Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 12 de 12
Filtrar
Más filtros

Banco de datos
País/Región como asunto
Tipo del documento
Intervalo de año de publicación
1.
N Engl J Med ; 383(11): 1018-1027, 2020 09 10.
Artículo en Inglés | MEDLINE | ID: mdl-32905674

RESUMEN

BACKGROUND: Factor VIII replacement products have improved the care of patients with hemophilia A, but the short half-life of these products affects the patients' quality of life. The half-life of recombinant factor VIII ranges from 15 to 19 hours because of the von Willebrand factor chaperone effect. BIVV001 (rFVIIIFc-VWF-XTEN) is a novel fusion protein designed to overcome this half-life ceiling and maintain high sustained factor VIII activity levels. Data are lacking on the safety and pharmacokinetics of single-dose BIVV001. METHODS: In this phase 1-2a open-label trial, we consecutively assigned 16 previously treated men (18 to 65 years of age) with severe hemophilia A (factor VIII activity, <1%) to receive a single intravenous injection of recombinant factor VIII at a dose of 25 IU per kilogram of body weight (lower-dose group) or 65 IU per kilogram (higher-dose group). This injection was followed by a washout period of at least 3 days. The patients then received a single intravenous injection of BIVV001 at the same corresponding dose of either 25 IU or 65 IU per kilogram. Adverse events and pharmacokinetic measurements were assessed. RESULTS: No inhibitors to factor VIII were detected and no hypersensitivity or anaphylaxis events were reported up to 28 days after the injection of single-dose BIVV001. The geometric mean half-life of BIVV001 was three to four times as long as that of recombinant factor VIII (37.6 hours vs. 9.1 hours in the lower-dose group and 42.5 vs. 13.2 hours in the higher-dose group); the area under the curve (AUC) for product exposure was six to seven times as great in the two dose groups (4470 hours vs. 638 hours × IU per deciliter in the lower-dose group and 12,800 hours vs. 1960 hours × IU per deciliter in the higher-dose group). After the injection of BIVV001 in the higher-dose group, the mean factor VIII level was in the normal range (≥51%) for 4 days and 17% at day 7, which suggested the possibility of a weekly interval between treatments. CONCLUSIONS: In a small, early-phase study involving men with severe hemophilia A, a single intravenous injection of BIVV001 resulted in high sustained factor VIII activity levels, with a half-life that was up to four times the half-life associated with recombinant factor VIII, an increase that could signal a new class of factor VIII replacement therapy with a weekly treatment interval. No safety concerns were reported during the 28-day period after administration. (Funded by Sanofi and Sobi; ClinicalTrials.gov number, NCT03205163.).


Asunto(s)
Factor VIII/metabolismo , Hemofilia A/tratamiento farmacológico , Proteínas Recombinantes de Fusión/administración & dosificación , Adulto , Relación Dosis-Respuesta a Droga , Factor VIII/antagonistas & inhibidores , Semivida , Hemofilia A/metabolismo , Humanos , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Estructura Molecular , Proteínas Recombinantes de Fusión/efectos adversos , Proteínas Recombinantes de Fusión/farmacocinética , Adulto Joven
3.
Expert Rev Hematol ; 16(sup1): 19-37, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36920859

RESUMEN

BACKGROUND: Decades of research have transformed hemophilia from severely limiting children's lives to a manageable disorder compatible with a full, active life, for many in high-income countries. The direction of future research will determine whether exciting developments truly advance health equity for all people with hemophilia (PWH). National Hemophilia Foundation (NHF) and American Thrombosis and Hemostasis Network conducted extensive inclusive all-stakeholder consultations to identify the priorities of people with inherited bleeding disorders and those who care for them. RESEARCH DESIGN AND METHODS: Working group (WG) 1 of the NHF State of the Science Research Summit distilled the community-identified priorities for hemophilia A and B into concrete research questions and scored their feasibility, impact, and risk. RESULTS: WG1 defined 63 top priority research questions concerning arthropathy/pain/bone health, inhibitors, diagnostics, gene therapy, the pediatric to adult transition of care, disparities faced by the community, and cardiovascular disease. This research has the potential to empower PWH to thrive despite lifelong comorbidities and achieve new standards of wellbeing, including psychosocial. CONCLUSIONS: Collaborative research and care delivery will be key to capitalizing on current and horizon treatments and harnessing technical advances to improve diagnostics and testing, to advance health equity for all PWH.


Hemophilia is the best known of the inherited bleeding disorders (BD). This is a rare condition that causes disproportionate bleeding, often into joints and vital organs. Factor replacement, injecting recombinant or plasma-based clotting factor products directly into the vein, became commonplace to control the disorder in the 1990s and 2000s. Prophylaxis, or injecting replacement factor every few days into people with hemophilia (PWH), has revolutionized patients' lives. In the last few years, other advances in new therapies have entered this space, such as non-factor replacement therapies and gene therapy. With many more research advances on the horizon, the National Hemophilia Foundation (NHF) initiated a State of the Science Research Summit in 2020. This event was attended by over 880 interested parties to help design an agenda of research priorities for inherited BDs for the next decade, based on community consultations. NHF formed multiple Working Groups (WG), each exploring a theme resulting from the community consultations, and presenting their results at the Summit. Led by 2 hematologists who manage and treat PWH daily, the 21-community member WG1 assigned to hemophilia A and B divided into 7 subgroups to identify and organize research priorities for different topic areas. The outcomes focused on prioritizing patients' needs, technological advances, and research in the areas of greatest potential for PWH and those who care for them. The results are a roadmap for the future execution of a research plan that truly serves the community.


Asunto(s)
Hemofilia A , Medicina , Adulto , Humanos , Niño , Estados Unidos , Hemofilia A/diagnóstico , Hemofilia A/terapia , Atención a la Salud , Investigación
4.
Physiol Genomics ; 43(18): 1038-48, 2011 Sep 22.
Artículo en Inglés | MEDLINE | ID: mdl-21771879

RESUMEN

Regulatory SNPs (rSNPs) reside primarily within the nonprotein coding genome and are thought to disturb normal patterns of gene expression by altering DNA binding of transcription factors. Nevertheless, despite the explosive rise in SNP association studies, there is little information as to the function of rSNPs in human disease. Serum response factor (SRF) is a widely expressed DNA-binding transcription factor that has variable affinity to at least 1,216 permutations of a 10 bp transcription factor binding site (TFBS) known as the CArG box. We developed a robust in silico bioinformatics screening method to evaluate sequences around RefSeq genes for conserved CArG boxes. Utilizing a predetermined phastCons threshold score, we identified 8,252 strand-specific CArGs within an 8 kb window around the transcription start site of 5,213 genes, including all previously defined SRF target genes. We then interrogated this CArG dataset for the presence of previously annotated common polymorphisms. We found a total of 118 unique CArG boxes harboring a SNP within the 10 bp CArG sequence and 1,130 CArG boxes with SNPs located just outside the CArG element. Gel shift and luciferase reporter assays validated SRF binding and functional activity of several new CArG boxes. Importantly, SNPs within or just outside the CArG box often resulted in altered SRF binding and activity. Collectively, these findings demonstrate a powerful approach to computationally define rSNPs in the human CArGome and provide a foundation for similar analyses of other TFBS. Such information may find utility in genetic association studies of human disease where little insight is known regarding the functionality of rSNPs.


Asunto(s)
Polimorfismo de Nucleótido Simple/genética , Secuencias Reguladoras de Ácidos Nucleicos/genética , Secuencia de Bases , Biología Computacional , Secuencia Conservada/genética , Genoma Humano/genética , Histonas/genética , Humanos , Internet , Anotación de Secuencia Molecular , Datos de Secuencia Molecular , Familia de Multigenes/genética , Regiones Promotoras Genéticas/genética , Reproducibilidad de los Resultados , Factor de Respuesta Sérica/metabolismo , Sitio de Iniciación de la Transcripción
5.
J Thromb Haemost ; 19(6): 1436-1446, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33587824

RESUMEN

BACKGROUND: Fitusiran, an investigational small interfering RNA therapy, reduces antithrombin production to rebalance hemostasis in people with hemophilia A or B, with or without inhibitors. OBJECTIVES: To evaluate the safety and efficacy of fitusiran treatment for people with moderate/severe hemophilia A or B with inhibitors. PATIENTS/METHODS: In this open-label phase 1, part D study, 17 males with hemophilia A or B with inhibitors received three once-monthly subcutaneous injections of fitusiran 50 mg (n = 6) or 80 mg (n = 11); followed for up to 112 days. Endpoints included safety (primary), pharmacokinetics/pharmacodynamics (secondary), annualized bleeding rate, and patient-reported outcomes (exploratory). RESULTS: The most common adverse event was injection site erythema (n = 8). No thrombotic events were reported. At nadir, mean (standard error of the mean [SEM]) antithrombin activity decreased from baseline by 82.0% (2.2) and 87.4% (0.7) in the 50 mg and 80 mg groups, respectively. Antithrombin reduction was associated with increased thrombin generation. 11/17 (64.7%) participants had no bleeds during the observation period (mean [standard deviation] 69.4 [16.3] days). Mean (SEM) changes from baseline in Haemophilia Quality of Life Questionnaire for Adults total (-9.2 [2.9]) and physical health (-12.3 [3.9]) domain scores suggested clinically meaningful improvement. CONCLUSIONS: Monthly fitusiran was generally well tolerated, lowered antithrombin levels from baseline, and resulted in improved thrombin generation. These preliminary results suggest that monthly fitusiran treatment may reduce bleeding episodes and improve quality of life in participants with hemophilia A or B with inhibitors.


Asunto(s)
Hemofilia A , Hemofilia B , Acetilgalactosamina , Adulto , Antitrombinas/efectos adversos , Hemofilia A/diagnóstico , Hemofilia A/tratamiento farmacológico , Hemofilia B/diagnóstico , Hemofilia B/tratamiento farmacológico , Hemofilia B/genética , Humanos , Masculino , Calidad de Vida , ARN Interferente Pequeño
7.
Cell Rep ; 22(8): 1945-1955, 2018 02 20.
Artículo en Inglés | MEDLINE | ID: mdl-29466723

RESUMEN

Sirtuin 3 (SIRT3) is a NAD+-dependent deacetylase downregulated in aging and age-associated diseases such as cancer and neurodegeneration and in high-fat diet (HFD)-induced metabolic disorders. Here, we performed a small-molecule screen and identified an unexpected metabolic vulnerability associated with SIRT3 loss. Azaserine, a glutamine analog, was the top compound that inhibited growth and proliferation of cells lacking SIRT3. Using stable isotope tracing of glutamine, we observed its increased incorporation into de novo nucleotide synthesis in SIRT3 knockout (KO) cells. Furthermore, we found that SIRT3 KO cells upregulated the diversion of glutamine into de novo nucleotide synthesis through hyperactive mTORC1 signaling. Overexpression of SIRT3 suppressed mTORC1 and growth in vivo in a xenograft tumor model of breast cancer. Thus, we have uncovered a metabolic vulnerability of cells with SIRT3 loss by using an unbiased small-molecule screen.


Asunto(s)
Nucleótidos/biosíntesis , Sirtuina 3/deficiencia , Bibliotecas de Moléculas Pequeñas/farmacología , Secuencia de Aminoácidos , Animales , Azaserina/farmacología , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Glutamina/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Ratones Noqueados , Ratones Desnudos , Regiones Promotoras Genéticas/genética , Transducción de Señal/efectos de los fármacos , Sirtuina 3/metabolismo , Regulación hacia Arriba/efectos de los fármacos
8.
Curr Protoc Hum Genet ; 87: 11.16.1-11.16.14, 2015 Oct 06.
Artículo en Inglés | MEDLINE | ID: mdl-26439713

RESUMEN

Thousands of alternative exons are spliced out of messenger RNA to increase protein diversity. High-throughput sequencing of short cDNA fragments (RNA-seq) generates a genome-wide snapshot of these post-transcriptional processes. RNA-seq reads yield insights into the regulation of alternative splicing by revealing the usage of known or unknown splice sites as well as the expression level of exons. Constitutive exons are never covered by split alignments, whereas alternative exonic parts are located within highly expressed splicing junctions. The ratio between reads including or excluding exons, also known as percent spliced in index (PSI), indicates how efficiently sequences of interest are spliced into transcripts. This protocol describes a method to calculate the PSI without prior knowledge of splicing patterns. It provides a quantitative, global assessment of exon usage that can be integrated with other tools that identify differential isoform processing. Novel, complex splicing events along a genetic locus can be visualized in an exon-centric manner and compared across conditions.


Asunto(s)
Empalme Alternativo , Secuenciación de Nucleótidos de Alto Rendimiento , Transcriptoma , Biología Computacional/métodos , Exones , Perfilación de la Expresión Génica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Anotación de Secuencia Molecular , Análisis de Secuencia de ARN , Programas Informáticos
9.
PLoS One ; 10(8): e0133751, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26241044

RESUMEN

Genome-scale expression data on the absolute numbers of gene isoforms offers essential clues in cellular functions and biological processes. Smooth muscle cells (SMCs) perform a unique contractile function through expression of specific genes controlled by serum response factor (SRF), a transcription factor that binds to DNA sites known as the CArG boxes. To identify SRF-regulated genes specifically expressed in SMCs, we isolated SMC populations from mouse small intestine and colon, obtained their transcriptomes, and constructed an interactive SMC genome and CArGome browser. To our knowledge, this is the first online resource that provides a comprehensive library of all genetic transcripts expressed in primary SMCs. The browser also serves as the first genome-wide map of SRF binding sites. The browser analysis revealed novel SMC-specific transcriptional variants and SRF target genes, which provided new and unique insights into the cellular and biological functions of the cells in gastrointestinal (GI) physiology. The SRF target genes in SMCs, which were discovered in silico, were confirmed by proteomic analysis of SMC-specific Srf knockout mice. Our genome browser offers a new perspective into the alternative expression of genes in the context of SRF binding sites in SMCs and provides a valuable reference for future functional studies.


Asunto(s)
Proteínas Musculares/genética , Miocitos del Músculo Liso/metabolismo , ARN Mensajero/genética , Elemento de Respuesta al Suero/genética , Factor de Respuesta Sérica/metabolismo , Navegador Web , Animales , Sitios de Unión , Proteínas Portadoras/genética , Colon/citología , Simulación por Computador , Biblioteca de Genes , Genes Reporteros , Proteínas Fluorescentes Verdes , Código de Histonas , Histonas/metabolismo , Canales Iónicos/genética , Yeyuno/citología , Ratones , Ratones Noqueados , Ratones Transgénicos , Especificidad de Órganos , Proteómica , Factor de Respuesta Sérica/deficiencia , Transcriptoma
10.
Science ; 349(6251): 982-6, 2015 Aug 28.
Artículo en Inglés | MEDLINE | ID: mdl-26315439

RESUMEN

Human mutations that truncate the massive sarcomere protein titin [TTN-truncating variants (TTNtvs)] are the most common genetic cause for dilated cardiomyopathy (DCM), a major cause of heart failure and premature death. Here we show that cardiac microtissues engineered from human induced pluripotent stem (iPS) cells are a powerful system for evaluating the pathogenicity of titin gene variants. We found that certain missense mutations, like TTNtvs, diminish contractile performance and are pathogenic. By combining functional analyses with RNA sequencing, we explain why truncations in the A-band domain of TTN cause DCM, whereas truncations in the I band are better tolerated. Finally, we demonstrate that mutant titin protein in iPS cell-derived cardiomyocytes results in sarcomere insufficiency, impaired responses to mechanical and ß-adrenergic stress, and attenuated growth factor and cell signaling activation. Our findings indicate that titin mutations cause DCM by disrupting critical linkages between sarcomerogenesis and adaptive remodeling.


Asunto(s)
Cardiomiopatía Dilatada/genética , Cardiomiopatía Dilatada/fisiopatología , Conectina/genética , Conectina/fisiología , Células Madre Pluripotentes Inducidas/fisiología , Mutación Missense , Miocitos Cardíacos/fisiología , Sarcómeros/fisiología , Agonistas Adrenérgicos beta/farmacología , Cardiomiopatía Dilatada/patología , Células Cultivadas , Conectina/química , Frecuencia Cardíaca , Humanos , Isoproterenol/farmacología , Proteínas Mutantes/química , Proteínas Mutantes/fisiología , Contracción Miocárdica , ARN/genética , ARN/metabolismo , Sarcómeros/ultraestructura , Análisis de Secuencia de ARN , Transducción de Señal , Estrés Fisiológico
11.
Congenit Heart Dis ; 7(2): 183-8, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-21718459

RESUMEN

Epicardial pacemaker leads placed during childhood are often not removed when transvenous systems are placed later in life. The risk of complications related to retained pacemaker leads and generators is not clear but is generally considered low. We report the case of a 23-year-old pregnant woman who presented with left upper quadrant pain at 20 weeks gestation. The patient was born with {S,L,L} transposition of the great arteries and had high-grade conduction disease in infancy compelling epicardial pacemaker placement. A standard transvenous pacemaker was placed at age 9 years, without removal of the epicardial system. The patient's abdominal pain was attributed to herniation of abdominal contents through a diaphragmatic defect at the site of the abandoned epicardial pacing wire. Her pain improved spontaneously but worsened later in pregnancy leading to repair of the diaphragmatic hernia via anterolateral thoracotomy at 30 weeks gestation. The procedure was well tolerated by mother and fetus. At 38 3/7 weeks gestation, the patient underwent uneventful delivery by cesarean section for breech presentation. This case illustrates the importance of multidisciplinary collaboration in the care of women with congenital heart disease.


Asunto(s)
Electrodos Implantados/efectos adversos , Bloqueo Cardíaco/terapia , Hernia Diafragmática , Marcapaso Artificial/efectos adversos , Complicaciones Cardiovasculares del Embarazo/etiología , Transposición de los Grandes Vasos/complicaciones , Femenino , Bloqueo Cardíaco/etiología , Hernia Diafragmática/diagnóstico por imagen , Hernia Diafragmática/etiología , Hernia Diafragmática/cirugía , Humanos , Pericardio , Embarazo , Complicaciones Cardiovasculares del Embarazo/diagnóstico por imagen , Complicaciones Cardiovasculares del Embarazo/cirugía , Radiografía , Toracotomía , Adulto Joven
12.
AMIA Annu Symp Proc ; : 269-73, 2003.
Artículo en Inglés | MEDLINE | ID: mdl-14728176

RESUMEN

As routine use of on-line progress notes in US Department of Veterans Affairs facilities grew rapidly in the past decade, health information managers and clinicians began to notice that authors sometimes copied text from old notes into new notes. Other sources of duplication were document templates that inserted boilerplate text or patient data into notes. Word-processing and templates aided the transition to electronic notes, but enabled author copying and sometimes led to lengthy, hard-to-read records stuffed with data already available on-line. Investigators at a VA center recognized for pioneering a fully electronic record system analyzed author copying and template-generated duplication with adapted plagiarism-detection software. Nine percent of progress notes studied contained copied or duplicated text. Most copying and duplication was benign, but some introduced misleading errors into the record and some seemed possibly unethical or potentially unsafe. High-risk author copying occurred once for every 720 notes, but one in ten electronic charts contained an instance of high-risk copying. Careless copying threatens the integrity of on-line records. Clear policies, practitioner consciousness-raising and development of effective monitoring procedures are recommended to protect the value of electronic patient records.


Asunto(s)
Sistemas de Registros Médicos Computarizados/normas , Garantía de la Calidad de Atención de Salud , Hospitales de Veteranos/organización & administración , Humanos , Auditoría Médica , Política Organizacional , Estados Unidos
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA