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1.
Mol Cell ; 51(5): 632-46, 2013 Sep 12.
Artículo en Inglés | MEDLINE | ID: mdl-24034695

RESUMEN

The neurotrophin receptor TrkC was recently identified as a dependence receptor, and, as such, it triggers apoptosis in the absence of its ligand, NT-3. The molecular mechanism for apoptotic engagement involves the double cleavage of the receptor's intracellular domain, leading to the formation of a proapoptotic "killer" fragment (TrkC KF). Here, we show that TrkC KF interacts with Cobra1, a putative cofactor of BRCA1, and that Cobra1 is required for TrkC-induced apoptosis. We also show that, in the developing chick neural tube, NT-3 silencing is associated with neuroepithelial cell death that is rescued by Cobra1 silencing. Cobra1 shuttles TrkC KF to the mitochondria, where it promotes Bax activation, cytochrome c release, and apoptosome-dependent apoptosis. Thus, we propose that, in the absence of NT-3, the proteolytic cleavage of TrkC leads to the release of a killer fragment that triggers mitochondria-dependent apoptosis via the recruitment of Cobra1.


Asunto(s)
Apoptosis/fisiología , Mitocondrias/metabolismo , Proteínas Nucleares/metabolismo , Receptor trkC/metabolismo , Animales , Embrión de Pollo/metabolismo , Citocromos c/metabolismo , Citosol/metabolismo , Ganglios Espinales/citología , Ganglios Espinales/metabolismo , Silenciador del Gen , Humanos , Ratones , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Neuronas/metabolismo , Neurotrofina 3/metabolismo , Neurotrofina 3/farmacología , Proteínas Nucleares/genética , Fragmentos de Péptidos/metabolismo , Proteínas de Unión al ARN , Receptor trkC/genética , Proteína X Asociada a bcl-2/metabolismo
2.
Proc Natl Acad Sci U S A ; 110(8): 3017-22, 2013 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-23341610

RESUMEN

The TrkC neurotrophin receptor belongs to the functional dependence receptor family, members of which share the ability to induce apoptosis in the absence of their ligands. Such a trait has been hypothesized to confer tumor-suppressor activity. Indeed, cells that express these receptors are thought to be dependent on ligand availability for their survival, a mechanism that inhibits uncontrolled tumor cell proliferation and migration. TrkC is a classic tyrosine kinase receptor and therefore generally considered to be a proto-oncogene. We show here that TrkC expression is down-regulated in a large fraction of human colorectal cancers, mainly through promoter methylation. Moreover, we show that TrkC silencing by promoter methylation is a selective advantage for colorectal cell lines to limit tumor cell death. Furthermore, reestablished TrkC expression in colorectal cancer cell lines is associated with tumor cell death and inhibition of in vitro characteristics of cell transformation, as well as in vivo tumor growth. Finally, we provide evidence that a mutation of TrkC detected in a sporadic cancer is a loss-of-proapoptotic function mutation. Together, these data support the conclusion that TrkC is a colorectal cancer tumor suppressor.


Asunto(s)
Neoplasias del Colon/genética , Receptor trkC/genética , Apoptosis , Línea Celular Tumoral , Metilación de ADN , Regulación hacia Abajo , Genes Supresores de Tumor , Humanos , Ligandos , Regiones Promotoras Genéticas , Proto-Oncogenes Mas
3.
Eur J Surg Oncol ; 50(9): 108483, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38897095

RESUMEN

BACKGROUND AND AIMS: Alveolar soft part sarcoma (ASPS) is an ultra-rare chemo-resistant sarcoma in children, occurring preferentially in young adults. We aimed to describe and compare its clinical presentation and behaviour in children and young adults to determine whether the same therapeutic strategy should be addressed for both populations. METHODS: National retrospective multicentre study of children (0-18 years) vs. young adults (19-30 years) included in the "ConticaBase" sarcoma database, treated for ASPS between 2010 and 2019 with pathology reviewed via the NETSARC + network. RESULTS: Overall, 45 patients were identified, 19 children (42%) and 26 young adults (58%). All ASPS diagnoses were confirmed with TFE3 rearrangement by immunohistochemistry or FISH. All clinical characteristics were balanced between both populations with frequent metastases at diagnosis (8/19 vs. 10/26). The therapeutic strategy was based on surgery (17/19 vs. 21/26), radiotherapy (8/19 vs. 12/26) ± systemic treatment (8/19 vs. 9/26). In patients with initially localized disease, metastatic relapse occurred only in adults (8/16), whereas metastatic progression was present in both metastatic groups (5/8 vs. 8/10). After a median follow-up of 5.2 years (range, 0.2-12.2), 5-year EFS was 74% [95%CI, 56-96] vs. 47% [30-74] (p = 0.071) respectively, and 5-year OS was 95% [85-100] vs. 85% [70-100] (p = 0.84). For localized tumours, 5-year MFS was 100% [100-100] vs. 60% [39-91] (p = 0.005). The 5-year OS of all patients with metastasis at diagnosis was 80.2% (62.2%-100%). CONCLUSIONS: ASPS appears to have the overall same clinical characteristics, but a more aggressive behaviour in young adults than in children. However, despite frequent metastases at diagnosis, long-term survival is high in both groups. Overall, the same therapeutic strategies may be considered for both populations.


Asunto(s)
Sarcoma de Parte Blanda Alveolar , Humanos , Sarcoma de Parte Blanda Alveolar/terapia , Sarcoma de Parte Blanda Alveolar/patología , Adolescente , Masculino , Femenino , Adulto , Niño , Adulto Joven , Estudios Retrospectivos , Preescolar , Francia/epidemiología , Lactante , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Recién Nacido
4.
Pediatr Pulmonol ; 59(3): 642-651, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38088209

RESUMEN

RATIONALE: The use of long-term noninvasive respiratory support is increasing in children along with an extension of indications, in particular in children with central nervous system (CNS) disorders. OBJECTIVE: The aim of this study was to describe the characteristics of children with CNS disorders treated with long-term noninvasive respiratory support in France. METHODS: Data were collected from 27 French pediatric university centers through an anonymous questionnaire filled for every child treated with noninvasive ventilatory support ≥3 months on 1st June 2019. MAIN RESULTS: The data of 182 patients (55% boys, median age: 10.2 [5.4;14.8] years old [range: 0.3-25]) were collected: 35 (19%) patients had nontumoral spinal cord injury, 22 (12%) CNS tumors, 63 (35%) multiple disabilities, 26 (14%) central alveolar hypoventilation and 36 (20%) other CNS disorders. Seventy five percent of the patients were treated with noninvasive ventilation (NIV) and 25% with continuous positive airway pressure (CPAP). The main investigations performed before CPAP/NIV initiation were nocturnal gas exchange recordings, alone or coupled with poly(somno)graphy (in 29% and 34% of the patients, respectively). CPAP/NIV was started in an acute setting in 10% of the patients. Median adherence was 8 [6;10] hours/night, with 12% of patients using treatment <4 h/day. Nasal mask was the most common interface (70%). Airway clearance techniques were used by 31% of patients. CONCLUSION: CPAP/NIV may be a therapeutic option in children with CNS disorders. Future studies should assess treatment efficacy and patient reported outcome measures.


Asunto(s)
Enfermedades del Sistema Nervioso Central , Ventilación no Invasiva , Apnea Central del Sueño , Masculino , Niño , Humanos , Adolescente , Femenino , Ventilación no Invasiva/métodos , Presión de las Vías Aéreas Positiva Contínua/métodos , Resultado del Tratamiento , Enfermedades del Sistema Nervioso Central/complicaciones , Enfermedades del Sistema Nervioso Central/terapia
5.
J Pain ; 22(4): 440-453, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33227509

RESUMEN

Oral amitriptyline hydrochloride (amitriptyline) is ineffective against some forms of chronic pain and is often associated with dose-limiting adverse events. We evaluated the potential effectiveness of high-dose topical amitriptyline in a preliminary case series of chemotherapy-induced peripheral neuropathy patients and investigated whether local or systemic adverse events associated with the use of amitriptyline were present in these patients. We also investigated the mechanism of action of topically administered amitriptyline in mice. Our case series suggested that topical 10% amitriptyline treatment was associated with pain relief in chemotherapy-induced peripheral neuropathy patients, without the side effects associated with systemic absorption. Topical amitriptyline significantly increased mechanical withdrawal thresholds when applied to the hind paw of mice, and inhibited the firing responses of C-, Aß- and Aδ-type peripheral nerve fibers in ex vivo skin-saphenous nerve preparations. Whole-cell patch-clamp recordings on cultured sensory neurons revealed that amitriptyline was a potent inhibitor of the main voltage-gated sodium channels (Nav1.7, Nav1.8, and Nav1.9) found in nociceptors. Calcium imaging showed that amitriptyline activated the transient receptor potential cation channel, TRPA1. Our case series indicated that high-dose 10% topical amitriptyline could alleviate neuropathic pain without adverse local or systemic effects. This analgesic action appeared to be mediated through local inhibition of voltage-gated sodium channels. PERSPECTIVE: Our preliminary case series suggested that topical amitriptyline could provide effective pain relief for chemotherapy-induced peripheral neuropathy patients without any systemic or local adverse events. Investigation of the mechanism of this analgesic action in mice revealed that this activity was mediated through local inhibition of nociceptor Nav channels.


Asunto(s)
Amitriptilina/farmacología , Analgésicos no Narcóticos/farmacología , Antineoplásicos/efectos adversos , Dolor Nociceptivo/tratamiento farmacológico , Nociceptores/efectos de los fármacos , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Canal Catiónico TRPA1/efectos de los fármacos , Bloqueadores del Canal de Sodio Activado por Voltaje/farmacología , Canales de Sodio Activados por Voltaje/efectos de los fármacos , Administración Tópica , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Amitriptilina/administración & dosificación , Amitriptilina/efectos adversos , Analgésicos no Narcóticos/administración & dosificación , Analgésicos no Narcóticos/efectos adversos , Animales , Conducta Animal/efectos de los fármacos , Niño , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Canal de Sodio Activado por Voltaje NAV1.7 , Canal de Sodio Activado por Voltaje NAV1.8 , Canal de Sodio Activado por Voltaje NAV1.9 , Bloqueadores del Canal de Sodio Activado por Voltaje/administración & dosificación , Bloqueadores del Canal de Sodio Activado por Voltaje/efectos adversos , Adulto Joven
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