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1.
Ther Innov Regul Sci ; 57(3): 401, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-37022645
2.
Ther Innov Regul Sci ; 57(3): 399-400, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36719596

RESUMO

The following is an introduction from the guest editors for the Bayesian Clinical Trials series.


Assuntos
Teorema de Bayes , Ensaios Clínicos como Assunto
3.
Ther Innov Regul Sci ; 57(3): 436-444, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36459346

RESUMO

The Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) of the U.S. Food and Drug Administration (FDA) have been leaders in protecting and promoting the U.S. public health by helping to ensure that safe and effective drugs and biological products are available in the United States for those who need them. The null hypothesis significance testing approach, along with other considerations, is typically used to demonstrate the effectiveness of a drug or biological product. The Bayesian framework presents an alternative approach to demonstrate the effectiveness of a treatment. This article discusses the Bayesian framework for drug and biological product development, highlights key settings in which Bayesian approaches may be appropriate, and provides recent examples of the use of Bayesian approaches within CDER and CBER.


Assuntos
Produtos Biológicos , Humanos , Estados Unidos , Preparações Farmacêuticas , Avaliação de Medicamentos , Teorema de Bayes , United States Food and Drug Administration
4.
Clin Cancer Res ; 28(12): 2488-2492, 2022 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-35135839

RESUMO

On July 16, 2021, the FDA approved belumosudil, a kinase inhibitor, for adult and pediatric patients 12 years and older with chronic GvHD (cGvHD) after failure of at least two prior lines of systemic therapy. Approval was based on the results of Study KD025-213, which included 65 patients with cGvHD treated with belumosudil 200 mg daily in an open-label, single-arm cohort. Efficacy was determined by the overall response rate (ORR) through Cycle 7 Day 1, which included complete response (CR) or partial response (PR) according to the 2014 NIH consensus criteria, and durability of response. The ORR through Cycle 7 Day 1 was 75% [95% confidence interval (CI), 63-85]; 6% of patients achieved a CR, and 69% achieved a PR. The median duration of response was 1.9 months (95% CI, 1.2-2.9), and 62% (95% CI, 46-74) of responding patients remained alive without new systemic therapy for at least 12 months from response. The common adverse reactions were infections, asthenia, nausea, diarrhea, dyspnea, cough, edema, hemorrhage, abdominal pain, musculoskeletal pain, headache, phosphate decreased, gamma-glutamyl transferase increased, lymphocytes decreased, and hypertension. Additional study is warranted to confirm safety with long-term use.


Assuntos
Antineoplásicos , Doença Enxerto-Hospedeiro , Acetamidas , Adulto , Antineoplásicos/farmacologia , Criança , Aprovação de Drogas , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Humanos , Inibidores de Proteínas Quinases/efeitos adversos
5.
BMC Med Res Methodol ; 14: 121, 2014 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-25417040

RESUMO

BACKGROUND: The intraclass correlation coefficient (ICC) is widely used in biomedical research to assess the reproducibility of measurements between raters, labs, technicians, or devices. For example, in an inter-rater reliability study, a high ICC value means that noise variability (between-raters and within-raters) is small relative to variability from patient to patient. A confidence interval or Bayesian credible interval for the ICC is a commonly reported summary. Such intervals can be constructed employing either frequentist or Bayesian methodologies. METHODS: This study examines the performance of three different methods for constructing an interval in a two-way, crossed, random effects model without interaction: the Generalized Confidence Interval method (GCI), the Modified Large Sample method (MLS), and a Bayesian method based on a noninformative prior distribution (NIB). Guidance is provided on interval construction method selection based on study design, sample size, and normality of the data. We compare the coverage probabilities and widths of the different interval methods. RESULTS: We show that, for the two-way, crossed, random effects model without interaction, care is needed in interval method selection because the interval estimates do not always have properties that the user expects. While different methods generally perform well when there are a large number of levels of each factor, large differences between the methods emerge when the number of one or more factors is limited. In addition, all methods are shown to lack robustness to certain hard-to-detect violations of normality when the sample size is limited. CONCLUSIONS: Decision rules and software programs for interval construction are provided for practical implementation in the two-way, crossed, random effects model without interaction. All interval methods perform similarly when the data are normal and there are sufficient numbers of levels of each factor. The MLS and GCI methods outperform the NIB when one of the factors has a limited number of levels and the data are normally distributed or nearly normally distributed. None of the methods work well if the number of levels of a factor are limited and data are markedly non-normal. The software programs are implemented in the popular R language.


Assuntos
Interpretação Estatística de Dados , Modelos Estatísticos , Projetos de Pesquisa , Análise de Variância , Teorema de Bayes , Intervalos de Confiança , Humanos , Reprodutibilidade dos Testes , Software
6.
Nat Immunol ; 15(12): 1134-42, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25344726

RESUMO

Loss of function of the kinase IRAK4 or the adaptor MyD88 in humans interrupts a pathway critical for pathogen sensing and ignition of inflammation. However, patients with loss-of-function mutations in the genes encoding these factors are, unexpectedly, susceptible to only a limited range of pathogens. We employed a systems approach to investigate transcriptome responses following in vitro exposure of patients' blood to agonists of Toll-like receptors (TLRs) and receptors for interleukin 1 (IL-1Rs) and to whole pathogens. Responses to purified agonists were globally abolished, but variable residual responses were present following exposure to whole pathogens. Further delineation of the latter responses identified a narrow repertoire of transcriptional programs affected by loss of MyD88 function or IRAK4 function. Our work introduces the use of a systems approach for the global assessment of innate immune responses and the characterization of human primary immunodeficiencies.


Assuntos
Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Quinases Associadas a Receptores de Interleucina-1/genética , Mutação , Fator 88 de Diferenciação Mieloide/genética , Adolescente , Criança , Pré-Escolar , Análise por Conglomerados , Feminino , Perfilação da Expressão Gênica , Humanos , Imunidade Inata/genética , Imunidade Inata/imunologia , Lactente , Quinases Associadas a Receptores de Interleucina-1/imunologia , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Doenças da Imunodeficiência Primária , Transcriptoma
7.
Cancer Biomark ; 6(1): 33-48, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20164540

RESUMO

Biomarkers for early detection of cancer have great clinical diagnostic potential. Numerous reports have documented the generation of humoral immune responses that are triggered in response to changes in protein expression patterns in tumor tissues and these biomarkers are referred to as tumor associated antigens (TAAs). Using a high-throughput technology, we previously identified 65 proteins as diagnostically useful TAAs by profiling the humoral immune responses in ovarian cancer (OVCA) patients. Here we determined the expression status of some of those TAAs in tissues from OVCA patients. The protein expression patterns of 4 of those 65 antigens, namely NASP, RCAS1, Nijmegen breakage syndrome1 (NBS1) and eIF5A, along with p53 and Her2 (known molecular prognosticators) and two proteins that interact with NBS1, MRE11 and RAD50, were assessed by immunohistochemistry (IHC). NASP and RCAS1 proteins were more frequently expressed in ovarian cancer tissues than with normal ovarian tissue and serous cystadenomas and MRE11 was less frequently expressed. When evaluated simultaneously, only NASP and MRE11 remained statistically significant with sensitivity of 66% and specificity of 89%. None of these proteins' expression levels were prognostic for survival. Together, our results indicate that occurrence of humoral immune responses against some of these TAAs in OVCA patients is triggered by antigen protein overexpression.


Assuntos
Antígenos de Neoplasias/administração & dosagem , Biomarcadores Tumorais/análise , Neoplasias Ovarianas/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/biossíntese , Autoantígenos/biossíntese , Cistadenoma Seroso/diagnóstico , Cistadenoma Seroso/metabolismo , Proteínas de Ligação a DNA/biossíntese , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Proteína Homóloga a MRE11 , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Proteínas Nucleares/biossíntese , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sensibilidade e Especificidade , Análise Serial de Tecidos , Adulto Jovem
8.
Brain Behav Immun ; 23(8): 1148-55, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19643176

RESUMO

Cancer treatment is known to have significant immuno-suppressive/dysregulatory effects. Psychological distress and depression, which often accompany cancer diagnosis and treatment, can also suppress or dysregulate endocrine and immune function. Cell-mediated immunity (CMI) is critical for protection against a host of pathogens to which cancer patients may be particularly susceptible. CMI is also important for defense against some tumors. This study explored relationships among depressive symptoms, cortisol secretion, and CMI responses in 72 women with metastatic breast cancer. Depressive symptoms were assessed with the Center for Epidemiologic Studies-Depression Scale (CES-D). Saliva was sampled throughout the day over a 3-day period to obtain a physiologic index of diurnal cortisol concentrations and rhythmicity, which is associated with breast cancer survival time. CMI for specific antigens was measured following intradermal administration of seven commonly encountered antigens (tuberculin, tetanus, diphtheria, Streptococcus, Candida, Trichophyton, and Proteus). Analyses adjusting for relevant medical and treatment variables indicated that women reporting more depressive symptoms showed suppressed immunity as measured by lower average induration size. Women with higher mean diurnal cortisol concentrations also showed suppressed immunity as indicated by a decreased number of antigens to which positive reactions were measured. This study highlights the relationships among depression, stress, and immune function in the context of advanced breast cancer.


Assuntos
Neoplasias da Mama/imunologia , Neoplasias da Mama/psicologia , Depressão/imunologia , Depressão/psicologia , Hidrocortisona/análise , Ritmo Circadiano , Feminino , Humanos , Hidrocortisona/imunologia , Sistema Hipotálamo-Hipofisário/imunologia , Imunidade Celular , Modelos Lineares , Pessoa de Meia-Idade , Metástase Neoplásica , Seleção de Pacientes , Sistema Hipófise-Suprarrenal/imunologia , Escalas de Graduação Psiquiátrica , Saliva/química , Saliva/imunologia , Estresse Psicológico/imunologia
9.
Cancer Epidemiol Biomarkers Prev ; 16(11): 2396-405, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18006929

RESUMO

Currently, no effective tool exists for screening or early diagnosis of head and neck squamous cell carcinoma (HNSCC). Here, we describe an approach for cancer detection based on analysis of patterns of serum immunoreactivity against a panel of biomarkers selected using microarray-based serologic profiling and specialized bioinformatics. We biopanned phage display libraries derived from three different HNSCC tissues to generate 5,133 selectively cloned tumor antigens. Based on their differential immunoreactivity on protein microarrays against serum immunoglobulins from 39 cancer and 41 control patients, we reduced the number of clones to 1,021. The performance of a neural network model (Multilayer Perceptron) for cancer classification on a data set of 80 HNSCC and 78 control samples was assessed using 10-fold cross-validation repeated 100 times. A panel of 130 clones was found to be adequate for building a classifier with sufficient sensitivity and specificity. Using these 130 markers on a completely new and independent set of 80 samples, an accuracy of 84.9% with sensitivity of 79.8% and specificity of 90.1% was achieved. Similar performance was achieved by reshuffling of the data set and by using other classification models. The performance of this classification approach represents a significant improvement over current diagnostic accuracy (sensitivity of 37% to 46% and specificity of 24%) in the primary care setting. The results shown here are promising and show the potential use of this approach toward eventual development of diagnostic assay with sufficient sensitivity and specificity suitable for detection of early-stage HNSCC in high-risk populations.


Assuntos
Autoanticorpos/sangue , Biomarcadores Tumorais/sangue , Carcinoma de Células Escamosas/diagnóstico , Neoplasias de Cabeça e Pescoço/diagnóstico , Autoanticorpos/imunologia , Bacteriófago T7/genética , Biomarcadores Tumorais/imunologia , Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/imunologia , Epitopos/imunologia , Feminino , Biblioteca Gênica , Neoplasias de Cabeça e Pescoço/sangue , Neoplasias de Cabeça e Pescoço/imunologia , Humanos , Imunoglobulina G/imunologia , Masculino , Redes Neurais de Computação , Análise Serial de Proteínas/métodos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
10.
Expert Opin Med Diagn ; 1(1): 3-15, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23489265

RESUMO

Proteomic and genomic technologies have been developed that can simultaneously detect large panels of cancer biomarkers in body fluids such as serum, plasma, sputum, saliva or urine. These approaches provide great promise for the early detection of cancer, but have thrust the field into the era of diagnostic multianalyte-based cancer tests with few, if any, models for the implementation of such tests. These multianalyte tests may be based on the detection of serum antibodies to tumor antigens, the presence of cancer-related proteins in serum or the presence of tumor-specific genomic changes that appear in plasma as free DNA. The application of noninvasive diagnostic approaches to detect early stage cancer will provide the physician with greater presymptomatic periods for clinical intervention, but it is uncertain how the various forces will impact their implementation in a patient care setting. Utilization will be balanced by medical follow-up pathways, commercial/reimbursement factors and regulatory issues that influence implementation of new devices in the marketplace.

11.
Cancer Res ; 66(2): 1181-90, 2006 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-16424057

RESUMO

A noninvasive screening test would significantly facilitate early detection of epithelial ovarian cancer. This study used a combination of high-throughput selection and array-based serologic detection of many antigens indicative of the presence of cancer, thereby using the immune system as a biosensor. This high-throughput selection involved biopanning of an ovarian cancer phage display library using serum immunoglobulins from an ovarian cancer patient as bait. Protein macroarrays containing 480 of these selected antigen clones revealed 65 clones that interacted with immunoglobulins in sera from 32 ovarian cancer patients but not with sera from 25 healthy women or 14 patients having other benign or malignant gynecologic diseases. Sequence analysis data of these 65 clones revealed 62 different antigens. Among the markers, we identified some known antigens, including RCAS1, signal recognition protein-19, AHNAK-related sequence, nuclear autoantogenic sperm protein, Nijmegen breakage syndrome 1 (Nibrin), ribosomal protein L4, Homo sapiens KIAA0419 gene product, eukaryotic initiation factor 5A, and casein kinase II, as well as many previously uncharacterized antigenic gene products. Using these 65 antigens on protein microarrays, we trained neural networks on two-color fluorescent detection of serum IgG binding and found an average sensitivity and specificity of 55% and 98%, respectively. In addition, the top 6 of the most specific clones resulted in an average sensitivity and specificity of 32% and 94%, respectively. This global approach to antigenic profiling, epitomics, has applications to cancer and autoimmune diseases for diagnostic and therapeutic studies. Further work with larger panels of antigens should provide a comprehensive set of markers with sufficient sensitivity and specificity suitable for clinical testing in high-risk populations.


Assuntos
Antígenos de Neoplasias/análise , Biomarcadores Tumorais/análise , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/imunologia , Biblioteca de Peptídeos , Antígenos de Neoplasias/genética , Estudos de Casos e Controles , Diagnóstico Diferencial , Feminino , Perfilação da Expressão Gênica , Doenças dos Genitais Femininos/diagnóstico , Doenças dos Genitais Femininos/imunologia , Humanos , Programas de Rastreamento , Sensibilidade e Especificidade
12.
OMICS ; 10(4): 499-506, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-17233560

RESUMO

The immune system retains memory of current and past infections and can sense the presence of cancer by elaborating autoantibodies to tumor proteins. In the presence of an autoimmune disease, the immune system is an efficient, natural biosensor. Therefore we exploit the immune system through a high-throughput process to isolate disease-specific epitopes for diagnostic and therapeutic purposes. These cloned disease-specific antigens are robotically spotted onto protein microarrays and interrogated with serum from the subjects under analyses. These arrays deliver personalized profiles of antigenic exposures and therapeutic targets for personalized immunotherapy. The immune system is the ultimate biosensor, superior to anything a human could create and ready to be exploited for biotechnology and biomedicine.


Assuntos
Epitopos/análise , Sistema Imunitário/química , Sistema Imunitário/metabolismo , Análise Serial de Proteínas , Humanos
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