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Although some studies have reported on the levels and clinical significance of peripheral blood neutrophil/lymphocyte ratio (NLR) in cervical cancer, the role of NLR levels and their changes preoperatively and postoperatively in early cervical cancer remain unclear. Our analyses explored the preoperative and postoperative NLR in 203 patients with stage I-IIA cervical cancer and evaluated the relationship between NLR changes, clinicopathological characteristics, and patient prognosis. The cut-off preoperative and postoperative NLR values were determined using receiver operating characteristic curve analysis. Preoperative NLR correlated with age, menopausal status, tumor size, and vascular infiltration, whereas postoperative NLR correlated with tumor differentiation. Patients with cervical cancer with a high preoperative NLR had significantly shorter overall survival (OS) and progression-free survival (PFS) than other patients, whereas PFS was significantly lower in the high postoperative NLR group. When comparing postoperative and preoperative NLR values, we observed a significantly higher rate of increase in postmenopausal patients and those without vascular infiltration than that among premenopausal patients and those with vascular infiltration. However, no clear difference in prognosis was observed between the groups with increased and decreased NLR. Therefore, a high peripheral blood NLR may predict a poor prognosis in patients with early cervical cancer. The effect of NLR changes on the prognosis of patients with cervical cancer requires further verification in multicenter studies.
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BACKGROUND: Hepatocellular carcinoma (HCC) metastasis and recurrence lead to therapy failure, which are closely associated with the proteome. However, the role of post-translational modification (PTM) in HCC, especially for the recently discovered lysine crotonylation (Kcr), is elusive. RESULTS: We investigated the correlation between crotonylation and HCC in 100 tumor tissues and performed stable isotope labeling by amino acids and liquid chromatography tandem mass spectrometry in HCC cells, and we found that crotonylation was positively correlated with HCC metastasis, and higher crotonylation in HCC cells facilitated cell invasiveness. Through bioinformatic analysis, we found that the crotonylated protein SEPT2 was significantly hypercrotonylated in highly invasive cells, while the decrotonylated mutation of SEPT2-K74 impaired SEPT2 GTPase activity and inhibited HCC metastasis in vitro and in vivo. Mechanistically, SIRT2 decrotonylated SEPT2, and P85α was found to be the downstream effector of SEPT2. Moreover, we identified that SEPT2-K74cr was correlated with poor prognosis and recurrence in HCC patients, thus indicating its clinical potential as an independent prognostic factor. CONCLUSIONS: We revealed the role of nonhistone protein crotonylation in regulating HCC metastasis and invasion. Crotonylation facilitated cell invasion through the crotonylated SEPT2-K74-P85α-AKT pathway. High SEPT2-K74 crotonylation predicted poor prognosis and a high recurrence rate in HCC patients. Our study revealed a novel role of crotonylation in promoting HCC metastasis.
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Introduction: Advanced biliary tract carcinoma (BTC) has a poor prognosis and few treatment options. We compared the efficacy of the PD-1 monoclonal antibody (PD-1-mAb) combined regimens with the standard chemotherapy in the first-line and second-line treatment of advanced BTC. Methods: We retrospectively assessed the patients with advanced BTC, who received treatment at the First Affiliated Hospital of Sun Yat-Sen University and the Sun Yat-Sen University Cancer Center. The patients were treated with PD-1-mAb combined regimens or standard chemotherapy at the first line or treated with PD-1-mAb combined regimens or systematic therapy at the second line. Further subgroup analyses were assessed to identify superior regimens. Results: This study included 210 patients. The first-line PD-1-mAb combination group (n = 83) achieved longer median PFS (mPFS) (7.3 vs 5.3 months, p=0.001) and median OS (mOS) (15.6 vs 11.4 months, p=0.002) than the first-line standard chemotherapy group (n=76). Similarly, the second-line PD-1-mAb combination group (n=50) yielded longer mPFS (6.1 vs 2.6 months, p<0.001) and mOS (11.7 vs 7.2 months, p=0.008) than the second-line systematic therapy group (n=51). Subgroup analyses showed that the PD-1-mAb combined with TKI group achieved better mPFS than the chemotherapy group whether in the first-line (HR = 0.468, p=0.005) or the second-line setting (HR = 0.45, p=0.009), but did not achieve superiority in mOS (both p>0.05). Compared with the chemotherapy group, the PD-1-mAb combined with chemotherapy group achieved longer mOS (HR = 0.53, p=0.023) in the first-line setting and longer mPFS in the second-line setting (HR = 0.54, p=0.044). Conclusion: The PD-1-mAb combination therapy is superior to the standard chemotherapy in advanced or unresectable BTC, whether as a first-line or second-line treatment. Among the combination therapy, both the PD-1-mAb combined with TKI and combined with standard chemotherapy were promising options for advanced BTC patients.
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BACKGROUND: The proteinuria remission in hepatitis B virus-associated glomerulonephritis (HBV-GN) patients with massive proteinuria treated with antiviral therapy was low. Tacrolimus (TAC) is effective in primary nephropathy and can inhibit HBV infection by inhibiting HBV binding to sodium taurocholate cotransporting polypeptide on liver cells. This study evaluated the efficacy and safety of TAC combined with ETV compared with entecavir (ETV) monotherapy in HBV-GN. METHODS: Patients diagnosed with HBV-GN were recruited for this prospective, randomized, controlled, multicenter, single-blinded study in China. Patients were given TAC and ETV therapy (the TAC+ETV group) or placebo and ETV therapy (the ETV group) for 26 weeks. The efficacy endpoints included proteinuria remission, including complete and partial remission (CR and PR), the change of 24-hour proteinuria (24 h UP) and HBV DNA titer. The safety endpoints were the incidence of HBV virologic breakthrough and adverse events. RESULTS: There were 14 patients in the TAC+ETV group and 17 patients in the ETV group. In the intention-to-treat analyses, 64.3% (9/14) of patients in the TAC+ETV group and 58.8% (10/17) in the ETV group achieved PR or CR at 26 weeks (P=0.38). At week 14, 42.9% (6/14) and 41.2% (7/17) of patients in the TAC+ETV group and the ETV group, respectively, achieved PR or CR (P=0.23). At week 26, the 24 h UP had decreased by 2.63±6.33 g from baseline in the TAC+ETV group and 1.42±4.34 g in the ETV group (P=0.55). The serum albumin increased by 11.1±7.30 g/L from baseline in the TAC+ETV group and 3.81±5.09 g/L in the ETV group (P<0.001). Log10 HBV DNA decreased by 1.49±2.04 from baseline in the TAC+ETV group and 2.47±2.08 in the ETV group (P=0.37); 28.6% (4/14) patients had HBV DNA virologic breakthrough in the ETV group, while none in the TAC+ETV group (P=0.29). CONCLUSIONS: In adult HBV-GN patients, TAC and ETV combination therapy may significantly improve serum albumin levels without increasing the risk of HBV reactivation compared with entecavir monotherapy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03062813.
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Glomerulonefrite , Hepatite B Crônica , Adulto , Antivirais/uso terapêutico , DNA Viral/farmacologia , DNA Viral/uso terapêutico , Glomerulonefrite/induzido quimicamente , Glomerulonefrite/tratamento farmacológico , Guanina/análogos & derivados , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Humanos , Estudos Prospectivos , Proteinúria/induzido quimicamente , Proteinúria/tratamento farmacológico , Albumina Sérica/farmacologia , Albumina Sérica/uso terapêutico , Método Simples-Cego , Tacrolimo/farmacologia , Tacrolimo/uso terapêutico , Resultado do TratamentoRESUMO
Hemangioblastoma (HB) is an abnormal intracranial buildup of blood vessels that exhibit a great potential for hemorrhage. Surgical options are limited, and few medications are available for treatment. We show here by immunohistochemical analysis that HB lesions display highly increased levels of VEGF expression and macrophage/microglia infiltration compared with those in normal brain tissues. In the meantime, TNF superfamily 15 (TNFSF15) (also known as vascular endothelial growth inhibitor), an antiangiogenic cytokine, is highly expressed in normal brain blood vessels but diminished in HB lesions. We set up a brain hemangioma model by using mouse bEnd.3 cells of a T antigen-transformed endothelial cell line that produce a large amount of VEGF. When implanted in mouse brains, these cells form lesions that closely resemble the pathologic characteristics of HB. Retroviral infection of bEnd.3 cells with TNFSF15 leads to inhibition of VEGF production and retardation of hemangioma formation. Similar results are obtained when wild-type bEnd.3 cells are implanted in the brains of transgenic mice overexpressing TNFSF15. Additionally, TNFSF15 treatment results in enhanced pericyte coverage of the blood vessels in the lesions together with reduced inflammatory cell infiltration and decreased hemorrhage. These findings indicate that the ability of TNFSF15 to counterbalance the abnormally highly angiogenic and inflammatory potential of the microenvironment of HB is of therapeutic value for the treatment of this disease.-Yang, G.-L., Han, Z., Xiong, J., Wang, S., Wei, H., Qin, T.-T., Xiao, H., Liu, Y., Xu, L.-X., Qi, J.-W., Zhang, Z.-S., Jiang, R., Zhang, J., Li, L.-Y. Inhibition of intracranial hemangioma growth and hemorrhage by TNFSF15.
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Terapia Baseada em Transplante de Células e Tecidos , Modelos Animais de Doenças , Células Endoteliais/transplante , Hemangioma/prevenção & controle , Hemorragias Intracranianas/prevenção & controle , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Animais , Apoptose , Proliferação de Células , Células Endoteliais/citologia , Hemangioma/metabolismo , Hemangioma/patologia , Humanos , Hemorragias Intracranianas/metabolismo , Hemorragias Intracranianas/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Prognóstico , Células Tumorais Cultivadas , Microambiente Tumoral , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/administração & dosagemRESUMO
BACKGROUND: Recurrent hepatocellular carcinoma (rHCC) patients with microvascular invasive (MVI) positive at first resection usually had poorly differentiated tumors and worse survivals. The optimal treatment for this population remains to be elucidated. METHODS: We retrospectively analyzed 319 rHCC patients with MVI-positive at first resection from June, 2009 to June, 2017. Survival and costs between curative treatments [re-resection (RR) and radiofrequency ablation (RFA)] and transarterial chemoembolization (TACE) were compared. Subgroup comparisons were made in patients in Barcelona Clinic Liver Cancer (BCLC) stage 0-A and BCLC stage B-C, respectively. A one-to-one propensity score matching (PSM) was used to diminish bias. RESULTS: In BCLC stage 0-A, 98 received RR/RFA, and 49 received TACE. The median overall survival (OS) of RR/RFA group was not reached, while the OS of TACE group was 26.3 months (P=0.001). After matching, the OS of the RR/RFA group was longer than that of the TACE group (39.5 vs. 26.3 months, P=0.045). In BCLC stage B-C, 137 patients received TACE, 11 received RR and 24 received RFA. The median OS was 29.8 months, 17.9 months and 11.1 months for RR, RFA and TACE group, respectively. No significant difference was found between RR and TACE (P=0.237) or RFA and TACE (P=0.484) after matching. Costs of the TACE group was significantly lower than that of the RR group but similar to that of the RFA group. CONCLUSION: RR/RFA provided better survival outcomes for rHCC patients with MVI-positive at first resection in selected BCLC stage 0-A. In selected BCLC stage B-C, TACE shared a similar efficacy with RR and RFA but a lower cost than RR.
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Using genome-wide screening and TCGA-based data analysis, we identified a DNA methylation-related gene named metallothionein-1G (MT1G), which may play an important role in hepatocellular carcinoma (HCC). In this study, we found that MT1G expression was silenced in 4/6 HCC cell lines and negatively related to aberrant promoter hypermethylation. Its mRNA level was restored with demethylation treatment. Moreover, MT1G downregulation at both the transcriptional and protein level was also detected in 8 pairs of clinical HCC samples compared with its expression in adjacent normal tissues. Ectopic expression of MT1G in silenced HCC cell lines inhibited colony formation, suppressed cell migration and invasion, and repressed xenograft tumor growth in nude mice. In contrast, knockdown of MT1G by short hairpin RNA showed the opposite effect on cell proliferation and the malignant phenotype. Moreover, our data showed that MT1G suppressed tumor invasion and metastasis mainly through regulating the expression of proteins in the matrix metalloproteinase family (MMP) and modulating the epithelial-mesenchymal transition (EMT) process. To our surprise, the data from TCGA showed that hypermethylation of MT1G is associated with good survival of HCC patients. In conclusion, our study demonstrated that MT1G acts as a tumor suppressor gene in HCC development, but its clinical potential in HCC requires further evaluation.
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OBJECTIVE: To investigate the impact of heart valve calcification (HVC) on cardiovascular outcomes in patients on maintenance hemodialysis (MHD). METHODS: We enrolled 302 Chinese patients on MHD between 2009 and 2011 including 99 with HVC identified by echocardiography screening. All the patients were followed up for 2 years and survival analysis was performed with all-cause mortality, cardiovascular mortality and new onset cardiovascular events as the endpoints. Cox regression analysis was used for analyzing the impact of heart valve calcification on the cardiovascular outcomes of the patients. RESULTS: The mean age of the total patients was 58.2∓15.0 years when receiving the initial MHD, and 53.6% were male patients. The overall mortality, cardiovascular mortality and new on-set cardiovascular events in HVC and non-HVC groups were 30.3% vs 16.3%, 22.2% vs 6.9%, and 48.5% vs 25.6%, respectively (P<0.05). Kaplan-Meier survival analysis showed a significant difference in all-cause mortality (P=0.006), cardiovascular mortality (P<0.001) and new-onset cardiovascular events (P<0.001) between HVC and non-HVC groups. After adjustment, Cox regression analysis identified HVC as a risk factor for increased all-cause mortality (HR=1.88; 95%CI: 1.11-3.19), cardiovascular mortality (HR=3.47, 95%CI: 1.76-6.84) and cardiovascular events (HR=1.64, 95% CI: 1.09-2.47). CONCLUSIONS: HVC is an independent risk factor for increased cardiovascular mortality and new cardiovascular events in patients on MHD.
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Calcinose/patologia , Doenças das Valvas Cardíacas/patologia , Diálise Renal , Adulto , Idoso , Ecocardiografia , Feminino , Doenças das Valvas Cardíacas/mortalidade , Valvas Cardíacas/patologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
Lymphangiogenesis is essential in embryonic development but is rare in adults. It occurs, however, in many disease conditions including cancers. Vascular endothelial growth factor-C/D (VEGF-C/D) and VEGF receptor-3 (Vegfr3) play a critical role in the regulation of lymphangiogenesis. We investigated how the VEGF-C/Vegfr3 signalling system is regulated by tumour necrosis factor superfamily member 15 (Tnfsf15), an endothelium-derived cytokine. We report here that Tnfsf15, which is known to induce apoptosis in vascular endothelial cells, can promote lymphatic endothelial cell (LEC) growth and migration, stimulate lymphangiogenesis, and facilitate lymphatic circulation. Treatment of mouse LECs with Tnfsf15 results in up-regulation of Vegfr3 expression; this can be inhibited by gene silencing of death domain-containing receptor-3 (DR3; Tnfrsf25), a cell surface receptor for Tnfsf15, with siRNA, or by blocking Tnfsf15-DR3 interaction with a Tnfsf15 neutralizing antibody, 4-3H. Additionally, Tnfsf15/DR3 signalling pathways in LECs include activation of NF-κB. Tnfsf15-overexpressing transgenic mice exhibit a marked enhancement of lymph drainage; this is confirmed by treatment of wild-type mice with intraperitoneal injection of recombinant Tnfsf15. Moreover, systemic treatment of pregnant Tnfsf15 transgenic mice with 4-3H leads to inhibition of embryonic lymphangiogenesis. Our data indicate that Tnfsf15, a cytokine produced largely by endothelial cells, facilitates lymphangiogenesis by up-regulating Vegfr3 gene expression in LECs, contributing to the maintenance of the homeostasis of the circulatory system. This finding also suggests that Tnfsf15 may be of potential value as a therapeutic tool for the treatment of lymphoedema.
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Células Endoteliais/metabolismo , Linfangiogênese , Vasos Linfáticos/metabolismo , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Movimento Celular , Proliferação de Células , Células Cultivadas , Relação Dose-Resposta a Droga , Células Endoteliais/efeitos dos fármacos , Injeções Intraperitoneais , Linfa/metabolismo , Linfangiogênese/efeitos dos fármacos , Vasos Linfáticos/citologia , Vasos Linfáticos/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , NF-kappa B/metabolismo , Interferência de RNA , Membro 25 de Receptores de Fatores de Necrose Tumoral/genética , Membro 25 de Receptores de Fatores de Necrose Tumoral/metabolismo , Proteínas Recombinantes/administração & dosagem , Transdução de Sinais , Fatores de Tempo , Transfecção , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/administração & dosagem , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Regulação para Cima , Fator C de Crescimento do Endotélio Vascular/metabolismoRESUMO
Tumor necrosis factor superfamily 15 (TNFSF15) suppresses angiogenesis by specifically inducing apoptosis in proliferating endothelial cells. Death receptor 3 (DR3), a member of the TNF receptor superfamily (TNFRSF25), has been identified as a receptor for TNFSF15 to activate T cells. It is unclear, however, whether DR3 mediates TNFSF15 activity on endothelial cells. Here we show that siRNA-mediated knockdown of DR3 in an in vivo Matrigel angiogenesis assay, or in adult bovine aortic endothelial (ABAE) cell cultures, leads to resistance of endothelial cells to TNFSF15-induced apoptosis. Interestingly, DR3-depleted cells also exhibited markedly diminished responsiveness to TNFα cytotoxicity, even though DR3 is not a receptor for TNFα. Treatment of the cells with either TNFSF15 siRNA or a TNFSF15-neutralizing antibody, 4-3H, also results in a significant inhibition of TNFα-induced apoptosis. Mechanistically, DR3 siRNA treatment gives rise to an increase of ERK1/2 MAPK activity, and up-regulation of the anti-apoptotic proteins c-FLIP and Bcl-2, thus strengthening apoptosis-resisting potential in the cells. These findings indicate that DR3 mediates TNFSF15-induced endothelial cell apoptosis, and that up-regulation of TNFSF15 expression stimulated by TNFα is partly but significantly responsible for TNFα-induced apoptosis in endothelial cells.
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Apoptose/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Membro 25 de Receptores de Fatores de Necrose Tumoral/metabolismo , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Animais , Western Blotting , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/metabolismo , Caspases/metabolismo , Bovinos , Linhagem Celular , Doxorrubicina/farmacologia , Células Endoteliais/metabolismo , Células Endoteliais/fisiologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Expressão Gênica , Camundongos Endogâmicos C57BL , Neovascularização Fisiológica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Interferência de RNA , Membro 25 de Receptores de Fatores de Necrose Tumoral/genética , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genéticaRESUMO
BACKGROUND: In this study, the serum B-cell activating factor belonging to tumor necrosis factor family (BAFF) levels in patients with myeloperoxidase (MPO)-antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) were measured, and their clinical significance was further analyzed. METHODS: One hundred twenty-one patients with MPO-AAV were enrolled in this study. Eighty-three patients had active vasculitis and 38 were in remission. Fifty-five healthy individuals were used as healthy controls. The levels of serum BAFF were assessed using commercial available enzyme-linked immunosorbent assay kits. The correlations between serum BAFF and Birmingham Vasculitis Activity Score, erythrocyte sedimentation rate and MPO-ANCA were further evaluated. RESULTS: The levels of serum BAFF of patients with MPO-AAV in both active (6.06±5.02 ng/mL) and remission phases (3.60±3.83 ng/mL) were significantly higher than those in healthy controls (0.87±0.31 ng/mL) (P<0.001, respectively). The serum BAFF levels in patients with active vasculitis were significantly higher than those in remission (P<0.001). Serum BAFF levels were significantly correlated with Birmingham Vasculitis Activity Score (r=0.320, P<0.001) and erythrocyte sedimentation rate value (r=0.311, P<0.01) in all patients, but no correlation was found between the levels of serum BAFF and MPO-ANCA. Using receiver-operating characteristics statistics, the cutoff values of serum BAFF level for indicating the presence of MPO-AAV and active vasculitis were 1.58 and 4.20 ng/mL, respectively. CONCLUSIONS: The levels of serum BAFF were elevated in patients with MPO-AAV and associated with disease activity, but they were not related with the levels of MPO-ANCA.
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Anticorpos Anticitoplasma de Neutrófilos/sangue , Fator Ativador de Células B/sangue , Peroxidase/sangue , Vasculite/sangue , Adulto , Idoso , Fator Ativador de Células B/biossíntese , Biomarcadores/sangue , Citoplasma/imunologia , Citoplasma/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Neutrófilos/patologia , Peroxidase/imunologia , Vasculite/imunologia , Vasculite/patologiaRESUMO
AIM: Immunoglobulin A nephropathy (IgAN) is the most common glomerulonephritis with various histological and clinical phenotypes. N-acetylgalactosamine (GalNAc) exposure plays a pivotal role in the pathogenesis of IgAN. The aim of the current study is to investigate whether GalNAc exposure of serum IgA1 was associated with clinical and pathological manifestation of IgAN. METHODS: Sera from 199 patients with biopsy proved IgAN were collected. Clinical and pathological manifestations were collected. Biotinylated Helix aspersa were used in ELISA to examine GalNAc exposure on IgA1 molecules. Patients were divided into two groups according to the GalNAc exposure rate less or more than 0.4. RESULTS: Age, gender, and serum creatinine were comparable between the two groups. Univariate analysis showed that significantly higher urinary protein excretion rate but less severe glomerular sclerosis and tubularinterstitial fibrosis were observed in the lower GalNAc exposure group. Multivariate regression analysis demonstrated that adjusted by age and gender, the GalNAc exposure rate more than 0.4 was a risk factor of glomerular sclerosis and tubularinterstitial fibrosis, OR*(95% CI) were 2.76 (1.19-6.37) and 2.49 (1.18-5.25), respectively. CONCLUSION: Immunoglobulin A nephropathy patients with lower proteinuria had higher GalNAc exposure rates. The GalNAc exposure rate more than 0.4 was a risk factor of severe chronic renal tissue change.
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Acetilgalactosamina/toxicidade , Glomerulonefrite por IGA/patologia , Imunoglobulina A/sangue , Glomérulos Renais/patologia , Túbulos Renais/patologia , Adulto , Atrofia , Feminino , Fibrose , Glomerulonefrite por IGA/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Regressão , EscleroseRESUMO
Mouse bone marrow-derived Lin(-)-Sca-1(+) endothelial progenitor cell (EPC) has pluripotent abilities such as supporting neovascularization. Vascular endothelial growth factor (VEGF) receptor 1 (VEGFR1) (Flt1) recognizes various VEGF isoforms and is critically implicated in a wide range of physiological and pathological settings, including vasculogenesis. Mouse EPC expresses two isoforms of VEGFR1: mFlt1, which transmits ligand-induced signals; and sFlt1, which acts as a negative regulator by sequestering ligands of VEGF receptors. How the relative levels of mFlt1 and sFlt1 are regulated is not yet clear. We report here that tumor necrosis factor superfamily 15 (TNFSF15) (also known as VEGI or TL1A), an endothelial cell-secreted cytokine, simultaneously promotes mFlt1 degradation and up-regulates sFlt1 expression in EPC, giving rise to disruption of VEGF- or PlGF-induced activation of eNOS and MAPK p38 and effective inhibition of VEGF-driven, EPC-supported vasculogenesis in a murine Matrigel implant model. TNFSF15 treatment of EPC cultures facilitates Akt deactivation-dependent, ubiquitin-assisted degradation of mFlt1 and stimulates sFlt1 expression by activating the PKC, Src, and Erk1/2 signaling pathway. Additionally, TNFSF15 promotes alternative splicing of the Flt1 gene in favor of sFlt1 production by down-regulating nuclear protein Jumonji domain-containing protein 6 (Jmjd6), thus alleviating Jmjd6-inhibited sFlt1 expression. These findings indicate that TNFSF15 is a key component of a molecular mechanism that negatively modulates EPC-supported vasculogenesis through regulation of the relative levels of mFlt1 and sFlt1 in EPC.
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Regulação da Expressão Gênica/fisiologia , Neovascularização Fisiológica/fisiologia , Proteólise , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/fisiologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Processamento Alternativo/fisiologia , Análise de Variância , Animais , Western Blotting , Colágeno , Combinação de Medicamentos , Células Endoteliais/metabolismo , Laminina , Ligantes , Camundongos , Microscopia de Fluorescência , Isoformas de Proteínas/metabolismo , Proteoglicanas , Células-Tronco/metabolismo , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismoRESUMO
AIM: B cell activating factor belonging to the tumour necrosis factor family (BAFF) and a proliferation inducing ligand (APRIL) are two tumour necrosis factor (TNF)-like cytokines that were found to be elevated in many autoimmune diseases. Anti-glomerular basement membrane (GBM) disease is a typical severe autoimmune disease characterized by raised serum anti-GBM antibodies. In this study we aimed to detect the serum levels of BAFF and APRIL in patients with anti-GBM disease, and their clinical significance was further analyzed. METHODS: Forty-seven patients with anti-GBM disease were enrolled in this study. Forty-eight healthy individuals were used as normal controls. The levels of serum BAFF and APRIL were assessed using commercially available enzyme linked immunosorbent assay kits. The association between the levels of serum BAFF and APRIL, and the clinical and pathological parameters were further evaluated. RESULTS: The serum levels of BAFF and APRIL in patients with anti-GBM disease were significantly higher than that in normal controls (12.3 ± 14.1 ng/mL vs. 0.9 ± 0.3 ng/mL, P < 0.001; 19.1 ± 22.9 ng/mL vs. 1.6 ± 4.6 ng/mL, P < 0.001), respectively. The levels of serum APRIL were correlated with the titres of anti-GBM antibodies (r = 0.347, P = 0.041), and the levels of serum BAFF were associated with the percentage of glomeruli with crescents (r = 0.482, P = 0.015) in patients with anti-GBM disease. CONCLUSION: The levels of serum BAFF and APRIL were raised in patients with anti-GBM disease and might be associated with disease activity and kidney damage.
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Doença Antimembrana Basal Glomerular/diagnóstico , Fator Ativador de Células B/sangue , Rim/patologia , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/sangue , Adulto , Doença Antimembrana Basal Glomerular/sangue , Doença Antimembrana Basal Glomerular/patologia , Autoanticorpos/sangue , Biomarcadores/sangue , Biópsia , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Rim/imunologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Índice de Gravidade de Doença , Regulação para Cima , Adulto JovemRESUMO
BACKGROUND: B-cell-activating factor belonging to the tumor necrosis factor family (BAFF) has been found to have the function of activating B cells and participating in the class switching of B cells; however, its clinical application needs further study. In the present study, the serum BAFF levels of patients with IgA nephropathy (IgAN) with different histopathological phenotypes were measured. METHODS: Levels of serum BAFF in 153 patients with IgAN, 55 healthy controls and 20 disease controls were recorded using commercially available ELISA kits. Their correlations with clinical and histopathological features of patients with IgAN were further evaluated. RESULTS: Levels of serum BAFF in patients with IgAN were significantly higher than in controls. Serum BAFF levels were significantly higher in patients with mesangial hypercellularity and segmental glomerulosclerosis than in those without. Serum BAFF levels were associated with the severity of tubular atrophy/interstitial fibrosis. Serum BAFF levels were significantly positively correlated with estimated glomerular filtration rate and serum creatinine. Patients with elevated serum BAFF levels showed significantly greater severity in clinical and histopathological stages. CONCLUSION: Levels of serum BAFF were elevated in patients with IgAN and were associated with clinical and pathological features of the disease. Serum BAFF levels could be a noninvasive biomarker for monitoring disease severity of IgAN.
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Fator Ativador de Células B/sangue , Glomerulonefrite por IGA/sangue , Glomerulonefrite por IGA/patologia , Adulto , Feminino , Humanos , MasculinoRESUMO
AIM: To improve the outcome of orthotopic transplantation in a mouse model, we used an absorbable gelatin sponge (AGS) in nude mice to establish an orthotopic implantation tumor model. METHODS: MHCC-97L hepatocellular carcinoma (HCC) cells stably expressing the luciferase gene were injected into the subcutaneous region of nude mice. One week later, the ectopic tumors were harvested and transplanted into the left liver lobe of nude mice. The AGS was used to establish the nude mouse orthotopic implantation tumor model. The tumor suppressor gene, paired box gene 5 (PAX5), which is a tumor suppressor in HCC, was transfected into HCC cells to validate the model. Tumor growth was measured by bioluminescence imaging technology. Semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) and histopathology were used to confirm the tumorigenicity of the implanted tumor from the MHCC-97L cell line. RESULTS: We successfully developed an orthotopic transplantation tumor model in nude mice with the use of an AGS. The success rate of tumor transplantation was improved from 60% in the control group to 100% in the experimental group using AGS. The detection of fluorescent signals showed that tumors grew in all live nude mice. The mice were divided into 3 groups: AGS-, AGS+/PAX5- and AGS+/PAX5+. Tumor size was significantly smaller in PAX5 transfected nude mice compared to control mice (P < 0.0001). These fluorescent signal results were consistent with observations made during surgery. Pathologic examination further confirmed that the tissues from the ectopic tumor were HCC. Results from RT-PCR proved that the HCC originated from MHCC-97L cells. CONCLUSION: Using an AGS is a convenient and efficient way of establishing an indirect orthotopic liver transplantation tumor model with a high success rate.
Assuntos
Carcinoma Hepatocelular/terapia , Modelos Animais de Doenças , Neoplasias Hepáticas/terapia , Transplante de Neoplasias , Animais , Linhagem Celular Tumoral , Gelatina/química , Humanos , Luminescência , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos NusRESUMO
Using a randomized multistage cluster sampling, we studied the factors associated with the prevalence, awareness, treatment and control of hypertension (defined as systolic and diastolic blood pressure (BP) measurements ≥140 and 90 mm Hg, respectively, or current drug treatment for hypertension) in a representative sample of the urban Chinese population. The participants were 18-74 years of age and had lived for at least 5 years in an area comprising 33 communities in three cities (Shenyang, Anshan and Jinzhou) in China. A total of 28 830 people were selected; the overall response rate was 87.4% (25 196/28 830). The overall prevalence of hypertension was 28.7% (7237/25 196). Of those with hypertension, 42.9% (3107/7237) were aware of their condition, 28.2% (2042/7237) were receiving treatment and 3.7% (264/7237) were considered controlled. More than half (57.8%) of the hypertensives did not think that high BP would endanger their lives. Multivariate analysis revealed that age, gender, education, occupation, income, body mass index, waist circumference and a family history of hypertension correlated significantly with the prevalence of hypertension. Among all the hypertensives, higher awareness (determined by odds ratios; 95% confidence intervals) was noted for persons who were white-collar workers (1.29; 1.08, 1.53, respectively), overweight (1.48; 1.30, 1.69), obese (3.37; 2.76, 4.11) or had a family history of hypertension (3.07; 2.76, 3.42). Among the individuals aware of their hypertension, treatment was more common in those with a higher level of education and less common among individuals consuming ≥2 alcoholic drinks per day (0.65; 0.52, 0.83). Controlled hypertension was much less common among older persons, and participants who were former smokers (0.49; 0.26, 0.91). The results indicate that more attention is needed to improve the awareness of the potentially fatal nature of hypertension in urban China.
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Conhecimentos, Atitudes e Prática em Saúde/etnologia , Hipertensão/etnologia , Hipertensão/terapia , Aceitação pelo Paciente de Cuidados de Saúde/etnologia , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Adolescente , Adulto , Idoso , Consumo de Bebidas Alcoólicas/etnologia , China/epidemiologia , Análise por Conglomerados , Feminino , Inquéritos Epidemiológicos/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Fumar/etnologia , População Urbana/estatística & dados numéricos , Adulto JovemRESUMO
UNLABELLED: Objective. Anti-C1q antibodies are common in sera from patients with lupus nephritis (LN) and are associated with disease activity. The current study aimed to further investigate the prevalence of serum IgG anti-C1q antibody, its subclass distribution and their clinical and pathological association in patients with LN. METHODS: Sera were collected from 150 patients with renal biopsy-proven LN, diagnosed from 2000 to 2006 in our hospital, 30 patients with systemic lupus erythematosus (SLE) without clinical evidence of renal involvement (non-renal SLE, NR-SLE) and 63 healthy donors. ELISA was used to detect serum IgG anti-C1q antibody and its subclass. Their clinical and pathological associations were further analysed. RESULTS: The prevalence of IgG anti-C1q antibody in LN (84/150, 56%) was significantly higher than that in NR-SLE (6/30, 20%) and healthy controls (3/63, 4.8%) (P < 0.005, P < 0.001, respectively). The prevalence of anti-C1q antibody in patients with diffuse proliferative renal lesions (class IV) (59/82, 71.95%) was significantly higher than that in those with non-diffuse proliferative renal lesions (class II + III) (12/26, 46.15%, P = 0.016) and class V (13/42, 30.95%, P < 0.001). The prevalence of IgG2 (60/135, 44.44%) was significantly higher than that of IgG1 (37/135, 27.41%) and IgG3 (25/135, 18.52%) (P < 0.005, P < 0.001, respectively). IgG2 was associated with the occurrence of arthritis (P < 0.05), higher serum creatinine (P < 0.05) and lower serum C3 (P < 0.05). Of the 38 LN patients with sera both in active phase and in remission, 17 were anti-C1q antibody-positive in active phase and the antibody levels decreased in all and turned to negative in 9 (52.94%) in remission. Meanwhile, the ratio of turning negative of IgG1, IgG2 and IgG3 anti-C1q was 33%(2/6), 53.85% (7/13) and 100% (7/7), respectively. CONCLUSIONS: Anti-C1q antibodies are prevalent in LN and are closely associated with diffuse proliferative lesions. IgG2 anti-C1q might be pathogenic and IgG3 anti-C1q might be a more specific biomarker for monitoring disease activity.
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Autoanticorpos/sangue , Complemento C1q/imunologia , Imunoglobulina G/sangue , Nefrite Lúpica/imunologia , Adulto , Povo Asiático , Autoanticorpos/classificação , Estudos de Casos e Controles , China , Feminino , Humanos , Imunoglobulina G/classificação , Lúpus Eritematoso Sistêmico/imunologia , Nefrite Lúpica/etiologia , Nefrite Lúpica/patologia , Masculino , Adulto JovemRESUMO
Aberrant glycosylation of serum IgA1 was considered as an initial event and involvement in the pathogenesis of IgAN. We previously demonstrated that aberrant glycosylation of serum IgA1 was associated with pathologic phenotype of IgAN. The present study is to investigate if abnormal sialylation of IgA1 affects renal survival of IgAN. 127 patients with biopsy-proven IgAN were enrolled and followed up to 8 years. Seventy-nine healthy and 75 patients with non-IgAN renal diseases were selected as controls. Alpha 2, 6 sialic acid (SA) of serum IgA1 was measured by sandwich-ELISA. Renal survival rate was estimated by Kaplan-Meier method. Alpha 2, 6 SA level in patients with IgAN was lower than that in healthy controls (0.92+/-0.14 vs. 0.98+/-0.12, P=0.001) and non-IgAN glomerulonephritis (0.92+/-0.14 vs. 1.00+/-0.18, n=53, P=0.001). Patients with IgAN in Low SA Group were no significant differences compared with patients in Normal SA Group in age, gender, hypertension, serum creatinine, and excretion of proteinuria. Renal cumulative survival rate was 53.3% in patients in Low SA Group and 83.5% in Normal SA Group (P=0.0008). The lower the alpha 2, 6 SA level of serum IgA1 in patients with IgAN was, the worse their renal survival rate was. Although patients in Low SA Group had worse renal function evaluated by eGFR, there was no significant difference in various CKD stages in non-IgAN renal function controls (n=42, P=0.352). Alpha 2, 6 SA level of serum IgA1 was associated with the prognosis of patients with IgAN and could serve as a predictor of poor prognosis in IgAN.
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Glomerulonefrite por IGA/sangue , Glomerulonefrite por IGA/mortalidade , Imunoglobulina A/sangue , Ácido N-Acetilneuramínico/sangue , Adulto , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , PrognósticoRESUMO
BACKGROUND: IgA nephropathy (IgAN) is the most common glomerulonephritis with various histologic and clinical phenotypes. The mechanisms underlying the pathogenesis of IgAN remained unclear. But now altered O-glycosylation of serum IgA1 observed in these patients was considered to be a key contributory factor. The aim of the current study is to investigate whether aberrantly glycosylated IgA1 was associated with pathologic phenotypes of IgAN. METHODS: Sera from 107 patients with IgAN recently diagnosed were collected. Fifty patients were with mild mesangial proliferative IgAN, the others were with focal proliferative and sclerosing IgAN. Sera from 22 normal blood donors were used as normal controls. Biotinylated lectins were used in enzyme-linked immunosorbent assay (ELISA) to examine different glycans on IgA1 molecules. The alpha2,6 sialic acid was detected by elderberry bark lectin (SNA), the exposure of terminal galactose (Gal) and N-acetylgalactosamine (GalNAc) were detected by arachis hypogaea [peanut agglutinin (PNA)] and vilsa villosa lectin (VVL), respectively. The serum IgA1 glycans levels corrected by serum IgA1 concentrations were compared between patients and controls. RESULTS: Reduced terminal alpha2,6 sialic acid (1.16 +/- 0.21 vs. 0.98 +/- 0.31) (P= 0.008) and galactosylation (0.30 +/- 0.29 vs. 0.16 +/- 0.19) (P= 0.029) increased exposure of (GalNAc) (0.00 vs. 0.03) (P= 0.024) were demonstrated in serum IgA1 from patients with IgAN as compared with those in controls. More important, the exposures of 2,6 sialic acid and Gal were significantly decreased, especially in patients with focal proliferative and sclerosing IgAN compared with that in patients with mild mesangial proliferative IgAN (0.91 +/- 0.34 vs. 1.05 +/- 0.25) (P= 0.014) (0.108 +/- 0.137 vs. 0.221 +/- 0.219) (P= 0.018). However, no significant difference was found between patients with mild mesangial proliferative IgAN and normal controls (P > 0.05). The exposure of GalNAc of serum IgA1 from patients with focal proliferative and sclerosing IgAN was significantly higher than that of controls (P= 0.017), but had no statistical difference with that of patients with mild mesangial proliferative IgAN. CONCLUSION: The desialylation and degalactosylation of IgA1 in sera of patients with IgAN were closely associated with pathologic phenotypes.