Gene Therapy for Pediatric Cancer: State of the Art and Future Perspectives.

While modern treatments have led to a dramatic improvement in survival for pediatric malignancy, toxicities are high and a significant proportion of patients remain resistant. Gene transfer offers the prospect of highly specific therapies for childhood cancer. "Corrective" genes may be transferred to overcome the genetic abnormalities present in the precancerous cell. Alternatively, genes can be introduced to render the malignant cell sensitive to therapeutic drugs. The tumor can also be attacked by decreasing its blood supply with genes that inhibit vascular growth. Another possible approach is to modify normal tissues with genes that make them more resistant to conventional drugs and/or radiation, thereby increasing the therapeutic index. Finally, it may be possible to attack the tumor indirectly by using genes that modify the behavior of the immune system, either by making the tumor more immunogenic, or by rendering host effector cells more efficient. Several gene therapy applications have already been reported for pediatric cancer patients in preliminary Phase 1 studies. Although no major clinical success has yet been achieved, improvements in gene delivery technologies and a better understanding of mechanisms of tumor progression and immune escape have opened new perspectives for the cure of pediatric cancer by combining gene therapy with standard therapeutic available treatments.

Dominance of the proximal coordinate frame in determining the locations of hippocampal place cell activity during navigation.

The place-specific activity of hippocampal cells provides downstream structures with information regarding an animal's position within an environment and, perhaps, the location of goals within that environment. In rodents, recent research has suggested that distal cues primarily set the orientation of the spatial representation, whereas the boundaries of the behavioral apparatus determine the locations of place activity. The current study was designed to address possible biases in some previous research that may have minimized the likelihood of observing place activity bound to distal cues. Hippocampal single-unit activity was recorded from six freely moving rats as they were trained to perform a tone-initiated place-preference task on an open-field platform. To investigate whether place activity was bound to the room- or platform-based coordinate frame (or both), the platform was translated within the room at an "early" and at a "late" phase of task acquisition (Shift 1 and Shift 2). At both time points, CA1 and CA3 place cells demonstrated room-associated and/or platform-associated activity, or remapped in response to the platform shift. Shift 1 revealed place activity that reflected an interaction between a dominant platform-based (proximal) coordinate frame and a weaker room-based (distal) frame because many CA1 and CA3 place fields shifted to a location intermediate to the two reference frames. Shift 2 resulted in place activity that became more strongly bound to either the platform- or room-based coordinate frame, suggesting the emergence of two independent spatial frames of reference (with many more cells participating in platform-based than in room-based representations).