RESUMO
INTRODUCTION: Next-generation sequencing (NGS) of cell-free circulating tumor DNA (cfDNA) enables noninvasive genomic analysis of NSCLC patients. Although plasma-detected genomic alterations (GAs) have been shown to predict targeted therapy response, evidence of durability of response is lacking or limited to small cohorts as is the impact of cfDNA NGS results on clinical decisions. METHODS: This retrospective study of stage IIIB/IV NSCLC patients between the years 2014 and 2017 in Israel used cfDNA NGS (Guardant360; Guardant Health, Inc., Redwood City, California) to identify targetable GAs. RESULTS: We consecutively tested 116 NSCLC patients, 41.4% before first-line therapy (group A), 34.5% upon progression on chemotherapy or immunotherapy (group B1), and 24.1% upon progression on EGFR tyrosine kinase inhibitors (group B2). Targetable GAs were found in 31% of group A (15 of 48 patients), 32.5% in group B1 (13 of 40 patients) and 71% in group B2 (20 of 28 patients). Treatment decision was changed to targeted therapy in 23% (11 of 48 patients), 25% (10 of 40 patients) and 32% (9 of 28 patients), respectively (total cohort 26%; 30/116). Objective response rate (Response Evaluation Criteria in Solid Tumors) was 43% (12 of 28 patients) including one complete response, partial response in 39% (11 of 28 patients), stable disease in 32% (9 of 28 patients), and progressive disease in 25% (7 of 28 patients). Disease control rate was 75% for 5 months median treatment duration. CONCLUSIONS: Comprehensive cfDNA testing impacted clinical decisions in one-quarter to one-third of initial and subsequent lines of treatment in advanced NSCLC patients. This retrospective study extends previous reports by showing that responses based on cfDNA are durable and change treatment decisions at initial presentation and at progression.
Assuntos
DNA Tumoral Circulante/genética , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias Pulmonares/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
CD200, a membrane glycoprotein of the immunoglobulin superfamily, is overexpressed in CLL. Soluble in serum CD200 (sCD200) is correlated with poor prognosis in CLL. ADAM (a disintegrin and metalloproteinase) enzymes are implicated in membrane protein shedding. ADAM28 mRNA expression in CLL was correlated with plasma sCD200 levels, and release into culture from CLL cells. siRNA for ADAM28 decreased release of sCD200 from cultures and transfection of a cloned ADAM28 gene into CD200(+) cells enhanced release of sCD200. Our data support the hypothesis that ADAM28 plays a role in the shedding of CD200 from B-cell CLL cells.
Assuntos
Proteínas ADAM/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Antígenos CD/metabolismo , Leucemia Linfocítica Crônica de Células B/metabolismo , Proteínas de Membrana/metabolismo , Proteínas ADAM/antagonistas & inibidores , Proteínas ADAM/genética , Proteína ADAM10 , Proteína ADAM17 , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/genética , Western Blotting , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais CultivadasRESUMO
BACKGROUND: Human leukocyte antigen G (HLA-G) is a non-classical Ib molecule in the major histocompatibility complex. HLA-G has important immunosuppressive properties, and in the context of cardiac transplantation, is associated with a low risk of cellular rejection. A 14-bp insertion/deletion polymorphism in exon 8 of the HLA-G gene is associated with messenger RNA (mRNA) stability and expression of HLA-G. This study analyzed the relationship between HLA-G polymorphisms and serum HLA-G levels in patients after cardiac transplantation to determine if any specific HLA-G genotype is associated with cellular rejection. METHODS: Ninety-four heart transplant patients were genotyped for the 14-bp polymorphism. Serum HLA-G levels and cellular rejection grades were evaluated in all patients. RESULTS: The 14-bp polymorphism was significantly associated with serum HLA-G expression. Patients with the -14-bp/-14-bp genotype had significantly higher mean serum HLA-G levels (88.2 U/ml) than those patients with the +14-bp/-14-bp (52.8 U/ml) and +14-bp/+14-bp (32.2 U/ml) genotypes (p = 0.004). The -14 bp/-14-bp genotype was significantly associated with fewer episodes of cellular rejection. CONCLUSIONS: This study suggests that the 14-bp deletion in the HLA-G gene plays an important role in the expression of HLA-G and thus might be a clinically useful genetic indicator for cellular rejection risk after cardiac transplantation.
Assuntos
Rejeição de Enxerto/genética , Antígenos HLA/genética , Transplante de Coração/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Polimorfismo Genético/genética , Deleção de Sequência/genética , Adulto , Feminino , Seguimentos , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Rejeição de Enxerto/imunologia , Antígenos HLA/sangue , Antígenos HLA-G , Antígenos de Histocompatibilidade Classe I/sangue , Humanos , Imunidade Celular/genética , Masculino , Pessoa de Meia-Idade , Medição de Risco , Resultado do TratamentoRESUMO
Genetic relationships among 50 fruiting-mei (Prunus mume Sieb. et Zucc.) cultivars from China and Japan were investigated, using 767 amplified fragment length polymorphism (AFLP) and 103 single nucleotide polymorphism (SNP) markers. The polymorphism among the cultivars was found to be 69.77%, based on EcoR I + Mse I AFLP primer pairs. The sequence alignment of 11 group sequences, derived from 50 samples, yielded 103 SNPs; the total length of genomic sequences was 3683 bp. Among these SNPs, 73 were heterozygous in the loci of different cultivars. The SNP distribution was 58% transition, 40% transversion, and 2% InDels. There was also 1 trinucleotide deletion. AFLP and SNP markers allowed us to evaluate the genetic diversity of these 50 fruiting-mei cultivars. The 2 derived cladograms did display some differences: all cultivars formed 2 subclusters (1A and 1B) in the cladogram based on AFLP polymorphisms, and formed 3 subclusters (2A, 2B, and 2C) in the cladogram based on SNP polymorphisms; and, in the cladogram based on AFLP polymorphisms, most cultivars from the Guangdong to Fujian provinces (G-F) in China, from the Yunnan, Hunan, and Sichuan provinces (Y-S-H) in China, and from Japan grouped in cluster 1A, and 18 (78.26%) of 23 cultivars from Jiangsu to Zhejiang provinces in China (J-Z) grouped in cluster 1B. The results demonstrate that mei cultivars from Japan are clustered with cultivars from China, and support the hypothesis that mei in Japan were introduced from China. Cultivars from the J-Z region of China have more genetic similarities. Cultivars from the G-F and Y-S-H regions have fewer genetic similarities and suggest more germplasm exchanges in the past.
