RESUMO
Histiocytosis is a heterogeneous group of disease entities, comprised by two main categories, namely Langerhans and non-Langerhans cell histiocytoses. Central nervous system involvement in histiocytosis is considered very rare and is often secondary to affection of anatomically related bone structures and/or multi-organ disease. We present a never-before described case of rare childhood histiocytosis with hybrid features of Langerhans cell histiocytosis and juvenile xanthogranuloma confined to the central nervous system in a 2- and a half-year-old boy with distinct treatment response to clofarabine. The case also emphasizes the diagnostic significance of stereotactic brain biopsy.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Doenças do Sistema Nervoso Central/diagnóstico , Doenças do Sistema Nervoso Central/tratamento farmacológico , Clofarabina/uso terapêutico , Histiocitose/diagnóstico , Histiocitose/tratamento farmacológico , Biópsia , Encéfalo/patologia , Doenças do Sistema Nervoso Central/patologia , Pré-Escolar , Histiocitose/patologia , Humanos , Masculino , Técnicas EstereotáxicasRESUMO
Ovarian high-grade serous carcinomas (HGSCs) and invasive low-grade serous carcinomas (LGSCs) are considered to be distinct entities. In particular, LGSCs are thought to arise from non-invasive serous borderline ovarian tumors (SBOTs) and show poor responsiveness to conventional chemotherapy. The pro-apoptotic effects of CD40 ligand (CD40L) have been demonstrated in HGSC, though the underlying mechanisms are not fully understood. Conversely, the therapeutic potential of the CD40L-CD40 system has yet to be evaluated in LGSC. We now show that CD40 protein is focally expressed on tumor cells in two of five primary LGSCs compared with no expression in eight primary SBOTs. Treatment with CD40L or agonistic CD40 antibody decreased the viability of LGSC-derived MPSC1 and VOA1312 cells, but not SBOT3.1 cells. Small interfering RNA (siRNA) targeting CD40 was used to show that it is required for these reductions in cell viability. CD40L treatment increased cleaved caspase-3 levels in MPSC1 cells though, surprisingly, neither pan-caspase inhibitor nor caspase-3 siRNA reversed or even attenuated CD40L-induced cell death. In addition, CD40-induced cell death was not affected by knockdown of the mitochondrial proteins apoptosis-inducing factor (AIF) and endonuclease G (EndoG). Interestingly, CD40L-induced cell death was blocked by necrostatin-1, an inhibitor of receptor-interacting protein 1 (RIP1), and attenuated by inhibitors of RIP3 (GSK'872) or MLKL (mixed lineage kinase domain-like; necrosulfonamide). Our results indicate that the upregulation of CD40 may be relatively common in LGSC and that CD40 activation induces RIP1-dependent, necroptosis-like cell death in LGSC cells.
Assuntos
Antígenos CD40/genética , Ligante de CD40/farmacologia , Cistadenocarcinoma Seroso/genética , Regulação Neoplásica da Expressão Gênica , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Neoplasias Ovarianas/genética , Proteínas de Ligação a RNA/genética , Acrilamidas/farmacologia , Anticorpos/farmacologia , Fator de Indução de Apoptose/antagonistas & inibidores , Fator de Indução de Apoptose/genética , Fator de Indução de Apoptose/metabolismo , Antígenos CD40/agonistas , Antígenos CD40/antagonistas & inibidores , Antígenos CD40/metabolismo , Ligante de CD40/genética , Ligante de CD40/metabolismo , Caspase 3/genética , Caspase 3/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Progressão da Doença , Endodesoxirribonucleases/antagonistas & inibidores , Endodesoxirribonucleases/genética , Endodesoxirribonucleases/metabolismo , Feminino , Humanos , Imidazóis/farmacologia , Indóis/farmacologia , Gradação de Tumores , Complexo de Proteínas Formadoras de Poros Nucleares/antagonistas & inibidores , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Proteínas de Ligação a RNA/antagonistas & inibidores , Proteínas de Ligação a RNA/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/antagonistas & inibidores , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Transdução de Sinais , Sulfonamidas/farmacologiaRESUMO
Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS) is an inflammatory CNS disorder characterized by 1) subacute onset of cerebellar and brainstem symptoms, 2) peripontine contrast-enhancing perivascular lesions with a "salt-and-pepper" appearance on MRI, and 3) angiocentric, predominantly T-lymphocytic infiltration as revealed by brain biopsy. Inflammatory diseases including neuroinfections, CNS lymphoma and neurosarcoidosis must be excluded. Since CLIPPERS was described in 2010, many patients might have been misdiagnosed in the past. We therefore searched medical records from a large tertiary neurological center, the Department of Neurology at Rigshospitalet, Copenhagen University Hospital, for patients discharged between 1999 and 2013 with a diagnosis of "sarcoidosis with other localization", "other acute disseminating demyelination", "other demyelinating disease in the CNS" or "encephalitis, myelitis or encephalomyelitis". Of 206 identified patients, 24 had been examined by brain biopsy and were included for further evaluation. Following clinical, neuroradiological and neuropathological review, 3 patients (12.5%) were reclassified as having CLIPPERS. Median long-term follow-up was 75 months. The present results suggest that clinical re-evaluation of patients previously diagnosed with unspecified inflammatory demyelinating CNS disease or atypical neurosarcoidosis may increase the detection rate of CLIPPERS. Further, potentially severe neurological deficits and progressive parenchymal atrophy on MRI may suggest neurodegenerative features, which emphasizes the need for early immunomodulatory treatment.
Assuntos
Doenças do Sistema Nervoso Central/complicações , Doenças do Sistema Nervoso Central/tratamento farmacológico , Inflamação/complicações , Inflamação/tratamento farmacológico , Esteroides/uso terapêutico , Adulto , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Complexo CD3/metabolismo , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Medula Espinal/efeitos dos fármacos , Adulto JovemRESUMO
BACKGROUND: We have recently demonstrated that GnRH-I or -II can induce apoptosis in immortalized human granulosa cells by activating the caspase signaling cascade. Whether GnRH-I or -II can affect other regulators such as Bcl-2 family members, IGF-I, or gap junctions and the mechanisms involved are unknown. METHODS: Immortalized human granulosa cells were treated with GnRH-I, GnRH-II, IGF-I, or antide (a GnRH-I receptor antagonist), in various combinations. Cell proliferation and apoptotic changes were evaluated by cell counting, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and immunoblotting. Activated or total protein expression of IGF-I receptor, Akt, connexin 43 (Cx43), or caspase-3 with and without dominant-negative Akt (an Akt-suppressing vector), wortmannin (a phosphatidylinositol-3-kinase inhibitor), or Cx43 small interfering RNA transfection were assessed by immunoblotting. Gap junctional communication was determined by dye transfer assay. RESULTS: GnRH-I or -II inhibited cell proliferation, induced TUNEL-positive cells, and increased caspase-3 activities but had no effects on Bcl-2 family members. IGF-I increased cell proliferation, decreased TUNEL-positive cells and caspase-3 activities, and increased Akt activities, and these effects were attenuated by GnRH-I or -II. Effects of IGF-I on caspase-3 activities were attenuated by dominant-negative Akt or wortmannin. GnRH-I or -II decreased dye transfer, increased Cx43 phosphorylation, and increased caspases-3 activities even after Cx43 knockdown. CONCLUSION: GnRH-I or -II induces apoptosis in human granulosa cells through a caspase-3-dependent extrinsic pathway rather than a Bcl-2 family-dependent intrinsic pathway and attenuates the antiapoptotic action of IGF-I through Akt. Cx43-induced gap junctional changes do not initiate granulosa cell apoptosis but likely result from apoptosis induced by GnRH-I or -II.
Assuntos
Apoptose , Conexina 43/metabolismo , Hormônio Liberador de Gonadotropina/análogos & derivados , Hormônio Liberador de Gonadotropina/farmacologia , Células da Granulosa/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Apoptose/fisiologia , Linhagem Celular Transformada , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Conexina 43/genética , Regulação para Baixo/efeitos dos fármacos , Interações Medicamentosas , Feminino , Hormônio Liberador de Gonadotropina/metabolismo , Células da Granulosa/metabolismo , Células da Granulosa/patologia , Células da Granulosa/fisiologia , Humanos , Camundongos , Transdução de Sinais/efeitos dos fármacos , TransfecçãoRESUMO
E-cadherin is a cell-cell adhesion protein and tumor suppressor that is silenced in many malignancies. E-cadherin is thought to suppress tumor cell growth by antagonizing ß-catenin signaling. However, the role of E-cadherin in ovarian cancer progression is still controversial. In this study, we showed that loss of E-cadherin induced ovarian cancer cell growth and constitutive activation of phosphoinositide 3-kinase (PI3K)/Akt signaling by the inhibition of phosphatase and tensin homolog (PTEN) transcription through the downregulation of early growth response gene 1 (Egr1). In addition, immunofluorescence microscopy and T-cell factor promoter/luciferase reporter assays showed that E-cadherin loss was associated with enhanced nuclear ß-catenin signaling. Constitutive activation of PI3K/Akt signaling reinforced nuclear ß-catenin signaling by inactivating glycogen synthase kinase-3ß indicating cross-talk between the PI3K/Akt and ß-catenin signaling pathways. Finally, we found that E-cadherin negatively regulates tumor cell growth, in part, by positively regulating PTEN expression via ß-catenin-mediated Egr1 regulation, thus influencing PI3K/Akt signaling. In summary, endogenous E-cadherin inhibits PI3K/Akt signaling by antagonizing ß-catenin-Egr1-mediated repression of PTEN expression. Thus, the loss of E-cadherin itself may contribute to dysregulated PI3K/Akt signaling through its effects on PTEN, or it may exacerbate the frequent activation of PI3K/Akt signaling that occurs as a result of overexpression, mutation and/or amplification.
Assuntos
Caderinas/fisiologia , Proteína 1 de Resposta de Crescimento Precoce/fisiologia , Neoplasias Ovarianas/patologia , PTEN Fosfo-Hidrolase/genética , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , beta Catenina/fisiologia , Contagem de Células , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , PTEN Fosfo-Hidrolase/fisiologia , Transdução de Sinais , Transcrição GênicaRESUMO
We examined whether distinct Ca2+ stores differentially control basal and gonadotropin (GTH-II)-releasing hormone (GnRH)-evoked GTH-II release, long-term GTH-II secretion and contents, and GTH-II-beta mRNA expression in goldfish. Thapsigargin (Tg)-sensitive Ca2+ stores mediated neither caffeine-evoked GTH-II release, nor salmon (s)GnRH- and chicken (c)GnRH-II-stimulated secretion; the latter responses were previously shown to involve ryanodine (Ry)-sensitive Ca2+ stores. Surprisingly, Tg decreased basal GTH-II release. This response was attenuated by prior exposure to sGnRH and caffeine, but was insensitive to the phosphatase inhibitor okadaic acid, the inhibitor of constitutive release brefeldin A and cGnRH-II. GTH-II-beta mRNA expression was decreased at 24 h by 2 microm Tg, and by inhibiting (10 microm Ry) and stimulating (1 nm Ry) Ry receptors. Transient increases in GTH-II-beta mRNA were observed at 2 h and 12 h following 10 microm and 1 nm Ry treatment, respectively. Effects of Tg, Ry and GnRH on long-term GTH-II secretion, contents and apparent production differed from one another, and these changes were not well correlated with changes in GTH-II-beta mRNA expression. Our data show that GTH-II secretion, storage and transcription can be independently controlled by distinct Ca2+ stores.
Assuntos
Cálcio/metabolismo , Inibidores Enzimáticos/farmacologia , Hormônio Liberador de Gonadotropina/análogos & derivados , Hormônio Liberador de Gonadotropina/farmacologia , Gonadotropinas Hipofisárias/genética , Tapsigargina/farmacologia , Animais , Sinalização do Cálcio/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Exocitose/efeitos dos fármacos , Feminino , Expressão Gênica/efeitos dos fármacos , Carpa Dourada , Gonadotropinas Hipofisárias/metabolismo , Masculino , Hipófise/metabolismo , RNA Mensageiro/análise , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Vesículas Secretórias/metabolismoRESUMO
The goldfish brain contains at least two forms of gonadotropin-releasing hormone (GnRH): sGnRH and cGnRH-II. In goldfish sGnRH and cGnRH-II are present both in the brain and pituitary, and exert direct effects via specific GnRH receptors stimulating growth hormone (GH) and gonadotropin hormone (GtH) synthesis and secretion. In this study, we investigated the effects of sGnRH and cGnRH-II on GtH subunit (alpha, FSH-beta and LH-beta) and GH mRNA levels in the goldfish pituitary in vivo and in vitro. Injection of goldfish with sGnRH or cGnRH-II (4 microg/fish) stimulated GtH-alpha, FSH-beta and LH-beta mRNA levels after 24 h. For in vitro studies, goldfish pituitary fragments were treated continuously for 12 h with 10(-7) M sGnRH or cGnRH-II. Both sGnRH and cGnRH-II stimulated GtH-alpha, FSH-beta, LH-beta and GH mRNA levels, however, cGnRH-II appeared to have a more pronounced effect. Similar experiments were carried out using cultured dispersed goldfish pituitary cells. In this study, treatments for 12 h with 10(-7) M sGnRH or cGnRH-II also stimulated GtH and GH gene expression. The present results provide a basis for the investigation of the signal transduction pathways that mediate GnRH-induced changes in GtH subunit and GH mRNA levels in the goldfish pituitary.