Alzheimer's Disease (AD) represents a major health problem without effective treatments. As t... more Alzheimer's Disease (AD) represents a major health problem without effective treatments. As the incidence of the disease will continue to rise, it is imperative to find new treatment options to halt or slow disease progression. In recent years, several groups have begun to study the utility of low total dose radiation therapy (LTDRT) to inhibit some of the pathological features of AD and improve cognition in a variety of animal models. These preclinical studies have led to Phase 1 and 2 trials in different centers around the world. In this review, we present and interpret the pre-clinical evidence report some preliminary clinical data from a Phase 2 trial in early-stage AD patients.
RCC accounts for 9 out of 10 cases of kidney cancer. Approximately 65,150 new cases and 13,680 de... more RCC accounts for 9 out of 10 cases of kidney cancer. Approximately 65,150 new cases and 13,680 deaths are expected from this disease in 2013. There is urgent clinical need for better treatment options as RCC responds poorly to current chemotherapy. A major limitation to developing new treatments is that the molecular mechanisms responsible for inappropriate cell survival and chemoresistance are unknown. One pathway suggested to be involved in vitro is the JAK2/STAT. We hypothesized that there would be altered expression of the members and regulators of the JAK/STAT pathways in RCC. We utilized samples from normal (n=14), benign (n=6), and histological Fuhrman grades: Grade 1 (n=3), Grade 2 (n=10), Grade 3 (n=14), and Grade 4 (n=3). We analyzed 31 human RCC samples as well as the normal and benign samples with Affymetrix human gene microarrays and Western Blot technology. The samples were all clear cell renal carcinomas verified by a Beaumont Hospital pathologist. We analyzed 22,148 genes and altered gene ...
Assessment of Cell Proliferation in Clinical Practice, 1992
Cellular proliferation is an integral part of the maintenance of the organism. While many tissues... more Cellular proliferation is an integral part of the maintenance of the organism. While many tissues in the adult are essentially non-dividing, others, the socalled cell renewal systems, are in a constant state of division, maturation and loss, for example in skin and gut. The process of homeostasis keeps the balance between cell production and cell loss so that the cell proliferation rate is exactly balanced by cell loss. It is a fundamental part of the development of cancer that there is a loss of this homeostatic control such that cell production becomes uncontrolled, with cells proliferating faster than they are lost. It is now generally recognised that the rate of tumour cell proliferation can be a major factor in determining the success of treatment. This is certainly the case for the treatment of tumours by fractionated radiotherapy (Fowler 1986; Withers et al. 1988) and is expected to be true for chemotherapy when there are also intervals between treatments. In the case of radiotherapy, clinical trials are underway to assess strategies to overcome tumour cell proliferation during treatment by means of accelerated fractionation schedules when, in the extreme, the overall treatment time has been reduced to 12 days without a break, giving three fractions per day (Saunders et al. 1988). Of course, cell proliferation during treatment will not be a problem with all tumours. Many may be satisfactorily treated by conventional schedules. It would clearly be of considerable value, therefore, if those tumours for which cell proliferation may be a problem could be identified prior to treatment, allowing a rational selection of patients for accelerated treatment (Wilson et al. 1988).
Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics, 2004
The radiation-modifying action of docetaxel in experimental systems is well established. Docetaxe... more The radiation-modifying action of docetaxel in experimental systems is well established. Docetaxel is also an increasingly important drug for the treatment of cancer in concurrent radiotherapy protocols. However, the mechanisms of docetaxel radiosensitization are not fully understood. We have investigated the magnitude and mechanisms of docetaxel radiosensitization in vitro in four human colorectal cancer cell lines (SW480, SW707, SW48, and HT29) with widely differing radiosensitivities. Cell survival curves were generated for a range of docetaxel concentrations (5-20 nM) alone and for X-rays (1-5 Gy) +/- 10 or 20 nM docetaxel (for 24 h before irradiation). Cell cycle distributions and apoptotic frequencies were measured during the treatments. Sensitivity to docetaxel alone was similar in all cell lines and could be attributed to massive induction of apoptosis (60-80% by 24 h). Radiosensitivity varied widely; the surviving fractions at 2 Gy in the most resistant (HT29) and most sensitive (SW28) lines were 0.81 and 0.13, respectively. Exposure to 10 nM docetaxel induced a progressive accumulation of SW480, SW707, and SW48 cells in G2/M. After 24 h, 55-70% of the cells were in G2/M. It is likely, therefore, that accumulation in this radiosensitive phase of the cell cycle contributes significantly to radiosensitization by the drug.
Mesenchymal-epithelial transition factor (MET), a receptor tyrosine kinase, is expressed in head ... more Mesenchymal-epithelial transition factor (MET), a receptor tyrosine kinase, is expressed in head and neck squamous cell carcinomas (HNSCC) and is involved in tumor progression and associated with poor prognosis. MET can be inhibited by crizotinib, a potent ATP-competitive kinase inhibitor. We examined the effects of combining crizotinib and radiation in a pre-clinical HNSCC model. Nine HNSCC cell lines were screened for MET expression, copy-number amplification and mutational status. The in vitro effects of crizotinib and radiation were assessed with clonogenic survival assays. MET signaling proteins were assessed with western blot and receptor tyrosine kinase array. Tumor growth-delay experiments with UT-SCC-14 and UT-SCC-15 oral tongue xenografts were used to assess in vivo tumor radiosensitivity. All nine HNSCC cell lines showed a varying degree of MET protein and RNA expression. Increased MET copy number was not present. MET was expressed after irradiation both in vitro and in v...
It is widely accepted that variable biorepository specimen handling conditions can significantly ... more It is widely accepted that variable biorepository specimen handling conditions can significantly alter outcomes of clinical research studies, suggesting the need for a metric for sample analyte protein integrity. In line with the National Cancer Institute (NCI) Best Practices, it is vital that the integrity of specimens used for biomarker studies are of the highest standard to ensure validity of the data they generate and confidence in the application of new findings to clinical management. We describe the creation of a program to discover proteins in biorepository samples that can be utilized to assess the integrity of stored specimens for protein-based biomarker studies, similar to the universally accepted quality metric for RNA, the RNA Integrity Number, or RIN. The study mimics potential variation in pre-analytical conditions which may result in proteolysis and other proteome-associated changes and employs surface-enhanced laser desorption time-of-flight mass spectrometry (SELDI...
The Beaumont BioBank model is a multidisciplinary facility that is designed to provide access and... more The Beaumont BioBank model is a multidisciplinary facility that is designed to provide access and opportunity for research-minded clinicians to become involved in research without the need for their own research infrastructure, thus increasing the research effort across the Health System. We describe a biobank model that works primarily in operating rooms for tissue collection and utilizes a generic consent process to facilitate rapid and accurate collection of biospecimens. The model combines both a biorepository that collects specimens based on clinical questions and also a translational research facility that undertakes biomarker-based research on those specimens in a seamless and efficient process. We believe that the Beaumont BioBank model would be readily applicable and reproducible in other academic healthcare systems.
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology, 2014
To investigate temporal changes in global gene expression and pathways involved in the response t... more To investigate temporal changes in global gene expression and pathways involved in the response to irradiation during phases of growth inhibition, recovery and repopulation in a human head and neck squamous cell cancer (HNSCC) xenograft. Low passage head and neck squamous cancer cells (UT-14-SCC) were injected into the flanks of female nu/nu mice to generate xenografts. After tumors reached a size of 500 mm3, they were treated with either sham RT or 15Gy in one fraction. At different time points, days 0, 3, and 10 for controls and days 4, 7, 12, and 21 after irradiation, the tumors were harvested for global gene expression analysis and pathway analysis. The tumors showed growth inhibition through days 4-7 and began the transition to regrowth around the day 12 time point. When comparing the pooled controls to each day of treatment, there were 22, 119, 125, and 25 differentially expressed genes on days 4, 7, 12, and 21 respectively using a p⩽0.01 and a 2-fold cut-off. Gene Ontology (G...
Alzheimer's Disease (AD) represents a major health problem without effective treatments. As t... more Alzheimer's Disease (AD) represents a major health problem without effective treatments. As the incidence of the disease will continue to rise, it is imperative to find new treatment options to halt or slow disease progression. In recent years, several groups have begun to study the utility of low total dose radiation therapy (LTDRT) to inhibit some of the pathological features of AD and improve cognition in a variety of animal models. These preclinical studies have led to Phase 1 and 2 trials in different centers around the world. In this review, we present and interpret the pre-clinical evidence report some preliminary clinical data from a Phase 2 trial in early-stage AD patients.
RCC accounts for 9 out of 10 cases of kidney cancer. Approximately 65,150 new cases and 13,680 de... more RCC accounts for 9 out of 10 cases of kidney cancer. Approximately 65,150 new cases and 13,680 deaths are expected from this disease in 2013. There is urgent clinical need for better treatment options as RCC responds poorly to current chemotherapy. A major limitation to developing new treatments is that the molecular mechanisms responsible for inappropriate cell survival and chemoresistance are unknown. One pathway suggested to be involved in vitro is the JAK2/STAT. We hypothesized that there would be altered expression of the members and regulators of the JAK/STAT pathways in RCC. We utilized samples from normal (n=14), benign (n=6), and histological Fuhrman grades: Grade 1 (n=3), Grade 2 (n=10), Grade 3 (n=14), and Grade 4 (n=3). We analyzed 31 human RCC samples as well as the normal and benign samples with Affymetrix human gene microarrays and Western Blot technology. The samples were all clear cell renal carcinomas verified by a Beaumont Hospital pathologist. We analyzed 22,148 genes and altered gene ...
Assessment of Cell Proliferation in Clinical Practice, 1992
Cellular proliferation is an integral part of the maintenance of the organism. While many tissues... more Cellular proliferation is an integral part of the maintenance of the organism. While many tissues in the adult are essentially non-dividing, others, the socalled cell renewal systems, are in a constant state of division, maturation and loss, for example in skin and gut. The process of homeostasis keeps the balance between cell production and cell loss so that the cell proliferation rate is exactly balanced by cell loss. It is a fundamental part of the development of cancer that there is a loss of this homeostatic control such that cell production becomes uncontrolled, with cells proliferating faster than they are lost. It is now generally recognised that the rate of tumour cell proliferation can be a major factor in determining the success of treatment. This is certainly the case for the treatment of tumours by fractionated radiotherapy (Fowler 1986; Withers et al. 1988) and is expected to be true for chemotherapy when there are also intervals between treatments. In the case of radiotherapy, clinical trials are underway to assess strategies to overcome tumour cell proliferation during treatment by means of accelerated fractionation schedules when, in the extreme, the overall treatment time has been reduced to 12 days without a break, giving three fractions per day (Saunders et al. 1988). Of course, cell proliferation during treatment will not be a problem with all tumours. Many may be satisfactorily treated by conventional schedules. It would clearly be of considerable value, therefore, if those tumours for which cell proliferation may be a problem could be identified prior to treatment, allowing a rational selection of patients for accelerated treatment (Wilson et al. 1988).
Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics, 2004
The radiation-modifying action of docetaxel in experimental systems is well established. Docetaxe... more The radiation-modifying action of docetaxel in experimental systems is well established. Docetaxel is also an increasingly important drug for the treatment of cancer in concurrent radiotherapy protocols. However, the mechanisms of docetaxel radiosensitization are not fully understood. We have investigated the magnitude and mechanisms of docetaxel radiosensitization in vitro in four human colorectal cancer cell lines (SW480, SW707, SW48, and HT29) with widely differing radiosensitivities. Cell survival curves were generated for a range of docetaxel concentrations (5-20 nM) alone and for X-rays (1-5 Gy) +/- 10 or 20 nM docetaxel (for 24 h before irradiation). Cell cycle distributions and apoptotic frequencies were measured during the treatments. Sensitivity to docetaxel alone was similar in all cell lines and could be attributed to massive induction of apoptosis (60-80% by 24 h). Radiosensitivity varied widely; the surviving fractions at 2 Gy in the most resistant (HT29) and most sensitive (SW28) lines were 0.81 and 0.13, respectively. Exposure to 10 nM docetaxel induced a progressive accumulation of SW480, SW707, and SW48 cells in G2/M. After 24 h, 55-70% of the cells were in G2/M. It is likely, therefore, that accumulation in this radiosensitive phase of the cell cycle contributes significantly to radiosensitization by the drug.
Mesenchymal-epithelial transition factor (MET), a receptor tyrosine kinase, is expressed in head ... more Mesenchymal-epithelial transition factor (MET), a receptor tyrosine kinase, is expressed in head and neck squamous cell carcinomas (HNSCC) and is involved in tumor progression and associated with poor prognosis. MET can be inhibited by crizotinib, a potent ATP-competitive kinase inhibitor. We examined the effects of combining crizotinib and radiation in a pre-clinical HNSCC model. Nine HNSCC cell lines were screened for MET expression, copy-number amplification and mutational status. The in vitro effects of crizotinib and radiation were assessed with clonogenic survival assays. MET signaling proteins were assessed with western blot and receptor tyrosine kinase array. Tumor growth-delay experiments with UT-SCC-14 and UT-SCC-15 oral tongue xenografts were used to assess in vivo tumor radiosensitivity. All nine HNSCC cell lines showed a varying degree of MET protein and RNA expression. Increased MET copy number was not present. MET was expressed after irradiation both in vitro and in v...
It is widely accepted that variable biorepository specimen handling conditions can significantly ... more It is widely accepted that variable biorepository specimen handling conditions can significantly alter outcomes of clinical research studies, suggesting the need for a metric for sample analyte protein integrity. In line with the National Cancer Institute (NCI) Best Practices, it is vital that the integrity of specimens used for biomarker studies are of the highest standard to ensure validity of the data they generate and confidence in the application of new findings to clinical management. We describe the creation of a program to discover proteins in biorepository samples that can be utilized to assess the integrity of stored specimens for protein-based biomarker studies, similar to the universally accepted quality metric for RNA, the RNA Integrity Number, or RIN. The study mimics potential variation in pre-analytical conditions which may result in proteolysis and other proteome-associated changes and employs surface-enhanced laser desorption time-of-flight mass spectrometry (SELDI...
The Beaumont BioBank model is a multidisciplinary facility that is designed to provide access and... more The Beaumont BioBank model is a multidisciplinary facility that is designed to provide access and opportunity for research-minded clinicians to become involved in research without the need for their own research infrastructure, thus increasing the research effort across the Health System. We describe a biobank model that works primarily in operating rooms for tissue collection and utilizes a generic consent process to facilitate rapid and accurate collection of biospecimens. The model combines both a biorepository that collects specimens based on clinical questions and also a translational research facility that undertakes biomarker-based research on those specimens in a seamless and efficient process. We believe that the Beaumont BioBank model would be readily applicable and reproducible in other academic healthcare systems.
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology, 2014
To investigate temporal changes in global gene expression and pathways involved in the response t... more To investigate temporal changes in global gene expression and pathways involved in the response to irradiation during phases of growth inhibition, recovery and repopulation in a human head and neck squamous cell cancer (HNSCC) xenograft. Low passage head and neck squamous cancer cells (UT-14-SCC) were injected into the flanks of female nu/nu mice to generate xenografts. After tumors reached a size of 500 mm3, they were treated with either sham RT or 15Gy in one fraction. At different time points, days 0, 3, and 10 for controls and days 4, 7, 12, and 21 after irradiation, the tumors were harvested for global gene expression analysis and pathway analysis. The tumors showed growth inhibition through days 4-7 and began the transition to regrowth around the day 12 time point. When comparing the pooled controls to each day of treatment, there were 22, 119, 125, and 25 differentially expressed genes on days 4, 7, 12, and 21 respectively using a p⩽0.01 and a 2-fold cut-off. Gene Ontology (G...
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Papers by George Wilson