Observation and control in a model of a cell population affected by radiation

The effect of radiation on a cell population is described by a two-dimensional nonlinear system of differential equations. If the radiation rate is not too high, the system is known to have an asymptotically stable equilibrium. First, for the monitoring of this effect, the concept of observability is applied. For the case when the total number of cells is observed, without distinction between healthy and affected cells, a so-called observer system is constructed, which, at least near the equilibrium state, makes it possible to recover the dynamics of both the healthy and the affected cells, from the observation of the total number of cells without distinction. Results of simulations with illustrative data are also presented. If we want to control the system into a required new equilibrium state, and maintain this new equilibrium by a constant control, a technique of theory of optimal control can be applied to construct a feedback control system

A general framework for quantifying the effects of DNA repair inhibitors on radiation sensitivity as a function of dose

Purpose. Current methods for quantifying effects of DNA repair modifiers on radiation sensitivity assume a constant effect independent of the radiation dose received. The aim of this study was to develop and evaluate a modelling strategy by which radiation dose dependent effects of DNA repair inhibitors on clonogenic survival might be identified and their significance assessed. Methods. An indicator model that allowed quantification of the Sensitiser Effect on Radiation response as a function of Dose (SERD) was developed. This model was fitted to clonogenic survival data derived from human tumour and rodent fibroblast cell lines irradiated in the presence and absence of chemical inhibitors of poly(ADP-ribose) polymerase (PARP) activity. Results. PARP inhibition affected radiation response in a cell cycle and radiation dose dependent manner, and was also associated with significant radiation-independent effects on clonogenic survival. Application of the SERD method enabled identification of components of the radiation response that were significantly affected by PARP inhibition and indicated the magnitude of the effects on each component. Conclusion. The proposed approach improves on current methods of analysing effects of DNA repair modification on radiation response. Furthermore, it may be generalised to account for other parameters such as proliferation or dose rate to enable its use in the context of fractionated or continuous radiation exposures

NASA Light Emitting Diode Medical Applications from Deep Space to Deep Sea

This work is supported and managed through the NASA Marshall Space Flight Center-SBIR Program. LED-technology developed for NASA plant growth experiments in space shows promise for delivering light deep into tissues of the body to promote wound healing and human tissue growth. We present the results of LED-treatment of cells grown in culture and the effects of LEDs on patients’ chronic and acute wounds. LED-technology is also biologically optimal for photodynamic therapy of cancer and we discuss our successes using LEDs in conjunction with light-activated chemotherapeutic drugs

Eye Disease and Development

This research advances the hypothesis that cross-country variation in the historical incidence of eye disease has influenced the current global distribution of per capita income. The theory is that pervasive eye disease diminished the incentive to accumulate skills, thereby delaying the fertility transition and the take-off to sustained economic growth. In order to estimate the influence from eye disease incidence empirically, we draw on an important fact from the field of epidemiology: Exposure to solar ultraviolet B radiation (UVB-R) is an underlying determinant of several forms of eye disease; the most important being cataract, which is currently the leading cause of blindness worldwide. Using a satellite-based measure of UVB-R, we document that societies more exposed to UVB-R are poorer and underwent the fertility transition with a significant delay compared to the forerunners. These findings are robust to the inclusion of an extensive set of climate and geography controls. Moreover, using a global data set on economic activity for all terrestrial grid cells we show that the link between UVB-R and economic development survives the inclusion of country fixed effect.Comparative development, eye disease, climate

Results from a Phase 1 Study of Sodium Selenite in Combination with Palliative Radiation Therapy in Patients with Metastatic Cancer.

In preclinical studies, selenite had single agent activity and radiosensitized tumors in vivo. Here we report results from a Phase 1 trial in 15 patients with metastatic cancer treated with selenite (5.5 to 49.5 mg) orally as a single dose 2 hours before each radiation therapy (RT) treatment. Patients received RT regimens that were standard of care. The primary objective of the study was to assess the safety of this combination therapy. Secondary objectives included measurement of pharmacokinetics (PK) and evaluation of efficacy. Endpoints included assessment of PK, toxicity, tumor response, and pain before and after treatment. The half-life of selenite was 18.5 hours. There were no adverse events attributable to selenite until the 33 mg dose level, at which the primary toxicities were grade 1 GI side effects. One patient treated with 49.5 mg had grade 2 GI toxicity. Although this was not a DLT, it was felt that the highest acceptable dose in this patient population was 33 mg. Most patients had stabilization of disease within the RT fields, with some demonstrating objective evidence of tumor regression. Most patients had a marked improvement in pain and seven out of nine patients with prostate cancer had a decrease in PSA ranging from 11-78%. Doses up to 33 mg selenite were well tolerated in combination with RT. A randomized, well controlled study is needed at the 33 mg dose level to determine if selenite results in clinically meaningful improvements in the response to palliative RT

Improving treatment of glioblastoma: new insights in targeting cancer stem cells effectively

Glioblastoma is the most common primary malignant brain tumour in the adult population. Despite multimodality treatment with surgery, radiotherapy and chemotherapy, outcomes are very poor, with less than 15% of patients alive after two years. Increasing evidence suggests that glioblastoma stem cells (GSCs) are likely to play an important role in the biology of this disease and are involved in treatment resistance and tumour recurrence following standard therapy. My thesis aims to address two main aspects of this research area: 1) optimization of methods to evaluate treatment responses of GSCs and their differentiated counterparts (non-GSCs), with a particular focus on a tissue culture model that resembles more closely the tumoral niche; 2) characterization of cell division and centrosome cycle of GSCs, investigating possible differences between these cells and non-GSCs, that would allow the identification of targets for new therapeutic strategies against glioblastomas. In the first part of my project, I optimized a clonogenic survival assay, to compare sensitivity of GSCs and non-GSCs to various treatments, and I developed the use of a 3-dimentional tissue culture system, that allows analysis of features and radiation responses of these two subpopulations in the presence of specific microenvironmental factors from the tumoral niche. In the second part, I show that GSCs display mitotic spindle abnormalities more frequently than non-GSCs and that they have distinctive features with regards to the centrosome cycle. I also demonstrate that GSCs are more sensitive than non-GSCs to subtle changes in Aurora kinase A activity, which result in a rapid increase in polyploidy and subsequently in senescence, with a consistent reduction in clonogenic survival. Based on these findings, I propose that kinases involved in the centrosome cycle need to be explored as a novel strategy to target GSCs effectively and improve outcomes of glioblastoma patients

The effect of cyclophosphamide on salt taste in mice

Chemotherapy is a common cancer treatment, yet it has many severe side effects including altered taste. Patients report that salt taste is most affected by chemotherapy. The salt taste transduction system has yet to be fully elucidated. Type I taste cells are thought to be responsible in part for salt taste. The goal of this study was to determine how cyclophosphamide (CYP), a common chemotherapeutic agent, affects salt taste in mice. This involved two experiments. The first experiment examined how an induced conditioned taste aversion (CTA) to NaCl (salt) would change following CYP treatment. The second used a brief access test to observe how NaCl preference changed before and after either a single dose or multiple dose CYP treatment. We hypothesized that CYP would affect Type I taste cells leading to changes in salt preference, that CYP would reduce salt aversion, and that multiple doses would affect multiple salt taste cell types leading to more significant changes in salt preference. Our results demonstrated that after treatment, CYP mice had higher NaCl lick rates than control mice. This occurred in two phases, initially around day 8 and again around day 18. CTA mice maintained an aversion to NaCl following treatment, indicating a pathway protected from CYP disturbance. A single CYP injection and multiple CYP injections had the same effects on mice, indicating that this methodology is not useful in disturbing multiple salt taste cell populations. These data support that there are at least two salt taste transduction pathways in mice

Effect of variations in atelectasis on tumor displacement during radiation therapy for locally advanced lung cancer

Purpose Atelectasis (AT), or collapsed lung, is frequently associated with central lung tumors. We investigated the variation of atelectasis volumes during radiation therapy and analyzed the effect of AT volume changes on the reproducibility of the primary tumor (PT) position. Methods and materials Twelve patients with lung cancer who had AT and 10 patients without AT underwent repeated 4-dimensional fan beam computed tomography (CT) scans during radiation therapy per protocols that were approved by the institutional review board. Interfraction volume changes of AT and PT were correlated with PT displacements relative to bony anatomy using both a bounding box (BB) method and change in center of mass (COM). Linear regression modeling was used to determine whether PT and AT volume changes were independently associated with PT displacement. PT displacement was compared between patients with and without AT. Results The mean initial AT volume on the planning CT was 189 cm3 (37-513 cm3), and the mean PT volume was 93 cm3 (12-176 cm3). During radiation therapy, AT and PT volumes decreased on average 136.7 cm3 (20-369 cm3) for AT and 40 cm3 (−7 to 131 cm3) for PT. Eighty-three percent of patients with AT had at least one unidirectional PT shift that was greater than 0.5 cm outside of the initial BB during treatment. In patients with AT, the maximum PT COM shift was ≥0.5 cm in all patients and \u3e1 cm in 58% of patients (0.5-2.4 cm). Changes in PT and AT volumes were independently associated with PT displacement (P \u3c .01), and the correlation was smaller with COM (R2 = 0.58) compared with the BB method (R2 = 0.80). The median root mean squared PT displacement with the BB method was significantly less for patients without AT (0.45 cm) compared with those with AT (0.8cm, P = .002). Conclusions Changes in AT and PT volumes during radiation treatment were significantly associated with PT displacements that often exceeded standard setup margins. Repeated 3-dimensional imaging is recommended in patients with AT to evaluate for PT displacements during treatment. Summary This study analyzed 12 patients with atelectasis and 10 patients without atelectasis who underwent repeat 4-dimensional fan beam computed tomography during radiation therapy. Patients with atelectasis had significantly greater tumor displacements than patients without atelectasis, and these tumor displacements often exceeded standard setup margins. Patients with atelectasis may benefit from repeated 3-dimensional imaging during radiation therapy and possible replanning for large tumor displacements

Marrow-derived stromal cell delivery on fibrin microbeads can correct radiation-induced wound-healing deficits.

Skin that is exposed to radiation has an impaired ability to heal wounds. This is especially true for whole-body irradiation, where even moderate nonlethal doses can result in wound-healing deficits. Our previous attempts to administer dermal cells locally to wounds to correct radiation-induced deficits were hampered by poor cell retention. Here we improve the outcome by using biodegradable fibrin microbeads (FMBs) to isolate a population of mesenchymal marrow-derived stromal cells (MSCs) from murine bone marrow by their specific binding to the fibrin matrix, culture them to high density in vitro, and deliver them as MSCs on FMBs at the wound site. MSCs are retained locally, proliferate in site, and assist wounds in gaining tensile strength in whole-body irradiated mice with or without additional skin-only exposure. MSC-FMBs were effective in two different mouse strains but were ineffective across a major histocompatability barrier. Remarkably, irradiated mice whose wounds were treated with MSC-FMBs showed enhanced hair regrowth, suggesting indirect effect on the correction of radiation-induced follicular damage. Further studies showed that additional wound-healing benefit could be gained by administration of granulocyte colony-stimulating factor and AMD3100. Collagen strips coated with haptides and MSCs were also highly effective in correcting radiation-induced wound-healing deficits