Radiobiological effects of altering dose rate in filter-free photon beams.

To validate that altering radiotherapy dose rate through either changing pulse repetition frequency or instantaneous dose rate does not have an effect on cell survival, two human carcinoma and a hamster lung cell line were irradiated with various beam settings. Varian TrueBeam linac with a flattening filter free mode of operation was used for all experiments. The results obtained indicate that either method of changing dose rate has no effect on cell survival in the three cell lines studied. Filtered and filter free modes were also compared in treatments with protracted dose delivery which significantly increases overall treatment time. Cell survival indicated no difference between filter and filter free beam delivery in any of the protraction schemes. An increase in survival was seen in both modes upon protracting dose delivery to 15, 30 or 60 min rather than delivering acutely. Further, analysis of induced DNA double-strand breaks via the γH2AX assay showed no difference between filtered and unfiltered beams. The following study suggests that increasing dose rate is an acceptable manner of decreasing radiotherapy treatment time that does not have any detrimental effects on in vitro cell eradication.

SU-E-T-01: Applications of 6MV FFF Photon Beams in Optimizing Radiobiological Response for Respiratory-Gated Liver SBRT.

PURPOSE: To establish a radiobiological basis for gated stereotactic body radiotherapy of primary and metastatic liver cancers using volumetric arc radiotherapy in a flattening filter free (FFF) mode. METHODS: Human cervical carcinoma, SiHa, non-small cell lung carcinoma, H460, and Chinese hamster V79 cells were irradiated in a water bath with 6MV photons from a Varian TrueBeam linear accelerator. To establish dose-response and its sensitivity to dose rate following acute irradiation, doses of 2, 4, 6, 8 and 10 Gy were delivered in FFF mode at 400 and 1200 MU/min. To investigate whether removal of the flattening filter affects cell response, doses of 5 and 10 Gy were delivered to SiHa and H460 cells in FFF and filtered modes at 400 MU/min. Finally, to assess the effect of protracting dose delivery by gating, a dose of 10 Gy was delivered to SiHa and H460 cells acutely and also over 15, 30 and 60 min. RESULTS: Dose-response over doses examined was independent of dose rate in FFF mode. Differences in cell survival following irradiation in FFF and filtered modes were not significant. However a significant increase in survival for both H460 and SiHa cells was observed for 15 min split-dose irradiation compared to acute irradiation but further increase in irradiation time to 60 min did not affect cell survival. CONCLUSIONS: Dose rate and presence of a flattening filter showed no effect on cell survival, however, survival was significantly affected when dose delivery time was protracted to that typical of conformal field therapy. Volumetric arc based gated SBRT may be beneficial for tumor cell kill, though the gating window and duty cycle have to be balanced against the effect of dose delivery protraction. Research Support (Varian Medical Systems).

Chronic fatigue syndrome--a neuroimmunological model.

The aetiological and pathophysiological basis of chronic fatigue syndrome (CFS) remains a controversial field of inquiry in the research community. While CFS and similar disease conditions such as fibromyalgia (FM) and post-infectious encephalopathy have been the focus of intense scrutiny for the past 20 years, results of research were often contradictory and a cohesive pathological model has remained elusive. However, recent developments in understanding the unique immunophysiology of the brain may provide important clues for the development of a truly comprehensive explanation of the pathology of CFS. We argue that CFS pathogenesis lies in the influence of peripheral inflammatory events on the brain and the unique immunophysiology of the central nervous system. There is also evidence that CFS patients have a relative immunodeficiency that predisposes to poor early control of infection that leads to chronic inflammatory responses to infectious insults. The neurological and endocrine changes have been described in CFS patients support the view that CFS has an inflammatory pathogenesis when considered as a whole. An inflammatory model of disease also provides an explanation for the marked female sex bias associated with CFS. This review therefore posits the hypothesis that CFS as a disease of long-term inflammatory processes of the brain. We will also provide an investigative framework that could be used to justify the use of anti-TNF biological agents as a reliable and effective treatment approach to CFS, a syndrome that to date remains frustratingly difficult for both patients and health care professionals to manage.

The mode of binding of potential transition-state analogs to acetylcholinesterase.

Phenylacetone, 4-phenyl-2-butanone, and 4-oxopentyltrimethylammonium chloride were tested as potential transition state analogs for eel acetylcholinesterase (acetylcholine hydrolase, EC 3.1.1.7). Phenylacetone is a competitive inhibitor of the enzyme but not a transition state analog, since its binding constant is similar to that for the substrate phenyl acetate. 4-Phenyl-2-butanone binds 6-18 times more tightly than the inhibitors 4-phenyl-2-butanol and N-benzylacetamide and the substrate benzyl acetate and also blocks inactivation of the enzyme with methanesulfonyl fluoride. However, its binding is independent of pH in the range 5-7.5, whereas both V and V/Km for benzyl acetate hydrolysis decrease with decreasing pH in this range. These data indicate a specific but weak interaction between the ketone carbonyl and the enzyme, but probably do not justify considering this compound a transition state analog. 4-oxopentyltrimethylammonium iodide has previously been shown to bind about 125 times more strongly than the substrate acetylcholamine. It also binds about 375 times more strongly than the alcohol 4-hydroxypentyltrimethylammonium iodide. Furthermore, the ketone protects the enzyme from inactivation by methansulfony fluoride, while the corresponding quaternary ammonium alcohol accelerates this inactivation reaction. This additional information confirms that the ketone is a transition state analog.