Compare and contrast: pediatric cancer versus adult malignancies.

Cancer is a leading cause of death in both adults and children, but in terms of absolute numbers, pediatric cancer is a relatively rare disease. The rarity of pediatric cancer is consistent with our current understanding of how adult malignancies form, emphasizing the view of cancer as a genetic disease caused by the accumulation and selection of unrepaired mutations over time. However, considering those children who develop cancer merely as stochastically "unlucky" does not fully explain the underlying aetiology, which is distinct from that observed in adults. Here, we discuss the differences in cancer genetics, distribution, and microenvironment between adult and pediatric cancers and argue that pediatric tumours need to be seen as a distinct subset with their own distinct therapeutic challenges. While in adults, the benefit of any treatment should outweigh mostly short-term complications, potential long-term effects have a much stronger impact in children. In addition, clinical trials must cope with low participant numbers when evaluating novel treatment strategies, which need to address the specific requirements of children.

AATF/Che-1 acts as a phosphorylation-dependent molecular modulator to repress p53-driven apoptosis.

Following genotoxic stress, cells activate a complex signalling network to arrest the cell cycle and initiate DNA repair or apoptosis. The tumour suppressor p53 lies at the heart of this DNA damage response. However, it remains incompletely understood, which signalling molecules dictate the choice between these different cellular outcomes. Here, we identify the transcriptional regulator apoptosis-antagonizing transcription factor (AATF)/Che-1 as a critical regulator of the cellular outcome of the p53 response. Upon genotoxic stress, AATF is phosphorylated by the checkpoint kinase MK2. Phosphorylation results in the release of AATF from cytoplasmic MRLC3 and subsequent nuclear translocation where AATF binds to the PUMA, BAX and BAK promoter regions to repress p53-driven expression of these pro-apoptotic genes. In xenograft experiments, mice exhibit a dramatically enhanced response of AATF-depleted tumours following genotoxic chemotherapy with adriamycin. The exogenous expression of a phospho-mimicking AATF point mutant results in marked adriamycin resistance in vivo. Nuclear AATF enrichment appears to be selected for in p53-proficient endometrial cancers. Furthermore, focal copy number gains at the AATF locus in neuroblastoma, which is known to be almost exclusively p53-proficient, correlate with an adverse prognosis and reduced overall survival. These data identify the p38/MK2/AATF signalling module as a critical repressor of p53-driven apoptosis and commend this pathway as a target for DNA damage-sensitizing therapeutic regimens.

Targeted endothelial gene delivery by ultrasonic destruction of magnetic microbubbles carrying lentiviral vectors.

PURPOSE: Site specific vascular gene delivery is a promising tool for treatment of cardiovascular diseases. By combining ultrasound mediated microbubble destruction with site specific magnetic targeting of lentiviruses, we aimed to develop a technique suitable for systemic application. METHODS: The magnetic nanoparticle coupling to lipid microbubbles was confirmed by absorbance measurements. Association of fluorescent lentivirus to magnetic microbubbles (MMB) was determined by microscopy and flow cytometry. Functionality and efficiency of GFP-encoding lentiviral MMB transduction was evaluated by endothelial (HMEC) GFP expression and cytotoxicity was measured by MTT reduction. RESULTS: Microbubbles with a mean diameter of 4.3 ± 0.04 µm were stable for 2 days, readily magnetizable and magnetically steerable in vitro and efficiently associated with lentivirus. Exposure of eGFP-encoding lentiviral MMB to human endothelial cells followed by application of an external static magnetic field (30 min) and ultrasonic destruction of the microbubbles did not markedly affect cellular viability. Finally, this combination led to a 30-fold increase in transduction efficiency compared to application of naked virus alone. CONCLUSIONS: By associating microbubbles with magnetic iron nanoparticles, these function as carriers for lentiviruses achieving tissue specific deposition at the site of interest.

Temozolomide and Other Alkylating Agents in Glioblastoma Therapy.

The alkylating agent temozolomide (TMZ) together with maximal safe bulk resection and focal radiotherapy comprises the standard treatment for glioblastoma (GB), a particularly aggressive and lethal primary brain tumor. GB affects 3.2 in 100,000 people who have an average survival time of around 14 months after presentation. Several key aspects make GB a difficult to treat disease, primarily including the high resistance of tumor cells to cell death-inducing substances or radiation and the combination of the highly invasive nature of the malignancy, i.e., treatment must affect the whole brain, and the protection from drugs of the tumor bulk-or at least of the invading cells-by the blood brain barrier (BBB). TMZ crosses the BBB, but-unlike classic chemotherapeutics-does not induce DNA damage or misalignment of segregating chromosomes directly. It has been described as a DNA alkylating agent, which leads to base mismatches that initiate futile DNA repair cycles; eventually, DNA strand breaks, which in turn induces cell death. However, while much is assumed about the function of TMZ and its mode of action, primary data are actually scarce and often contradictory. To improve GB treatment further, we need to fully understand what TMZ does to the tumor cells and their microenvironment. This is of particular importance, as novel therapeutic approaches are almost always clinically assessed in the presence of standard treatment, i.e., in the presence of TMZ. Therefore, potential pharmacological interactions between TMZ and novel drugs might occur with unforeseeable consequences.