Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
1.
J Neurooncol ; 153(2): 225-237, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33963961

RESUMEN

PURPOSE: Tumor infiltration by immunosuppressive myeloid cells or tumor-associated macrophages (TAMs) contributes to tumor progression and metastasis. In contrast to their adult counterparts, higher TAM signatures do not correlate with aggressive tumor behavior in pediatric brain tumors. While prominent TAM infiltrates exist before and after radiation, the degree to which irradiated macrophages and microglia support progression or leptomeningeal metastasis remains unclear. Patients with medulloblastoma often present with distant metastases and tumor recurrence is largely incurable, making them prime candidates for the study of novel approaches to prevent neuroaxis dissemination and recurrence. METHODS: Macrophage depletion was achieved using CSF-1 receptor inhibitors (CSF-1Ri), BLZ945 and AFS98, with or without whole brain radiation in a variety of medulloblastoma models, including patient-derived xenografts bearing Group 3 medulloblastoma and a transgenic Sonic Hedgehog (Ptch1+/-, Trp53-/-) medulloblastoma model. RESULTS: Effective reduction of microglia, TAM, and spinal cord macrophage with CSF-1Ri resulted in negligible effects on the rate of local and spinal recurrences or survival following radiation. Results were comparable between medulloblastoma subgroups. While notably few tumor-infiltrating lymphocytes (TILs) were detected, average numbers of CD3+ TILs and FoxP3+ Tregs did not differ between groups following treatment and tumor aggressiveness by Ki67 proliferation index was unaltered. CONCLUSION: In the absence of other microenvironmental influences, medulloblastoma-educated macrophages do not operate as tumor-supportive cells or promote leptomeningeal recurrence in these models. Our data add to a growing body of literature describing a distinct immunophenotype amid the medulloblastoma microenvironment and highlight the importance of appropriate pediatric modeling prior to clinical translation.


Asunto(s)
Neoplasias Cerebelosas , Meduloblastoma , Transducción de Señal , Niño , Proteínas Hedgehog , Humanos , Factor Estimulante de Colonias de Macrófagos , Macrófagos , Proteínas Tirosina Quinasas Receptoras , Receptor de Factor Estimulante de Colonias de Macrófagos , Microambiente Tumoral
2.
Gynecol Oncol ; 157(1): 106-114, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31954538

RESUMEN

OBJECTIVE: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) and SMARCA4-deficient undifferentiated uterine sarcoma (SMARCA4-DUS) are rare and aggressive tumors, primarily affecting pre- and perimenopausal women. Inactivating SMARCA4 mutations are thought to be the driving molecular events in the majority of these tumors. Here, we report the clinical course of a family with germline SMARCA4 mutation and compare large cohorts of these rare tumor types. METHODS: We extracted clinico-pathological medical record data for the family with germline SMARCA4 mutation. Clinico-genomic data from SCCOHT and SMARCA4-DUS cohorts were retrospectively extracted from the archives of a large CLIA-certified reference molecular laboratory. RESULTS: We identified a single family with an inherited germline SMARCA4 mutation, in which two different family members developed either SCCOHT or SMARCA4-DUS, both of whom died within one year of diagnosis, despite aggressive surgical, chemotherapy and immunotherapy treatment. Retrospective comparative analysis of large SCCOHT (n = 48) and SMARCA4-DUS (n = 17) cohorts revealed that SCCOHT patients were younger (median age: 28.5 vs. 49.0) and more likely to have germline SMARCA4 alterations (37.5% vs. 11.8%) than SMARCA4-DUS patients. CONCLUSIONS: Growing understanding of the role SMARCA4 plays in the pathogenesis of these rare cancers may inform recommended genetic testing and counseling in families with these tumor types.


Asunto(s)
Carcinoma de Células Pequeñas/genética , ADN Helicasas/genética , Mutación de Línea Germinal , Hipercalcemia/genética , Proteínas Nucleares/genética , Neoplasias Ováricas/genética , Sarcoma/genética , Factores de Transcripción/genética , Neoplasias Uterinas/genética , Adulto , Carcinoma de Células Pequeñas/patología , Carcinoma de Células Pequeñas/terapia , Diferenciación Celular/fisiología , Estudios de Cohortes , ADN Helicasas/deficiencia , Femenino , Humanos , Hipercalcemia/patología , Hipercalcemia/terapia , Persona de Mediana Edad , Proteínas Nucleares/deficiencia , Neoplasias Ováricas/patología , Neoplasias Ováricas/terapia , Pronóstico , Estudios Retrospectivos , Sarcoma/patología , Sarcoma/terapia , Factores de Transcripción/deficiencia , Neoplasias Uterinas/patología , Neoplasias Uterinas/terapia
3.
Gynecol Oncol ; 157(2): 357-366, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32156473

RESUMEN

OBJECTIVE: Genomic alterations of BCOR via ZC3H7B-BCOR fusion or BCOR internal tandem duplication (ITD) define a subset of endometrial stromal sarcoma (ESS). The goals of this study were to: 1) determine the molecular landscape of BCOR-rearranged ESS, 2) to identify novel BCOR fusion gene partners in ESS and their associated clinicopathological characteristics, and 3) to potentially unravel targetable genomic alterations in BCOR-mutated ESS. METHODS: A retrospective database search of a CLIA-certified molecular laboratory was performed for uterine sarcomas that contained BCOR rearrangements or BCOR ITD. The cases were previously assayed by comprehensive genomic profiling via both DNA- and RNA-based targeted next generation sequencing during the course of clinical care. Clinicopathological and genomic data was centrally re-reviewed. RESULTS: We identify largest cohort of BCOR-rearranged ESS to date (n = 40), which included 31 cases with canonical ZC3H7B-BCOR fusion as well as 8 cases with novel BCOR gene rearrangement partners, such as BCOR-L3MBTL2, EP300-BCOR, BCOR-NUTM2G, BCOR-RALGPS1, BCOR-MAP7D2, RGAG1-BCOR, ING3-BCOR, BCOR-NUGGC, KMT2D-BCOR, CREBBP-BCOR and 1 case with BCOR internal rearrangement. Re-review of cases with novel rearrangements demonstrated sarcomas with spindle, epithelioid or small round cell components and frequent myxoid stromal change. Comprehensive genomic profiling revealed high frequency of CDK4 and MDM2 amplification in 38% and 45% of BCOR-rearranged cases, respectively, and homozygous deletion of CDKN2A, which encodes an inhibitor of CDK4 in 28% of cases. Notably, CDK4 and MDM2 amplification was absent in all cases from 15 different ESS cases harboring BCOR ITD. CONCLUSIONS: Alterations of CDK4 pathway members, for which targeted therapy is clinically available (i.e. palbociclib), via CDK4 amplification or CDKN2A loss, contributes to the pathogenesis of BCOR-rearranged uterine sarcomas, which may have therapeutic implications.


Asunto(s)
Quinasa 4 Dependiente de la Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Represoras/genética , Sarcoma/genética , Neoplasias Uterinas/genética , Adulto , Estudios de Cohortes , Bases de Datos Genéticas , Femenino , Amplificación de Genes , Reordenamiento Génico , Genómica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Leiomiosarcoma/genética , Leiomiosarcoma/patología , Inestabilidad de Microsatélites , Persona de Mediana Edad , Estudios Retrospectivos , Sarcoma/patología , Sarcoma Estromático Endometrial/genética , Sarcoma Estromático Endometrial/patología , Neoplasias Uterinas/patología
4.
J Alzheimers Dis ; 6(6): 605-22; discussion 673-81, 2004 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-15665401

RESUMEN

Intraneuronal deposition of microtubule-associated protein tau in filamentous aggregates constitutes a pathological hallmark of neurofibrillary degeneration that is characteristic of Alzheimer's disease (AD) and related disorders known collectively as tauopathies. Formation of such fibril inclusions, consisting of hyperphosphorylated tau in multiple isoforms, correlates with the severity of cognitive decline in AD. How neurofibrillary pathology evolves in tauopathy remains unclear at present, but availability of a cellular model with robust tau aggregation will permit experimental scrutiny of the mechanistic process leading to such neurodegeneration. Through the use of a serial transfection strategy in conjunction with a tau minigene construct, we succeeded in generating conditional transfectants of human neuronal lineage that overproduce wild-type human brain tau in isoforms 4R0N, 3R1N and 4R1N via TetOff and ecdysone inducible expression mechanisms. Such transgenic overexpression of tau in multiple isoforms facilitated the assembly of filamentous tau aggregates that exhibit immunoreactivities, physicochemical properties, and ultrastructural attributes reminiscent of those found in human tauopathies. The conditional tau transfectants thus provide us with a useful tool to elucidate the molecular and cellular events leading to neurofibrillary degeneration and a convenient means to test hypothetical mechanisms implicated in the etiopathogenesis of AD and related tauopathies.


Asunto(s)
Ovillos Neurofibrilares/metabolismo , Ovillos Neurofibrilares/patología , Neuronas/metabolismo , Neuronas/patología , Proteínas tau/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Anticuerpos Monoclonales/inmunología , Encéfalo/inmunología , Encéfalo/metabolismo , Encéfalo/patología , Agregación Celular/genética , Células Clonales , Trastornos del Conocimiento/genética , Trastornos del Conocimiento/patología , Cartilla de ADN , Técnica del Anticuerpo Fluorescente , Humanos , Immunoblotting , Inmunoglobulina G/inmunología , Proteínas Asociadas a Microtúbulos/metabolismo , Degeneración Nerviosa/genética , Degeneración Nerviosa/metabolismo , Degeneración Nerviosa/patología , Ovillos Neurofibrilares/inmunología , Neuronas/inmunología , Fosforilación , Transfección , Proteínas tau/genética , Proteínas tau/inmunología
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA