The schistosome excretory system: a key to regulation of metabolism, drug excretion and host interaction

There is a gulf between the enormous information content of the various genome projects and the understanding of the life of the parasite in the host. In vitro studies with adult Schistosoma mansoni using several substrates suggest that the excretory system contains both P-glycoproteins and multiresistance proteins. If both these families of protein were active in vivo, they could regulate parasite metabolism and be responsible for the excretion of drugs. During skin penetration, membrane-impermeant molecules of a wide range of molecular weights can be taken into the cercaria and schistosomulum through the nephridiopore, through the surface membrane or through both. We speculate that this uptake process might stimulate novel signalling pathways involved in growth and development.

A study of the biological effects of modulated 6 MV radiation fields

The delivery of spatially modulated radiation fields has been shown to impact on in vitro cell survival responses. To study the effect of modulated fields on cell survival, dose response curves were determined for human DU-145 prostate, T98G glioma tumour cells and normal primary AGO-1552 fibroblast cells exposed to modulated and non-modulated field configurations delivered using a 6 MV Linac with multi-leaf collimator. When exposed to uniform fields delivered as a non-modulated or modulated configuration, no significant differences in survival were observed with the exception of DU-145 cells at a dose of 8 Gy (p = 0.024). Survival responses were determined for exposure to non-uniform-modulated beams in DU-145 and T98G and showed no deviation from the survival response observed following uniform non-modulated exposures. The results of these experiments indicate no major deviation in response to modulated fields compared to uniform exposures.

Radiation and the genome: from risks to opportunities for therapeutic exploitation

On 1 December 2009, the Radiation and Cancer Biology Committee of the British Institute of Radiology (BIR) held a one-day conference on the theme of radiation and the genome. Talks covered genomic instability (its importance for radiation-induced carcinogenesis and potential for exploitation in the development of novel chemoradiotherapy combinations) and the prospects of exploiting knowledge of the genome to understand how individual genetic variation can impact on a patient's likelihood of developing toxicity following radiotherapy. The meeting also provided an overview of stem cell biology and its relevance for radiotherapy in terms of both tumour (somatic) and normal tissue (germline) sensitivity to radiation. Moreover, the possibility of manipulating stem cells to reduce radiation-induced normal tissue damage was considered.

Molecular biology: the key to personalised treatment in radiation oncology?

We know considerably more about what makes cells and tissues resistant or sensitive to radiation than we did 20 years ago. Novel techniques in molecular biology have made a major contribution to our understanding at the level of signalling pathways. Before the “New Biology” era, radioresponsiveness was defined in terms of physiological parameters designated as the five Rs. These are: repair, repopulation, reassortment, reoxygenation and radiosensitivity. Of these, only the role of hypoxia proved to be a robust predictive and prognostic marker, but radiotherapy regimens were nonetheless modified in terms of dose per fraction, fraction size and overall time, in ways that persist in clinical practice today. The first molecular techniques were applied to radiobiology about two decades ago and soon revealed the existence of genes/proteins that respond to and influence the cellular outcome of irradiation. The subsequent development of screening techniques using microarray technology has since revealed that a very large number of genes fall into this category. We can now obtain an adequately robust molecular signature, predicting for a radioresponsive phenotype using gene expression and proteomic approaches. In parallel with these developments, functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) can now detect specific biological molecules such as haemoglobin and glucose, so revealing a 3D map of tumour blood flow and metabolism. The key to personalised radiotherapy will be to extend this capability to the proteins of the molecular signature that determine radiosensitivity.

Differential modulation of a radiation-induced bystander effect in glioblastoma cells by pifithrin-alpha and wortmannin

The implication of radiation-induced bystander effect (RIBE) for both radiation protection and radiotherapy has attracted significant attention, but a key question is how to modulate the RIBE. The present study found that, when a fraction of glioblastoma cells in T98G population were individually targeted with precise helium particles through their nucleus, micronucleus (MN) were induced and its yield increased non-linearly with radiation dose. After co-culturing with irradiated cells, additional MN could be induced in the non-irradiated bystander cells and its yield was independent of irradiation dose, giving direct evidence of a RIBE. Further results showed that the RIBE could be eliminated by pifithrin-alpha (p53 inhibitor) but enhanced by wortmannin (PI3K inhibitor). Moreover, it was found that nitric oxide (NO) contributed to this RIBE, and the levels of NO of both irradiated cells and bystander cells could be extensively diminished by pifithrin-alpha but insignificantly reduced by wortmannin. Our results indicate that RIBE can be modulated by p53 and PI3K through a NO-dependent and NO-independent pathway, respectively. (C) 2009 Elsevier B.V. All rights reserved.

The modification of PLA and PLGA using electron-beam radiation

The degradable polymers polylactide (PLA) and polylactide-co-glycolide (PLGA) have found widespread use in modern medical practice. However, their slow degradation rates and tendency to lose strength before mass have caused problems. The aim of this study was to ascertain whether treatment with e-beam radiation could address these problems. Samples of PLA and PLGA were manufactured and placed in layered stacks, 8.1 mm deep, before exposure to 50 kGy of e-beam radiation from a 1.5 MeV accelerator. Gel permeation chromatography testing showed that the molecular weight of both materials was depth-dependent following irradiation, with samples nearest to the treated surface showing a reduced molecular weight. Samples deeper than 5.4 mm were unaffected. Computer modeling of the transmission of a 1.5 MeV e-beam in these materials corresponded well with these findings. An accelerated mass-loss study of the treated materials found that the samples nearest the irradiated surface initiated mass loss earlier, and at later stages showed an increased percentage mass loss. It was concluded that e-beam radiation could modify the degradation of bioabsorbable polymers to potentially improve their performance in medical devices, specifically for improved orthopedic fixation.