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1.
JACC Clin Electrophysiol ; 7(3): 333-342, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33736753

RESUMO

OBJECTIVES: The goal of this study was to characterize the location and electrophysiological properties of left atrial appendage (LAA) atrial tachycardia (AT). BACKGROUND: The LAA has been reported to be a source of AT and atrial fibrillation (AF) triggers. METHODS: This study retrospectively reviewed ATs mapped to the LAA. Activation and entrainment mapping were used to determine the mechanism and localize each AT circuit/origin. RESULTS: From 2014 to 2018, a total of 45 patients (mean age 65 ± 10 years; 69% male) had 51 LAA ATs: 43 (84%) after AF ablation and 8 de novo (no prior AF). Overall, 50 (98%) were due to localized re-entry/micro-re-entry, whereas only 1 was a focal triggered AT. All 50 micro-re-entrant LAA ATs were mapped to the anterior base (70%) or LAA ridge (30%), and all were successfully treated with focal ablation; no case required LAA isolation. After successful ablation of the initial AT at the LAA base, 23 (62%) of 37 patients with AF also had inducible macro-re-entrant peri-mitral flutter, but none had AF triggers from inside the LAA. CONCLUSIONS: LAA ATs are almost always micro-re-entrant in mechanism and originate from either the anterior base or LAA ridge. AT originating from inside the LAA body is very rare. The anterior and ridge aspects of the LAA-left atrium junction seem to be arrhythmogenic hotspots prone to localized re-entry. These ATs are treatable with focal ablation without LAA isolation but are frequently associated with macro-re-entrant peri-mitral flutter.


Assuntos
Apêndice Atrial , Fibrilação Atrial , Ablação por Cateter , Idoso , Apêndice Atrial/diagnóstico por imagem , Apêndice Atrial/cirurgia , Fibrilação Atrial/epidemiologia , Fibrilação Atrial/cirurgia , Feminino , Humanos , Masculino , Estudos Retrospectivos , Taquicardia
2.
J Clin Immunol ; 41(3): 610-620, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33411154

RESUMO

PURPOSE: Newborn screening (NBS) quantifies T cell receptor excision circles (TREC) and identifies infants with T cell lymphopenia (TCL). This study elucidates the demographics, laboratory characteristics, genetics, and clinical outcomes following live viral vaccine administration of term infants with transient or persistent idiopathic TCL. METHODS: A single-center retrospective analysis was performed from September 2010 through June 2018. Laboratory variables were compared with Mann-Whitney tests. Correlations between initial TREC levels and T cell counts were determined by Spearman tests. RESULTS: Twenty-two transient and 21 persistent TCL infants were identified. Males comprised 68% of the transient and 52% of the persistent TCL cohorts. Whites comprised 23% of the transient and 29% of the persistent cohorts. Median initial TREC levels did not differ (66 vs. 60 TRECs/µL of blood, P = 0.58). The transient cohort had higher median initial CD3+ (2135 vs. 1169 cells/µL, P < 0.001), CD4+ (1460 vs. 866 cells/µL, P < 0.001), and CD8+ (538 vs. 277 cells/µL, P < 0.001) counts. The median age of resolution for the transient cohort was 38 days. Genetic testing revealed 2 genes of interest which warrant further study and several variants of uncertain significance in immunology-related genes in the persistent cohort. 19 transient and 14 persistent subjects received the initial rotavirus and/or MMRV immunization. No adverse reactions to live viral vaccines were reported in either cohort. CONCLUSION: Transient and persistent TCL infants differ by demographic, laboratory, and clinical characteristics. Select transient and persistent TCL patients may safely receive live attenuated viral vaccines, but larger confirmatory studies are needed.


Assuntos
Linfopenia/epidemiologia , Linfócitos T , Contagem de Linfócito CD4 , Suscetibilidade a Doenças , Feminino , Humanos , Recém-Nascido , Contagem de Linfócitos , Linfopenia/diagnóstico , Linfopenia/etiologia , Masculino , Triagem Neonatal , New York/epidemiologia , Vigilância em Saúde Pública , Estudos Retrospectivos , Vacinação , Vacinas Virais/administração & dosagem , Vacinas Virais/imunologia
3.
FEBS Lett ; 594(22): 3751-3764, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33037626

RESUMO

Bcr-abl1 oncogene causes a shift in the transcription start site of the SMS1 gene (SGMS1) encoding the sphingomyelin (SM) synthesizing enzyme, sphingomyelin synthase 1 (SMS1). This results in an mRNA with a significantly shorter 5'-UTR, called 7-SGMS1, which is translated more efficiently than another transcript (IIb-SGMS1) with a longer 5'UTR in Bcr-abl1-positive cells. Here, we determine the effects of these alternative 5'UTRs on SMS1 translation and investigate the key features underlying such regulation. First, the presence of the longer IIb 5'UTR is sufficient to greatly impair translation of a reporter gene. Deletion of the upstream open reading frame (-164 nt) or of the predicted stem-loops in the 5'UTR of IIb-SGMS1 has minimal effects on SGMS1 translation. Conversely, deletion of nucleotides -310 to -132 enhanced transcription of IIb-SGMS1 to reach that of 7-SGMS1. We thus suggest that regulatory features within nucleotides -310 and -132 modulate IIb-SGMS1 translation efficiency.


Assuntos
Proteínas de Fusão bcr-abl/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Transferases (Outros Grupos de Fosfato Substituídos)/genética , Transferases (Outros Grupos de Fosfato Substituídos)/metabolismo , Regiões 5' não Traduzidas , Regulação Neoplásica da Expressão Gênica , Células HeLa , Humanos , Conformação de Ácido Nucleico , Biossíntese de Proteínas , RNA Mensageiro/química , Sítio de Iniciação de Transcrição
4.
Clin Cancer Res ; 25(20): 6160-6169, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31337644

RESUMO

PURPOSE: Immune checkpoint inhibitors (ICI) are effective in only a minority of patients with esophagogastric cancer (EGC). Here, we aimed to identify predictors of durable clinical benefit to ICI in EGC. EXPERIMENTAL DESIGN: Patients with advanced EGC treated with ICIs at Memorial Sloan Kettering Cancer Center (New York, NY) were identified. Clinicopathologic variables were assessed. In patients profiled by MSK-IMPACT-targeted sequencing, outcomes were correlated with tumor genomic features. RESULTS: One-hundred sixty-one patients were treated with ICIs (110 with anti-PD-1/PD-L1 antibodies and 51 with anti-CTLA-4 and PD-1/PD-L1 antibodies). The median progression-free survival (PFS) and overall survival (OS) were 1.7 and 4.9 months, respectively. Greater number of disease sites (≥3), liver metastases, treatment with ≥3 prior therapies and ECOG performance status ≥2 were associated with poorer PFS and OS. Patients treated with combination ICI and those with PD-L1-positive tumors had improved outcomes. There was no difference in outcomes between patients treated with antibiotics during or in the 2 months preceding ICI treatment versus those who were not. Occurrence of irAEs was associated with improved OS. In genomically profiled tumors (n = 89), survival was associated with increasing tumor mutation burden (TMB). However, in multivariable analyses and when microsatellite unstable (MSI) patients were excluded, a significant association was no longer observed. CONCLUSIONS: In patients with advanced EGC, heavily pretreated patients, those with high-volume disease and/or poor PS were less likely to benefit from ICI. irAEs were associated with improved OS. TMB correlated with improved survival, but this association was not observed when MSI-high patients were excluded.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Biomarcadores Tumorais/genética , Neoplasias Esofágicas/tratamento farmacológico , Junção Esofagogástrica/patologia , Neoplasias Gástricas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Análise Mutacional de DNA , Neoplasias Esofágicas/imunologia , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Intervalo Livre de Progressão , Critérios de Avaliação de Resposta em Tumores Sólidos , Estudos Retrospectivos , Neoplasias Gástricas/genética , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/mortalidade , Adulto Jovem
5.
J Cardiovasc Electrophysiol ; 30(10): 1773-1785, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31225670

RESUMO

BACKGROUND: Ablation of atrial tachycardia (AT) that occurs after cardiac surgery or prior ablation often requires complex lesion sets. In combination with the pre-existing atrial scar, these lesion sets may result in inadvertent intra-atrial conduction block. This study reports the phenomenon of incidental isolation of right atrial (RA) regions that occurs secondary to AT ablation, which in some cases results in profound bradycardia due to sinus exit block. METHODS AND RESULTS: Intracardiac electrograms were examined in consecutive patients who underwent AT ablation in the RA. Cases of localized isolation of the RA were defined as areas that developed electrical dissociation during ablation. Of 132 patients having ablation in both the RA free wall and the cavotricuspid isthmus (CTI), 10 (7.6%) developed unintentional isolation of the lateral RA. Five of these patients had prior mitral valve surgery, comprising 12.2% of all 41 patients with mitral surgery who underwent ablation in the CTI and the RA free wall. All patients with regional isolation had a pre-existing scar in the lateral wall of the RA. In six patients, isolation of the lateral RA resulted in profound bradycardia due to exit block from the peri-sinus node myocardium. CONCLUSIONS: Complex ablation lesions in patients with prior valve surgery, prior ablation, or atrial myopathy may result in unintended localized conduction block in the RA. In some cases, isolation of the lateral RA can result in complete sinus exit block with profound bradycardia requiring pacemaker implantation.


Assuntos
Flutter Atrial/cirurgia , Função do Átrio Direito , Bradicardia/etiologia , Ablação por Cateter/efeitos adversos , Átrios do Coração/cirurgia , Frequência Cardíaca , Taquicardia Supraventricular/cirurgia , Potenciais de Ação , Idoso , Idoso de 80 Anos ou mais , Flutter Atrial/diagnóstico , Flutter Atrial/fisiopatologia , Bradicardia/diagnóstico , Bradicardia/fisiopatologia , Bradicardia/terapia , Estimulação Cardíaca Artificial , Feminino , Átrios do Coração/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Fatores de Risco , Taquicardia Supraventricular/diagnóstico , Taquicardia Supraventricular/fisiopatologia , Fatores de Tempo , Resultado do Tratamento
6.
Cell ; 173(2): 321-337.e10, 2018 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-29625050

RESUMO

Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFß signaling, p53 and ß-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these pathways, and 57% percent of tumors had at least one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy.


Assuntos
Bases de Dados Genéticas , Neoplasias/patologia , Transdução de Sinais/genética , Genes Neoplásicos , Humanos , Neoplasias/genética , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteínas Wnt/genética , Proteínas Wnt/metabolismo
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