Molecular classification and prediction of metastatic potential in early malignant melanoma: improvement of prognostic accuracy by quantitative in situ proteomic analysis

The incidence of cutaneous malignant melanoma continues to increase every year, and remains the leading cause of skin cancer death in industrialized countries. In spite of the aggressive nature of advanced melanoma, there are no standard biological assays in clinical usage that can predict metastasis. This may be due, in part, to the inadequacy of reproducible assessment of protein expression using traditional immunohistochemistry. This dissertation will discuss the use of tissue microarrays combined with quantitative in situ molecular analysis of protein expression to allow prediction of melanoma metastasis. Through the identification and validation of novel prognostic biomarkers, we seek to identify subsets of patients that are at high or low risk for melanoma recurrence or melanoma-related death. Some of these biomarkers may also serve as potential targets for future biologic therapy in melanoma, a disease for which no effective medical treatment is currently available. We demonstrate that quantitative assessment of a small number of markers is predictive of metastasis and outcome, augmenting the current system of prognosis.The dissertation begins with a brief introduction on the current state of melanoma diagnosis, staging, and treatment, as well as a review of current efforts to understand the biology of melanoma progression and metastasis. The fundamentals of tissue microarray technology are then described. Critical aspects of quantitative immunohistochemistry, including a description of the Automated Quantitative Analysis (AQUA) system developed in our laboratory, are also addressed. The second chapter demonstrates the use of tissue microarray technology to examine melanoma specimens by the current field standard, with a study of activating transcription factor 2 (ATF2); an example of semi-quantitative immunohistochemical analysis of protein expression. The third chapter provides validation of the AQUA technology on melanoma tissue by evaluation of the human homologue of murine double minute 2 protein (HDM2). Chapter four demonstrates an example of the critical--and beneficial--aspect of subcellular compartmentalization that the AQUA system provides, demonstrating that the ratio of cytoplasmic-to-nuclear expression of activator protein 2 (AP-2) predicts outcome in melanoma patients. The last chapter draws these concepts together and presents results from the analysis of 50 protein biomarkers in melanoma. It also introduces the use of a number of statistical methods (traditional and novel) employed to develop an optimal biomarker set for future analyses

Calculating Unit Costs of Production and Using the Information for Enterprise Analysis and Decision Making on the Ranch

INTRODUCTION Unit Cost of Production (UCOP) and Enterprise Analysis are tools that ranch managers have been encouraged to utilize in making decisions to improve profit. Managers who have adopted these tools have found them to be valuable in identifying opportunities and problem areas in enterprises on the ranch. HISTORY OF THE DEVELOPMENT OF UNIT COSTS OF PRODUCTION FOR USE IN RANCH MANAGEMENT DECISIONS The late 1970s and 1980s were challenging times financially for farm and ranch businesses, forcing many to exit the industry. In the early 1990s, the National Cattlemen’s Association Integrated Resource Management (IRM) subcommittee developed Standardized Performance Analysis (SPA), which was based on production and economic measures. The SPA analysis was designed in relation to the guidelines of the Farm Financial Standard’s Task Force for agriculture, with the overall goal of helping ranchers to utilize and understand financial records in the management of their operations. A number of agricultural economists in Cooperative Extension such as Dr. Jim McGrann Ph.D., Texas A&M and Dr. Harlan Hughes Ph.D., North Dakota State University, were foundational in developing financial and production record keeping methods as well as software for producers to use in the analysis of their businesses. THE USE OF UNIT COST OF PRODUCTION AND ENTERPRISE ANALYSIS IS IMPORTANT TO LONG TERM RANCH BUSINESS SUCCESS The old adage “you can’t manage what you don’t measure” is still true in relation to managing the ranch business. Knowing UCOP and the economic contribution of each enterprise on the ranch are foundational tools for making effective decisions in the management of ranch resources. However, a critical first step in calculating UCOP is to actually have production and financial records. These records do not have to be complicated, but they must be accurate and thorough. Records also need to allow for the allocation of expenses to different enterprises within the ranch. Many computerized financial record keeping programs are designed to easily track and allocate expense within enterprises

Calculating Unit Costs of Production and Using the Information for Enterprise Analysis and Decision Making on the Ranch

INTRODUCTION Unit Cost of Production (UCOP) and Enterprise Analysis are tools that ranch managers have been encouraged to utilize in making decisions to improve profit. Managers who have adopted these tools have found them to be valuable in identifying opportunities and problem areas in enterprises on the ranch. HISTORY OF THE DEVELOPMENT OF UNIT COSTS OF PRODUCTION FOR USE IN RANCH MANAGEMENT DECISIONS The late 1970s and 1980s were challenging times financially for farm and ranch businesses, forcing many to exit the industry. In the early 1990s, the National Cattlemen’s Association Integrated Resource Management (IRM) subcommittee developed Standardized Performance Analysis (SPA), which was based on production and economic measures. The SPA analysis was designed in relation to the guidelines of the Farm Financial Standard’s Task Force for agriculture, with the overall goal of helping ranchers to utilize and understand financial records in the management of their operations. A number of agricultural economists in Cooperative Extension such as Dr. Jim McGrann Ph.D., Texas A&M and Dr. Harlan Hughes Ph.D., North Dakota State University, were foundational in developing financial and production record keeping methods as well as software for producers to use in the analysis of their businesses. THE USE OF UNIT COST OF PRODUCTION AND ENTERPRISE ANALYSIS IS IMPORTANT TO LONG TERM RANCH BUSINESS SUCCESS The old adage “you can’t manage what you don’t measure” is still true in relation to managing the ranch business. Knowing UCOP and the economic contribution of each enterprise on the ranch are foundational tools for making effective decisions in the management of ranch resources. However, a critical first step in calculating UCOP is to actually have production and financial records. These records do not have to be complicated, but they must be accurate and thorough. Records also need to allow for the allocation of expenses to different enterprises within the ranch. Many computerized financial record keeping programs are designed to easily track and allocate expense within enterprises

Uncertainty and Informed Choice: Unmasking \u3cem\u3eDaubert\u3c/em\u3e

This Article will first examine why it is that plaintiffs have been unable to prove causation under the Daubert guidelines in toxic tort litigation. Second, it will look at the two existing models for informed choice litigation medical malpractice and products liability-and demonstrate why neither of these models gives toxic tort plaintiffs a fair opportunity to recover for the deprivation of patient autonomy against drug manufacturers who have breached their duty to warn of known or knowable risks. Finally, this Article will explore the elements of a causation-free informed choice cause of action. It will suggest the appropriate standard for defining materiality of risk in informed choice where the goal is to protect patient autonomy, and having established the substantive right to recovery, the Article will then suggest a measure of damages for depriving the patient of her right to autonomous decisionmaking