RESUMEN
To determine the transmission potential of severe acute respiratory syndrome coronavirus 2 in Iran in 2020, we estimated the reproduction number as 4.4 (95% CI 3.9-4.9) by using a generalized growth model and 3.5 (95% CI 1.3-8.1) by using epidemic doubling time. The reproduction number decreased to 1.55 after social distancing interventions were implemented.
Asunto(s)
Betacoronavirus/crecimiento & desarrollo , Control de Enfermedades Transmisibles/organización & administración , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/transmisión , Modelos Estadísticos , Pandemias , Neumonía Viral/epidemiología , Neumonía Viral/transmisión , Betacoronavirus/patogenicidad , COVID-19 , Prueba de COVID-19 , Técnicas de Laboratorio Clínico/métodos , Control de Enfermedades Transmisibles/métodos , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/prevención & control , Humanos , Incidencia , Irán/epidemiología , Pandemias/prevención & control , Distanciamiento Físico , Neumonía Viral/diagnóstico , Neumonía Viral/prevención & control , SARS-CoV-2 , Factores de TiempoRESUMEN
BACKGROUND: Neddylation inhibition, affecting posttranslational protein function and turnover, is a promising therapeutic approach to cancer. We report vulnerability to MLN4924 or pevonedistat (a neddylation inhibitor) in a subset of glioblastoma (GBM) preclinical models and identify biomarkers, mechanisms, and signatures of differential response. METHODS: GBM sequencing data were queried for genes associated with MLN4924 response status; candidates were validated by molecular techniques. Time-course transcriptomics and proteomics revealed processes implicated in MLN4924 response. RESULTS: Vulnerability to MLN4924 is associated with elevated S-phase populations, re-replication, and DNA damage. Transcriptomics and shotgun proteomics depict PTEN signaling, DNA replication, and chromatin instability pathways as significant differentiators between sensitive and resistant models. Loss of PTEN and its nuclear functions is associated with resistance to MLN4924. Time-course proteomics identified elevated TOP2A in resistant models through treatment. TOP2A inhibitors combined with MLN4924 prove synergistic. CONCLUSIONS: We show that PTEN status serves as both a novel biomarker for MLN4924 response in GBM and reveals a vulnerability to TOP2A inhibitors in combination with MLN4924.
Asunto(s)
Glioblastoma , Fosfohidrolasa PTEN , Inhibidores de Topoisomerasa II , Humanos , Apoptosis , Línea Celular Tumoral , Ciclopentanos/farmacología , Ciclopentanos/uso terapéutico , Glioblastoma/tratamiento farmacológico , Proteína NEDD8/metabolismo , Fosfohidrolasa PTEN/genética , Pirimidinas/farmacología , Inhibidores de Topoisomerasa II/farmacología , Inhibidores de Topoisomerasa II/uso terapéutico , Resistencia a AntineoplásicosRESUMEN
The CRISPR-Cas9 system has raised hopes for developing personalized gene therapies for complex diseases. Its application for genetic and epigenetic therapies in humans raises concerns over immunogenicity of the bacterially derived Cas9 protein. Here we detect antibodies to Streptococcus pyogenes Cas9 (SpCas9) in at least 5% of 143 healthy individuals. We also report pre-existing human CD8+T cell immunity in the majority of healthy individuals screened. We identify two immunodominant SpCas9 T cell epitopes for HLA-A*02:01 using an enhanced prediction algorithm that incorporates T cell receptor contact residue hydrophobicity and HLA binding and evaluated them by T cell assays using healthy donor PBMCs. In a proof-of-principle study, we demonstrate that Cas9 protein can be modified to eliminate immunodominant epitopes through targeted mutation while preserving its function and specificity. Our study highlights the problem of pre-existing immunity against CRISPR-associated nucleases and offers a potential solution to mitigate the T cell immune response.