RESUMO
OBJECTIVE: To evaluate the surgical outcomes of a modified technique for treating congenital cilial entropion in children, which involves reducing tension step by step in the epicanthus and lower eyelid incision. METHODS: The observational group consisted of 153 pediatric patients (81 males and 72 females) who were treated using the modified technique, whereas the control group included 124 patients (68 males and 56 females) who were treated using the rotating suture surgery. All the participants were bilateral. Surgical outcomes were classified as good, fair, or poor, and the recurrence rate, scar condition, inferior eyelid position, and patient satisfaction were also assessed. RESULTS: The mean follow-up period was 9.13 ± 3.50 months (range: 3-14 months) for the observational group and 6.93 ± 4.51 months (range: 3-14 months) for the control group. In the observational group, surgical success with "good" outcomes was achieved in 300 eyes (98.04%), compared to 224 eyes (90.32%) in the control group. No recurrence occurred in the observational group, whereas the recurrence rate in the control group was 4.43%. Postoperative scar formation was mild in the observational group. The average scar score was 1.27 ± 0.96 in the observational group and 2.70 ± 0.99 in the control group, with a statistically significant difference (P < 0.001). Neither overcorrection nor postoperative ectropion was observed in both groups. CONCLUSION: The modified technique effectively corrected medial entropion and trichiasis in the lower eyelid, resulting in stable postoperative outcomes, mild scar formation, quick recovery, flexible eyelid motility, and stable ocular surface. Therefore, it can be widely applied to children with congenital entropion and trichiasis.
Assuntos
Entrópio , Pálpebras , Técnicas de Sutura , Humanos , Entrópio/cirurgia , Feminino , Masculino , Pré-Escolar , Criança , Pálpebras/cirurgia , Resultado do Tratamento , Blefaroplastia/métodos , Satisfação do Paciente , Lactente , Seguimentos , Recidiva , Cicatriz/prevenção & controle , Cicatriz/cirurgia , Cicatriz/etiologia , Estudos RetrospectivosRESUMO
A significant variation in chromatin accessibility is an epigenetic feature of leukemia. The cause of this variation in leukemia, however, remains elusive. Here, we identify SMARCA5, a core ATPase of the imitation switch (ISWI) chromatin remodeling complex, as being responsible for aberrant chromatin accessibility in leukemia cells. We find that SMARCA5 is required to maintain aberrant chromatin accessibility for leukemogenesis and then promotes transcriptional activation of AKR1B1, an aldo/keto reductase, by recruiting transcription co-activator DDX5 and transcription factor SP1. Higher levels of AKR1B1 are associated with a poor prognosis in leukemia patients and promote leukemogenesis by reprogramming fructose metabolism. Moreover, pharmacological inhibition of AKR1B1 has been shown to have significant therapeutic effects in leukemia mice and leukemia patient cells. Thus, our findings link the aberrant chromatin state mediated by SMARCA5 to AKR1B1-mediated endogenous fructose metabolism reprogramming and shed light on the essential role of AKR1B1 in leukemogenesis, which may provide therapeutic strategies for leukemia.
Assuntos
Frutose , Humanos , Animais , Camundongos , Frutose/metabolismo , Cromatina/metabolismo , Aldeído Redutase/metabolismo , Aldeído Redutase/genética , Leucemia/metabolismo , Leucemia/patologia , Leucemia/genética , Proteínas Cromossômicas não Histona/metabolismo , Proteínas Cromossômicas não Histona/genética , Montagem e Desmontagem da Cromatina , Carcinogênese/metabolismo , Carcinogênese/patologia , Carcinogênese/genética , Linhagem Celular Tumoral , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Adenosina TrifosfatasesRESUMO
Myelodysplastic syndrome (MDS) is a group of clonal hematopoietic neoplasms originating from hematopoietic stem progenitor cells (HSPCs). We previously identified frequent roundabout guidance receptor 1 (ROBO1) mutations in patients with MDS, while the exact role of ROBO1 in hematopoiesis remains poorly delineated. Here, we report that ROBO1 deficiency confers MDS-like disease with anemia and multilineage dysplasia in mice and predicts poor prognosis in patients with MDS. More specifically, Robo1 deficiency impairs HSPC homeostasis and disrupts HSPC pool, especially the reduction of megakaryocyte erythroid progenitors, which causes a blockage in the early stages of erythropoiesis in mice. Mechanistically, transcriptional profiling indicates that Cdc42, a member of the Rho-guanosine triphosphatase family, acts as a downstream target gene for Robo1 in HSPCs. Overexpression of Cdc42 partially restores the self-renewal and erythropoiesis of HSPCs in Robo1-deficient mice. Collectively, our result implicates the essential role of ROBO1 in maintaining HSPC homeostasis and erythropoiesis via CDC42.
Assuntos
Eritropoese , Síndromes Mielodisplásicas , Animais , Humanos , Camundongos , Eritropoese/genética , Síndromes Mielodisplásicas/genética , Proteínas do Tecido Nervoso/genética , Prognóstico , Receptores Imunológicos/genética , Proteínas RoundaboutRESUMO
The bone marrow microenvironment (BMM) can regulate leukemia stem cells (LSCs) via secreted factors. Increasing evidence suggests that dissecting the mechanisms by which the BMM maintains LSCs may lead to the development of effective therapies for the eradication of leukemia. Inhibitor of DNA binding 1 (ID1), a key transcriptional regulator in LSCs, previously identified by us, controls cytokine production in the BMM, but the role of ID1 in acute myeloid leukemia (AML) BMM remains obscure. Here, we report that ID1 is highly expressed in the BMM of patients with AML, especially in BM mesenchymal stem cells, and that the high expression of ID1 in the AML BMM is induced by BMP6, secreted from AML cells. Knocking out ID1 in mesenchymal cells significantly suppresses the proliferation of cocultured AML cells. Loss of Id1 in the BMM results in impaired AML progression in AML mouse models. Mechanistically, we found that Id1 deficiency significantly reduces SP1 protein levels in mesenchymal cells cocultured with AML cells. Using ID1-interactome analysis, we found that ID1 interacts with RNF4, an E3 ubiquitin ligase, and causes a decrease in SP1 ubiquitination. Disrupting the ID1-RNF4 interaction via truncation in mesenchymal cells significantly reduces SP1 protein levels and delays AML cell proliferation. We identify that the target of Sp1, Angptl7, is the primary differentially expression protein factor in Id1-deficient BM supernatant fluid to regulate AML progression in mice. Our study highlights the critical role of ID1 in the AML BMM and aids the development of therapeutic strategies for AML.
Assuntos
Proteína 7 Semelhante a Angiopoietina , Proteína 1 Inibidora de Diferenciação , Leucemia Mieloide Aguda , Animais , Camundongos , Proteína 7 Semelhante a Angiopoietina/genética , Proteína 7 Semelhante a Angiopoietina/metabolismo , Medula Óssea/metabolismo , Modelos Animais de Doenças , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Microambiente Tumoral , Humanos , Proteína 1 Inibidora de Diferenciação/metabolismoRESUMO
BACKGROUND: This study aims to determine the influence of vitrectomy combined with macular epiretinal membrane dissection and internal limiting membrane (ILM) peeling and phacoemulsification on choroidal vasculature in patients with unilateral idiopathic epiretinal membrane (IERM) and concurrent cataract using optical coherence tomography (OCT). METHODS: This retrospective study included 26 eyes of 26 patients (8 males and 18 females) with unilateral IERM without vitreomacular traction (VMT) (group 1) and the patients' fellow eyes (n = 26, group 2). Three-port 25-G pars plana vitrectomy (PPV) combined with macular epiretinal membrane dissection and ILM peeling and phacoemulsification was performed on all patients. The comprehensive ophthalmologic examinations of all patients involved OCT measurements at every visit before and after surgery, and the choroidal thickness (CT), central macular thickness (CMT) and choroidal vascularity index (CVI) were calculated. RESULTS: The mean age of the IERM patients was 66.58 ± 7.06 years. Postoperatively, best corrected visual acuity (BCVA) was significantly greater than baseline (P = 0.023). The CVI of the IERM eyes was significantly lower (P < 0.01) than that of the fellow eyes at baseline. The subfoveal CT in the IERM eyes was lower than that in the fellow eyes (P = 0.023), but there was, no significant difference in the average CT between the two groups at baseline (P = 0.071). In eyes with IERM, the CVI significantly increased at 1 week, 1 month (P < 0.001), and 3 months (P = 0.049) postoperatively, the subfoveal CT was markedly thickened 1 month after surgery (P = 0.001), the temporal 3 mm and nasal CT significantly increased at 1 week and 1 month postoperatively (P = 0.041, P = 0.022 for temporal 3 mm; P < 0.001, P = 0.047 for nasal 1.5 mm; P = 0.01, P = 0.001 for nasal 3 mm), and only the temporal 3 mm CT increased significantly at 3 months postoperatively (P = 0.017). The baseline CMT of the IERM eyes was significantly thicker than that of the fellow eyes (P < 0.001). CMT significantly decreased at 3 months postoperatively in IERM eyes(P = 0.033). CONCLUSIONS: The increase in the CVI in the IERM eyes without VMT after combined PPV with ILM peeling and phacoemulsification persists for at least 3 months.
Assuntos
Membrana Epirretiniana , Facoemulsificação , Masculino , Feminino , Humanos , Pessoa de Meia-Idade , Idoso , Membrana Epirretiniana/cirurgia , Vitrectomia/métodos , Estudos Retrospectivos , Retina , Tomografia de Coerência Óptica/métodos , Transtornos da VisãoRESUMO
The patients with relapsed and refractory diffuse large B-cell lymphoma (DLBCL) have poor prognosis, and a novel and effective therapeutic strategy for these patients is urgently needed. Although ubiquitin-specific protease 1 (USP1) plays a key role in cancer, the carcinogenic effect of USP1 in B-cell lymphoma remains elusive. Here we found that USP1 is highly expressed in DLBCL patients, and high expression of USP1 predicts poor prognosis. Knocking down USP1 or a specific inhibitor of USP1, pimozide, induced cell growth inhibition, cell cycle arrest and autophagy in DLBCL cells. Targeting USP1 by shRNA or pimozide significantly reduced tumor burden of a mouse model established with engraftment of rituximab/chemotherapy resistant DLBCL cells. Pimozide significantly retarded the growth of lymphoma in a DLBCL patient-derived xenograft (PDX) model. USP1 directly interacted with MAX, a MYC binding protein, and maintained the stability of MAX through deubiquitination, which promoted the transcription of MYC target genes. Moreover, pimozide showed a synergetic effect with etoposide, a chemotherapy drug, in cell and mouse models of rituximab/chemotherapy resistant DLBCL. Our study highlights the critical role of USP1 in the rituximab/chemotherapy resistance of DLBCL through deubiquitylating MAX, and provides a novel therapeutic strategy for rituximab/chemotherapy resistant DLBCL.
Assuntos
Linfoma Difuso de Grandes Células B , Linfoma não Hodgkin , Animais , Camundongos , Humanos , Rituximab/uso terapêutico , Pimozida/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Linfoma não Hodgkin/tratamento farmacológico , Proteases Específicas de Ubiquitina/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Aberrant self-renewal of leukemia initiation cells (LICs) drives aggressive acute myeloid leukemia (AML). Here, we report that UHRF1, an epigenetic regulator that recruits DNMT1 to methylate DNA, is highly expressed in AML and predicts poor prognosis. UHRF1 is required for myeloid leukemogenesis by maintaining self-renewal of LICs. Mechanistically, UHRF1 directly interacts with Sin3A-associated protein 30 (SAP30) through two critical amino acids, G572 and F573 in its SRA domain, to repress gene expression. Depletion of UHRF1 or SAP30 derepresses an important target gene, MXD4, which encodes a MYC antagonist, and leads to suppression of leukemogenesis. Further knockdown of MXD4 can rescue the leukemogenesis by activating the MYC pathway. Lastly, we identified a UHRF1 inhibitor, UF146, and demonstrated its significant therapeutic efficacy in the myeloid leukemia PDX model. Taken together, our study reveals the mechanisms for altered epigenetic programs in AML and provides a promising targeted therapeutic strategy against AML.
Assuntos
Leucemia Mieloide Aguda , Humanos , Carcinogênese , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Histona Desacetilases , Leucemia Mieloide Aguda/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismoRESUMO
PURPOSE: To evaluate the surgical outcomes of pediatric congenital blepharoptosis with poor Bell's phenomenon (BP) treated with modified levator muscle complex suspension. METHODS: Forty-two pediatric congenital blepharoptosis patients with poor BP were treated with modified levator muscle complex suspension, and their major surgical outcomes such as marginal reflex distance1 (MRD1), palpebral fissure height (PFH), and postoperative lagophthalmos were retrospectively reviewed. RESULTS: The mean follow-up was 10.28 ± 9.89 months (range 3-32 Months). Surgical success was achieved in 54 (87.1%) of 62 eyelids at the final visit, including excellent results in 46 (74.2%) eyelids, good results in 8 (12.9%) eyelids, and poor results in 8 (12.9%) eyelids, respectively. The postoperative PFH of affected eyes (7.97 ± 1.47 mm) was significantly improved compared with that before surgery (3.58 ± 1.31 mm). The mean MRD1 was improved from - 1.48 ± 1.36 mm before surgery to 2.94 ± 1.46 mm after surgery. The postoperative MRD1 was ≥ 3 mm in 46 eyelids and < 3 mm in 16 eyelids. The mean lagophthalmos was 1.42 ± 1.20 mm 3 months after surgery. All of the patients presented complete blink postoperatively. Postoperative complications were rarely observed during follow-up. No patient had exposure keratitis, but blepharoptosis recurred in 6 patients (8 eyelids). All patients had satisfactory eyelid symmetry and contour. No complications were observed until the last visit. CONCLUSIONS: The modified method results complete blink, mild, and quick recovery of lagophthalmos, flexible eyelid motility, stable ocular surface, and it is simple to perform with few complications and a low recurrence rate at 12.9%, which is worth to wide application on poor Bell's phenomenon blepharoptosis.
Assuntos
Blefaroplastia , Blefaroptose , Doenças Palpebrais , Humanos , Criança , Blefaroplastia/métodos , Estudos Retrospectivos , Músculos Oculomotores/cirurgia , Blefaroptose/cirurgia , Blefaroptose/congênito , Pálpebras/cirurgia , Doenças Palpebrais/cirurgia , Resultado do TratamentoRESUMO
Rituximab/chemotherapy relapsed and refractory B cell lymphoma patients have a poor overall prognosis, and it is urgent to develop novel drugs for improving the therapy outcomes. Here, we examined the therapeutic effects of chidamide, a new histone deacetylase (HDAC) inhibitor, on the cell and mouse models of rituximab/chemotherapy resistant B-cell lymphoma. In Raji-4RH/RL-4RH cells, the rituximab/chemotherapy resistant B-cell lymphoma cell lines (RRCL), chidamide treatment induced growth inhibition and G0/G1 cell cycle arrest. The primary B-cell lymphoma cells from Rituximab/chemotherapy relapsed patients were sensitive to chidamide. Interestingly, chidamide triggered the cell death with the activation of autophagy in RRCLs, likely due to the lack of the pro-apoptotic proteins. Based on the RNA-seq and chromatin immunoprecipitation (ChIP) analysis, we identified BTG1 and FOXO1 as chidamide target genes, which control the autophagy and the cell cycle, respectively. Moreover, the combination of chidamide with the chemotherapy drug cisplatin increased growth inhibition on the RRCL in a synergistic manner, and significantly reduced the tumor burden of a mouse lymphoma model established with engraftment of RRCL. Taken together, these results provide a theoretic and mechanistic basis for further evaluation of the chidamide-based treatment in rituximab/chemotherapy relapsed and refractory B-cell lymphoma patients.
Assuntos
Aminopiridinas/uso terapêutico , Autofagia , Benzamidas/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Linfoma de Células B/tratamento farmacológico , Proteínas de Neoplasias/metabolismo , Aminopiridinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Autofagossomos/efeitos dos fármacos , Autofagossomos/metabolismo , Autofagossomos/ultraestrutura , Autofagia/efeitos dos fármacos , Benzamidas/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Proteína Forkhead Box O1/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Linfoma de Células B/patologia , Masculino , Camundongos Nus , Pessoa de Meia-Idade , Recidiva , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genéticaRESUMO
OBJECTIVE: Although benzene is a confirmed environmental carcinogen, the mechanism of its carcinogenicity remains largely unclear. The suggested oncogene, miR-221, is elevated and plays important roles in various tumors, but its role in benzene-induced carcinogenesis remains unknown. METHODS: In the present study, we constructed hydroquinone (HQ, a representative metabolite of benzene with biological activity)-transformed malignant cell line (16HBE-t) and analyzed the level of miR-221 in it with qRT-PCR. Exosomes from 16HBE-t cells incubated with or without an miR-221 inhibitor were isolated by ultracentrifugation, characterized by transmission electron microscopy and laser scanning confocal microscope, and then transfected into 16HBE cells. The effects of exosomal miR-221 on apoptosis induced by HQ in recipient cells were determined using flow cytometry. RESULTS: The amount of miR-221 in 16HBE-t was significantly increased compared with controls. When recipient cells ingested exosomes derived from 16HBE-t, miR-221 was increased, and apoptosis induced by HQ was inhibited. Blocking miR-221 in 16HBE-t using an inhibitor did not significantly alter miR-221 or apoptosis in recipient cells. CONCLUSION: Exosomal miR-221 secreted by 16HBE-t inhibits apoptosis induced by HQ in normal recipient cells.
Assuntos
Apoptose , Exossomos , Hidroquinonas , MicroRNAs , Brônquios/citologia , Linhagem Celular Transformada , Células Epiteliais , HumanosRESUMO
The gut microbiota plays a critical role in obesity and lipid metabolism disorder. Chokeberry (Aronia melanocarpa L.) are rich in polyphenols with various physiological and pharmacological activities. We determined serum physiological parameters and fecal microbial components by using related kits, liquid chromatography-mass spectrometry (LC-MS) and 16S rRNA gene sequencing every 10 days. Real-time PCR analysis was used to measure gene expression of bile acids (BAs) and lipid metabolism in liver and adipose tissues. We analyzed the effects of different Chokeberry polyphenol (CBPs) treatment time on obesity and lipid metabolism in high fat diet (HFD)-fed rats. The results indicated that CBPs treatment prevents obesity, liver steatosis and improves dyslipidemia in HFD-fed rats. CBPs modulated the composition of the gut microbiota with the extended treatment time, reducing the Firmicutes/Bacteroidetes ratio (F/B ratio) and increasing the relative abundance of Bacteroides, Prevotella, Akkermansia and other bacterial species associated with anti-obesity properties. We found that CBPs treatment gradually decreased the total BAs pool and particularly reduced the relative content of cholic acid (CA), deoxycholic acid (DCA) and enhanced the relative content of chenodeoxycholic acid (CDCA). These changes were positively correlated Bacteroides, Prevotella and negatively correlated with Clostridium, Eubacterium, Ruminococcaceae. In liver and white adipose tissues, the gene expression of lipogenesis, lipolysis and BAs metabolism were regulated after CBPs treatment in HFD-fed rats, which was most likely mediated through FXR and TGR-5 signaling pathway to improve lipid metabolism. In addition, the mRNA expression of PPARγ, UCP1 and PGC-1α were upregulated markedly in interscapular brown adipose tissue (iBAT) after CBPs treatment. We confirmed that CBPs could reduce the body weight of HFD-fed rats by accelerating energy homeostasis and thermogenesis in iBAT. Finally, the fecal microbiota transplantation (FMT) experiment results demonstrated that FMT from CBPs-treated rats failed to reduce the weight of HFD-fed rats. However, FMT from CBPs-treated rats improved dyslipidemia and reshaped gut microbiota in HFD-fed rats. In conclusion, CBPs treatment improved obesity and complications by regulating gut microbiota in HFD-fed rats. The gut microbiota plays an important role in BAs metabolism after CBPs treatment, and BAs have therefore emerged as major effectors in microbe-host signaling events that influence host lipid metabolism, energy metabolism and thermogenesis.
RESUMO
SETD2, the histone H3 lysine 36 methyltransferase, previously identified by us, plays an important role in the pathogenesis of hematologic malignancies, but its role in myelodysplastic syndromes (MDSs) has been unclear. In this study, low expression of SETD2 correlated with shortened survival in patients with MDS, and the SETD2 levels in CD34+ bone marrow cells of those patients were increased by decitabine. We knocked out Setd2 in NUP98-HOXD13 (NHD13) transgenic mice, which phenocopies human MDS, and found that loss of Setd2 accelerated the transformation of MDS into acute myeloid leukemia (AML). Loss of Setd2 enhanced the ability of NHD13+ hematopoietic stem and progenitor cells (HSPCs) to self-renew, with increased symmetric self-renewal division and decreased differentiation and cell death. The growth of MDS-associated leukemia cells was inhibited though increasing the H3K36me3 level by using epigenetic modifying drugs. Furthermore, Setd2 deficiency upregulated hematopoietic stem cell signaling and downregulated myeloid differentiation pathways in the NHD13+ HSPCs. Our RNA-seq and chromatin immunoprecipitation-seq analysis indicated that S100a9, the S100 calcium-binding protein, is a target gene of Setd2 and that the addition of recombinant S100a9 weakens the effect of Setd2 deficiency in the NHD13+ HSPCs. In contrast, downregulation of S100a9 leads to decreases of its downstream targets, including Ikba and Jnk, which influence the self-renewal and differentiation of HSPCs. Therefore, our results demonstrated that SETD2 deficiency predicts poor prognosis in MDS and promotes the transformation of MDS into AML, which provides a potential therapeutic target for MDS-associated acute leukemia.
Assuntos
Anemia Refratária com Excesso de Blastos/patologia , Calgranulina B/fisiologia , Histona-Lisina N-Metiltransferase/deficiência , Histona-Lisina N-Metiltransferase/fisiologia , Leucemia Mieloide Aguda/etiologia , Anemia Refratária com Excesso de Blastos/genética , Anemia Refratária com Excesso de Blastos/metabolismo , Animais , Calgranulina B/biossíntese , Calgranulina B/genética , Transformação Celular Neoplásica , Células Cultivadas , Decitabina/farmacologia , Regulação para Baixo , Regulação Leucêmica da Expressão Gênica , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/patologia , Código das Histonas/efeitos dos fármacos , Histona-Lisina N-Metiltransferase/biossíntese , Histona-Lisina N-Metiltransferase/genética , Proteínas de Homeodomínio/genética , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Síndromes Mielodisplásicas/patologia , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Proteínas de Fusão Oncogênica/genética , Prognóstico , Proteínas Recombinantes/uso terapêutico , Fatores de Tempo , Análise Serial de Tecidos , TranscriptomaRESUMO
The past few years have witnessed rapid advances in the immunotherapies for non-small-cell lung cancer (NSCLC). CIMAvax-EGF is a therapeutic vaccine against lung cancer independently developed by Cuba. It can exert its anti-tumor effect by forming epidermal growth factor (EGF) antibodies to block the binding of EGF to EGF receptor. So far stage both phases â ¡ and â ¢ trials have proved its effectiveness and long-term safety,and phases â ¢ and â £ trials are underway. A deeper understanding of the role of CIMAvax-EGF in NSCLC will accelerate the application of immunotherapy. This article summarizes the recent advances of CIMAvax-EGF R&D and its application in treating NSCLC.
Assuntos
Vacinas Anticâncer/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Fator de Crescimento Epidérmico , Neoplasias Pulmonares/tratamento farmacológico , Anticorpos , Receptores ErbB , HumanosRESUMO
PURPOSE: To investigate the involvement of activin receptor-like kinase 5 (ALK5) in human Tenon's capsule fibroblasts (HTFs) transdifferentiation and fibrosis. METHODS: (1) Cultured HTFs were treated with transforming growth factor beta 1 (TGF-ß1) at different concentrations for different durations, mRNA expression of ALK5 and plasminogen activator inhibitor-1 (PAI-1) was measured by quantitative polymerase chain reaction (PCR) while protein expression of ALK5, α-smooth muscle actin (α-SMA), and extracellular matrix deposition including fibronectin (FN) and collagen I (Col1) was assessed by western blot. HTFs with or without TGF-ß1 were also treated with an ALK5 activity inhibitor, SB-431542, and fibrosis-related genes were assessed. (2) HTFs were transduced with ALK5 lentivirus (ALK5-OE group) or empty lentivirus (NC-OE) with or without the treatment of SB-431542. Protein expression of ALK5, α-SMA, FN, and Col1 was evaluated. (3) HTFs in the ALK5-OE group and NC-OE group were subjected to a scratch-wound assay and their migratory activities assessed. RESULTS: (1) TGF-ß1, in a concentration-dependent manner, upregulated ALK5 and PAI-1 expressions in the HTFs, which peaked between 24 and 36 h. These changes were associated with increases in protein levels of FN, Col1, and α-SMA. These TGF-ß1 effects were blocked by the ALK5 inhibitor SB-431542. (2) Similarly, overexpression of ALK5 by lentiviral vector significantly increased protein expression of α-SMA, FN, and Col1. Addition of TGF-ß1 to the ALK5-OE cells did not produce additional expression of any of the marker proteins. The upregulation of extracellular matrix and α-SMA can be reduced by SB-431542. (3) In ALK5-OE group, HTFs migration was significantly increased compared with normal control and TGF-ß1 could still promote ALK5-OE cells migration. CONCLUSIONS: Our findings suggest that ALK5 is an important mediator of HTFs fibrosis. ALK5 is a potential therapeutic target to suppress scar formation after filtration surgery.
Assuntos
Fibroblastos/patologia , Regulação da Expressão Gênica , Glaucoma/genética , Proteínas Serina-Treonina Quinases/genética , RNA Mensageiro/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Cápsula de Tenon/patologia , Adulto , Western Blotting , Transdiferenciação Celular , Células Cultivadas , Fibroblastos/metabolismo , Fibrose/genética , Fibrose/metabolismo , Fibrose/patologia , Glaucoma/metabolismo , Glaucoma/patologia , Humanos , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Proteínas Serina-Treonina Quinases/biossíntese , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/biossíntese , Cápsula de Tenon/metabolismoRESUMO
Oleuropein (OLE) is a natural secoiridoid that is derived from Olea europaea. OLE possesses cardioprotective effects in experimental models of hypertension, myocardial infarction, atherosclerosis and hyperlipidaemia. In the present study, the effects of OLE on experimental autoimmune myocarditis (EAM) were evaluated. EAM in rats were induced by subcutaneous injections of porcine cardiac myosin. Cardiac function parameters, myocardial pathology, myocardial inflammatory cell infiltration and nuclear factor kappa-B (NF-κB) expression were measured. Our data showed that the postmyocarditis rats exhibited increased left ventricular end systolic diameters, left ventricular end diastolic diameters, left ventricular end-diastolic pressures (LVEDP), and decreased ejection fractions. However, OLE significantly suppressed these changes in EAM rats. Histological analysis revealed that myosin induced miliary foci of discolouration on endocardial surfaces and extensive myocardial injuries with inflammatory cell infiltration were significantly improved by OLE therapy. A definitive positive correlation between the histological scores and LVEDP was observed. Moreover, OLE inhibited CD4+, CD8+ cells and macrophage infiltration in myocardium and decreased the serum production of tumour necrosis factor-a (TNF-a), interleukin-1ß (IL-1ß) and IL-6 in EAM rats. Expectedly, the myocardial levels of NF-κB p65, p-IκBa, IKKa were significantly attenuated by OLE, indicating the inhibitory effects of OLE on the NF-κB pathway. Furthermore, OLE decreased the myocardial expressions of phosphorylated-p38 MAPK, phosphorylated-ERK, and did not change the levels of p38 MAPK and ERK in EAM rats. Collectively, our results suggest that OLE effectively prevents the development of myocarditis, at least in part, by inhibiting the MAPKs and NF-κB mediated inflammatory responses.
Assuntos
Doenças Autoimunes/prevenção & controle , Cardiotônicos/farmacologia , Iridoides/farmacologia , Miocardite/prevenção & controle , Animais , Doenças Autoimunes/induzido quimicamente , Doenças Autoimunes/metabolismo , Doenças Autoimunes/fisiopatologia , Miosinas Cardíacas , Citocinas/sangue , Modelos Animais de Doenças , Glucosídeos Iridoides , Masculino , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Miocardite/induzido quimicamente , Miocardite/metabolismo , Miocardite/fisiopatologia , Miocárdio/citologia , Miocárdio/metabolismo , NF-kappa B/metabolismo , Ratos Endogâmicos Lew , Transdução de Sinais/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
PURPOSE: To introduce several new ocular biomechanical parameters for comparison between keratoconic and normal eyes using an analysis method based on corneal dynamic deformation video recorded by corneal visualization Scheimpflug technology (Corvis ST; Oculus Optikgeräte GmbH, Wetzlar, Germany). METHODS: This comparative study comprised 52 keratoconic eyes of 43 patients with keratoconus and 52 normal eyes of 52 controls. An analysis method (PolyU [Labview 2009; National Instrument, Austin, TX]) was developed to introduce several new ocular biomechanical parameters and to compare the difference between keratoconic and normal eyes. The repeatability of the new parameters measurement was evaluated and compared with the Corvis ST measurement. Receiver operating characteristic curves were used to establish a cutoff value for the new biomechanical parameters. RESULTS: Intraclass correlation coefficients of the deformation amplitude, peak distance, corneal concave radius of curvature, maximum deformation area, maximum corneal inward velocity and outward velocity (Vin, max and Vout, max) were high in both the keratoconic and normal eyes (all intraclass correlation coefficients > 0.75). The measurement agreement of the PolyU analysis method and Corvis ST was good. Most of the biomechanical parameters of patients with keratoconus were significantly different from those of the controls. In the receiver operating characteristic analysis, the Vin, max was the best predictive parameter with an area under the curve of 0.79. CONCLUSIONS: The corneal deformation video recorded by the Corvis ST provides useful information for the study of ocular biomechanics. Most of the new ocular biomechanical parameters were significantly different between keratoconic and normal eyes. Further research is needed to develop more comprehensive clinical applications with these new ocular biomechanical parameters.
Assuntos
Córnea/fisiopatologia , Diagnóstico por Imagem/métodos , Técnicas de Diagnóstico Oftalmológico , Elasticidade/fisiologia , Ceratocone/fisiopatologia , Adolescente , Adulto , Fenômenos Biomecânicos/fisiologia , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Gravação em Vídeo , Adulto JovemRESUMO
PURPOSE OF THE STUDY: To explore the characteristic of connective tissue growth factor (CTGF) on the phenotype transition, extracellular matrix (ECM) synthesis and proliferation of human Tenon's capsule fibroblasts (HTFs). MATERIALS AND METHODS: HTFs were obtained from patients during cataract surgery and induced by CTGF (1 to 100 µg/L). Western blot and immunofluorescence were performed to observe the expression of alpha smooth muscle actin (α-SM-actin) protein. The levels of mRNAs were quantified by real-time PCR. Col I and FN expression at both protein and RNA levels were tested after induction by CTGF and transforming growth factor ß (TGF-ß), respectively. Statistical significance was assumed if p < 0.05. RESULTS: CTGF upregulated the expression of α-SM-actin in cultured HTFs. Its maximum effect at protein level attained under the optimal concentration of 50 µg/L at the peak time of 48 hours, though still weaker than the effect of TGF-ß1 (10 µg/L, p < 0.05). The expression of Col I and FN at both protein and mRNA levels was elevated by the induction of CTGF (50 µg/L) (p < 0.01) and TGF-ß1 (10 µg/L) (p < 0.05), while CTGF (50 µg/L) showed a greater effect than the latter (p < 0.05). CTGF (1 to100 µg/L) increased the proliferation of HTFs significantly (p < 0.05). CONCLUSIONS: CTGF induced the phenotype transition of HTFs individually and significantly promoted their proliferation. Moreover, it promoted ECM synthesis, thus demonstrating its role as a crucial factor in fibrosis. Thus, CTGF could potentially be a safer and more efficient target than TGF-ß at suppressing scar formation after filtering surgery.
Assuntos
Fator de Crescimento do Tecido Conjuntivo/fisiologia , Fibroblastos/citologia , Miofibroblastos/citologia , Cápsula de Tenon/citologia , Actinas/genética , Actinas/metabolismo , Idoso , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Células Cultivadas , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Fator de Crescimento do Tecido Conjuntivo/farmacologia , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/fisiologia , Feminino , Fibroblastos/efeitos dos fármacos , Fibronectinas/genética , Fibronectinas/metabolismo , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Miofibroblastos/efeitos dos fármacos , Fenótipo , RNA Mensageiro/metabolismo , Cápsula de Tenon/efeitos dos fármacos , Fator de Crescimento Transformador beta/farmacologia , Fator de Crescimento Transformador beta/fisiologiaRESUMO
OBJECTIVE: To evaluate the clinical value of endoscopic hemostasis in acute nonvariceal upper gastrointestinal bleeding. METHODS: This was a retrospective study of 223 patients with acute nonvariceal upper gastrointestinal bleeding and receiving endoscopic treatment who were admitted to Peking University Third Hospital between January 1, 2005 and December 31, 2009. Endoscopic diagnosis, lesion location, lesion size and stigmata of recent hemorrhage were recorded. Stigmata of recent hemorrhage was evaluated by Forrest classification. All the patients were scored by Rockall for rehemorrhage and death risk. Endoscopic treatment comprised medicine aspersing, injection, thermocoagulation, clips and combination therapy. RESULTS: Hemorrhagic lesions of Forrest Ia-IIb were selected for endoscopic treatment, in which 214 patients(96.0%,214/223) underwent first endoscopic hemostasis successfully, while rehemorrhage occurred in 34 patients(15.2%,34/223). The first hemostatic achievement rate was 80.7%(180/223). And 17 patients received surgery or died because of endoscopic treatment failure. Total effective rate of endoscopic treatment was 92.4%(206/223). The total effective rates of Rockall high-risk group, moderate-risk group and low-risk group were 80%(40/50),95.7%(156/163) and 100%(10/10) respectively. The effective rates of epinephrine injection and combination therapy were 92.6%(137/148) and 77.6%(38/49) respectively. The rehemorrgagic rates of epinephrine injection and combination therapy were 14.2%(21/148) and 18.4%(9/49) respectively. The proportion of combination therapy in the second attempt at endoscopic therapy was 65.0%(13/20), and the achievement rate was 61.5%(8/13). CONCLUSION: Endoscopic hemostatic therapy is the preferred emergency treatment in acute nonvariceal upper gastrointestinal bleeding. Endoscopic treatment should be used for emorrhagic lesions of Forrest Ia-IIb. Endoscopic therapy could be completely hemostatic in Rockall low-risk group. Rockall score directly influences endoscopic treatment effectiveness.
Assuntos
Úlcera Duodenal/complicações , Hemorragia Gastrointestinal/terapia , Hemostase Endoscópica/métodos , Úlcera Gástrica/complicações , Adulto , Idoso , Feminino , Hemorragia Gastrointestinal/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
OBJECTIVE: To determine risk factors associated with failure of endoscopic therapy in acute non-variceal upper gastrointestinal bleeding (ANVUGIB ). METHODS: This was a retrospective cohort study of 223 patients admitted to Peking University Third Hospital between 1 January 2005 and 31 December 2009, with acute non-variceal upper gastrointestinal bleeding. Data on clinical presentation, laboratory test, endoscopic findings, and treatment outcomes were collected. Risk factors for treatment failure were identified using multivariable Logistic regression with backward selection. RESULTS: Therapeutic failure rate was 19.3%(43/223). In univariate analysis, the two groups had significant difference in age, history of gastrointestinal bleeding, ASA, shock, haemoglobin level, Hct, PLT, time of endoscopic treatment, gastric ulcer, duodenal ulcer, lesion size and active spurting of blood. Multivariate Logistic regression analysis revealed that shock [odds ratio (OR) 3.058, 95% confidence interval (CI) 1.295-7.221], history of gastrointestinal bleeding (OR 2.809, 95% CI 1.207-6.539), PLT>100×109/L (OR 0.067, 95% CI 0.009-0.497), active spurting of blood (OR 10.390, 95% CI 2.835-38.080) and lesion size≥2.0 cm (OR 7.111, 95% CI 1.628-31.069) were risk factors associated with failure of endoscopic therapy. The number of comorbidities>1 (OR 9.580,95%CI 1.383-66.390) and active spurting of blood (OR 9.971, 95% CI 1.820-54.621) were factors related with need for surgical intervention or death. CONCLUSION: Patients with shock, history of gastrointestinal bleeding, PLT<100×109/L, active spurting of blood and large lesion size, have high risks for continued bleeding or rebleeding after endoscopic treatment. These patients may be more likely to benefit from aggressive post-hemostasis care.
Assuntos
Endoscopia Gastrointestinal/métodos , Hemorragia Gastrointestinal/cirurgia , Hemostase Endoscópica , Úlcera Péptica/complicações , Doença Aguda , Adulto , Idoso , Estudos de Coortes , Feminino , Hemorragia Gastrointestinal/etiologia , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento , Trato Gastrointestinal Superior/cirurgiaRESUMO
OBJECTIVE: To study the changes of neutral alpha-glucoside activity in the epididymis of heroin-dependent and heroin-withdrawal rats, and to investigate the effects of intervention with purine nucleotide (AMP and GMP). METHODS: Eighty Wistar rats were randomly divided into 8 groups of equal number, control, nucleotide, heroin, heroin + nucleotide, 3 d withdrawal, 9 d withdrawal, 3 d nucleotide (nucleotide administrated for 3 days after heroin withdrawal) and 9 d nucleotide (nucleotide administrated for 9 days after heroin withdrawal). Neutral alpha-glucosidase activity in the epididymis was detected in each group of rats. RESULTS: Compared with the control group, neutral alpha-glucoside activity was markedly decreased in the heroin group (P < 0.05), and also in the 3 d and 9 d withdrawal groups, although with no significant differences (P > 0.05). CONCLUSION: Heroin reduces neutral alpha-glucoside activity in the epididymis of rats, and this effect may continue for some time after drug withdrawal, while purine nucleotide can keep neutral alpha-glucosidase activity in a relatively stable state.