Belinda Seto

Rapamycin and mTOR: a serendipitous discovery and implications for breast cancer

Rapamycin was discovered more than thirty years ago from a soil sample from the island of Rapa Nui. It was isolated from Streptomyces hygroscopicus and initial characterization focused on its antifungal activities. Subsequent characterization showed that it has immunosuppressive properties and has been used successfully to reduce organ rejection with kidney transplantation. Rapamycin has proven to be a versatile compound with several seemingly unrelated properties, including antifungal, immunosuppressive, and anticancer. The National Cancer Institute (NCI) Developmental Therapeutics Program demonstrated that rapamycin inhibited cell growth in tumor cell lines. These observations stimulated research to explore the underlying mechanism of anti-tumor activities. Cell growth inhibition involves binding to the mammalian Target of Rapamycin (mTOR). The mTOR signaling pathway is critical to cell growth, proliferation, and survival and rapamycin inhibits these hallmark processes of cancer. Binding of growth factors activates mTOR signaling, which in turn leads to downstream phosphorylation of protein kinases, e.g., p70S6 kinase and lipid kinases in the phosphorylation of phosphoinositides. Understanding of mTOR signaling provided the biological basis for targeted chemotherapeutics development, including several rapamycin analogues for treating breast and other cancers.

History of Medical Ethics and Perspectives on Disparities in Minority Recruitment and Involvement in Health Research

&NA; The legitimate and successful recruitment of minorities as research participants in clinical trials should be addressed from an ethical and historical perspective. To gain an appreciation of the challenges, to develop strategies and to overcome the disparities of minority involvement in clinic trials, it is essential to be cognizant of previous violations and abuses of ethics and human rights. Also significant are major legislation, regulations and federal initiatives that resulted from those abuses. From history, we have learned we cannot generalize data and assume that, if we have the majority group in clinical trials, then we can accurately apply that data to minorities. There are cultural and environmental differences; thus, it is absolutely crucial that researchers approach recruitment of minority groups with cultural competence and cultural sensitivity. Federal regulations and legislation set the framework for protection of human participants in research.

Moving toward multimedia electronic health records: how do we get there?

This report, based on a workshop jointly sponsored the National Institute of Biomedical Imaging and Biomedical Engineering and the Office of the National Coordinator for Health Information Technology, examines the role and value of images as multimedia data in electronic health records (EHRs). The workshop, attended by a wide range of stakeholders, was motivated in part by the absence of image data from discussions of meaningful use of health information technology. Collectively, the workshop presenters and participants argued that images are not ancillary data and should be central to health information systems to facilitate clinical decisions and higher quality, efficiency, and safety of care. They emphasized that the imaging community has already developed standards that form the basis of interoperability. Despite the apparent value of images, workshop participants also identified challenges and barriers to their implementation within EHRs. Weighing the opportunities and challenges, workshop participants provided their perspectives on possible paths forward toward fully multimedia EHRs.

Issues in regulatory guidelines for data monitoring committees.

As clinical trials have emerged as the major research method for evaluating new interventions, the process for monitoring intervention safety and benefit has also evolved. The Data Monitoring Committee (DMC) has become the standard approach to implement this responsibility for many Phase III trials. Recent draft guidelines on the operation of DMCs by the Food and Drug Administration (FDA) have raised issues that need further clarification or discussion, especially for industry sponsored trials. These include, the time when DMCs are needed, the role of the independent statistician to support the DMC, and sponsor participation at DMC meetings. This paper provides an overview of these issues, based on the discussions at the January, 2003 workshop sponsored by Duke Clinical Research Institute.

Introduction to metrology series

The molecular bases of health and disease have become increasingly well understood in the past 20 years, leading to the need for tests that can provide such information in objective, reproducible forms for clinical research and practice. Much of this clinical information needed by contemporary medicine is referred to as biomarkers. A widely accepted definition of a biomarker, used by both National Institute of Health (NIH) and Food and Drug Administration, is ‘‘a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or a response to a therapeutic intervention.’’ The term ‘‘biomarker’’ is often assumed to imply a laboratory test, but it can also refer to a clinical measurement like blood pressure or the output of a clinical imaging scan. During the past two decades, remarkable advances in medical imaging technology have made it possible to obtain from clinical images high resolution anatomic, functional, metabolic, and physiologic information, all of which reflect in some way the molecular substrate of the healthy or diseased tissue, organ or person being imaged. With appropriate calibration, most of these imaging technologies can provide quantitative information about some properties of the material with which the energy has interacted. For example:

Proline reductase: A sensitive fluorometric assay with o-phthalaldehyde

Abstract A rapid and sensitive fluorometric assay for measuring the activity of proline reductase is described. The product of the enzymic reaction, δ-aminovalerate, is converted to a highly fluorescent derivative by reaction with o -phthalaldehyde. The water-soluble fluorescent product exhibits an excitation maximum at 340 nm and an emission maximum at 455 nm. The fluorophor reacts specifically with δ-aminovalerate without any interference from proline.

NIH Workshop on Clinical Translation of Molecular Imaging Probes and Technology—Meeting Report

A workshop on “Clinical Translation of Molecular Imaging Probes and Technology” was held August 2, 2013 in Bethesda, Maryland, organized and supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB). This workshop brought together researchers, clinicians, representatives from pharmaceutical companies, molecular probe developers, and regulatory science experts. Attendees met to talk over current challenges in the discovery, validation, and translation of molecular imaging (MI) probes for key clinical applications. Participants also discussed potential strategies to address these challenges. The workshop consisted of 4 sessions, with 14 presentations and 2 panel discussions. Topics of discussion included (1) challenges and opportunities for clinical research and patient care, (2) advances in molecular probe design, (3) current approaches used by industry and pharmaceutical companies, and (4) clinical translation of MI probes. In the presentations and discussions, there were general agreement that while the barriers for validation and translation of MI probes remain high, there are pressing clinical needs and development opportunities for targets in cardiovascular, cancer, endocrine, neurological, and inflammatory diseases. The strengths of different imaging modalities, and the synergy of multimodality imaging, were highlighted. Participants also underscored the continuing need for close interactions and collaborations between academic and industrial partners, and federal agencies in the imaging probe development process.

Multifunctional Nanoscale Delivery Systems for Nucleic Acids

Nanoscale systems have emerged in the past two decades as attractive platforms for delivering nucleic acids in vivo while performing other therapeutic or diagnostic functions, though their full potential for improving human health has yet to be realized in the clinic. Bioengineering techniques have been crucial for modifying and optimizing synthetic and viral delivery systems to include drugs, imaging agents and targeting moieties as well as reducing toxicity effects and increasing delivery efficiency and specificity. Directed delivery technologies can complement these nanoscale systems to localize therapy in vivo. The use of nucleic acid analogs can also enhance therapeutic efficacy under ideal circumstances. This chapter will review some of the recent developments in RNA and DNA delivery research with a focus on progress toward human therapies, the challenges that have been encountered, and the engineering approaches that have been employed. In addition to on-going work on the optimization of delivery systems, three challenging areas are identified: (1) the development of heterogeneous, three-dimensional microenvironments for testing delivery systems, (2) imaging approaches to understand the dynamic interactions of systems from administration through delivery in the human population, and (3) development and translation of directed technologies capable of enhancing delivery in a clinical setting and producing a sustained therapeutic effect.