroscopia/métodos , Humanos , Instabilidade Articular/cirurgia , Ligamentos Laterais do Tornozelo/cirurgia , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
This study aimed to screen miRNA biomarkers for melanoma progression. Raw melanoma data were downloaded from the Gene Expression Omnibus (GSE34460, GSE35579, GSE18509, and GSE24996) and the Cancer Genome Atlas (TCGA). Then, all differentially expressed miRNAs (DEmiRNAs) between benign vs. primary, metastatic vs. benign, and metastatic vs. primary groups were obtained in the GSE34460 and GSE35579 datasets, and the miRNAs related to disease progression were further screened. Then, the miRNA-gene network was constructed, followed by enrichment, survival, and cluster analyses. Differentially expressed genes (DEGs), tumor-infiltrating immune cells, and tumor mutation burden (TMB) between subtypes were analyzed. miRNAs were verified in the GSE18509 and GSE24996 datasets. A total of 132 and 209 DEmiRNAs were obtained in the GSE34460 and GSE35579 datasets, respectively, and 27 DEmiRNAs related to disease progression were screened. hsa-miR-106b-5p, hsa-miR-27b-3p, and hsa-miR-141-3p had a higher degree and were regulated by numerous genes in the miRNA-gene network. Moreover, four miRNAs were associated with prognosis: hsa-let-7c-5p, hsa-miR-130b-3p, hsa-miR-142-3p, and hsa-miR-509-3p. Furthermore, the bidirectional hierarchical clustering of 27 miRNAs was classified into three subtypes, and TMB and four types of immune cells, including activated dendritic cells, naïve CD4 T cells, M1 macrophages, and plasma cells, showed significant differences among the three subtypes. The expression levels of most miRNAs in the GSE18509 and GSE24996 datasets were consistent with those in the training dataset. These miRNAs, including hsa-let-7c-5p, hsa-miR-130b-3p, and hsa-miR-142-3p, and activated dendritic cells, naïve CD4 T cells, M1 macrophages, and plasma cells may play vital roles in the pathogenesis of melanoma.
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Melanoma , MicroRNAs , Biomarcadores Tumorais/genética , Progressão da Doença , Perfilação da Expressão Gênica , Humanos , Melanoma/genética , MicroRNAs/genética , MicroRNAs/metabolismoRESUMO
Ulcerative colitis (UC) is a common chronic nonspecific intestinal inflammation of unknown etiology associated with a low cure rate and a high relapse rate. Hair follicle mesenchymal stem cells (HF-MSCs) are a class of pluripotent stem cells that have differentiation potential and strong proliferation ability. Nuclear factor red system related factor (Nrf-2) is a key factor in the oxidative stress response. Dextran sulfate sodium- (DSS-) induced rat UC models closely mimic human UC in terms of symptoms and histological changes. Animals were divided into five groups, including a healthy group and UC model rats treated with normal saline, Nrf-2, HF-MSCs, or Nrf-2-expressing HF-MSC group. Based on the expression of intestinal stem cells, inflammatory factors, anti-inflammatory factors, and disease activity index scores, Nrf-2-expressing HF-MSCs had the most obvious therapeutic effect under the same treatment regimen. This study provided a new potential clinical treatment option for ulcerative colitis.
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Colite Ulcerativa/prevenção & controle , Sulfato de Dextrana/toxicidade , Folículo Piloso/química , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/citologia , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Citocinas/metabolismo , Masculino , Fator 2 Relacionado a NF-E2/química , Ratos , Ratos Sprague-Dawley , Transdução de SinaisRESUMO
BACKGROUND: ID1 is associated with resistance to the first generation of EGFR tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC). However, the effect of ID1 expression on osimertinib resistance in EGFR T790M-positive NSCLC is not clear. METHODS: We established a drug-resistant cell line, H1975/OR, from the osimertinib-sensitive cell line H1975. Alterations in ID1 protein expression and Epithelial-mesenchymal transition (EMT)-related proteins were detected with western blot analysis. RT-PCR was used to evaluate the differences of gene mRNA levels. ID1 silencing and overexpression were used to investigate the effects of related gene on osimertinib resistance. Cell Counting Kit-8 (CCK8) was used to assess the proliferation rate in cells with altered of ID1 expression. Transwell assay was used to evaluate the invasion ability of different cells. The effects on the cell cycle and apoptosis were also compared using flow cytometry. RESULTS: In our study, we found that in osimertinib-resistant NSCLC cells, the expression level of the EMT-related protein E-cadherin was lower than that of sensitive cells, while the expression level of ID1 and vimentin were higher than those of sensitive cells. ID1 expression levels was closely related to E-cadherin and vimentin in both osimertinib-sensitive and resistant cells. Alteration of ID1 expression in H1975/OR cells could change the expression of E-cadherin. Downregulating ID1 expression in H1975/OR cells could inhibit cell proliferation, reduce cell invasion, promote cell apoptosis and arrested the cell cycle in the G1/G0 stage phase. Our study suggests that ID1 may induce EMT in EGFR T790M-positive NSCLC, which mediates drug resistance of osimertinib. CONCLUSIONS: Our study revealed the mechanism of ID1 mediated resistance to osimertinib in EGFR T790M-positive NSCLC through EMT, which may provide new ideas and methods for the treatment of EGFR mutated NSCLC after osimertinib resistance.
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Acrilamidas/farmacologia , Compostos de Anilina/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Proteína 1 Inibidora de Diferenciação/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Apoptose , Caderinas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Receptores ErbB/genética , Humanos , Proteína 1 Inibidora de Diferenciação/genética , Neoplasias Pulmonares/genética , Mutação , Inibidores de Proteínas Quinases/farmacologiaRESUMO
BACKGROUND: The minichromosome maintenance (MCM) protein complex is important for DNA replication. Moreover, the expression of specific MCM complex components has been associated with the survival of hepatocellular carcinoma (HCC) patients. However, the expression and functional roles of minichromosome maintenance complex component 4 (MCM4) in HCC development and progression have not yet been explored. We analyzed the expression and clinical significance of MCM4, including its association with liver cancer patient survival. METHODS: Oncomine, UALCAN, and HCCDB (a database of HCC expression atlas) were used to characterize the expression of MCM4 in tumor and normal tissues. The expression of MCM4 at the protein level was confirmed based on immunohistochemistry (IHC) data obtained from the Human Protein Atlas (HPA) database. The level of MCM4 was measured in tumor and adjacent normal tissues by RT-qPCR, western blot and IHC staining. The copy number alterations (CNAs) and mutations in MCM4 were analyzed by cBioPortal, whereas the co-expression genes of MCM4 in HCC were obtained from Oncomine, and used for gene ontology and pathway analysis via the NetworkAnalyst 3.0 tool, to explore the predictive signaling pathway in HCC. RESULTS: The levels of MCM4 messenger (m)RNA and protein were found to be significantly higher in liver cancer tissues than in normal liver tissues. Kaplan-Meier analysis showed that the upregulation of MCM4 was significantly negatively correlated with the survival of HCC patients. CONCLUSIONS: Our data suggest that MCM4 may be used as a potential prognostic marker and therapeutic target for HCC.
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OBJECTIVE: To analyze the prognostic significance of the pretreatment platelet/lymphocyte ratio (PLR) for targeted therapy in patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC). METHODS: We conducted a retrospective study of 96 patients with EGFR-mutated advanced NSCLC who were treated at Dongguan People's Hospital, Southern Medical University from May 2014 to December 2017. All patients received EGFR-targeted therapy until disease progression, unacceptable toxicity, or other factors. Approximately 3 days before the initial treatment, data including a detailed clinical history, physical examination, radiographic results, pathological diagnosis, and laboratory parameters including complete blood cell counts and albumin levels were evaluated. RESULTS: Patients in the PLR ≥ 190 group had shorter progression-free survival (PFS) than those in the PLR < 190 group. Furthermore, the 1-year PFS rate was worse in the PLR ≥ 190 group than in the PLR< 190 group. Multivariate analysis indicated the possible role of PLR as a prognostic factor for patients with advanced NSCLC who received EGFR-targeted therapy. CONCLUSIONS: Pretreatment PLR may be an independent prognostic factor for patients with NSCLC receiving EGFR tyrosine kinase inhibitor treatment. Further studies are needed to identify the impact of PLR on EGFR-mutated NSCLC.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Linfócitos , Mutação , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Estudos RetrospectivosRESUMO
[This retracts the article DOI: 10.1186/s12935-019-1055-z.].
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Background: Nerve block shows some potential in alleviating pain after mammaplasty. This systematic review and meta-analysis aims to investigate the efficacy of nerve block for pain control after mammaplasty.Methods: The databases including PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases are systematically searched for collecting the randomized controlled trials (RCTs) regarding the impact of nerve block on pain intensity after mammaplasty.Results: This meta-analysis has included four RCTs. Compared with the control group after mammaplasty, nerve block results in remarkably reduced pain scores. At 1, 3, and 6 h, the scores are -1.84; -2.49 to -1.20 (mean difference (MD; 95% confidence interval (CI)); p < .00001, -1.04; -1.47 to -0.62; p < .00001; and -0.96; -1.48 to -0.43; p = .0004, respectively. At 24 h, nerve block shows no significant impact on pain scores: 0.31; -1.05 to 0.43; p = .41. The standard MD of analgesic consumption is significantly reduced after nerve block: -1.27; -1.73 to -0.82; p < .00001.Conclusions: Nerve block is associated with substantially reduced pain intensity at 1 h, 3 h, and 6 h, as well as decreased analgesic consumption after mammaplasty. Therefore, a nerve block is a valuable tool for postoperative care after mammaplasty and should be recommended for the surgery.
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Mamoplastia , Bloqueio Nervoso , Manejo da Dor/métodos , Dor Pós-Operatória/terapia , Analgésicos/uso terapêutico , Intervalos de Confiança , Feminino , Humanos , Mamoplastia/efeitos adversos , Medição da Dor , Dor Pós-Operatória/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND/AIMS: The dysregulation of circABCB10 may play an critical role in tumor progression. However, its function in liver cancer (HCC) is still unclear. Therefore, this experimental design is based on circABCB10 to explore the pathogenesis of HCC. METHODS: The expression of circABCB10 and miR-670-3p in HCC tissues was detected by RT-qPCR. CCK-8, Brdu incorporation, colony formation and transwell assays were used to determine the effect of circABCB10 on HCC cell proliferation and migration. Target gene prediction and screening, luciferase reporter assays were used to validate downstream target genes of circABCB10 and miR-670-3p. HMG20A expression was detected by RT-qPCR and Western blotting. The tumor changes in mice were detected by in nude mice. RESULTS: CircABCB10 was significantly increased in HCC tissues and cell lines, and high CircABCB10 expression was directly associated with low survival in HCC patients. Silencing of circABCB10 inhibited proliferation and invasion of hepatocellular carcinoma. In addition, circABCB10 acted as a sponge of miR-670-3p to upregulate HMG20A expression. In addition, overexpression of miR-670-3p or knockdown of HMG20A reversed the carcinogenic effects of circABCB10 in HCC. There was a negative correlation between the expression of circABCB10 and miR-670-3p, and a positive correlation between the expression of circABCB10 and HMG20A in HCC tissues. CONCLUSION: circABCB10 promoted HCC progression by modulating the miR-670-3p/HMG20A axis, and circABCB10 may be a potential therapeutic target for HCC.Trail registration JL1H384739, registered at Sep 09, 2014.
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Solar ultraviolet B (UVB) radiation is known to trigger inflammation, oxidative stress and apoptotic responses through various signaling pathways, which eventually lead to skin cancer. The present study investigated whether liquiritin suppresses UVBinduced skin injury in vivo and in vitro using SKH1 hairless mice and HACAT cells, respectively. The animals were exposed to UVB irradiation (180 mJ/cm2) for 20 min, followed by liquiritin treatment. The findings indicated that UVB exposure resulted in the excessive release of proinflammatory cytokines, including interleukin (IL)1ß, tumor necrosis factor (TNF)α, IL18, IL6 and cyclooxygenase (COX)2, which were dependent on the tolllike receptor (TLR)4/myeloid differentiation factor 88 (MyD88)/nuclear factorκB (NFκB) signaling pathway. Oxidative stress was also observed, evidenced by reduced antioxidants and elevated oxidants. Apoptosis, examined using terminal deoxynucleotidyl transferase dUTP nick end labeling and crystal violet staining, suggested that UVB irradiation caused cell death in vivo and in vitro, which was closely associated with p38/cJun Nterminal kinase and caspase activity. Of note, liquiritin treatment in mice and cells exposed to UVB showed reduced inflammatory response, oxidative stress and apoptosis through inhibiting the activation of TLR4/MyD88/NFκB mitogenactivated protein kinases and caspase pathways, and downregulating the release of oxidants. Overall, the data revealed that liquiritin may be a useful compound against UVBinduced skin injury.
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Apoptose , Flavanonas/uso terapêutico , Glucosídeos/uso terapêutico , Inflamação/tratamento farmacológico , Transdução de Sinais , Pele/efeitos da radiação , Raios Ultravioleta , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Caspases/metabolismo , Morte Celular/efeitos dos fármacos , Morte Celular/efeitos da radiação , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Citocinas/metabolismo , Feminino , Flavanonas/farmacologia , Glucosídeos/farmacologia , Humanos , Inflamação/patologia , Inflamação/prevenção & controle , Mediadores da Inflamação/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Oxidantes/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/efeitos da radiação , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação , Pele/efeitos dos fármacos , Pele/patologia , Receptor 4 Toll-Like/metabolismoRESUMO
Melanoma, is a highly aggressive and the most lethal form of skin cancer, and is known to be resistant to current therapeutic modalities. Interferon (IFN)-α2b is an immunostimulatory cytokine and is used to treat melanoma by inhibiting proliferation and promoting apoptosis of cells. However, there is a need to improve the efficacy of IFN-α2b. Inhibitor of growth family member 4 (ING4) has been reported to function as a tumor suppressor and is involved in regulating cell cycle progression, apoptosis, cell migration and invasion. Previously studies have also reported that caspase-3, caspase-8, poly (ADP-ribose) polymerase (PARP) and Fas/Fas ligand (FasL) pathways are involved in the process of apoptosis. In the present study, it was investigated whether overexpression of ING4 is able to enhance IFN-α2b response in human melanoma cells. It was determined that the overexpression of ING4 was able to increase the effects of IFN-α2b, and induce cell death and apoptosis in melanoma cells. Furthermore, the overexpression of ING4 resulted in decreased expression of PARP, caspase-3 and -8. The expression of cleaved PARP, cleaved caspase-3, cleaved caspase-8, Fas and FasL was increased in the A375 melanoma cell line. These results demonstrate that the overexpression of ING4 is able to enhance the anti-melanoma activity of IFN-α2b. These findings provide a potential therapeutic strategy where a combination of ING4 overexpression and IFN-α2b treatment may lead to higher levels of apoptosis in melanoma cells.
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Melanoma, the most aggressive form of skin cancer, is notoriously resistant to all current available therapies. Inhibitor of growth 4 (ING4), a novel member of the ING family of proteins, has previously been shown to play a critical role in the development of multiple tumors by regulating apoptosis, proliferation, cell cycle progress, migration and invasion. However, the functional role of ING4 in human melanoma remains unclear. To fully understand its potential role in human melanoma, in the present study, lentivirus (LV)ING4 and LVING4short hairpin RNA were constructed and transfected into human melanoma A375 cells. First, the effect of overexpressing or downregulating ING4 on the apoptosis of the transfected melanoma cells and cluster of differentiation (CD)3+ T cells was investigated. In the present study, we found that the late apoptotic cells, and not the early apoptotic cells, were more in LV-ING4 group compared with LV-control, and both the early and late apoptosis of CD3+ T cells was significantly observed in A375 cells transfected with LV-ING4 compared with LV-control. Importantly, it was determined whether the overexpression of ING4 significantly induce apoptotic cell death via Fas/FasL (Fas death receptor/FasL) pathway activation and downregulation of poly(ADPribose) polymerase, caspase3 and caspase8 in the melanoma cells and CD3+ T cells. These results demonstrated that overexpression of ING4 can induce the apoptosis of melanoma cells and CD3+ T cells through signaling pathways such as the Fas/FasL pathway, and that ING4 gene therapy for melanoma treatment is a novel approach.
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Proteínas de Ciclo Celular/genética , Proteína Ligante Fas/genética , Proteínas de Homeodomínio/genética , Melanoma/genética , Proteínas Supressoras de Tumor/genética , Receptor fas/genética , Apoptose/genética , Caspase 8/genética , Proteínas de Ciclo Celular/administração & dosagem , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Proteínas de Homeodomínio/administração & dosagem , Humanos , Lentivirus/genética , Melanoma/patologia , Transfecção , Proteínas Supressoras de Tumor/administração & dosagemRESUMO
BACKGROUND: Inhibitor of growth 4 (ING4) plays a role in regulating the cell cycle, apoptosis, cell invasion and migration, but the mechanisms involved remain to be elucidated. OBJECTIVE: To explore how ING4 affects human malignant melanoma A375 cells. METHODS: Recombinant lentiviral vectors (A375/pLenO-GTP-ING4) were constructed and transfected into A375 cells (experimental group). The impact of ING4 on the proliferation and apoptosis of A375 cells was investigated in in vitro and in vivo experiments in mice using the MTT assay and flow cytometry. RESULTS: In the experimental group, optical density was lower and apoptotic cells were more frequent from days 2-5 (p = 0.000 and p < 0.01); there were smaller xenografts and more apoptotic cells in mice (all p < 0.05); moreover, increased levels of Fas, cleaved caspase-8 and caspase-3, and decreased levels of FasL and procyclic acidic repetitive protein were observed in vitro and in vivo. CONCLUSION: ING4 might suppress proliferation and enhance apoptosis in human malignant melanoma cells by activating Fas-induced apoptosis in a caspase-8-dependent pathway.
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Apoptose , Proteínas de Transporte/genética , Caspase 8/genética , DNA de Neoplasias/genética , Regulação Neoplásica da Expressão Gênica , Melanoma Experimental/patologia , Proteínas Supressoras de Tumor/genética , Receptor fas/genética , Animais , Western Blotting , Proteínas de Transporte/biossíntese , Caspase 8/biossíntese , Proliferação de Células , Citometria de Fluxo , Humanos , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/genética , Camundongos , Camundongos Nus , Proteínas Recombinantes , Células Tumorais Cultivadas , Proteínas Supressoras de Tumor/biossíntese , Receptor fas/biossínteseRESUMO
The aim of the present study was to investigate the effect of gelsolin (GSN) on the proliferation and invasion of the 786-0 clear cell renal cell carcinoma (ccRCC) cell line in vitro. A GSN overexpression lentiviral vector was constructed and transfected into 7860 ccRCC cells in vitro. A 3-(4,5-dimethylthiazol2yl)2,5diphenyltetrazolium bromide (MTT) assay was conducted to detect the effect of GSN on the proliferation and adhesion ability of the 7860 ccRCC cells, and a Transwell invasion assay was used to determine the effect of GSN on the invasion of 7860 ccRCC cells. In addition, the expression levels of invasionassociated proteins, matrix metalloproteinase (MMP)2, MMP9 and Ecadherin were analyzed by ELISA and western blotting. The MTT assay demonstrated a significantly lower optical density value for the 7860/GSN cells compared with that of the 7860/green fluorescent protein (GFP) and 7860 cells following 24 and 48h culture (P<0.05). The mean penetration rate of the 7860/GSN cells was significantly lower than that of the 7860/GFP and 7860 cells (P<0.05) according to the Transwell invasion assay. The expression levels of MMP2 and MMP9 were significantly decreased in the 7860/GSN cells, when compared with the 7860/GFP and 7860 cells following a 48h transfection, according to ELISA (P<0.001). Furthermore, in the 7860/GSN cells, the expression levels of MMP2 and MMP9 were markedly decreased, while the expression of Ecadherin was markedly increased. Thus, the overexpression of GSN may inhibit the proliferation, adhesion ability and invasion of 7860 ccRCC cells. Additionally, GSN downregulated the expression of MMP2 and MMP9, and upregulated the expression of Ecadherin in the 7860 ccRCC cells, which may have suppressed the invasion ability of the 786-0 ccRCC cells.
Assuntos
Carcinoma de Células Renais/genética , Proliferação de Células , Gelsolina/genética , Neoplasias Renais/genética , Invasividade Neoplásica/genética , Regulação para Cima , Caderinas/análise , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Humanos , Rim/metabolismo , Rim/patologia , Neoplasias Renais/patologia , Metaloproteinase 2 da Matriz/análise , Metaloproteinase 9 da Matriz/análise , Invasividade Neoplásica/patologia , TransfecçãoRESUMO
OBJECTIVES: The efficacy of gene overexpression of CASP5, a caspase family member, in angiogenesis in vitro and its mechanisms were clarified. METHODS: Human full-length CASP5 gene was delivered into human microvascular endothelial HMEC-1 cells by recombinant lentivirus. The infection was estimated by green fluorescent protein. MTT method was used to analyze the efficacy of gene overexpression in cell proliferation ability, and Matrigel was used to estimate its effects in angiogenesis ability of cells. Meanwhile, Western blot was used to analyze the effects of CASP5 gene overexpression on the expression levels of angpt-1, angpt-2, Tie2 and VEGF-1 in the cells, which were signaling pathway factors related to angiogenesis. RESULTS: Recombinant lentivirus containing human full-length CASP5 gene was packed and purified successfully, with virus titer of 1×10(8) TU/ml. The recombinant lentivirus was used to infect HMEC-1 cells with MOI of 1, leading to a cell infection rate of 100%. There were no significant effects of CASP5 gene overexpression on both cell proliferation ability and the expression level of angpt-1. Meanwhile, expressions of angpt-2 and VEGF-1 were both enhanced, while Tie2 expression was inhibited. Results indicated that CASP5 gene overexpression promoted angiogenesis of HMEC-1 cells. CONCLUSION: CASP5 gene overexpression significantly promoted angiogenesis ability of HMEC-1 cells, which was probably achieved by inhibiting angpt-1/Tie2 and promoting VEGF-1 signal pathway.
Assuntos
Caspases/biossíntese , Células Endoteliais/enzimologia , Neovascularização Fisiológica , Angiopoietina-2/genética , Angiopoietina-2/metabolismo , Caspases/genética , Linhagem Celular , Proliferação de Células , Indução Enzimática , Vetores Genéticos , Humanos , Lentivirus/genética , Receptor TIE-2/genética , Receptor TIE-2/metabolismo , Transdução de Sinais , Fatores de Tempo , Transdução Genética , Transfecção , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
BACKGROUND: Inhibitor of growth 4 (ING4) has deserved attention as a tumor suppressor gene in many malignant tumors. In our study, we investigated ING4 immunoexpression in gastrointestinal stromal tumors (GISTs) and its prognostic value. METHOD: The expression of ING4 and Ki67 was investigated in 41 samples of various risk gastrointestinal stromal tumors by immunohistochemical technique. The associations of ING4 expression and clinicopathological parameters, and prognosis of the patients, were analyzed by multivariate Cox regression analysis. RESULTS: ING4 expression showed a decreased trend from lower-risk to high-risk gastrointestinal stromal tumors, and an opposite trend for Ki67 expression. In lower-risk tumors, it was found the expression level of ING4 was 78.95 % ± 27.90 % and that of Ki67 was 4.42 % ± 3.75 %. However, in high-risk tumors, the expression level of ING4 was 9.23 % ± 7.66 % and that of Ki67 was 18.50 % ± 9.09 %. There was a strongly negative correlation between the expression levels of ING4 and Ki67. A significant difference was observed in the expression of ING4 between invasion and non-invasion (p < 0.001). The expression of ING4 was markedly correlated with tumor size (p < 0.001), mitotic index (p < 0.001), tumor necrosis (p = 0.021), invasion (p < 0.001), recurrence and metastasis (p = 0.021), and mortality (p < 0.001). CONCLUSION: The low expression level of ING4 protein was correlated with high-risk GISTs. ING4 might be involved in the progression of GISTs and inhibit its invasion. ING4 might be one of the prognostic indicators in GISTs.
Assuntos
Proteínas de Ciclo Celular/análise , Neoplasias Gastrointestinais/metabolismo , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/metabolismo , Tumores do Estroma Gastrointestinal/patologia , Proteínas de Homeodomínio/análise , Imuno-Histoquímica/métodos , Proteínas Supressoras de Tumor/análise , Adolescente , Adulto , Idoso , Proteínas de Ciclo Celular/metabolismo , Feminino , Neoplasias Gastrointestinais/mortalidade , Tumores do Estroma Gastrointestinal/mortalidade , Proteínas de Homeodomínio/metabolismo , Humanos , Antígeno Ki-67/metabolismo , Masculino , Pessoa de Meia-Idade , Inclusão em Parafina , Prognóstico , Modelos de Riscos Proporcionais , Taxa de Sobrevida , Proteínas Supressoras de Tumor/metabolismo , Adulto JovemRESUMO
BACKGROUND: Condylomata acuminata (CA) are caused by human papillomavirus. Most conventional therapies for CA have high recurrence rate. OBJECTIVES: To compare the recurrence rate of 5-aminolaevulinic acid photodynamic therapy (ALA-PDT) combined with CO2 laser and CO2 laser alone for CA treatment in mainland China. METHODS: In this meta-analysis, 2,048 cases of CA from 22 articles were divided into two groups. The treatment group was treated by using ALA-PDT combined with CO2 laser, and CO2 laser alone was applied in the control group. The recurrence rate of the two groups was calculated and compared. RESULTS: The recurrence rate was 42.67% (451/1,057) in the control group and 10.29% (102/991) in the treatment group, with a significant statistical difference between the two groups (χ(2) = 271.98, p < 0.0001). CONCLUSION: ALA-PDT combined with CO2 laser was more effective in decreasing the recurrence rate of CA compared with CO2 laser alone. It might offer a wide clinical application for CA treatment.