The cell division cycle is regulated through both transcriptional and post-transcriptional mechan... more The cell division cycle is regulated through both transcriptional and post-transcriptional mechanisms. The altered expression of a number of genes at the mRNA level is known to be essential for progression through the cell cycle, however, a comprehensive gene expression profile of human cells remains to be completed. Here we sought to monitor the differential gene expression of genes after the transition of G2 cells into G1 prior to the restriction point. GeneChip containing microarrays of oligonucleotides corresponding to over 12 000 human genes were employed to profile differential gene expression in G1 and G2. After three independent experiments the resultant data was filtered and a set of genes was compiled based on at least threefold-altered expression, no background noise in determining expression and observation in all experiments. Our analysis identified 154 genes that were elevated in G2 phase of cells as compared to early G1 phase including 15 novel genes. This number incl...
The notion of translational research has gained considerable currency over the past few years. Wh... more The notion of translational research has gained considerable currency over the past few years. While such an approach promises great scientific and clinical advances, the penumbra of translational research tends to incorporate prioritizing scientific projects based upon their potential for translation; tight financial connections between sponsors, scientists and clinical investigators; and sometimes research involving biological approaches for which there is little experience determining safety. It is these aspects of translational research that raise some serious ethical challenges. In this report, we examine three specific areas that raise ethical questions: (1) the potential implications of prioritizing research objectives based on the potential for translation; (2) cautions related to moving from bench to bedside (and back again); and (3) unique questions for translational research initiatives in academic medical centers. Based on this examination, it is clear that the financial and ethical costs as well as benefits of taking a translational approach need to be considered. In the meantime, exquisite attention needs to be paid whenever translational research is likely to affect the traditional fiduciary responsibilities of scientists, clinicians and institutions to research subjects, patients and students. Successful mechanisms that might be developed to address any untoward effects should be shared and evaluated.
The notion of translational research has gained considerable currency over the past few years. Wh... more The notion of translational research has gained considerable currency over the past few years. While such an approach promises great scientific and clinical advances, the penumbra of translational research tends to incorporate prioritizing scientific projects based upon their potential for translation; tight financial connections between sponsors, scientists and clinical investigators; and sometimes research involving biological approaches for which there is little experience determining safety. It is these aspects of translational research that raise some serious ethical challenges. In this report, we examine three specific areas that raise ethical questions: (1) the potential implications of prioritizing research objectives based on the potential for translation; (2) cautions related to moving from bench to bedside (and back again); and (3) unique questions for translational research initiatives in academic medical centers. Based on this examination, it is clear that the financial...
To improve medulloblastoma proton therapy. Although considered ideal for proton therapy, there ar... more To improve medulloblastoma proton therapy. Although considered ideal for proton therapy, there are potential disadvantages. Expected benefits include reduced radiation-induced cancer and circulatory complications, while avoiding small brain volumes of dose in-homogeneity when compared with conventional X-rays. Several aspects of proton therapy might contribute to reduced tumour control due to (a) the use of more homogenous dose levels which can result in under-dosage, (b) differences in relative biological effectiveness (RBE) between that prescription RBE of 1.1 and the RBE of brain and spinal cord (likely to exceed 1.1) and in medulloblastoma cells (where RBE is likely to be below 1.1). Such changes, although speculative for RBE, might result in potential underdosage of tumour cells and a higher bio-effect in brain tissue. Dose distributions for X-ray and proton treatment are compared, with allocation of likely RBE values for fast growing medullolastoma cells and stable central nervous system tissue. These physical and radiobiological factors are shown to combine to give a higher risk of tumour recurrence with further risks on tumour control when dose reduction schedules used for X-ray therapy are replicated for proton therapy for "low-risk" patients. The dose distributions and prescribed doses of proton therapy, taking into account RBE, in children and adults with medulloblastoma, need to be reconsidered.
The irradiation of cells results in delayed progression through the G2 phase of the cell cycle. T... more The irradiation of cells results in delayed progression through the G2 phase of the cell cycle. Treatment of irradiated HeLa cells with caffeine greatly reduces the G2-phase delay, while caffeine does not alter progression of cells through the cell cycle in unirradiated cells. In this report we demonstrate that treatment of HeLa cells with the kinase inhibitor staurosporine, but not with the inhibitor H7, also results in a reduction of the G2-phase arrest after irradiation. Cell cycle progression in unirradiated cells is unaffected by 4.4 nM (2 ng/ml) staurosporine, which releases the radiation-induced G2-phase arrest. In HeLa cells, the G2-phase delay after irradiation in S phase is accompanied by decreased expression of cyclin B1 mRNA. Coincident with the reduction in G2-phase delay, we observed an increase in cyclin B1 mRNA accumulation in irradiated, staurosporine-treated cells compared to cells treated with irradiation alone. Caffeine treatment of irradiated HeLa cells also resulted in an elevation in the levels of cyclin B1 message. These results support the hypothesis that diminished cyclin B1 mRNA levels influence G2-phase arrest to some degree. The findings that both staurosporine and caffeine treatments reverse the depression in cyclin B1 expression suggest that these two compounds may act on a common pathway of cell cycle control in response to radiation injury.
The cell division cycle is regulated through both transcriptional and post-transcriptional mechan... more The cell division cycle is regulated through both transcriptional and post-transcriptional mechanisms. The altered expression of a number of genes at the mRNA level is known to be essential for progression through the cell cycle, however, a comprehensive gene expression profile of human cells remains to be completed. Here we sought to monitor the differential gene expression of genes after the transition of G2 cells into G1 prior to the restriction point. GeneChip containing microarrays of oligonucleotides corresponding to over 12 000 human genes were employed to profile differential gene expression in G1 and G2. After three independent experiments the resultant data was filtered and a set of genes was compiled based on at least threefold-altered expression, no background noise in determining expression and observation in all experiments. Our analysis identified 154 genes that were elevated in G2 phase of cells as compared to early G1 phase including 15 novel genes. This number incl...
The notion of translational research has gained considerable currency over the past few years. Wh... more The notion of translational research has gained considerable currency over the past few years. While such an approach promises great scientific and clinical advances, the penumbra of translational research tends to incorporate prioritizing scientific projects based upon their potential for translation; tight financial connections between sponsors, scientists and clinical investigators; and sometimes research involving biological approaches for which there is little experience determining safety. It is these aspects of translational research that raise some serious ethical challenges. In this report, we examine three specific areas that raise ethical questions: (1) the potential implications of prioritizing research objectives based on the potential for translation; (2) cautions related to moving from bench to bedside (and back again); and (3) unique questions for translational research initiatives in academic medical centers. Based on this examination, it is clear that the financial and ethical costs as well as benefits of taking a translational approach need to be considered. In the meantime, exquisite attention needs to be paid whenever translational research is likely to affect the traditional fiduciary responsibilities of scientists, clinicians and institutions to research subjects, patients and students. Successful mechanisms that might be developed to address any untoward effects should be shared and evaluated.
The notion of translational research has gained considerable currency over the past few years. Wh... more The notion of translational research has gained considerable currency over the past few years. While such an approach promises great scientific and clinical advances, the penumbra of translational research tends to incorporate prioritizing scientific projects based upon their potential for translation; tight financial connections between sponsors, scientists and clinical investigators; and sometimes research involving biological approaches for which there is little experience determining safety. It is these aspects of translational research that raise some serious ethical challenges. In this report, we examine three specific areas that raise ethical questions: (1) the potential implications of prioritizing research objectives based on the potential for translation; (2) cautions related to moving from bench to bedside (and back again); and (3) unique questions for translational research initiatives in academic medical centers. Based on this examination, it is clear that the financial...
To improve medulloblastoma proton therapy. Although considered ideal for proton therapy, there ar... more To improve medulloblastoma proton therapy. Although considered ideal for proton therapy, there are potential disadvantages. Expected benefits include reduced radiation-induced cancer and circulatory complications, while avoiding small brain volumes of dose in-homogeneity when compared with conventional X-rays. Several aspects of proton therapy might contribute to reduced tumour control due to (a) the use of more homogenous dose levels which can result in under-dosage, (b) differences in relative biological effectiveness (RBE) between that prescription RBE of 1.1 and the RBE of brain and spinal cord (likely to exceed 1.1) and in medulloblastoma cells (where RBE is likely to be below 1.1). Such changes, although speculative for RBE, might result in potential underdosage of tumour cells and a higher bio-effect in brain tissue. Dose distributions for X-ray and proton treatment are compared, with allocation of likely RBE values for fast growing medullolastoma cells and stable central nervous system tissue. These physical and radiobiological factors are shown to combine to give a higher risk of tumour recurrence with further risks on tumour control when dose reduction schedules used for X-ray therapy are replicated for proton therapy for "low-risk" patients. The dose distributions and prescribed doses of proton therapy, taking into account RBE, in children and adults with medulloblastoma, need to be reconsidered.
The irradiation of cells results in delayed progression through the G2 phase of the cell cycle. T... more The irradiation of cells results in delayed progression through the G2 phase of the cell cycle. Treatment of irradiated HeLa cells with caffeine greatly reduces the G2-phase delay, while caffeine does not alter progression of cells through the cell cycle in unirradiated cells. In this report we demonstrate that treatment of HeLa cells with the kinase inhibitor staurosporine, but not with the inhibitor H7, also results in a reduction of the G2-phase arrest after irradiation. Cell cycle progression in unirradiated cells is unaffected by 4.4 nM (2 ng/ml) staurosporine, which releases the radiation-induced G2-phase arrest. In HeLa cells, the G2-phase delay after irradiation in S phase is accompanied by decreased expression of cyclin B1 mRNA. Coincident with the reduction in G2-phase delay, we observed an increase in cyclin B1 mRNA accumulation in irradiated, staurosporine-treated cells compared to cells treated with irradiation alone. Caffeine treatment of irradiated HeLa cells also resulted in an elevation in the levels of cyclin B1 message. These results support the hypothesis that diminished cyclin B1 mRNA levels influence G2-phase arrest to some degree. The findings that both staurosporine and caffeine treatments reverse the depression in cyclin B1 expression suggest that these two compounds may act on a common pathway of cell cycle control in response to radiation injury.
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Papers by Gillies McKenna