Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 5 de 5
Filtrar
1.
Clin Exp Rheumatol ; 38 Suppl 127(5): 26-34, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33025894

RESUMO

OBJECTIVES: This study aimed to characterise the burden of illness of patients with inadequately controlled hereditary periodic fevers (HPFs), during and outside of flares. It was focused on the burden to the patients and also considered the wider impact on their caregivers and families. METHODS: The target population was patients or caregivers of patients with clinically/genetically confirmed colchicine resistant FMF (crFMF), mevalonate kinase deficiency/hyperimmunoglobinaemia D with periodic fever syndrome (MKD/HIDS) or TRAPS, who were expected to flare at least once in a 6-month period based on patient history. Disease burden was captured during and between flares using an electronic diary (e-diary) with questions on patient functioning, emotional/social well-being and pain, using validated instruments. RESULTS: HPF-related symptoms such as fever, joint, muscle or bone pain and tiredness and fatigue were reported by patients both during and outside of a flare. The SF-10 Health Survey (SF-10v2) (paediatric patients) and SF-12 Health Survey (SF-12v2) (adult patients) showed that flares negatively impacted patients' psychosocial and physical health. Negative effect of on-flare status on health utility index score assessed by the Short-Form Six-Dimension (SF-6D) was significant only for crFMF patients. Furthermore, the Sheehan Disability Score (SDSv3) showing the on-flare status resulted in significant functional impairment in all 3 disease cohorts through assessment of impact on work/school, social and family life. CONCLUSIONS: crFMF, MKD/HIDS and TRAPS negatively affected the quality of life (QoL) of adult and paediatric patients, including their physical, mental, psychosocial health, and social functioning. There remains, however, a high number of unmet needs for these patients to reduce their disease burden.


Assuntos
Doenças Hereditárias Autoinflamatórias , Deficiência de Mevalonato Quinase , Adulto , Criança , Efeitos Psicossociais da Doença , Febre , Doenças Hereditárias Autoinflamatórias/diagnóstico , Humanos , Deficiência de Mevalonato Quinase/diagnóstico , Deficiência de Mevalonato Quinase/epidemiologia , Qualidade de Vida
2.
J Cell Sci ; 124(Pt 16): 2797-805, 2011 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-21807944

RESUMO

GDNF (glial cell line-derived neurotrophic factor) promotes the differentiation and migration of GABAergic neuronal precursors of the medial ganglionic eminence (MGE). These functions are dependent on the GPI-anchored receptor GFRα1, but independent of its two known transmembrane receptor partners RET and NCAM. Here we show that soluble GFRα1 is also able to promote differentiation and migration of GABAergic MGE neurons. These activities require endogenous production of GDNF. Although GDNF responsiveness is abolished in Gfra1(-/-) neurons, it can be restored upon addition of soluble GFRα1, a result that is only compatible with the existence of a previously unknown transmembrane signaling partner for the GDNF-GFRα1 complex in GABAergic neurons. The roles of two candidate transmembrane receptors previously implicated in GABAergic interneuron development--MET, a receptor for hepatocyte growth factor (HGF), and ErbB4, the neuregulin receptor--were examined. GDNF did not induce the activation of either receptor, nor did inhibition of MET or ErbB4 impair GDNF activity in GABAergic MGE neurons. Unexpectedly, however, inhibition of MET or HGF per se promoted neuronal differentiation and migration and enhanced the activity of GDNF on MGE neurons. These effects were dependent on endogenous GDNF and GFRα1, suggesting that MET signaling negatively regulates GDNF activity in the MGE. In agreement with this, Met mutant MGE neurons showed enhanced responses to GDNF and inhibition of MET or HGF increased Gfra1 mRNA expression in MGE cells. In vivo, expression of MET and GFRα1 overlapped in the MGE, and a loss-of-function mutation in Met increased Gfra1 expression in this region. Together, these observations demonstrate the existence of a novel transmembrane receptor partner for the GDNF-GFRα1 complex and uncover an unexpected interplay between GDNF-GFRα1 and HGF-MET signaling in the early diversification of cortical GABAergic interneuron subtypes.


Assuntos
Neurônios GABAérgicos/metabolismo , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Eminência Mediana/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Animais , Anticorpos Bloqueadores/farmacologia , Células COS , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Chlorocebus aethiops , Receptores ErbB/antagonistas & inibidores , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/patologia , Gânglios/patologia , Fator Neurotrófico Derivado de Linhagem de Célula Glial/imunologia , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Indóis/farmacologia , Eminência Mediana/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação/genética , Piperazinas/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/genética , Quinazolinas , Receptor ErbB-4 , Transdução de Sinais/genética , Sulfonamidas/farmacologia , Tirfostinas/farmacologia
3.
Drug Discov Today ; 28(11): 103773, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37730103

RESUMO

Neoantigen cancer vaccines harbor promise as next-generation immuno-oncology therapies, whereby cancer vaccines are tailored to the patient's tumor antigen and represent the future of personalized cancer therapy. While several biotech companies have ongoing development programs, little has been published about the true commercial potential of these innovative therapies and the challenges these products will face upon regulatory approval. In this paper, we provide an overview of neoantigen cancer vaccine development programs and discuss the commercial environment these therapies will face upon launch.


Assuntos
Vacinas Anticâncer , Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Vacinas Anticâncer/uso terapêutico , Antígenos de Neoplasias , Imunoterapia , Medicina de Precisão
4.
J Biol Chem ; 285(41): 31867-75, 2010 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-20682772

RESUMO

The signaling mechanisms by which neurotrophic receptors regulate neuronal survival and axonal growth are still incompletely understood. In the receptor tyrosine kinase RET, a receptor for GDNF (glial cell line-derived neurotrophic factor), the functions of the majority of tyrosine residues that become phosphorylated are still unknown. Here we have identified the protein-tyrosine phosphatase SHP2 as a novel direct interactor of RET and the first effector known to bind to phosphorylated Tyr(687) in the juxtamembrane region of the receptor. We show that SHP2 is recruited to RET upon ligand binding in a cooperative fashion, such that both interaction with Tyr(687) and association with components of the Tyr(1062) signaling complex are required for stable recruitment of SHP2 to the receptor. SHP2 recruitment contributes to the ability of RET to activate the PI3K/AKT pathway and promote survival and neurite outgrowth in primary neurons. Furthermore, we find that activation of protein kinase A (PKA) by forskolin reduces the recruitment of SHP2 to RET and negatively affects ligand-mediated neurite outgrowth. In agreement with this, mutation of Ser(696), a known PKA phosphorylation site in RET, enhances SHP2 binding to the receptor and eliminates the effect of forskolin on ligand-induced outgrowth. Together, these findings establish SHP2 as a novel positive regulator of the neurotrophic activities of RET and reveal Tyr(687) as a critical platform for integration of RET and PKA signals. We anticipate that several other phosphotyrosines of unknown function in neuronal receptor tyrosine kinases will also support similar regulatory functions.


Assuntos
Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Proteínas Proto-Oncogênicas c-ret/metabolismo , Transdução de Sinais/fisiologia , Animais , Células COS , Chlorocebus aethiops , Colforsina/farmacologia , Proteínas Quinases Dependentes de AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Fator Neurotrófico Derivado de Linhagem de Célula Glial/farmacologia , Camundongos , Mutação , Células NIH 3T3 , Células PC12 , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-ret/genética , Ratos , Transdução de Sinais/efeitos dos fármacos
5.
Melanoma Manag ; 6(4): MMT33, 2019 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-31871622

RESUMO

AIM: To describe treatment patterns among patients with stage III melanoma who underwent surgical excision in years 2011-2016, and assess outcomes among patients who subsequently received systemic adjuvant therapy versus watch-and-wait. METHODS: Chart review of 380 patients from 17 melanoma centers in North America, South America and Europe. RESULTS: Of 129 (34%) patients treated with adjuvant therapy, 85% received interferon α-2b and 56% discontinued treatment (mostly due to adverse events). Relapse-free survival was significantly longer for patients treated with adjuvant therapy versus watch-and-wait (hazard ratio = 0.63; p < 0.05). There was considerable heterogeneity in adjuvant treatment schedules and doses. Similar results were found in patients who received interferon-based adjuvant therapy. CONCLUSION: Adjuvant therapies with better safety/efficacy profiles will improve clinical outcomes in patients with stage III melanoma.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA