RESUMO
There was a typo in author Andrew Wahba's name in the initial online publication. The original article has been corrected.
RESUMO
PURPOSE: Medulloblastoma (MB) is the most common malignant brain tumor in children. Recent studies have shown the ability of natural killer (NK) cells to lyse MB cell lines in vitro, but in vivo successes remain elusive and the efficacy and fate of NK cells in vivo remain unknown. METHODS: To address these questions, we injected MB cells into the cerebellum of immunodeficient mice and examined tumor growth at various days after tumor establishment via bioluminescence imaging. NK cells were labeled with a fluorine-19 (19F) MRI probe and subsequently injected either intratumorally or contralaterally to the tumor in the cerebellum and effect on tumor growth was monitored. RESULTS: The 19F probe efficiently labeled the NK cells and exhibited little cytotoxicity. Fluorine-19 MRI confirmed the successful and accurate delivery of the labeled NK cells to the cerebellum of the mice. Administration of 19F-labeled NK cells suppressed MB growth, with the same efficacy as unlabeled cells. Immunohistochemistry confirmed the presence of NK cells within the tumor, which was associated with induction of apoptosis in tumor cells. NK cell migration to the tumor from a distal location as well as activation of apoptosis was also demonstrated by immunohstochemistry. CONCLUSIONS: Our results show that NK cells present a novel opportunity for new strategies in MB treatment. Further, 19F-labeled NK cells can suppress MB growth while enabling 19F MRI to provide imaging feedback that can facilitate study and optimization of therapeutic paradigms.
Assuntos
Neoplasias Cerebelares/prevenção & controle , Monitoramento de Medicamentos/métodos , Radioisótopos de Flúor/uso terapêutico , Células Matadoras Naturais/transplante , Imageamento por Ressonância Magnética/métodos , Meduloblastoma/prevenção & controle , Animais , Apoptose , Proliferação de Células , Neoplasias Cerebelares/imunologia , Neoplasias Cerebelares/patologia , Humanos , Meduloblastoma/imunologia , Meduloblastoma/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Medulloblastoma is the most common malignant pediatric brain tumor. Current treatments including surgery, craniospinal radiation and high-dose chemotherapy have led to improvement in survival. However, the risk for recurrence as well as significant long-term neurocognitive and endocrine sequelae associated with current treatment modalities underscore the urgent need for novel tumor-specific, normal brain-sparing therapies. It has also provided the impetus for research focused on providing a better understanding of medulloblastoma biology. The expectation is that such studies will lead to the identification of new therapeutic targets and eventually to an increase in personalized treatment approaches.
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Neoplasias Encefálicas/terapia , Meduloblastoma/terapia , Animais , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Tomada de Decisão Clínica , Ensaios Clínicos como Assunto , Humanos , Meduloblastoma/diagnóstico , Meduloblastoma/genética , Meduloblastoma/metabolismoRESUMO
Positive selection is a critical T cell developmental checkpoint that is driven by TCR signals. Enhanced positive selection toward the CD4 lineage occurs in the absence of Ikaros. One explanation for this phenotype is that Ikaros establishes the TCR signaling threshold that must be overcome for positive selection to occur. In the current study, this possibility is explored through the use of CD3zeta ITAM transgenic mice that express a CD3 zeta-chain with zero, one, or three ITAMs and an MHC class II (DO11.10)- or MHC class I (H-Y)-restricted TCR transgene. Using this system, we demonstrate that in the absence of Ikaros, thymocytes are able to mature into the CD4 lineage with reduced TCR signaling potential compared with that required to drive the maturation of wild-type thymocytes. We also demonstrate that maturation into the CD8 lineage is enhanced under conditions of reduced TCR signaling potential in the absence of Ikaros.
Assuntos
Complexo CD3/genética , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular/imunologia , Fator de Transcrição Ikaros/deficiência , Receptores de Antígenos de Linfócitos T/imunologia , Motivos de Aminoácidos , Animais , Western Blotting , Complexo CD3/imunologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Linhagem da Célula/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Fator de Transcrição Ikaros/genética , Fator de Transcrição Ikaros/imunologia , Camundongos , Camundongos Transgênicos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/imunologia , Linfócitos T/citologia , Linfócitos T/imunologiaRESUMO
Susceptibilities of 12 clinical Mycobacterium tuberculosis isolates to acidified sodium nitrite (ASN) were compared. The results demonstrate that 8 of the 12 isolates exhibited enhanced survival levels in 1.5 mM ASN compared to levels in medium alone, suggesting that low concentrations of reactive nitrogen intermediates have a hormetic effect on M. tuberculosis in vitro.
