RESUMO
PURPOSE: Minimally invasive glaucoma surgery is safer and effective surgical modality for patients with glaucoma. To compare the effect of axial length (AL) on the surgical outcomes of combined cataract surgery and ab interno trabeculotomy (phaco-LOT), a retrospective, non-randomized comparative study was performed. METHODS: In total, 458 eyes of 458 open-angle glaucoma patients who underwent phaco-LOT and were followed-up without any intervention for at least 6 months were enrolled. All were divided into a long-AL group (AL ≥ 26.0 mm, 123 eyes) and a not-long-AL group (AL < 26.0 mm, 335 eyes). The principal outcomes were the changes in intraocular pressure (IOP) and medication scores. We also sought a correlation between postoperative IOP spike and hyphema. RESULTS: Significant postoperative reductions in IOP and medication scores were apparent in all subjects. The IOP reductions were significant at all timepoints in the not-long-AL group, but not until 1 month postoperatively in the long-AL group, and the IOP change was significantly lower in the long-AL group from postoperative day 1 to 3 months. On subanalysis of subjects by age, the microhook used, the pre-operative IOP, and the medication score, a significantly higher incidence of IOP spike was observed in the long-AL group in weeks 1 and 2 (both p < 0.05), but this did not correlate with hyphema status, implying that a different mechanism was in play. CONCLUSION: Phaco-LOT was effective regardless of AL, but the postoperative IOP decrease was lower and the early postoperative incidence of IOP spike was higher in long-AL eyes.
Assuntos
Catarata , Glaucoma de Ângulo Aberto , Glaucoma , Hipotensão Ocular , Trabeculectomia , Humanos , Glaucoma de Ângulo Aberto/complicações , Glaucoma de Ângulo Aberto/cirurgia , Hifema/etiologia , Hifema/cirurgia , Estudos Retrospectivos , Trabeculectomia/efeitos adversos , Glaucoma/cirurgia , Pressão Intraocular , Malha Trabecular/cirurgia , Hipotensão Ocular/cirurgia , Catarata/complicações , Resultado do TratamentoRESUMO
Cardiac computed tomography (CT) is useful for the screening of coronary artery stenosis, and extracellular volume fraction (ECV) analysis by CT using new dedicated software is now available. Here, we evaluated the utility of ECV analysis using cardiac CT to predict patient prognosis in cases with dilated cardiomyopathy (DCM). We analyzed 70 cases with DCM and cardiac computed tomography (CT) with available late-phase images. We evaluated the ECV of the left ventricular myocardium (LVM) using commercially available software (Ziostation 2, Ziosoft Inc, Japan). ECV on LVM was 33.96 ± 5.04%. Major adverse cardiac events (MACE) occurred in 21 cases (30%). ECV of the LVM on CT, endo-systolic volume, and rate of significant valvular disease were significantly higher in cases with MACE than in those without (37.16 ± 5.91% vs. 32.59 ± 3.95%, 194 ± 109 vs. 138 ± 78 ml and 57% vs. 20%, all P values < 0.05). LVEF was significantly lower in cases with MACE than in those without (23 ± 8 vs. 31 ± 11%, P = 0.0024). The best cut-off value of ECV on LVM for prediction of MACE was 32.26% based on receiver operating characteristics analysis. Cases with ECV ≥ 32.26% had significantly higher MACE based on Kaplan-Meier analysis (P = 0.0032). Only ECV on LVM was an independent predictor of MACE based on a multivariate Cox proportional hazards model (P = 0.0354). Evaluation of ECV on LVM by CT is useful for predicting MACE in patients with DCM.
Assuntos
Cardiomiopatia Dilatada , Humanos , Cardiomiopatia Dilatada/diagnóstico por imagem , Imagem Cinética por Ressonância Magnética/métodos , Valor Preditivo dos Testes , Miocárdio , Prognóstico , Tomografia Computadorizada por Raios XRESUMO
Recently, myocardial extracellular volume (ECV) analysis has been measurable on computed tomography (CT) using new software. We evaluated the use of cardiac CT to estimate the myocardial ECV of left ventricular (LV) myocardium (LVM) to predict reverse remodeling (RR) in cases of atrial fibrillation (AF) after catheter ablation (CA). Four hundred and seven patients underwent CA for AF in our institution from April 2014 to Feb 2021. Of these, 33 patients (8%) with an LVEF ≤ 50% and who had undergone CT were included in our study. We estimated the LVM ECV using commercial software to analyze the CT data. RR was defined as an improvement in LVEF to > 50% after CA. LVEF increased to > 50% in 24 patients (73%) after CA. In all 24 patients, LVM ECV, LV end-diastolic and end-systolic volumes (LVEDV and LVESV), and the n-terminal fragment of pro-B-type natriuretic peptide (NT-proBNP) were significantly lower than in the other nine patients (P = 0.0037, 0.0273, 0.0443, and < 0.0001). On receiver operating characteristic curve analysis, the best cut-off of ECV, LVEDV, LVESV and NT-proBNP for the prediction of RR were 37.73%, 120 mL, 82 mL, and 1267 pg/mL, respectively. We newly defined the ENL (ECV, NT-proBNP, and LVEDV) score as the summed score for the presence or absence (1 or 0; maximum score = 3) of ECV, NT-proBNP, and LVEDV values less than or equal to each best cut-off value, and found that this score gave the highest area under the curve for the prediction of RR (0.9583, P < 0.0001). The ENL score may be useful for predicting RR in patients with AF undergoing CA.
Assuntos
Fibrilação Atrial , Ablação por Cateter , Humanos , Fibrilação Atrial/diagnóstico por imagem , Fibrilação Atrial/cirurgia , Volume Sistólico , Peptídeo Natriurético Encefálico , Miocárdio , Fragmentos de Peptídeos , Ablação por Cateter/métodosRESUMO
Low body mass index (BMI) is a predictor of adverse events in patients with ST-elevated myocardial infarction (STEMI) in Western countries. Because the average BMI of Asians is significantly lower than that of the Western population, the appropriate cut-off BMI value and its role in long-term mortality are unclear in Asian patients. Between January 2006 and December 2017, 1215 patients who underwent percutaneous coronary intervention (PCI) for acute STEMI and were alive at discharge (mean age, 67.7 years; male, 75.4%) were evaluated. The cut-off BMI value, which could predict all-cause mortality within 10 years, was detected using a survival classification and regression tree (CART) model. The causes of death according to the BMI value were evaluated in each group. Based on the CART model, the patients were divided into three groups (BMI < 18 kg/m2: 54 patients, 18 kg/m2 ≤ BMI ≤ 20 kg/m2: 109 patients, and BMI > 20 kg/m2: 1052 patients). The BMI decreased with age; with an increased BMI, patients with dyslipidemia, diabetes mellitus, and smoking habit increased. During the study period (median, 4.9 years), 194 patients (26.8%) died (cardiac death, 59 patients; non-cardiac death, 135 patients). All-cause mortality was more frequent as the BMI decreased (BMI < 18 kg/m2; 72.8%, 18 kg/m2 ≤ BMI ≤ 20 kg/m2; 40.5%, and BMI > 20 kg/m2; 22.8%; log-rank p < 0.001). Non-cardiac deaths were more frequent than cardiac deaths in all groups, and the dominance of non-cardiac death was highest in the lowest BMI group. Cut-off BMI values of 18 kg/m2 and 20 kg/m2 can predict long-term mortality after PCI in Asian STEMI survivors, whose cut-off value is lower than that in the Western populations. The main causes of death in this cohort differed according to the BMI values.
Assuntos
Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST , Idoso , Algoritmos , Povo Asiático , Índice de Massa Corporal , Humanos , Aprendizado de Máquina , Masculino , Intervenção Coronária Percutânea/efeitos adversos , Sistema de Registros , Fatores de Risco , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia , Sobreviventes , Resultado do TratamentoRESUMO
BACKGROUND: The atrial defibrillation threshold (ADFT) for internal cardioversion is theoretically related to the critical mass for sustaining atrial fibrillation (AF). OBJECTIVE: This study aimed to investigate the association of ADFT for internal cardioversion with the outcome of catheter ablation for non-paroxysmal AF (non-PAF). METHODS: We included 368 consecutive patients who underwent first-time catheter ablation for non-PAF. Based on the degree of ADFT recorded by the internal cardioversion before pulmonary vein isolation, we divided the patients into low ADFT (<20 J) and high ADFT (≥20 J) groups and analysed the association between ADFT and atrial tachyarrhythmia recurrence. RESULTS: There were 234 and 134 patients in the low and high ADFT groups, respectively. Of these, 39 patients (16.7%) and 41 (30.6%) patients, respectively, had atrial tachyarrhythmia recurrence during the 2.6±1.0 year follow-up. The high ADFT group showed a significantly higher atrial tachyarrhythmia recurrence than the low ADFT group (p=0.002). This finding was also noted in patients with long-standing persistent AF (p=0.032) but not in patients with persistent AF (p=0.159). The significant predictors of arrhythmia recurrence on multivariate analysis were high ADFT (p=0.004) and long-standing persistent AF (p=0.011). In multivariate analysis within the long-standing persistent AF group, only ADFT remained a significant risk factor for AF recurrence (p=0.035). CONCLUSIONS: The high ADFT of internal cardioversion was found to be a risk factor for post-catheter ablation recurrence in patients with long-standing persistent AF but not in those with persistent AF.
Assuntos
Fibrilação Atrial , Ablação por Cateter , Veias Pulmonares , Cardioversão Elétrica , Átrios do Coração , Humanos , Recidiva , Resultado do TratamentoRESUMO
Hippo signaling is modulated in response to cell density, external mechanical forces, and rigidity of the extracellular matrix (ECM). The Mps one binder kinase activator (MOB) adaptor proteins are core components of Hippo signaling and influence Yes-associated protein 1 (YAP1) and transcriptional co-activator with PDZ-binding motif (TAZ), which are potent transcriptional regulators. YAP1/TAZ are key contributors to cartilage and bone development but the molecular mechanisms by which the Hippo pathway controls chondrogenesis are largely unknown. Cartilage is rich in ECM and also subject to strong external forces - two upstream factors regulating Hippo signaling. Chondrogenesis and endochondral ossification are tightly controlled by growth factors, morphogens, hormones, and transcriptional factors that engage in crosstalk with Hippo-YAP1/TAZ signaling. Here, we generated tamoxifen-inducible, chondrocyte-specific Mob1a/b-deficient mice and show that hyperactivation of endogenous YAP1/TAZ impairs chondrocyte proliferation and differentiation/maturation, leading to chondrodysplasia. These defects were linked to suppression of SOX9, a master regulator of chondrogenesis, the expression of which is mediated by TEAD transcription factors. Our data indicate that a MOB1-dependent YAP1/TAZ-TEAD complex functions as a transcriptional repressor of SOX9 and thereby negatively regulates chondrogenesis.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Osteocondrodisplasias/genética , Fosfoproteínas/metabolismo , Fatores de Transcrição SOX9/metabolismo , Animais , Western Blotting , Técnicas de Cultura de Células , Proteínas de Ciclo Celular , Diferenciação Celular/genética , Proliferação de Células/genética , Condrócitos/metabolismo , Condrogênese/genética , Imunoprecipitação da Cromatina , Regulação da Expressão Gênica , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos , Osteocondrodisplasias/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais , Transativadores , Proteínas de Sinalização YAPRESUMO
Acorn worms, also known as enteropneust (literally, 'gut-breathing') hemichordates, are marine invertebrates that share features with echinoderms and chordates. Together, these three phyla comprise the deuterostomes. Here we report the draft genome sequences of two acorn worms, Saccoglossus kowalevskii and Ptychodera flava. By comparing them with diverse bilaterian genomes, we identify shared traits that were probably inherited from the last common deuterostome ancestor, and then explore evolutionary trajectories leading from this ancestor to hemichordates, echinoderms and chordates. The hemichordate genomes exhibit extensive conserved synteny with amphioxus and other bilaterians, and deeply conserved non-coding sequences that are candidates for conserved gene-regulatory elements. Notably, hemichordates possess a deuterostome-specific genomic cluster of four ordered transcription factor genes, the expression of which is associated with the development of pharyngeal 'gill' slits, the foremost morphological innovation of early deuterostomes, and is probably central to their filter-feeding lifestyle. Comparative analysis reveals numerous deuterostome-specific gene novelties, including genes found in deuterostomes and marine microbes, but not other animals. The putative functions of these genes can be linked to physiological, metabolic and developmental specializations of the filter-feeding ancestor.
Assuntos
Cordados não Vertebrados/genética , Evolução Molecular , Genoma/genética , Animais , Cordados não Vertebrados/classificação , Sequência Conservada/genética , Equinodermos/classificação , Equinodermos/genética , Família Multigênica/genética , Filogenia , Transdução de Sinais , Sintenia/genética , Fator de Crescimento Transformador betaRESUMO
Mps One Binder Kinase Activator (MOB)1A/1B are core components of the Hippo pathway that coactivate large tumor suppressor homolog (LATS) kinases. Mob1a/1b double deficiency in mouse liver (LMob1DKO) results in hyperplasia of oval cells and immature cholangiocytes accompanied by inflammatory cell infiltration and fibrosis. More than half of mutant mice die within 3 wk of birth. All survivors eventually develop liver cancers, particularly combined hepatocellular and cholangiocarcinomas (cHC-CCs) and intrahepatic cholangiocellular carcinomas (ICCs), and die by age 60 wk. Because this phenotype is the most severe among mutant mice lacking a Hippo signaling component, MOB1A/1B constitute the critical hub of Hippo signaling in mammalian liver. LMob1DKO liver cells show hyperproliferation, increased cell saturation density, hepatocyte dedifferentiation, enhanced epithelial-mesenchymal transition and cell migration, and elevated transforming growth factor beta(TGF-ß)2/3 production. These changes are strongly dependent on Yes-Associated Protein-1 (Yap1) and partially dependent on PDZ-binding motif (Taz) and Tgfbr2, but independent of connective tissue growth factor (Ctgf). In human liver cancers, YAP1 activation is frequent in cHC-CCs and ICCs and correlates with SMAD family member 2 activation. Drug screening revealed that antiparasitic macrocyclic lactones inhibit YAP1 activation in vitro and in vivo. Targeting YAP1/TAZ with these drugs in combination with inhibition of the TGF-ß pathway may be effective treatment for cHC-CCs and ICCs.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias dos Ductos Biliares/patologia , Carcinogênese/metabolismo , Colangiocarcinoma/patologia , Neoplasias Hepáticas/patologia , Fosfoproteínas/metabolismo , Fatores de Transcrição/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Aciltransferases , Animais , Neoplasias dos Ductos Biliares/metabolismo , Linhagem Celular Tumoral , Colangiocarcinoma/metabolismo , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Transição Epitelial-Mesenquimal , Genes Supressores de Tumor , Humanos , Hiperplasia/genética , Hiperplasia/patologia , Peptídeos e Proteínas de Sinalização Intracelular , Fígado/patologia , Neoplasias Hepáticas/metabolismo , Camundongos , Camundongos Knockout , Camundongos Nus , Fosfoproteínas/genética , Proteínas Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas de Sinalização YAPRESUMO
The Hippo signaling pathway is a vital suppressor of tumorigenesis that is often inactivated in human cancers. In normal cells, the Hippo pathway is triggered by external forces such as cell crowding, or changes to the extracellular matrix or cell polarity. Once activated, Hippo signaling down-regulates transcription supported by the paralogous cofactors YAP1 and TAZ. The Hippo pathway's functions in normal and cancer biology have been dissected by studies of mutant mice with null or conditional tissue-specific mutations of Hippo signaling elements. In this review, we attempt to systematically summarize results that have been gleaned from detailed in vivo characterizations of these mutants. Our goal is to describe the physiological roles of Hippo signaling in several normal organ systems, as well as to emphasize how disruption of the Hippo pathway, and particularly hyperactivation of YAP1/TAZ, can be oncogenic.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Fosfoproteínas/genética , Proteínas Serina-Treonina Quinases/genética , Transcrição Gênica , Animais , Polaridade Celular/genética , Matriz Extracelular/genética , Via de Sinalização Hippo , Humanos , Camundongos , Mutação/genética , Transdução de Sinais/genética , Transativadores , Fatores de Transcrição , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional , Proteínas de Sinalização YAPRESUMO
Highly vibrationally excited disulfur S2 in the X3Σg- and a1Δg states has been detected in the gaseous mixture of O3 and OCS irradiated with light at 266 nm. Generation of CO2 in the reaction system has been reported; however, no direct detection of sulfur atoms (S(3P) and S(1D)) has been made. In the present study, we have employed the two-photon laser-induced fluorescence (2P-LIF) technique to detect S(3P) and S(1D) directly and recorded the time profiles of the atoms at varying pressures of OCS. Kinetic analyses of the profiles show that (i) S(1D) is generated in the O(1D) + OCS reaction and consumed by the S(1D) + OCS reaction, and (ii) S(3P) is mainly generated in the O(1D) + OCS reaction instead of quenching of S(1D) by collisions with OCS and ambient gases. The vibrational levels v = 19 and 10 of the respective electronic states X3Σg- and a1Δg of S2 were detected in the O3/OCS/266 nm system. The two vibrational levels cannot be generated by the available energy of the S(3P) + OCS reaction, giving evidence that S2 in the X3Σg- and a1Δg states are generated by the S(1D) + OCS reaction.
Assuntos
Anomalias dos Vasos Coronários , Doenças Vasculares , Dissecação da Artéria Vertebral , Gravidez , Feminino , Humanos , Dissecação da Artéria Vertebral/diagnóstico por imagem , Dissecação da Artéria Vertebral/etiologia , Anomalias dos Vasos Coronários/diagnóstico por imagem , Doenças Vasculares/diagnóstico por imagem , Doenças Vasculares/etiologiaRESUMO
UNLABELLED: The transcription factor NF-κB is important for HIV-1 transcription initiation in primary HIV-1 infection and reactivation in latently HIV-1-infected cells. However, comparative analysis of the regulation and function of NF-κB in latently HIV-1-infected cells has not been done. Here we show that the expression of IκB-α, an endogenous inhibitor of NF-κB, is enhanced by latent HIV-1 infection via induction of the host-derived factor COMMD1/Murr1 in myeloid cells but not in lymphoid cells by using four sets of latently HIV-1-infected cells and the respective parental cells. IκB-α protein was stabilized by COMMD1, which attenuated NF-κB signaling during Toll-like receptor ligand and tumor necrosis factor alpha treatment and enhanced HIV-1 latency in latently HIV-1-infected cells. Activation of the phosphoinositol 3-kinase (PI3K)-JAK pathway is involved in COMMD1 induction in latently HIV-1-infected cells. Our findings indicate that COMMD1 induction is the NF-κB inhibition mechanism in latently HIV-1-infected cells that contributes to innate immune deficiency and reinforces HIV-1 latency. Thus, COMMD1 might be a double-edged sword that is beneficial in primary infection but not beneficial in latent infection when HIV-1 eradication is considered. IMPORTANCE: HIV-1 latency is a major barrier to viral eradication in the era of combination antiretroviral therapy. In this study, we found that COMMD1/Murr1, previously identified as an HIV-1 restriction factor, inhibits the proteasomal degradation of IκB-α by increasing the interaction with IκB-α in latently HIV-1-infected myeloid cells. IκB-α protein was stabilized by COMMD1, which attenuated NF-κB signaling during the innate immune response and enhanced HIV-1 latency in latently HIV-1-infected cells. Activation of the PI3K-JAK pathway is involved in COMMD1 induction in latently HIV-1-infected cells. Thus, the host-derived factor COMMD1 is beneficial in suppressing primary infection but enhances latent infection, indicating that it may be a double-edged sword in HIV-1 eradication.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , HIV-1/fisiologia , Interações Hospedeiro-Patógeno , Proteínas I-kappa B/metabolismo , Latência Viral , Linhagem Celular , Humanos , Inibidor de NF-kappaB alfaRESUMO
Visible- and red-light responsive vesicles were prepared by incorporating a ruthenium aqua complex having two alkyl chains on tridentate and asymmetrical bidentate ligands (proximal-2: [Ru(C10 tpy)(C10 pyqu)OH2 ](2+) , C10 tpy=4'-decyloxy-2,2';6',2"-terpyridine, C10 pyqu=2-[2'-(6'-decyloxy)-pyridyl]quinoline). The ruthenium complex of proximal-2 with closed alkyl chain geometry and a cylinder-like molecular shape exhibited photoisomerization to distal-2 with an open alkyl chain geometry and a cone-like shape, both in an aqueous solution and in vesicle dispersions. We observed that light irradiation of giant vesicles containing proximal-2 induced diverse morphological changes.
RESUMO
Ion-imaging and dispersed fluorescence spectroscopy are employed for the photodissociation dynamics study of methylamine in the photolysis wavelength range 205-213 nm. The methyl radical product is found to populate a wide range of ro-vibrational states, among which the CH3 fragment generated in the v = 0 state shows a bimodal kinetic energy distribution. The internal energy analysis of the NH2 counterproduct indicates that a lower kinetic energy component, which was observed only with the CH3(v=0) fragment, energetically matches the electronically excited Ã2A1 state. The dispersed fluorescence spectrum, whose band structure is assigned to the Ã2A1 â XÌ2B1 transition, provides evidence of the CH3(v=0) + NH2(Ã2A1) pathway. The branching mechanism of the product pathway is discussed in terms of nuclear dynamics in the long-range region, where the conical intersection between the excited- and ground-state potential energy surfaces can play a significant role.
RESUMO
Membrane fusion between host cells and HIV-1 is the initial step in HIV-1 infection, and plasma membrane fluidity strongly influences infectivity. In the present study, we demonstrated that GUT-70, a natural product derived from Calophyllum brasiliense, stabilized plasma membrane fluidity, inhibited HIV-1 entry, and down-regulated the expression of CD4, CCR5, and CXCR4. Since GUT-70 also had an inhibitory effect on viral replication through the inhibition of NF-κB, it is expected to be used as a dual functional and viral mutation resistant reagent. Thus, these unique properties of GUT-70 enable the development of novel therapeutic agents against HIV-1 infection.
Assuntos
Fármacos Anti-HIV/farmacologia , Cumarínicos/farmacologia , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Internalização do Vírus/efeitos dos fármacos , Antígenos CD4/genética , Linhagem Celular , Regulação para Baixo/efeitos dos fármacos , Interações Hospedeiro-Patógeno , Humanos , Células Jurkat , Fluidez de Membrana/efeitos dos fármacos , Receptores CCR5/genética , Receptores CXCR4/genética , Linfócitos T/efeitos dos fármacos , Linfócitos T/fisiologia , Linfócitos T/virologia , Replicação Viral/efeitos dos fármacosRESUMO
Activated protein C (APC) has an anticoagulant action and plays an important role in blood coagulation homeostasis. In addition to its anticoagulant action, APC is known to have cytoprotective effects, such as anti-apoptotic action and endothelial barrier protection, on vascular endothelial cells and monocytes. However, the effects of APC on DCs have not been clarified. To investigate the effects of APC on human DCs, monocytes were isolated from peripheral blood and DC differentiation induced with LPS. APC significantly inhibited the production of inflammatory cytokines TNF-α and IL-6 during differentiation of immature DCs to mature DCs, but did not inhibit the production of IL-12 and anti-inflammatory cytokine IL-10. Interestingly, treatment with 5 µg/mL, but not 25 µg/mL, of APC significantly enhanced production of IL-10. In addition, protein C, which is the zymogen of APC, did not affect production of these cytokines. On the other hand, flow cytometric analysis of DC's surface molecules indicated that APC does not significantly affect expression of CD83, a marker of mDC differentiation, and the co-stimulatory molecules CD40, CD80 and CD86. These results suggest that APC has anti-inflammatory effects on human DCs and may be effective against some inflammatory diseases in which the pathogenesis involves TNF-α and/or IL-6 production.
Assuntos
Células Dendríticas/imunologia , Proteína C/imunologia , Diferenciação Celular , Células Cultivadas , Células Dendríticas/citologia , Humanos , Interleucina-10/imunologia , Interleucina-12/imunologia , Interleucina-6/imunologia , Monócitos/citologia , Monócitos/imunologiaRESUMO
Radioimmunotherapy (RIT) is a therapy that combines a radioactive nucleotide with a monoclonal antibody (mAb). RIT enhances the therapeutic effect of mAb and reduces toxicity compared with conventional treatment. The purpose of this review is to summarize the current progress of RIT for treating non-Hodgkin's lymphoma (NHL) based on recent preclinical and clinical studies. The efficacy of RIT targeting the B-lymphocyte antigen cluster of differentiation 20 (CD20) has been demonstrated in clinical trials. Two radioimmunoconjugates targeting CD20, yttrium-90 (90Y)-ibritumomab-tiuxetan (Zevalin) and iodine-131 (131I)-tositumomab (Bexxar), have been approved in the USA Food and Drug Administration (FDA) for treating relapsed/refractory indolent or transformed NHL in 2002 and 2003, respectively. Although these two radioimmunoconjugates are effective and least toxic, they have not achieved popularity due to increasing access to novel therapies and the complexity of their delivery process. RIT is constantly evolving with the identification of novel targets and novel therapeutic strategies using newer radionuclides such as alpha-particle isotopes. Alpha-particles show very short path lengths and high linear energy transfer. These characteristics provide increased tumor cell-killing activities and reduced non-specific bystander responses on normal tissue. This review also discusses reviewed pre-targeted RIT (PRIT) and immuno-positron emission tomography (PET). PRIT potentially increases the dose of radionuclide delivered to tumors while toxicities to normal tissues are limited. Immuno-PET is a molecular imaging tracer that combines the high sensitivity of PET with the specific targeting capability of mAb. Immuno-PET strategies targeting CD20 and other antigens are currently being developed. The theragnostic approach by immuno-PET will be useful in monitoring the treatment response.
RESUMO
Primary effusion lymphoma (PEL) is a malignant B-cell lymphoma attributable to Kaposi sarcoma-associated herpesvirus (KSHV) infection. PEL is characterized by invasive behavior, showing recurrent effusions in body cavities. The clinical outcome and typical prognosis in patients with PEL are poor and potentially lethal. Clarification of the pathogenesis in PEL is urgently needed in order to develop novel therapies. PEL cells generally lack B-cell surface markers, and we therefore hypothesized that the B-cell transcription factor, PAX5, would be down-regulated in PEL. The expression of PAX5 is detected from the pro-B to the mature B-cell stage and is indispensable for the differentiation of B-cells. PAX5 was silenced in PEL cells via its promoter methylation. Up-regulation of PAX5 induced several genes coding for B-cell surface marker mRNA, but not protein level. PAX5 inhibited cell growth via G1 cell cycle arrest. PAX5 bound to RB and increased its protein expression. RB/E2F-regulated genes were significantly down-regulated in microarray analysis and PCR experiments. To elucidate the in vivo role of PAX5, we examined the restoration of PAX5 in a PEL mouse model. The ascites volume and organ invasions were significantly suppressed by PAX5 restoration. Reduction of PAX5 has played a crucial role in the oncogenesis of PEL, and PAX5 is a tumor suppressor in PEL. Targeting PAX5 could represent a novel therapeutic strategy for patients with PEL.