The logit binomial logistic dose response model is commonly used in applied research to model bin... more The logit binomial logistic dose response model is commonly used in applied research to model binary outcomes as a function of the dose or concentration of a substance. This model is easily tailored to assess the relative potency of two substances. Consequently, in instances where two such dose response curves are parallel so one substance can be viewed as a dilution of the other, the degree of that dilution is captured in the relative potency model parameter. It is incumbent that experimental researchers working in fields including biomedicine, environmental science, toxicology and applied sciences choose efficient experimental designs to run their studies to both fit their dose response curves and to garner important information regarding drug or substance potency. This article provides far-reaching practical design strategies for dose response model fitting and estimation of relative potency using key illustrations. These results are subsequently extended here to handle situations where the assessment of parallelism and the proper dose-scale are also of interest. Conclusions and recommended strategies are supported by both theoretical and simulation results.
Journal of reproduction and fertility. Supplement, 2000
The aim of this study was to examine inhibin production in granulosa-theca cell tumours (GTCT). T... more The aim of this study was to examine inhibin production in granulosa-theca cell tumours (GTCT). The experimental aims were: (i) to determine GTCT cell types that produce inhibin alpha- and betaA-subunits; (ii) to determine whether alpha- and betaA-subunit forms differ in GTCT fluid and normal equine follicular fluid (eFF); and (iii) to determine whether dimeric inhibin (alpha betaA) is present in GTCT plasma and tumour fluid. Plasma, tumour fluid and tumour tissue were collected from mares (n=6) with GTCT. Plasma and eFF were collected during the follicular phase from mares (n=4) undergoing normal cycles. Immunohistochemical examination of GTCT tumour sections showed strong inhibin alpha- and betaA-Subunit immunostaining in granulosa cells and polyhedral-shaped cells in the thecal-stromal layer. The presence of polyhedral-shaped cells was related to testosterone concentration in tumour fluid. Low molecular weight alpha-subunit forms were less abundant in tumour fluid than in eFF, wh...
Endothelial progenitor cells (EPCs) were first identified by Ashara et al. in 1997 (Asahara et al... more Endothelial progenitor cells (EPCs) were first identified by Ashara et al. in 1997 (Asahara et al. Science 275:964-967, 1997) and were thought to contribute to angiogenesis and vasculogenesis. Since their discovery, circulating levels of EPCs were found to serve as biomarkers as low levels correlate with increased cardiovascular events and death from cardiovascular causes (Werner et al. N Engl J Med 353:999-1007, 2005; Fadini et al. J Am Coll Cardiol 45:1449-1457, 2005; Hill et al. N Engl J Med 348:593-600, 2003; Schmidt-Lucke et al. Circulation 111:2981-2987, 2005). Additionally, EPC dysfunction has been associated with diabetes mellitus and other disease states. However, recently there has been a great deal of controversy in the field over the exact definition and function of an EPC. To help classify EPCs, they have been divided into two distinct groups (1) circulating angiogenic cells (also referred to as early EPCs) and (2) endothelial colony forming cells (also referred to as late outgrowth EPCs). Circulating angiogenic cells are believed to represent a cell population enriched in monocytes and exert their angiogenic effects via paracrine and signaling mechanisms whereas endothelial colony forming cells are true EPCs and may enhance angiogenesis and vasculogenesis by incorporating into the newly forming vessels. Here the isolation and identification of circulating angiogenic cells are described.
Cell therapy has enormous potential for the treatment of conditions of unmet medical need. Cell t... more Cell therapy has enormous potential for the treatment of conditions of unmet medical need. Cell therapy may be applied to diabetes mellitus in the context of beta cell replacement or for the treatment of diabetic complications. A large number of cell types including hematopoietic stem cells, mesenchymal stem cells, umbilical cord blood, conditioned lymphocytes, mononuclear cells, or a combination of these cells have been shown to be safe and feasible for the treatment of patients with diabetes mellitus. The first part of this review article will focus on the current perspective of the role of embryonic stem cells and inducible pluripotent stem cells for beta cell replacement and the current clinical data on cell-based therapy for the restoration of normoglycemia. The second part of this review will highlight the therapeutic role of MSCs in islet cells cotransplantation and the management of diabetes related vascular complications.
We performed genomewide gene expression analysis of 35 samples representing 6 common histologic s... more We performed genomewide gene expression analysis of 35 samples representing 6 common histologic subtypes of canine lymphoma and bioinformatics analyses to define their molecular characteristics. Three major groups were defined on the basis of gene expression profiles: (1) low-grade T-cell lymphoma, composed entirely by T-zone lymphoma; (2) high-grade T-cell lymphoma, consisting of lymphoblastic T-cell lymphoma and peripheral T-cell lymphoma not otherwise specified; and (3) B-cell lymphoma, consisting of marginal B-cell lymphoma, diffuse large B-cell lymphoma, and Burkitt lymphoma. Interspecies comparative analyses of gene expression profiles also showed that marginal B-cell lymphoma and diffuse large B-cell lymphoma in dogs and humans might represent a continuum of disease with similar drivers. The classification of these diverse tumors into 3 subgroups was prognostically significant, as the groups were directly correlated with event-free survival. Finally, we developed a benchtop diagnostic test based on expression of 4 genes that can robustly classify canine lymphomas into one of these 3 subgroups, enabling a direct clinical application for our results.
Multiple endocrine neoplasia type 2B (MEN 2B) is a rare disorder differentiated from MEN 2A prima... more Multiple endocrine neoplasia type 2B (MEN 2B) is a rare disorder differentiated from MEN 2A primarily by its extraendocrine features. This report describes the clinical spectrum and outcome of MEN 2B. Twenty-one patients underwent operation for manifestations of MEN 2B between 1970 and 1993. Median follow-up was 16.9 years. Diagnosis was made through family screening in nine, the development of medullary thyroid carcinoma (MTC) in seven, phenotypic features in four, and constipation in one. Median age at presentation of colonic dysfunction, MTC, and pheochromocytoma was 0.1, 16, and 28 years, respectively. Every patient had MTC. Fifteen (94%) of 16 patients undergoing primary thyroidectomies had multicentric disease, and seven (44%) had nodal metastases. Seven patients (33%) had pheochromocytoma, six bilateral and one malignant. Adrenalectomy was curative in every patient. Nineteen patients (90%) had colonic disturbances, typically chronic constipation from birth. Megacolon developed in 14 patients, and eight required colonic surgery. Every patient had the characteristic phenotype. Dominant features included neuromas of the tongue, buccal mucosa, lips, conjunctivae, and eyelids and a marfanoid habitus. Other features included high arched palate, corneal nerve thickening, and dental and skeletal abnormalities. Four patients died, two of metastatic MTC, one after operation for metastatic MTC, and one as a consequence of colonic perforation. Of 17 survivors, three have hepatic metastases from MTC, eight have nodal metastases, and six are well with normal or mildly elevated calcitonin levels. MEN 2B is characterized by a relatively aggressive form of MTC, bilateral pheochromocytoma, severe colonic dysfunction, and a multitude of other extraendocrine abnormalities. Early recognition of MEN 2B and early prophylactic thyroidectomy are essential. Colonic dysfunction has previously received little attention, and further investigation of the pathogenesis and treatment of this disorder is warranted.
The therapeutic potential of mesenchymal stem cell (MSC) transplantation for the treatment of isc... more The therapeutic potential of mesenchymal stem cell (MSC) transplantation for the treatment of ischemic conditions such as coronary artery disease, peripheral arterial disease, and stroke has been explored in animal models and early-phase clinical trials. A substantial database documents the safety profile of MSC administration to humans in a large number of disease states. The mechanism of the therapeutic effect of MSC transplantation in ischemic disease has been postulated to be due to paracrine, immunomodulatory, and differentiation effects. This review provides an overview of the potential role of MSC-based therapy for critical limb ischemia (CLI), the comparison of MSC cellular therapy with angiogenesis gene therapy in CLI, and the proposed mechanism of action of MSC therapy. Preclinical efficacy data in animal models of hindlimb ischemia, current early-phase human trial data, and considerations for future MSC-based therapy in CLI will also be discussed.
The logit binomial logistic dose response model is commonly used in applied research to model bin... more The logit binomial logistic dose response model is commonly used in applied research to model binary outcomes as a function of the dose or concentration of a substance. This model is easily tailored to assess the relative potency of two substances. Consequently, in instances where two such dose response curves are parallel so one substance can be viewed as a dilution of the other, the degree of that dilution is captured in the relative potency model parameter. It is incumbent that experimental researchers working in fields including biomedicine, environmental science, toxicology and applied sciences choose efficient experimental designs to run their studies to both fit their dose response curves and to garner important information regarding drug or substance potency. This article provides far-reaching practical design strategies for dose response model fitting and estimation of relative potency using key illustrations. These results are subsequently extended here to handle situations where the assessment of parallelism and the proper dose-scale are also of interest. Conclusions and recommended strategies are supported by both theoretical and simulation results.
Journal of reproduction and fertility. Supplement, 2000
The aim of this study was to examine inhibin production in granulosa-theca cell tumours (GTCT). T... more The aim of this study was to examine inhibin production in granulosa-theca cell tumours (GTCT). The experimental aims were: (i) to determine GTCT cell types that produce inhibin alpha- and betaA-subunits; (ii) to determine whether alpha- and betaA-subunit forms differ in GTCT fluid and normal equine follicular fluid (eFF); and (iii) to determine whether dimeric inhibin (alpha betaA) is present in GTCT plasma and tumour fluid. Plasma, tumour fluid and tumour tissue were collected from mares (n=6) with GTCT. Plasma and eFF were collected during the follicular phase from mares (n=4) undergoing normal cycles. Immunohistochemical examination of GTCT tumour sections showed strong inhibin alpha- and betaA-Subunit immunostaining in granulosa cells and polyhedral-shaped cells in the thecal-stromal layer. The presence of polyhedral-shaped cells was related to testosterone concentration in tumour fluid. Low molecular weight alpha-subunit forms were less abundant in tumour fluid than in eFF, wh...
Endothelial progenitor cells (EPCs) were first identified by Ashara et al. in 1997 (Asahara et al... more Endothelial progenitor cells (EPCs) were first identified by Ashara et al. in 1997 (Asahara et al. Science 275:964-967, 1997) and were thought to contribute to angiogenesis and vasculogenesis. Since their discovery, circulating levels of EPCs were found to serve as biomarkers as low levels correlate with increased cardiovascular events and death from cardiovascular causes (Werner et al. N Engl J Med 353:999-1007, 2005; Fadini et al. J Am Coll Cardiol 45:1449-1457, 2005; Hill et al. N Engl J Med 348:593-600, 2003; Schmidt-Lucke et al. Circulation 111:2981-2987, 2005). Additionally, EPC dysfunction has been associated with diabetes mellitus and other disease states. However, recently there has been a great deal of controversy in the field over the exact definition and function of an EPC. To help classify EPCs, they have been divided into two distinct groups (1) circulating angiogenic cells (also referred to as early EPCs) and (2) endothelial colony forming cells (also referred to as late outgrowth EPCs). Circulating angiogenic cells are believed to represent a cell population enriched in monocytes and exert their angiogenic effects via paracrine and signaling mechanisms whereas endothelial colony forming cells are true EPCs and may enhance angiogenesis and vasculogenesis by incorporating into the newly forming vessels. Here the isolation and identification of circulating angiogenic cells are described.
Cell therapy has enormous potential for the treatment of conditions of unmet medical need. Cell t... more Cell therapy has enormous potential for the treatment of conditions of unmet medical need. Cell therapy may be applied to diabetes mellitus in the context of beta cell replacement or for the treatment of diabetic complications. A large number of cell types including hematopoietic stem cells, mesenchymal stem cells, umbilical cord blood, conditioned lymphocytes, mononuclear cells, or a combination of these cells have been shown to be safe and feasible for the treatment of patients with diabetes mellitus. The first part of this review article will focus on the current perspective of the role of embryonic stem cells and inducible pluripotent stem cells for beta cell replacement and the current clinical data on cell-based therapy for the restoration of normoglycemia. The second part of this review will highlight the therapeutic role of MSCs in islet cells cotransplantation and the management of diabetes related vascular complications.
We performed genomewide gene expression analysis of 35 samples representing 6 common histologic s... more We performed genomewide gene expression analysis of 35 samples representing 6 common histologic subtypes of canine lymphoma and bioinformatics analyses to define their molecular characteristics. Three major groups were defined on the basis of gene expression profiles: (1) low-grade T-cell lymphoma, composed entirely by T-zone lymphoma; (2) high-grade T-cell lymphoma, consisting of lymphoblastic T-cell lymphoma and peripheral T-cell lymphoma not otherwise specified; and (3) B-cell lymphoma, consisting of marginal B-cell lymphoma, diffuse large B-cell lymphoma, and Burkitt lymphoma. Interspecies comparative analyses of gene expression profiles also showed that marginal B-cell lymphoma and diffuse large B-cell lymphoma in dogs and humans might represent a continuum of disease with similar drivers. The classification of these diverse tumors into 3 subgroups was prognostically significant, as the groups were directly correlated with event-free survival. Finally, we developed a benchtop diagnostic test based on expression of 4 genes that can robustly classify canine lymphomas into one of these 3 subgroups, enabling a direct clinical application for our results.
Multiple endocrine neoplasia type 2B (MEN 2B) is a rare disorder differentiated from MEN 2A prima... more Multiple endocrine neoplasia type 2B (MEN 2B) is a rare disorder differentiated from MEN 2A primarily by its extraendocrine features. This report describes the clinical spectrum and outcome of MEN 2B. Twenty-one patients underwent operation for manifestations of MEN 2B between 1970 and 1993. Median follow-up was 16.9 years. Diagnosis was made through family screening in nine, the development of medullary thyroid carcinoma (MTC) in seven, phenotypic features in four, and constipation in one. Median age at presentation of colonic dysfunction, MTC, and pheochromocytoma was 0.1, 16, and 28 years, respectively. Every patient had MTC. Fifteen (94%) of 16 patients undergoing primary thyroidectomies had multicentric disease, and seven (44%) had nodal metastases. Seven patients (33%) had pheochromocytoma, six bilateral and one malignant. Adrenalectomy was curative in every patient. Nineteen patients (90%) had colonic disturbances, typically chronic constipation from birth. Megacolon developed in 14 patients, and eight required colonic surgery. Every patient had the characteristic phenotype. Dominant features included neuromas of the tongue, buccal mucosa, lips, conjunctivae, and eyelids and a marfanoid habitus. Other features included high arched palate, corneal nerve thickening, and dental and skeletal abnormalities. Four patients died, two of metastatic MTC, one after operation for metastatic MTC, and one as a consequence of colonic perforation. Of 17 survivors, three have hepatic metastases from MTC, eight have nodal metastases, and six are well with normal or mildly elevated calcitonin levels. MEN 2B is characterized by a relatively aggressive form of MTC, bilateral pheochromocytoma, severe colonic dysfunction, and a multitude of other extraendocrine abnormalities. Early recognition of MEN 2B and early prophylactic thyroidectomy are essential. Colonic dysfunction has previously received little attention, and further investigation of the pathogenesis and treatment of this disorder is warranted.
The therapeutic potential of mesenchymal stem cell (MSC) transplantation for the treatment of isc... more The therapeutic potential of mesenchymal stem cell (MSC) transplantation for the treatment of ischemic conditions such as coronary artery disease, peripheral arterial disease, and stroke has been explored in animal models and early-phase clinical trials. A substantial database documents the safety profile of MSC administration to humans in a large number of disease states. The mechanism of the therapeutic effect of MSC transplantation in ischemic disease has been postulated to be due to paracrine, immunomodulatory, and differentiation effects. This review provides an overview of the potential role of MSC-based therapy for critical limb ischemia (CLI), the comparison of MSC cellular therapy with angiogenesis gene therapy in CLI, and the proposed mechanism of action of MSC therapy. Preclinical efficacy data in animal models of hindlimb ischemia, current early-phase human trial data, and considerations for future MSC-based therapy in CLI will also be discussed.
Uploads