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1.
Ann Diagn Pathol ; 42: 92-95, 2019 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-31445409

RESUMO

OBJECTIVES: Immunohistochemistry (IHC) can be a useful adjunct in diagnostic breast pathology, but best practices have not been clearly established. We sought to compare the patterns of p63 utilization between general pathologists (GP) and subspecialized breast pathologists (BP), analyze diagnostic discrepancy rates, and identify types of lesions requiring immunohistochemistry. METHODS: The pathology database was searched over 6-year period to identify breast needle core biopsy cases utilizing p63 and subsequent excision results. RESULTS: P63 was ordered more frequently by BP (2.3% of cores) compared to GP (1.1% of cores, p = 0.0005). The most frequent utilization of p63 by GP for benign lesions (44.0%) followed by invasive carcinomas (36.0%) while BP most frequently ordered p63 on invasive carcinomas (49.5%) and DCIS (26.6%). CONCLUSIONS: While IHC use may be thought to be most helpful to those with less experience or knowledge in breast pathology, these results suggest that utilization is increased with subspecialty training.

3.
Mol Genet Metab ; 121(2): 70-79, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28501294

RESUMO

The design and conduct of clinical studies to evaluate the effects of novel therapies on central nervous system manifestations in children with neuronopathic mucopolysaccharidoses is challenging. Owing to the rarity of these disorders, multinational studies are often needed to recruit enough patients to provide meaningful data and statistical power. This can make the consistent collection of reliable data across study sites difficult. To address these challenges, an International MPS Consensus Conference for Cognitive Endpoints was convened to discuss approaches for evaluating cognitive and adaptive function in patients with mucopolysaccharidoses. The goal was to develop a consensus on best practice for the design and conduct of clinical studies investigating novel therapies for these conditions, with particular focus on the most appropriate outcome measures for cognitive function and adaptive behavior. The outcomes from the consensus panel discussion are reported here.


Assuntos
Cognição , Mucopolissacaridoses/terapia , Sistema Nervoso Central/fisiopatologia , Criança , Ensaios Clínicos como Assunto , Determinação de Ponto Final , Humanos , Mucopolissacaridoses/fisiopatologia , Mucopolissacaridose I/fisiopatologia , Mucopolissacaridose I/terapia , Mucopolissacaridose II/fisiopatologia , Mucopolissacaridose II/terapia , Mucopolissacaridose III/fisiopatologia , Mucopolissacaridose III/terapia , Doenças do Sistema Nervoso/terapia , Modalidades de Fisioterapia
4.
Mol Genet Metab ; 118(2): 65-9, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27132782

RESUMO

Well-defined and reliable clinical outcome assessments are essential for determining whether a drug provides clinically meaningful treatment benefit for patients. In 2015, FDA convened a workshop, "Assessing Neurocognitive Outcomes in Inborn Errors of Metabolism." Topics covered included special challenges of clinical studies of inborn errors of metabolism (IEMs) and other rare diseases; complexities of identifying treatment effects in the context of the dynamic processes of child development and disease progression; and the importance of natural history studies. Clinicians, parents/caregivers, and participants from industry, academia, and government discussed factors to consider when developing measures to assess treatment outcomes, as well as tools and methods that may contribute to standardizing measures. Many issues examined are relevant to the broader field of rare diseases in addition to specifics of IEMs.


Assuntos
Testes de Estado Mental e Demência/normas , Erros Inatos do Metabolismo/tratamento farmacológico , Avaliação de Resultados (Cuidados de Saúde) , Doenças Raras/tratamento farmacológico , Cuidadores , Criança , Desenvolvimento Infantil , Ensaios Clínicos como Assunto , Progressão da Doença , Humanos , National Institutes of Health (U.S.) , Pais , Tecnologia de Sensoriamento Remoto , Estados Unidos , United States Food and Drug Administration
5.
BMC Med ; 14: 39, 2016 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-26926908

RESUMO

In life-threatening conditions such as cancer and rare diseases, where there is no cure and no U.S. Food and Drug Administration (FDA)-approved therapy, patients sometimes seek access to an unapproved, experimental therapy through expanded access programs as their last, best hope for treatment to save their lives. Since the 1980s, the policies and the practice of expanded access have evolved, but a common challenge remains that there is no obligation, and often little incentive, for manufacturers to offer expanded access programs, especially for individual patients. In recent years, online campaigns seeking access to an experimental therapy have become more common, paralleling growth in and representing an intersection of social media, digital health, and patient advocacy.Mackey and Schoenfeld have examined the evolution of expanded access policy, practice, and trends, as well as case studies of online campaigns to access experimental therapies, to arrive at several recommendations for the future of expanded access. This commentary puts their paper in context, examines their recommendations, and suggests further reforms.Please see related article: https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-016-0568-8.


Assuntos
Ensaios de Uso Compassivo/legislação & jurisprudência , Defesa do Paciente/legislação & jurisprudência , Mídias Sociais/legislação & jurisprudência , Humanos
6.
Mol Genet Metab ; 117(2): 66-83, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26597321

RESUMO

The US Food and Drug Administration (FDA) and National Organization for Rare Disease (NORD) convened a public workshop titled "Immune Responses to Enzyme Replacement Therapies: Role of Immune Tolerance Induction" to discuss the impact of anti-drug antibodies (ADAs) on efficacy and safety of enzyme replacement therapies (ERTs) intended to treat patients with lysosomal storage diseases (LSDs). Participants in the workshop included FDA staff, clinicians, scientists, patients, industry, and advocacy group representatives. The risks and benefits of implementing prophylactic immune tolerance induction (ITI) to reduce the potential clinical impact of antibody development were considered. Complications due to immune responses to ERT are being recognized with increasing experience and lengths of exposure to ERTs to treat several LSDs. Strategies to mitigate immune responses and to optimize therapies are needed. Discussions during the workshop resulted in the identification of knowledge gaps and future areas of research, as well as the following proposals from the participants: (1) systematic collection of longitudinal data on immunogenicity to better understand the impact of ADAs on long-term clinical outcomes; (2) development of disease-specific biomarkers and outcome measures to assess the effect of ADAs and ITI on efficacy and safety; (3) development of consistent approaches to ADA assays to allow comparisons of immunogenicity data across different products and disease groups, and to expedite reporting of results; (4) establishment of a system to widely share data on antibody titers following treatment with ERTs; (5) identification of components of the protein that are immunogenic so that triggers and components of the immune responses can be targeted in ITI; and (6) consideration of early ITI in patients who are at risk of developing clinically relevant ADA that have been demonstrated to worsen treatment outcomes.


Assuntos
Hidrolases/uso terapêutico , Doenças por Armazenamento dos Lisossomos/tratamento farmacológico , Animais , Terapia de Reposição de Enzimas , Humanos , Hidrolases/imunologia , Tolerância Imunológica , Doenças por Armazenamento dos Lisossomos/imunologia , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/uso terapêutico
7.
FEBS Lett ; 580(1): 58-62, 2006 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-16343488

RESUMO

Zhangfei (ZF) is a basic region-leucine zipper protein that has been implicated in herpesvirus infection cycle and related cellular processes. Here we show both in vivo and in vitro data demonstrating that ZF is a novel cellular binding partner of activating transcription factor 4 (ATF4) (or CREB2). We found that ZF competed with ATF4 to form ATF4-ZF heterodimeric complexes through the bZIP regions. ZF enhanced ATF4 binding to the cAMP response element (CRE), and augmented activation of a CRE reporter by ATF4, in response to MEK1 activation. These results suggest an important role of ZF in the MEK1-ATF4 signaling pathway.


Assuntos
Fator 4 Ativador da Transcrição/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , MAP Quinase Quinase 1/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Elementos de Resposta/fisiologia , Fator 4 Ativador da Transcrição/genética , Fatores de Transcrição de Zíper de Leucina Básica/genética , AMP Cíclico/metabolismo , Células HeLa , Herpesviridae/genética , Herpesviridae/metabolismo , Infecções por Herpesviridae/genética , Infecções por Herpesviridae/metabolismo , Humanos , MAP Quinase Quinase 1/genética , Proteínas Nucleares , Estrutura Terciária de Proteína/fisiologia , Proteínas de Ligação a RNA , Fatores de Transcrição , Replicação Viral/fisiologia
8.
Biochem Biophys Res Commun ; 339(4): 1238-45, 2006 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-16352292

RESUMO

Zhangfei is a basic region-leucine zipper (bZIP) transcription factor identified through its interaction with a herpesvirus-related host cell factor HCF1 (C1). Unlike most bZIP proteins, the mammalian Zhangfei protein does not bind DNA as homodimers. It is believed due to the absence of an asparagine residue in the basic region, which forms the DNA-recognition motif, NxxAAxxCR, in all bZIP proteins. Here, we report the identification and characterization of a novel Zhangfei homologue in Takifugu rubripes, which has an intact DNA-recognition motif by sequence analysis. We found that the pufferfish Zhangfei (pZF) appeared to have all the functional domains known in human Zhangfei, including the conserved HCF1-binding motif; however, pZF did not appear to bind DNA either. These findings suggest that the distinct property of the Zhangfei basic region is conserved during the evolution of vertebrates and that Zhangfei requires interaction with other proteins to regulate transcription from target promoters.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/química , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , DNA/química , DNA/metabolismo , Tetraodontiformes/metabolismo , Sequência de Aminoácidos , Animais , Fatores de Transcrição de Zíper de Leucina Básica/genética , Sítios de Ligação , Sequência Conservada , DNA/genética , Humanos , Dados de Sequência Molecular , Ligação Proteica , Homologia de Sequência de Aminoácidos , Tetraodontiformes/genética
9.
Biochem Biophys Res Commun ; 331(1): 113-9, 2005 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-15845366

RESUMO

Luman (or LZIP, CREB3) is a transcription factor with an endoplasmic reticulum (ER)-transmembrane domain. Due to its structural similarities with ATF6, it is thought that Luman might also be involved in cellular stress responses. Here we report that Luman can bind and activate transcription from the consensus unfolded protein response element (UPRE). Mutations that disrupted the binding of Luman to the UPREs impaired its ability to activate transcription from these sites. Overexpression of Luman stimulated transcription of EDEM, a downstream effector of the mammalian unfolded protein response involved in ER-associated degradation (ERAD). Unlike ATF6, however, Luman was not activated by proteolytic cleavage in response to endoplasmic reticulum stressors such as tunicamycin and thapsigargin. These results suggest that the activation of ERAD by Luman is likely through a pathway different from the common ER stress response, and that additional factor(s) are required for the activation of this Luman-mediated pathway.


Assuntos
Elementos de Resposta , Fatores de Transcrição/metabolismo , Ativação Transcricional , Sítios de Ligação , Sequência Consenso , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Retículo Endoplasmático/efeitos dos fármacos , Humanos , Proteínas de Membrana/biossíntese , Proteínas de Membrana/genética , Mutação , Dobramento de Proteína , RNA Mensageiro/biossíntese
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