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1.
Microbiol Spectr ; 10(1): e0156421, 2022 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-35019677

RESUMO

The emergence of SARS-CoV-2 created a crucial need for serology assays to detect anti-SARS-CoV-2 antibodies, which led to many serology assays entering the market. A trans-government collaboration was created in April 2020 to independently evaluate the performance of commercial SARS-CoV-2 serology assays and help inform U.S. Food and Drug Administration (FDA) regulatory decisions. To assess assay performance, three evaluation panels with similar antibody titer distributions were assembled. Each panel consisted of 110 samples with positive (n = 30) serum samples with a wide range of anti-SARS-CoV-2 antibody titers and negative (n = 80) plasma and/or serum samples that were collected before the start of the COVID-19 pandemic. Each sample was characterized for anti-SARS-CoV-2 antibodies against the spike protein using enzyme-linked immunosorbent assays (ELISA). Samples were selected for the panel when there was agreement on seropositivity by laboratories at National Cancer Institute's Frederick National Laboratory for Cancer Research (NCI-FNLCR) and Centers for Disease Control and Prevention (CDC). The sensitivity and specificity of each assay were assessed to determine Emergency Use Authorization (EUA) suitability. As of January 8, 2021, results from 91 evaluations were made publicly available (https://open.fda.gov/apis/device/covid19serology/, and https://www.cdc.gov/coronavirus/2019-ncov/covid-data/serology-surveillance/serology-test-evaluation.html). Sensitivity ranged from 27% to 100% for IgG (n = 81), from 10% to 100% for IgM (n = 74), and from 73% to 100% for total or pan-immunoglobulins (n = 5). The combined specificity ranged from 58% to 100% (n = 91). Approximately one-third (n = 27) of the assays evaluated are now authorized by FDA for emergency use. This collaboration established a framework for assay performance evaluation that could be used for future outbreaks and could serve as a model for other technologies. IMPORTANCE The SARS-CoV-2 pandemic created a crucial need for accurate serology assays to evaluate seroprevalence and antiviral immune responses. The initial flood of serology assays entering the market with inadequate performance emphasized the need for independent evaluation of commercial SARS-CoV-2 antibody assays using performance evaluation panels to determine suitability for use under EUA. Through a government-wide collaborative network, 91 commercial SARS-CoV-2 serology assay evaluations were performed. Three evaluation panels with similar overall antibody titer distributions were assembled to evaluate performance. Nearly one-third of the assays evaluated met acceptable performance recommendations, and two assays had EUAs revoked and were removed from the U.S. market based on inadequate performance. Data for all serology assays evaluated are available at the FDA and CDC websites (https://open.fda.gov/apis/device/covid19serology/, and https://www.cdc.gov/coronavirus/2019-ncov/covid-data/serology-surveillance/serology-test-evaluation.html).


Assuntos
Anticorpos Antivirais/sangue , Teste Sorológico para COVID-19/métodos , COVID-19/sangue , Ensaio de Imunoadsorção Enzimática/métodos , SARS-CoV-2/imunologia , COVID-19/diagnóstico , COVID-19/epidemiologia , COVID-19/virologia , Aprovação de Teste para Diagnóstico , Humanos , Laboratórios , Pandemias , SARS-CoV-2/genética , Sensibilidade e Especificidade , Glicoproteína da Espícula de Coronavírus/análise , Glicoproteína da Espícula de Coronavírus/imunologia , Estados Unidos/epidemiologia , United States Food and Drug Administration
2.
Clin Cancer Res ; 27(17): 4685-4689, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34083238

RESUMO

The FDA approved pembrolizumab on June 16, 2020, for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high [TMB-H; ≥10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. FDA granted the approval based on a clinically important overall response rate (29%; 95% confidence interval, 21-39) and duration of response (57% of responses lasting ≥ 12 months) in the subset of patients with TMB-H solid tumors (n = 102) spanning nine different tumor types enrolled in a multicenter single-arm trial (KEYNOTE-158). The efficacy of pembrolizumab was supported by the results of whole-exome sequencing (WES) analyses of TMB in additional patients enrolled across multiple pembrolizumab clinical trials, and a scientific understanding of the effects of PD-1 inhibition. Overall, the adverse event profile of pembrolizumab was similar to the adverse event profile observed in prior trials that supported the approval of pembrolizumab in other indications. This approval of pembrolizumab is the first time that the FDA has approved a cancer treatment for an indication based on TMB, and the fourth based on the presence of a biomarker rather than the primary site of origin.


Assuntos
Anticorpos Monoclonais Humanizados/genética , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Aprovação de Drogas , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/genética , Adulto , Criança , Humanos , Estudos Retrospectivos , Estados Unidos
3.
Artigo em Inglês | MEDLINE | ID: mdl-32914013

RESUMO

PURPOSE: Next-generation sequencing (NGS) oncology panels are becoming integral in hospital and academic settings to guide patient treatment and enrollment in clinical trials. Although NGS technologies have revolutionized decision-making for cancer therapeutics, physicians may face many challenges in parsing and prioritizing NGS-based test results to determine the best course of treatment for individual patients. On January 29, 2018, the US Food and Drug Administration held a public workshop entitled, "Weighing the Evidence: Variant Classification and Interpretation in Precision Oncology." Here, we discuss the presentations and discussion highlights across the four sessions of the workshop. METHODS: The goal of the public workshop was to engage stakeholders and solicit input from experts in precision oncology to discuss the integration of complex NGS data into patient management and regulatory innovation within the precision oncology community. The US Food and Drug Administration gathered representatives from academia, industry, patient advocacy, government, and professional organizations for a series of presentations followed by panel discussions. After the workshop, the transcript and speaker presentation slides were reviewed and summarized for manuscript preparation. RESULTS: Speakers and panelists provided diverse perspectives on the integration of NGS technology into patient care for oncology and on the complexities that surround data interpretation and sharing. Discussions highlighted the challenges with standardization for variant classification while expressing the utility of consensus recommendations among stakeholders in oncology for driving innovation in the era of precision medicine. CONCLUSION: As precision medicine advances, clear communication within the field of precision oncology will be key to creating an environment that facilitates the generation and sharing of data that have value to patients.

4.
Nat Struct Mol Biol ; 25(5): 372-383, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29686279

RESUMO

Iron metabolism is critical for sustaining life and maintaining human health. Here, we find that iron homeostasis is linked to facultative heterochromatin assembly and regulation of gene expression during adaptive genome control. We show that the fission yeast Clr4/Suv39h histone methyltransferase is part of a rheostat-like mechanism in which transcriptional upregulation of mRNAs in response to environmental change provides feedback to prevent their uncontrolled expression through heterochromatin assembly. Interestingly, proper iron homeostasis is required, as iron depletion or downregulation of iron transporters causes defects in heterochromatin assembly and unrestrained upregulation of gene expression. Remarkably, an unbiased genetic screen revealed that restoration of iron homeostasis is sufficient to re-establish facultative heterochromatin and proper gene control genome-wide. These results establish a role for iron homeostasis in facultative heterochromatin assembly and reveal a dynamic mechanism for reprogramming the genome in response to environmental changes.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Regulação Fúngica da Expressão Gênica/genética , Heterocromatina/metabolismo , Metiltransferases/metabolismo , RNA Fúngico/metabolismo , Proteínas de Schizosaccharomyces pombe/metabolismo , Schizosaccharomyces/metabolismo , Proteínas de Transporte/metabolismo , Montagem e Desmontagem da Cromatina/genética , Temperatura Baixa , Histona-Lisina N-Metiltransferase , Ferro/metabolismo , RNA Fúngico/genética , Schizosaccharomyces/genética , Transcrição Gênica/genética
5.
J Cell Sci ; 127(Pt 9): 1980-91, 2014 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-24569878

RESUMO

Cdc48, known as p97 or valosin-containing protein (VCP) in mammals, is an abundant AAA-ATPase that is essential for many ubiquitin-dependent processes. One well-documented role for Cdc48 is in facilitating the delivery of ubiquitylated misfolded endoplasmic reticulum proteins to the proteasome for degradation. By contrast, the role for Cdc48 in misfolded protein degradation in the nucleus is unknown. In the budding yeast Saccharomyces cerevisiae, degradation of misfolded proteins in the nucleus is primarily mediated by the nuclear-localized ubiquitin-protein ligase San1, which ubiquitylates misfolded nuclear proteins for proteasomal degradation. Here, we find that, although Cdc48 is involved in the degradation of some San1 substrates, it is not universally required. The difference in the requirement for Cdc48 correlates with the insolubility of the San1 substrate. The more insoluble the substrate, the more its degradation requires Cdc48. Expression of Cdc48-dependent San1 substrates in mutant cdc48 cells results in increased substrate insolubility, larger inclusion formation and reduced cell viability. Substrate ubiquitylation is increased in mutant cdc48 cells, suggesting that Cdc48 functions downstream of San1. Taken together, we propose that Cdc48 acts, in part, to maintain the solubility or reverse the aggregation of insoluble misfolded proteins prior to their proteasomal degradation.


Assuntos
Adenosina Trifosfatases/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Adenosina Trifosfatases/genética , Proteínas de Ciclo Celular/genética , Dobramento de Proteína , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Solubilidade , Ubiquitina/genética , Ubiquitina/metabolismo , Proteína com Valosina
6.
Mol Biol Cell ; 22(12): 1971-84, 2011 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-21508314

RESUMO

Nine human disorders result from the toxic accumulation and aggregation of proteins with expansions in their endogenous polyalanine (polyA) tracts. Given the prevalence of polyA tracts in eukaryotic proteomes, we wanted to understand the generality of polyA-expansion cytotoxicity by using yeast as a model organism. In our initial case, we expanded the polyA tract within the native yeast poly(Adenine)-binding protein Pab1 from 8A to 13A, 15A, 17A, and 20A. These expansions resulted in increasing formation of Pab1 inclusions, insolubility, and cytotoxicity that correlated with the length of the polyA expansion. Pab1 binds mRNA as part of its normal function, and disrupting RNA binding or altering cytoplasmic mRNA levels suppressed the cytotoxicity of 17A-expanded Pab1, indicating a requisite role for mRNA in Pab1 polyA-expansion toxicity. Surprisingly, neither manipulation suppressed the cytotoxicity of 20A-expanded Pab1. Thus longer expansions may have a different mechanism for toxicity. We think that this difference underscores the potential need to examine the cytotoxic mechanisms of both long and short expansions in models of expansion disorders.


Assuntos
Expansão das Repetições de DNA , Peptídeos/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Sequência de Aminoácidos , Agregação Celular , Proteínas de Ligação a DNA/metabolismo , Exodesoxirribonucleases/metabolismo , Mutação , Peptídeos/química , Fosfoproteínas/metabolismo , Proteína I de Ligação a Poli(A)/química , Proteína I de Ligação a Poli(A)/metabolismo , Proteoma , RNA Polimerase II/genética , RNA Mensageiro/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crescimento & desenvolvimento , Proteínas de Saccharomyces cerevisiae/genética
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