RESUMO
Cord blood (CB) natural killer (NK) cells are promising effector cells for tumor immunotherapy but are currently limited by immune-suppressive cytokines in the tumor microenvironment, such as transforming growth factor (TGF-ß). We observed that TGF-ß inhibits expression of activating receptors such as NKG2D and DNAM1 and decreases killing activity against glioblastoma tumor cells through inhibition of perforin secretion. To overcome the detrimental effects of TGF-ß, we engrafted a dominant negative TGF-ß receptor II (DNRII) on CB-derived NK cells by retroviral transduction and evaluated their ability to kill glioblastoma cells in the presence of TGF-ß. After manufacture using Good Manufacturing Practice-compliant methodologies and transduction with DNRII, CB-derived DNRII-transduced NK cells expanded to clinically relevant numbers and retained both their killing ability and their secretion of interferon-γ upon activation. More important, these cells maintained both perforin expression and NKG2D/DNMA1 expression in the presence of TGF-ß allowing for recognition and killing of glioblastoma tumor cells. Hence, NK cells expressing a DNRII should have a functional advantage over unmodified NK cells in the presence of TGF-ß-secreting tumors and may be an important therapeutic approach for patients with cancer.
Assuntos
Neoplasias Encefálicas/terapia , Sangue Fetal/citologia , Terapia Genética/métodos , Glioblastoma/terapia , Imunoterapia Adotiva/métodos , Células Matadoras Naturais/transplante , Proteínas Serina-Treonina Quinases/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Neoplasias Encefálicas/imunologia , Linhagem Celular Tumoral , Citocinas/metabolismo , Sangue Fetal/imunologia , Sangue Fetal/transplante , Genes Dominantes , Glioblastoma/imunologia , Humanos , Interferon gama/metabolismo , Células Jurkat , Células K562 , Células Matadoras Naturais/citologia , Células Matadoras Naturais/metabolismo , Perforina/metabolismo , Proteínas Serina-Treonina Quinases/genética , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Fatores de Crescimento Transformadores beta/genética , Fator de Crescimento Transformador beta/metabolismoRESUMO
Encephalocraniocutaneous lipomatosis (ECCL) is a rare congenital syndrome with an unknown etiology. Since 1970, around 60 cases have been reported in English literature. ECCL is usually classified by cutaneous lesions and non-progressive intracranial or spinal lipomas; however three cases of ECCL associated with low grade glioma (LGG) have been described. We report on the fourth case of LGG in a patient with ECCL; a grade II pilocytic astrocytoma with pilomyxoid features in a 3-month-old male, the youngest in literature.
Assuntos
Astrocitoma/diagnóstico , Oftalmopatias/diagnóstico , Lipomatose/diagnóstico , Síndromes Neurocutâneas/diagnóstico , Astrocitoma/terapia , Terapia Combinada , Oftalmopatias/terapia , Humanos , Lactente , Lipomatose/terapia , Masculino , Síndromes Neurocutâneas/terapia , Resultado do TratamentoRESUMO
We report a case of a four-year-old male who presented with symptoms of brainstem compression and lower cranial nerve neuropathies. MRI revealed a large, pre-pontine mass causing brainstem compression with an uncertain intra-axial component. Using diffusion tensor imaging (DTI) tractography and other imaging modalities, we were able to confirm that the lesion was extra-axial and did not involve the corticospinal tracts. In addition, DTI tractography illustrated that corticospinal tracts were displaced to the right obligating a left-sided approach. Upon resection, the mass was identified as a pre-pontine, extra-axial neurenteric cyst (NEC), which represents a rare finding in the pediatric population. The patient ultimately did well following the drainage and resection of the cyst wall and had excellent recovery. In this paper, we discuss the pathophysiology of and treatment options for NECs and explain how DTI tractography in our case assisted in planning the surgical approach.
Assuntos
Neoplasias Encefálicas/cirurgia , Imagem de Tensor de Difusão , Defeitos do Tubo Neural/cirurgia , Neurocirurgia/métodos , Ponte/cirurgia , Neoplasias Encefálicas/patologia , Pré-Escolar , Citocinas/metabolismo , Seguimentos , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Defeitos do Tubo Neural/patologiaRESUMO
Tumors of the CNS are the most common solid tumors diagnosed in childhood. As technology and research in cancer care are advancing, more specialties are involved in the diagnosis, treatment and follow-up of children with brain tumors. Multidisciplinary clinics have become the standard of care for cancer care throughout the USA, and specialty clinics focused on particular cancer types are gaining attention in improving the patient outcomes and satisfaction. We will discuss the role of multidisciplinary clinics, in an attempt to create preliminary guidelines on establishing and maintaining a multidisciplinary brain tumor clinic in order to optimize the care of the patients and their families.
Assuntos
Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/terapia , Pediatria , Adolescente , Neoplasias Encefálicas/mortalidade , Cuidadores/psicologia , Criança , Feminino , Humanos , Estudos Longitudinais , Masculino , Cuidados PaliativosRESUMO
CONTEXT: Proliferating cells reprogram their cellular glucose metabolism to meet the bioenergetic and biosynthetic demands and to maintain cellular redox homeostasis. Pyruvate kinase M (PKM) is a critical regulator of this metabolic reprogramming. However, whether estradiol-17ß (E2) reprograms cellular metabolism to support proliferation of human primary endometrial stromal cells (hESCs) and the molecular basis of this reprogramming are not well understood. OBJECTIVES: Our objectives were to study whether E2 induces reprogramming of glucose metabolism in hESCs and to investigate the potential roles of PKM2 in E2-induced metabolic reprogramming and proliferation of these cells. METHODS: The oxygen consumption rate and extracellular acidification rate were assessed by a Seahorse XF24 analyzer. PKM2 expression was assessed by real-time RT-PCR and immunoblotting. RESULTS: E2 induces a Warburg-like glucose metabolism in hESCs by inducing the expression of PKM. E2 also enhanced PKM splicing into the PKM2 isoform by upregulating the c-Myc-hnRNP axis. Furthermore, E2 induces PKM2 oxidation, phosphorylation, and nuclear translocation. In addition to its glycolytic function, PKM2 physically interacted with estrogen receptor-α (ERα) and functioned as an ERα coactivator. Small-molecule PKM2 activators ameliorated ERα transcriptional activity and abrogated the E2-induced hESC proliferation. CONCLUSIONS: We show for the first time that E2-induced hESC proliferation is associated with a shift in glucose metabolism toward aerobic glycolysis, and the molecular basis for this metabolic shift is linked to the effects of E2 on PKM2. In addition, PKM2 acts as a transcriptional coactivator for ERα and small-molecule PKM2 activators inhibit ERα transcriptional activity and reduce E2-induced cell proliferation.