RESUMO
The last decade has seen a substantial increase in research focused on the identification of blood-based biomarkers that have utility in Alzheimer's disease (AD). Blood-based biomarkers have significant advantages of being time- and cost-efficient as well as reduced invasiveness and increased patient acceptance. Despite these advantages and increased research efforts, the field has been hampered by lack of reproducibility and an unclear path for moving basic discovery toward clinical utilization. Here we reviewed the recent literature on blood-based biomarkers in AD to provide a current state of the art. In addition, a collaborative model is proposed that leverages academic and industry strengths to facilitate the field in moving past discovery only work and toward clinical use. Key resources are provided. This new public-private partnership model is intended to circumvent the traditional handoff model and provide a clear and useful paradigm for the advancement of biomarker science in AD and other neurodegenerative diseases.
Assuntos
Doença de Alzheimer/sangue , Biomarcadores/sangue , Comportamento Cooperativo , Parcerias Público-Privadas , Feminino , Humanos , Masculino , Reprodutibilidade dos TestesRESUMO
A blood test identifying patients at increased risk of pulmonary hypertension (PH) could streamline the investigative pathway. The prospective, multicenter CIPHER study aimed to develop a microRNA-based signature for detecting PH in breathless patients and enrolled adults with a high suspicion of PH who had undergone right heart catheterization (RHC). The CIPHER-MRI study was added to assess the performance of this CIPHER signature in a population with low probability of having PH who underwent cardiac magnetic resonance imaging (cMRI) instead of RHC. The microRNA signature was developed using a penalized linear regression (LASSO) model. Data were modeled both with and without N-terminal pro-brain natriuretic peptide (NT-proBNP). Signature performance was assessed against predefined thresholds (lower 98.7% CI bound of ≥0.73 for sensitivity and ≥0.53 for specificity, based on a meta-analysis of echocardiographic data), using RHC as the true diagnosis. Overall, 926 CIPHER participants were screened and 888 were included in the analysis. Of 688 RHC-confirmed PH cases, approximately 40% were already receiving PH treatment. Fifty microRNA (from 311 investigated) were algorithmically selected to be included in the signature. Sensitivity [97.5% CI] of the signature was 0.85 [0.80-0.89] for microRNA-alone and 0.90 [0.86-0.93] for microRNA+NT-proBNP, and the corresponding specificities were 0.33 [0.24-0.44] and 0.28 [0.20-0.39]. Of 80 CIPHER-MRI participants with evaluable data, 7 were considered PH-positive by cMRI whereas 52 were considered PH-positive by the microRNA signature. Due to low specificity, the CIPHER miRNA-based signature for PH (either with or without NT-proBNP in model) did not meet the prespecified diagnostic threshold for the primary analysis.
RESUMO
BACKGROUND: Screening of blood donors with nucleic acid testing (NAT) for human immunodeficiency virus (HIV) and hepatitis C virus (HCV) has been implemented recently in the United States. There are limited data, however, on the additional NAT yield of donors in developing countries in Asia where the prevalence of infection is higher. In addition, data on hepatitis B virus (HBV) NAT in high prevalence areas are minimal. STUDY DESIGN AND METHODS: A total of 5083 whole-blood donors at the Chiang Mai University Hospital, Thailand, blood bank were evaluated with a commercially available NAT assay (Procleix Ultrio, Gen-Probe, Inc.) to screen individual donations. RESULTS: No NAT yield cases were found for HIV-1 or HCV. There were 17 samples with discrepant HBV DNA NAT and hepatitis B surface antigen (HBsAg) tests, however. Seven of these were HBV DNA NAT-positive, HBsAg-negative; of these 7, 1 was NAT-positive at baseline, but negative on follow-up, and considered a false-positive, 1 had an acute infection, and 5 had chronic prevalent HBV infections, for a NAT yield of 6 in 4798 HBsAg negative donors (1:800). In addition there were 10 NAT-negative, HBsAg-positive serum samples. All were anti-hepatitis B core antigen immunoglobulin G-positive; on testing with a more sensitive NAT target capture assay, 5 were positive (1.8-20.6 IU/mL) and 5 were negative. CONCLUSION: Multiplex NAT screening of individual-donor serum samples in Northern Thailand detected approximately 1 per 800 HBV NAT-positive, HBsAg-negative donors. The especially high prevalence of HBV infection in Thailand and other Asian countries suggests that HBV NAT screening of donors will be more cost-effective than in other areas.
Assuntos
Doadores de Sangue/estatística & dados numéricos , Transfusão de Sangue/normas , DNA Viral/genética , HIV-1/genética , Hepacivirus/genética , Vírus da Hepatite B/genética , RNA Viral/genética , DNA Viral/sangue , HIV-1/isolamento & purificação , Hepacivirus/isolamento & purificação , Antígenos de Superfície da Hepatite B/análise , Antígenos de Superfície da Hepatite B/genética , Vírus da Hepatite B/isolamento & purificação , Hepatite C/sangue , Hepatite C/epidemiologia , Humanos , RNA Viral/sangue , Sífilis/sangue , Sífilis/epidemiologia , Tailândia , Estados UnidosRESUMO
Neutralizing antibody responses elicited during infection generally confer protection from infection. Hepatitis C virus (HCV) encodes two glycoproteins E1 and E2 that are essential for virus entry and are the major target for neutralizing antibodies. To assess whether both glycoproteins are required for the generation of a neutralizing antibody response, rodents were immunized with a series of glycoproteins comprising full length and truncated versions. Guinea pigs immunized with HCV-1 genotype 1a E1E2p7, E1E2 or E2 generated high titer anti-glycoprotein antibody responses that neutralized the infectivity of HCVpp and HCVcc expressing gps of the same genotype as the immunizing antigen. Less potent neutralization of viruses bearing the genotype 2 strain J6 gps was observed. In contrast, immunized mice demonstrated reduced anti-gp antibody responses, consistent with their minimal neutralizing activity. Immunization with E2 alone was sufficient to induce a high titer response that neutralized HCV pseudoparticles (HCVpp) bearing diverse glycoproteins and cell culture grown HCV (HCVcc). The neutralization titer was reduced 3-fold by the presence of lipoproteins in human sera. Cross-competition of the guinea pig anti-E1E2 immune sera with a panel of epitope mapped anti-E2 monoclonal antibodies for binding E2 identified a series of epitopes within the N-terminal domain that may be immunogenic in the immunized rodents. These data demonstrate that recombinant E2 and E1E2 can induce polyclonal antibody responses with cross-reactive neutralizing activity, supporting the future development of prophylactic and therapeutic vaccines.