RESUMEN
Coronary atherosclerotic disease is highly prevalent in chronic kidney disease (CKD). Although revascularization improves outcomes, procedural risks are increased in CKD, and unbiased data comparing coronary artery bypass grafting (CABG) and percutaneous intervention (PCI) in CKD are sparse. To compare outcomes of CABG and PCI in stage 3 to 5 CKD, we identified randomized trials comparing these procedures. Investigators were contacted to obtain individual, patient-level data. Ten of 27 trials meeting inclusion criteria provided data. These trials enrolled 3993 patients encompassing 526 patients with stage 3 to 5 CKD of whom 137 were stage 3b-5 CKD. Among individuals with stage 3 to 5 CKD, mortality through 5 years was not different after CABG compared with PCI (hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.67-1.46) or stage 3b-5 CKD (HR 1.29, CI 0.68-2.46). However, CKD modified the impact on survival free of myocardial infarction: it was not different between CABG and PCI for individuals with preserved kidney function (HR 0.97, CI 0.80-1.17), but was significantly lower after CABG in stage 3-5 CKD (HR 0.49, CI 0.29-0.82) and stage 3b-5 CKD (HR 0.23, CI 0.09-0.58). Repeat revascularization was reduced after CABG compared with PCI regardless, of baseline kidney function. Results were limited by unavailability of data from several trials and paucity of enrolled patients with stage 4-5 CKD. Thus, our patient-level meta-analysis of individuals with CKD randomized to CABG versus PCI suggests that CABG significantly reduces the risk of subsequent myocardial infarction and revascularization without affecting survival in these patients.
Asunto(s)
Puente de Arteria Coronaria/estadística & datos numéricos , Enfermedad de la Arteria Coronaria/mortalidad , Infarto del Miocardio/mortalidad , Intervención Coronaria Percutánea/estadística & datos numéricos , Insuficiencia Renal Crónica/complicaciones , Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/cirugía , Humanos , Incidencia , Infarto del Miocardio/prevención & control , Modelos de Riesgos Proporcionales , Ensayos Clínicos Controlados Aleatorios como Asunto , Análisis de SupervivenciaRESUMEN
During the COVID-19 pandemic, institutions developed ventilator allocation models. In one proposed model, neonates compete with adults for ventilators using a scoring system. Points are given for conditions that increase one- and five-year (y) mortality. For example, comparable points were added for adult conditions with mortality of 71.3% and for neonates with moderate or severe bronchopulmonary dysplasia (mod/sBPD). We hypothesized that this model overestimates mortality in neonates with BPD and would penalize these infants unfairly. There was little information available on 1 y and 5 y mortality risk for mod/sBPD. To evaluate this allocation protocol, a retrospective chart review was performed on infants born ≥22 weeks and weighing <1500 g admitted to Rainbow Babies and Children's Hospital in 2015 to identify babies with BPD. The main outcomes were 1 and 5 y mortality. In 2015, 28 infants were diagnosed with mod/s BPD based on NIH 2001 definition; 4 infants had modBPD and 24 had sBPD. All infants (100%) with modBPD survived to 5 y; 2 infants with sBPD died by 1 y (8%) and 22 survived (92%) to 1 y; 3 died (12.5%) by 5 y; and at least 13 survived (54%) to 5 y. Infants with mod/s BPD had lower-than-predicted 1 and 5 y mortality, suggesting the points assigned in the model are too high for these conditions. We believe this model would unfairly penalize these babies.
RESUMEN
Adenoids are part of the MALT. In the present study, we analyzed cell surface markers and cytolytic activity of adenoidal NK (A-NK) cells and compared them with NK cells derived from blood of the same donors (B-NK). NK cells comprised 0.67% (0.4-1.2%) of the total lymphoid population isolated from adenoids. The majority (median=92%) of the A-NK cells was CD56(bright)CD16(-). A-NK cells were characterized by the increased expression of activation-induced receptors. NKp44 was detected on >60%, CD25 on >40%, and HLA-DR on >50% of freshly isolated A-NK cells. Functional assays indicated that the cytotoxic machinery of A-NK is intact, and sensitive target cells are killed via natural cytotoxicity receptors, such as NKG2D. Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1; CD66) expression was up-regulated in 23% (median) of the A-NK cells by IL-2 activation but unchanged in B-NK cells. CEACAM1 inhibited the A-NK killing of target cells. CXCR4 was expressed on more than 40% A-NK cells prior to activation. Its ligand, CXCL12, was found in endothelial cells of the capillaries within the adenoid and in cells of the epithelial lining. In addition, A-NK cells migrated in vitro toward a gradient of CXCL12 in a dose-responsive manner, suggesting a role for this chemokine in A-NK cell recruitment and trafficking. We conclude that the A-NK cells are unique in that they display an activated-like phenotype and are different from their CD16(-) B-NK cell counterparts. This phenotype presumably reflects the chronic interaction of A-NK cells with antigens penetrating the body through the nasal route.
Asunto(s)
Tonsila Faríngea/metabolismo , Movimiento Celular , Supervivencia Celular , Células Asesinas Naturales/metabolismo , Tonsila Faríngea/inmunología , Tonsila Faríngea/patología , Antígenos CD/metabolismo , Antígeno CD56/metabolismo , Moléculas de Adhesión Celular/metabolismo , Quimiocina CXCL12/metabolismo , Niño , Citotoxicidad Inmunológica , Endotelio Vascular/citología , Endotelio Vascular/metabolismo , Proteínas Ligadas a GPI , Humanos , Interleucina-2/metabolismo , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/patología , Subfamilia K de Receptores Similares a Lectina de Células NK , Receptor 2 Gatillante de la Citotoxidad Natural , Fenotipo , Receptores de IgG/metabolismo , Receptores Inmunológicos/metabolismo , Receptores de Células Asesinas NaturalesRESUMEN
BACKGROUND AND OBJECTIVES: CKD patients have high mortality risk after myocardial infarction (MI). An adequate supply of coronary collaterals to the culprit vessel responsible for MI is associated with reduced risks of death and complications. Whether a diminished supply of collaterals contributes to the high risk in CKD patients is uncertain. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Quantitative coronary angiography was performed in a consecutive series of individuals with (n=58) and without (n=165) CKD (estimated GFR <60 ml/min per 1.73 m(2)) who underwent coronary angiography at the time of MI. Collateral supply was analyzed and candidate predictors were assessed in patient-level and individual artery-level models using logistic regression and ordered categorical regression, respectively. RESULTS: There were no significant differences in collateral supply among 58 CKD patients and 165 individuals with preserved renal function. Culprit artery collaterals were present in 25.0% of CKD patients compared with 27.2% of individuals with preserved renal function (P=0.76). The odds of having an adequate supply of culprit vessel collaterals were also not significantly different in individuals with and without CKD, respectively. CKD patients were 2.22-fold more likely to have visible collaterals to the nonculprit vessels in unadjusted analyses. The difference was not significant after correction for percent stenosis and comorbid factors. CONCLUSIONS: Our results do not support an independent association between CKD and diminished collateral supply to either the culprit or nonculprit vessels in MI. Additional studies are warranted to better define associations between myocardial capillary supply, collateral supply, and the full range of human CKD.
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Circulación Colateral , Angiografía Coronaria , Infarto del Miocardio/complicaciones , Infarto del Miocardio/diagnóstico por imagen , Insuficiencia Renal Crónica/complicaciones , Anciano , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND AND OBJECTIVES: In the general population, an early invasive strategy of routine coronary angiography is superior to a conservative strategy of selective angiography in patients who are admitted with unstable angina or non-ST segment elevation myocardial infarction (MI), but the effectiveness of this strategy in individuals with chronic kidney disease (CKD) is uncertain. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a collaborative meta-analysis with data provided by the main authors of identified trials to estimate the effectiveness of early angiography in patients with CKD. The Cochrane, Medline, and EMBASE databases were searched to identify randomized trials that compared invasive and conservative strategies in patients with unstable angina or non-ST MI. Pooled risks ratios were estimated using data from enrolled patients with estimated GFR <60 ml/min per 1.73 m(2). RESULTS: Five randomized trials that enrolled 1453 patients with CKD were included. An early invasive strategy was associated with nonsignificant reductions in all-cause mortality, nonfatal MI, and a composite of death or nonfatal MI. The invasive strategy significantly reduced rehospitalization. CONCLUSIONS: This collaborative study suggests that the benefits of an early invasive strategy are preserved in patients with CKD and that an early invasive approach reduces the risk for rehospitalization and is associated with trends of reduction in the risk for death and nonfatal re-infarction in patients with CKD. Coronary angiography should be considered for patients who have CKD and are admitted with non-ST elevation acute coronary syndromes.
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Angiografía Coronaria , Infarto del Miocardio/diagnóstico por imagen , Infarto del Miocardio/epidemiología , Insuficiencia Renal Crónica/epidemiología , Angina Inestable/diagnóstico por imagen , Angina Inestable/epidemiología , Diagnóstico Precoz , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de RiesgoRESUMEN
As initially described by K. Karre and colleagues in the missing self hypothesis, cells expressing self-MHC class I proteins are protected from NK cells attack. In contrast, reduction in the expression of MHC class I molecules due to viral infection or tumor transformation result in the killing of these "abnormal" cells by NK cells via NK-activating receptors. Thus, NK killing of target cells is determined by both negative signals coming from MHC class I proteins and by positive signals derived from the activating ligands. The bound peptide in MHC class I play an important role in the balanced recognition of NK cells. The peptide stabilizes the MHC complex and interacts directly with the NK inhibitory receptors, thus participating in the determination of the fate of the target cells. In this study we demonstrate that posttranslational modifications such as phosphorylation of the presented peptide altered the ability of NK cells to recognize MHC class I molecules. By using a consensus peptide (QYDDAVYKL) that binds HLA-Cw4 in which different positions in the bound peptide were modified by serine phosphorylation, we observed a reduction in KIR2DL1 binding that led to decreased protection from NK killing. Therefore, it might be possible that alteration in the phosphorylation pattern during tumor transformation or viral infection may result in less inhibition and, consequently, improved NK cell killing.
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Presentación de Antígeno/inmunología , Antígenos HLA-C/metabolismo , Células Asesinas Naturales/inmunología , Oligopéptidos/inmunología , Oligopéptidos/metabolismo , Receptores Inmunológicos/antagonistas & inhibidores , Receptores Inmunológicos/metabolismo , Ácidos/farmacología , Línea Celular Transformada , Pruebas Inmunológicas de Citotoxicidad , Antígenos HLA-C/inmunología , Humanos , Inmunoglobulina G/genética , Células Asesinas Naturales/metabolismo , Ligandos , Receptor 2 Gatillante de la Citotoxidad Natural , Fosforilación , Unión Proteica/inmunología , Procesamiento Proteico-Postraduccional/inmunología , Receptores Inmunológicos/genética , Receptores Inmunológicos/inmunología , Receptores KIR2DL1 , Proteínas Recombinantes de Fusión/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/inmunologíaRESUMEN
Efficient antitumor immune response requires the coordinated function of integrated immune components, but is finally exerted by the differentiated effector tumor-infiltrating lymphocytes (TIL). TIL cells comprise, therefore, an exciting platform for adoptive cell transfer (ACT) in cancer. In this study, we show that the inhibitory carcinoembryonic Ag cell adhesion molecule 1 (CEACAM1) protein is found on virtually all human TIL cells following preparation protocols of ACT treatment for melanoma. We further demonstrate that the CEACAM1 homophilic interactions inhibit the TIL effector functions, such as specific killing and IFN-gamma release. These results suggest that CEACAM1 may impair in vivo the antitumor response of the differentiated TIL. Importantly, CEACAM1 is commonly expressed by melanoma and its presence is associated with poor prognosis. Remarkably, the prolonged coincubation of reactive TIL cells with their melanoma targets results in increased functional CEACAM1 expression by the surviving tumor cells. This mechanism might be used by melanoma cells in vivo to evade ongoing destruction by tumor-reactive lymphocytes. Finally, CEACAM1-mediated inhibition may hinder in many cases the efficacy of TIL ACT treatment of melanoma. We show that the intensity of CEACAM1 expression on TIL cells constantly increases during ex vivo expansion. The implications of CEACAM1-mediated inhibition of TIL cells on the optimization of current ACT protocols and on the development of future immunotherapeutic modalities are discussed.
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Antígenos CD/metabolismo , Moléculas de Adhesión Celular/metabolismo , Citotoxicidad Inmunológica , Linfocitos Infiltrantes de Tumor/inmunología , Melanoma/inmunología , Animales , Antígenos CD/análisis , Antígenos CD/genética , Moléculas de Adhesión Celular/análisis , Moléculas de Adhesión Celular/genética , Línea Celular Tumoral , Supervivencia Celular , Técnicas de Cocultivo , Humanos , Linfocitos Infiltrantes de Tumor/química , Melanoma/metabolismo , Ratones , Regulación hacia ArribaRESUMEN
The NK killing activity is regulated by activating and inhibitory NK receptors. All of the activating ligands identified so far are either viral or stress-induced proteins. The class I MHC proteins are the ligands for most of the inhibitory NK receptors. However, in the past few years, several receptors have been identified that are able to inhibit NK killing independently of class I MHC recognition. We have previously demonstrated the existence of a novel inhibitory mechanism of NK cell cytotoxicity mediated by the homophilic carcinoembryonic Ag (CEA)-related cell adhesion molecule 1 (CEACAM1) interactions. In this study, we demonstrate that CEACAM1 also interacts heterophilically with the CEA protein. Importantly, we show that these heterophilic interactions of CEA and CEACAM1 inhibit the killing by NK cells. Because CEA is expressed on a wide range of carcinomas and commonly used as tumor marker, these results represent a novel role for the CEA protein enabling the escape of tumor cells from NK-mediated killing. We further characterize, for the first time, the CEACAM1-CEA interactions. Using functional and binding assays, we demonstrate that the N domains of CEACAM1 and CEA are crucial but not sufficient for both the CEACAM1-CEACAM1 homophilic and CEACAM1-CEA heterophilic interactions. Finally, we suggest that the involvement of additional domains beside the N domain in the heterophilic and homophilic interactions is important for regulating the balance between cis and trans interactions.
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Antígenos CD/fisiología , Antígenos de Diferenciación/fisiología , Antígeno Carcinoembrionario/fisiología , Moléculas de Adhesión Celular/metabolismo , Citotoxicidad Inmunológica/inmunología , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Animales , Antígenos CD/biosíntesis , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos de Diferenciación/biosíntesis , Antígenos de Diferenciación/genética , Antígenos de Diferenciación/metabolismo , Antígeno Carcinoembrionario/genética , Antígeno Carcinoembrionario/metabolismo , Línea Celular Transformada , Línea Celular Tumoral , Células Clonales , Citotoxicidad Inmunológica/genética , Humanos , Ratones , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/metabolismo , Fragmentos de Péptidos/fisiología , Unión Proteica/genética , Unión Proteica/inmunología , Estructura Terciaria de Proteína/genética , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Proteínas Recombinantes de Fusión/fisiología , Eliminación de Secuencia/inmunología , TransfecciónRESUMEN
For a proper development of the placenta, maternal NK cells should not attack the fetal extravillous cytotrophoblast cells. This inhibition of maternal NK cells is partially mediated via the nonclassical MHC class I molecule HLA-G. Recently, we demonstrated that HLA-G forms disulfide-linked high molecular complexes on the surface of transfected cells. In the present study, we demonstrate that HLA-G must associate with beta(2)m for its interaction with CD85J/leukocyte Ig-like receptor-1 (LIR-1). Although HLA-G free H chain complexes are expressed on the surface, they are not recognized and possibly interfere with CD85J/LIR-1 and HLA-G interaction. The formation of these complexes on the cell surface might represent a novel mechanism developed specifically by the HLA-G protein aimed to control the efficiency of the CD85J/LIR-1-mediated inhibition. We also show that endogenous HLA-G complexes are expressed on the cell surface. These findings provide novel insights into the delicate interaction between extravillous cytotrophoblast cells and NK cells in the decidua.