Targeting the inhibitor of apoptosis proteins as a novel therapeutic strategy in medulloblastoma.

Medulloblastoma is the most common malignant brain tumor of childhood. Novel therapeutic strategies are urgently needed to overcome cytotoxic resistance. We hypothesized that antiapoptotic signals contribute to resistance and that treatment with proapoptotic agents could increase the efficacy of conventional therapies.

A small-molecule IAP inhibitor overcomes resistance to cytotoxic therapies in malignant gliomas in vitro and in vivo.

We tested the use of the small-molecule Inhibitor of Apoptosis Protein (IAP) inhibitor LBW242 in combination with the standard-of-care therapies of irradiation and temozolomide for malignant gliomas. In vitro assays demonstrated that LBW242 enhanced the cytotoxic activity of radiotherapy, and clonogenic assays showed that the combination therapy led to a synergistic anti-glioma effect in multiple cell lines. Neurosphere assays revealed that the combination of radiation and LBW242 led to a pro-apoptotic effect in these glioma-initiating cell-enriched assays, with a corresponding inhibition of primary tumor cell growth.

High-frequency chest-wall oscillation in a noninvasive-ventilation-dependent patient with type 1 spinal muscular atrophy.

With the recent increased use of noninvasive ventilation, the prognoses of children with neuromuscular disease has improved significantly. However, children with muscle weakness remain at risk for recurrent respiratory infection and atelectasis. We report the case of a young girl with type 1 spinal muscular atrophy who was dependent on noninvasive ventilation, and in whom conventional secretion-clearance physiotherapy became insufficient to clear secretions.

ODC1 is a critical determinant of MYCN oncogenesis and a therapeutic target in neuroblastoma.

Neuroblastoma is a frequently lethal childhood tumor in which MYC gene deregulation, commonly as MYCN amplification, portends poor outcome. Identifying the requisite biopathways downstream of MYC may provide therapeutic opportunities. We used transcriptome analyses to show that MYCN-amplified neuroblastomas have coordinately deregulated myriad polyamine enzymes (including ODC1, SRM, SMS, AMD1, OAZ2, and SMOX) to enhance polyamine biosynthesis.

Mechanisms of embryonal tumor initiation: distinct roles for MycN expression and MYCN amplification.

The mechanisms causing persistence of embryonal cells that later give rise to tumors is unknown. One tumorigenic factor in the embryonal childhood tumor neuroblastoma is the MYCN protooncogene. Here we show that normal mice developed neuroblast hyperplasia in paravertebral ganglia at birth that completely regressed by 2 weeks of age.

FcgammaRIIA polymorphisms in Streptococcus pneumoniae infection.

Invasive pneumococcal disease continues to be a major cause of morbidity and mortality among children and adults worldwide. Effective host defence against Streptococcus pneumoniae depends on immunoglobulin G-mediated phagocytosis of the bacteria and it has been shown in vitro that the FcgammaRIIA polymorphism (FcgammaRIIA-R131 vs FcgammaRIIA-H131) determines the capacity of immunoglobulin G2-mediated phagocytosis via this receptor. In this study, we evaluated FcgammaRIIA polymorphisms in children with pneumococcal sepsis and a number of control groups in order to investigate a possible association of FcgammaRIIA genotypes with Streptococcus pneumoniae infection.