The Individual Piece

None provided

An Overview of Acute Myeloid Leukemia and Cancer Immunology: (i) Concepts and Therapeutic Strategies and (ii) RepSox as a Candidate Cell-Engineering Tool

This dissertation is intentionally broad in scope and describes the conceptual frameworks, research advances, and clinical successes that inspired a therapeutic vision that, in turn, prompted specific RepSox experiments (Jajosky, 2014). The goal of this dissertation is to guide and encourage students interested in engineering anti-cancer immune therapies by providing perspective and suggestions. Chapter I provides background on acute myeloid leukemia (AML), the cancer stem cell (CSC) theory, and the chemical reprogramming tool RepSox. Chapter II describes how tumor cells passively evade immune recognition and actively suppress immune cells to escape destruction. Immunotherapeutic strategies are described that increase tumor-cell immunogenicity and/or sensitize tumor cells to immune-mediated death. Chapter III reviews immune-cell defects induced by cancer-distorted microenvironments. Tumor cells alter local physical and metabolic conditions and distort surrounding stromal cells in ways that impair infiltrating immune cells and promote cancer progression. Strategies are described that can reverse immune-cell defects and improve anti-tumor immunity. Chapter IV highlights successful cancer immunotherapies, including patient-specific, FDA-approved, and AML leukemic stem cell (LSC)-targeted strategies. These therapies involve antibodies, activated immune cells, and/or immuno-modulatory agents designed to eradicate tumor cells, repair and activate dysfunctional immune cells, and reduce cancer-induced immune suppression in tumor microenvironments. Chapter V describes the features and rationale of a therapeutic vision that, in combination with recent clinical and research findings, guided this project and identified specific technical obstacles. Chapter VI is the published study -- entitled RepSox slows decay of CD34+ acute myeloid leukemia cells and decreases T cell immunoglobulin mucin-3 expression -- which describes how RepSox, a small molecule reprogramming tool and TGF-beta inhibitor, affects AML cells. The key findings are RepSox (1) slows decay of primary CD34+ AML cells from patients with diverse AML disease, (2) increases CXCL12 and MYC , and (3) accelerates loss of Tim 3, an inhibitory (immune-checkpoint) receptor, from the surface of AML cells. Thus, RepSox may promote in vitro engineering of patient-specific AML LSC-targeted therapies by prolonging survival of primitive CD34+ AML cells and increasing AML-cell immunogenicity via Tim-3 reduction. When envisioning the immunologic synapse between antigen-presenting AML cells and T cells, the actions of RepSox suggest RepSox might promote in vitro T-cell activation against primitive (relapse-causing) AML cells which represent the most problematic therapeutic target. Chapter VII discusses the potential therapeutic applications of these results in the context of AML and other cancers as well as unanswered questions and future research options. For example, the actions of RepSox suggest that its incorporation into pre-existing co-culture methods that exploit TCR agonists may enhance the activation of gammadelta T cells against a patient\u27s primitive AML cells and, thereby, help generate more effective immune-cell therapies. One goal of this dissertation is to encourage students to integrate new findings and conceptual frameworks from immunology, regenerative medicine, and cancer research when deciding which exciting research agendas to pursue

Occupational asthma: a review.

Occupational asthma is the most common form of occupational lung disease in the developed world at the present time. In this review, the epidemiology, pathogenesis/mechanisms, clinical presentations, management, and prevention of occupational asthma are discussed. The population attributable risk of asthma due to occupational exposures is considerable. Current understanding of the mechanisms by which many agents cause occupational asthma is limited, especially for low-molecular-weight sensitizers and irritants. The diagnosis of occupational asthma is generally established on the basis of a suggestive history of a temporal association between exposure and the onset of symptoms and objective evidence that these symptoms are related to airflow limitation. Early diagnosis, elimination of exposure to the responsible agent, and early use of inhaled steroids may play important roles in the prevention of long-term persistence of asthma. Persistent occupational asthma is often associated with substantial disability and consequent impacts on income and quality of life. Prevention of new cases is the best approach to reducing the burden of asthma attributable to occupational exposures. Future research needs are identified

Capacity of Public Health Surveillance to Comply with Revised International Health Regulations, USA

Most states have the reporting capacity to comply

PHSkb: A knowledgebase to support notifiable disease surveillance

BACKGROUND: Notifiable disease surveillance in the United States is predominantly a passive process that is often limited by poor timeliness and low sensitivity. Interoperable tools are needed that interact more seamlessly with existing clinical and laboratory data to improve notifiable disease surveillance. DESCRIPTION: The Public Health Surveillance Knowledgebase (PHSkb™) is a computer database designed to provide quick, easy access to domain knowledge regarding notifiable diseases and conditions in the United States. The database was developed using Protégé ontology and knowledgebase editing software. Data regarding the notifiable disease domain were collected via a comprehensive review of state health department websites and integrated with other information used to support the National Notifiable Diseases Surveillance System (NNDSS). Domain concepts were harmonized, wherever possible, to existing vocabulary standards. The knowledgebase can be used: 1) as the basis for a controlled vocabulary of reportable conditions needed for data aggregation in public health surveillance systems; 2) to provide queriable domain knowledge for public health surveillance partners; 3) to facilitate more automated case detection and surveillance decision support as a reusable component in an architecture for intelligent clinical, laboratory, and public health surveillance information systems. CONCLUSIONS: The PHSkb provides an extensible, interoperable system architecture component to support notifiable disease surveillance. Further development and testing of this resource is needed

Timeliness of Nongovernmental versus Governmental Global Outbreak Communications

To compare the timeliness of nongovernmental and governmental communications of infectious disease outbreaks and evaluate trends for each over time, we investigated the time elapsed from the beginning of an outbreak to public reporting of the event. We found that governmental sources improved the timeliness of public reporting of infectious disease outbreaks during the study period

Global Public Health Surveillance under New International Health Regulations

IHR 2005 establishes a global surveillance system for public health emergencies of international concern

Automated Identification of Acute Hepatitis B Using Electronic Medical Record Data to Facilitate Public Health Surveillance

Automatic identification of notifiable diseases from electronic medical records can potentially improve the timeliness and completeness of public health surveillance. We describe the development and implementation of an algorithm for prospective surveillance of patients with acute hepatitis B using electronic medical record data.Initial algorithms were created by adapting Centers for Disease Control and Prevention diagnostic criteria for acute hepatitis B into electronic terms. The algorithms were tested by applying them to ambulatory electronic medical record data spanning 1990 to May 2006. A physician reviewer classified each case identified as acute or chronic infection. Additional criteria were added to algorithms in serial fashion to improve accuracy. The best algorithm was validated by applying it to prospective electronic medical record data from June 2006 through April 2008. Completeness of case capture was assessed by comparison with state health department records.A final algorithm including a positive hepatitis B specific test, elevated transaminases and bilirubin, absence of prior positive hepatitis B tests, and absence of an ICD9 code for chronic hepatitis B identified 112/113 patients with acute hepatitis B (sensitivity 97.4%, 95% confidence interval 94-100%; specificity 93.8%, 95% confidence interval 87-100%). Application of this algorithm to prospective electronic medical record data identified 8 cases without false positives. These included 4 patients that had not been reported to the health department. There were no known cases of acute hepatitis B missed by the algorithm.An algorithm using codified electronic medical record data can reliably detect acute hepatitis B. The completeness of public health surveillance may be improved by automatically identifying notifiable diseases from electronic medical record data