All Anatomic Pathology residents are required to do a total of 4 months of research.
Residents are exposed to, and encouraged to participate in, clinical and laboratory research throughout the program. The National Institutes of Health (NIH) is the premier medical research institution in the United States. The residents can attend weekly departmental research conferences and data sessions, as well as numerous clinical and research conferences throughout the NIH campus. During the Residency Orientation, the residents rotate through the investigative laboratories within the department. They are provided with a written update of the departmental research activities. When the resident has chosen a research project and a scientific mentor, the project is reviewed and approved by the Program Directors.
Residents receive laboratory space, reagents, access to equipment, technical support, and guidance appropriate to fully support their research projects. They are encouraged to publish their research findings and continue the research independently in the future. Travel funds are provided for each resident to present his or her research findings at one national clinical or scientific meeting per year.
The Residency Training Program offers research training opportunities virtually unmatched internationally. Each resident develops a research program with any of the world-renowned scientists in the Laboratory of Pathology, CCR, NCI. Each resident plans a research project with a designated mentor and reviews the experimental plan with the Program Director. The residents are encouraged to choose exploratory projects, which lead to new discoveries and open new fields.
Residents are expected to serve as consultants and collaborators for clinical studies and case studies, which stem from findings made during routine diagnosis. During research rotations, each resident is provided with laboratory space, equipment, reagents and technical support. They show their research findings in weekly data clubs, and brainstorm ideas in weekly conferences and journal clubs. Research electives are concentrated in the later stages of the residency program. Residents receive 2 months of elective in the first year, 3 months of elective in the second year, and usually 5 months of elective in the third year. These elective periods may be used for research rotations, or further clinical electives, depending on the needs and interests of the resident.
Each resident is provided with travel funds to attend one scientific conference per year. At that time, the resident is responsible for a poster or platform presentation. Our residents have been highly successful at national meetings, and have been the recipients of numerous awards, including the Stowell-Orbison Award for the best resident presentation at the United States and Canadian Academy of Pathology Meeting. Residents also compete for and obtain sponsorship for outside research electives. This year, one of our residents was awarded the Arthur Purdy Stout Stipend allowing him to travel to Emory University to complete a collaborative research project between the NIH and their Department of Pathology. He will conduct an investigative study of inflammatory pseudotumors.
The type of project undertaken by residents has ranged from basic molecular genetics to applied hematopathology, surgical pathology case reviews, and pediatric tumor cell biology. Residents in our program have access to modern and sophisticated research laboratories. They receive instruction in the use of the laser capture dissection microscope in order to obtain purified cell populations for genomic and proteomic studies. The NCI has a gene microarray facility that permits residents to study patterns of gene expression in purified cell populations. All residents are fully funded for any research projects that they undertake during years 1-3 of the residency program. They may pursue these studies in the Laboratory of Pathology, NCI, or in any other research laboratory on the NIH campus, allowing them the flexibility to pursue their personal research interests.
Residents may review the research interests of program faculty and contact the investigator for more information. Research interests are briefly outlined below, by section.
a. Biochemical Pathology Section: Dr. David Roberts is conducting research on cell surface receptors and signal transduction pathways through which extracellular matrix proteins regulate cell behavior in several disease states. These studies will identify new molecular targets and provide a basis for designing novel pharmacological agents. The primary research projects in the laboratory are: 1) regulation of tumor angiogenesis by thrombospondins, 2) regulation of immune responses by thrombospondins, and 3) defining the host-pathogen interactions required for establishing disseminated infections by the yeast Candida albicans.
b. Clinical Cytogenetics Section: Dr. Diane Arthur's research focuses on the clinical and biological significance of chromosome abnormalities in human malignancies. Her group has been using both routine G-banding and newer molecular cytogenetic techniques, including fluorescence in-situ hybridization (FISH), comparative genomic hybridization (CGH) and multicolor spectral karyotyping (SKY), to study chromosome abnormalities in patients with familial or sporadic chronic lymphocytic leukemia. The goal of these studies is to determine which aberrations may be primary (i.e., important in initiation), and which are secondary (i.e., important in progression) of this leukemia. In the future, Dr. Arthur intends to investigate non-hematologic solid tumors using similar methods.
c. Clinical Proteomics: Clinical Proteomics uses a variety of proteomic-based approaches such as two-dimensional gel electrophoresis (2D-PAGE), laser capture microdissection, and highly sensitive mass spectrometry methods. Novel technologies including high-density protein arrays, antibody arrays, lysate arrays, and surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) analysis are also used for characterization of tumor cells. These techniques enable identification of new biomarkers, signal pathway profiles, and therapeutic targets of cancer. The use of this technology may generate important markers for early detection and/or therapeutic targets unique to certain phenotypes.
d. Cytopathology Section: Dr. Abati joined the Laboratory of Pathology, NCI, NIH in July of 1992. In 1996, she assumed the role of Chief of the Cytopathology Section. Her interests revolve around the application of ancillary techniques to cytopathology material. She has published widely on this topic, including the applications of immunocytochemistry, FISH, microdissection and PCR on archival cytology material. Dr. Abati participates in many editorial board activities (Clinical Cancer Research, Cancer Cytopathology, Diagnostic Cytopathology), and participates extensively in medical society work (President-elect of the Papanicolaou Society, American Society of Cytopathology committees). Most recently, she co-authored a new major textbook in her field, Modern Cytopathology, published by WB Saunders in 2003. Dr. Abati has many peer-reviewed publications in her field. Dr. Filie's interest involves the potential application of new sensitive and accurate techniques such as molecular markers and proteomics as a diagnostic tool in cytopathology. He has studied the utilization of polymerase chain reaction for the detection of loss of heterozygosity in aspirates of tall cell variant of papillary carcinoma. Currently, he is involved in the investigation of proteomics in the differential diagnosis of aspirates.
e. Developmental Biology Unit: Dr. Susan Mackem is interested in the regulation of patterning and morphogenesis during development. Her lab is analyzing the function of several T-box and homeobox genes involved in both early inductive-patterning and in later growth phases of limb development. Emphasis is on deciphering developmental function in both chick and mouse embryos, including the use of conditional transgenic expression and knock-out approaches as well as biochemical analyses of mechanisms of gene regulation. Genomic approaches to identifying in vivo transcriptional targets, including microarray analysis and chomatin IP are also being developed in parallel.
f. Flow Cytometry Unit: Dr. Maryalice Stetler-Stevenson is studying factors that are associated with a more aggressive clinical behavior in lymphomas. Current studies have identified a pattern of gene expression associated with a more aggressive behavior in Burkitt's lymphoma. She is investigating the action these genes may have in B-cell neoplasia. Dr. Stetler-Stevenson is also studying aneuploidy and cell-cycle fractions in benign and malignant tumors, both hematopoietic and solid, to determine the prognostic and diagnostic importance of these clinical laboratory determinations. Dr. Douglas W. Kingma provides the diagnostic flow cytometry support to the NIH Clinical Center. Besides his primary diagnostic responsibilities, Dr. Kingma oversees the training of residents and hematopathology fellows in diagnostic flow cytometry and provides vital collaborative research support to NIH Clinical Center principal investigators. His current studies include correlating hematologic and biologic responses to anti-idiotype-based immunotherapy.
g. Gene Regulation Section and Research Operations: Dr. David Levens studies the biochemical mechanisms employed during the transcription, processing and translation of RNA in order to identify pathology resulting from aberrant regulation. Currently, the Section has two interrelated areas of research: 1) the transcriptional regulation of c-myc, with special emphasis on mechanisms integrating multiple inputs; and 2) understanding how non-B DNA elements and associated factors participate in gene regulation, especially the FarUpStream Element (FUSE), the FUSE Binding Protein (FBP) and the FBP Interacting Repressor. These two-project overlap as FBP and FIR contribute to the proper regulation of c-myc; this regulation is disturbed in Xeroderman pigmentosum.
h. Hematopatholology Section: Dr. Elaine Jaffe conducts a major program in diagnostic and experimental hematopathology. While the emphasis is on clinical protocols based at NCI, collaborations exist with physicians in other categorical institutes. Dr. Jaffe supervises an internationally recognized consultation service that receives more than 1,600 cases per year in consultation from the general medical community. The Hematopathology Section continues its active research program on the molecular and immunological characterization of malignant lymphomas. Areas of emphasis include the interrelationship of Hodgkin's disease and the non-Hodgkin's lymphomas, T-cell lymphomas, and the role of Epstein-Barr virus in lymphoproliferative disorders
i. In-Situ Hybridization Unit: Dr. Stefanie Pittaluga is interested in studying the role of Epstein-Barr virus in a variety of lymphoproliferative disorders, including lymphomatoid granulomatosis. The in situ hybridization (ISH) service, although primarily clinically related, is developing chromogenic detection of frequently occurring chromosomal translocations in human lymphomas on tissue sections. These assays will help in further characterizing malignant lymphomas. This group is also involved in the development of ISH for the detection of a variety of chemokines and their receptors on tissue sections in lymphoproliferative disorders.
j. Molecular Diagnostics/Immunohistochemistry Unit: Dr. Mark Raffeld's investigations are concerned with the molecular abnormalities associated with different types of malignant lymphomas, and their application to clinical diagnosis. His current research interests include the molecular basis of indolent lymphoma progression and the functional effects of MYC gene coding-region mutations that are frequent in Burkitt's lymphomas.
k. Molecular Signaling Section: Dr. Elise Kohn is an internist and coordinates the Medical Gynecologic Oncology Clinic and serves as principal investigator on numerous clinical trials. Within the Laboratory of Pathology, she is investigating the convergence of prosurvival, angiogenesis and motility signals at common pathways in the local tumor microenvironment and how these events can be efficiently targeted therapeutically. This Section previously characterized the calcium influx inhibitory drug, CAI, in the laboratory and the clinic and this group has used CAI as a tool to regulate signaling events in the tumor and endothelial cell. The Section uses transcriptomics and proteomics to identify proteins important in tumor and endothelial cells. They have identified candidate genes contributing to ovca pathophysiology (CAIR-1/BAG-3, Granulin-Epithelin Precursor, GEP), and are now undergoing biochemical, molecular, and biological evaluation. The lab has developed models (in vitro, mouse and Drosophila) with which to dissect the role of these candidates in tumorigenesis and invasion to develop an integrated model of the physiology and pathophysiology of the epithelial stromal interface in ovarian cancer (ovca?). The Section is studying the signal transduction function of CAIR-1/BAG-3, identified as differentially expressed downstream of calcium influx blockade. These studies are being driven by dissection of protein functional domains and their cognate partners. They identified PLC-gamma and Hsp70 as partner proteins for CAIR-1 and have applied mutants to regulate their activity. The role of the BAG domain in protein survival has been demonstrated and is being studied using different injury mechanisms and domain mutants. Preliminary xenograft studies with the mutants demonstrate differential phenotypes. Clinical correlative studies are investigating the role of CAIR-1 expression in ovca. They have used both CGAP cDNA libraries we generated from microdissected ovca epithelium and novel proteomic technologies to identify a novel growth factor in ovca. GEP is differentially expressed between invasive ovca and tumors of low malignant potential in patient samples and regulates ovca survival as shown by anti-sense GEP transfection. Studies now focus on regulation of GEP production in ovca and GEP partner proteins in proliferation and invasion. A CRADA collaboration has been initiated for molecular therapeutics targeting GEP. The systematic approaches will identify additional candidate genes and will provide the ability to unravel the network of signaling interactions of these candidate genes with pathways required for the cell to accomplish the steps necessary for survival, proliferation, and invasion and metastases. They will apply discovery and candidate selection to survival, angiogenesis, and invasion model systems in place in the laboratory that allows them to efficiently query tumor/host interactions. Findings will be applied to clinical samples where differential invasiveness and autonomy of the tumors have been evaluated and linked to patient outcomes. This integrated approach has, and is expected to continue, to lead to identification of novel biomarkers and therapeutic targets. Together, these two lines of investigation have yielded new mechanistic information into the signaling underlying progression and survival in carcinomas, focusing on ovarian cancer.
l. Pathogenetics Unit: Dr. Michael Emmert-Buck investigates genetic alterations underlying tumor development and progression. Emphasis is placed on the study of human cancer as it occurs in vivo, and the integration of basic research, clinical information, and developing technologies. The three areas of focus are: 1) technology/methodology development, 2) prostate cancer, and c) multiple endocrine neoplasia type I (MEN1).
m. Pediatric Tumor Biology/Ultrastructural Pathology Section: Dr. Maria Tsokos has focused on two major areas of research: 1) the identification of markers and employment of techniques that help in the diagnosis and histogenetic characterization of Ewing's sarcoma, primitive neuroectodermal tumors (PNET), and rhabdomyosarcoma; and 2) the definition of histologic, biologic and other factors to predict the biologic aggressiveness of tumors.
n. Postmortem Pathology Section and Clinical Operations: Dr. David Kleiner works with the Liver Disease Section of the NIDDK, characterizing the hepatic pathologic changes in chronic viral hepatitis and steatohepatitis, both on initial presentation and following treatment. Of particular interest are prognostic indicators of progression of fibrosis in these diseases. He also collaborates with the Transplantation Branch, NIDDK, which is studying the histopathologic effects of novel immunosuppressive regimens on the development of renal transplant rejection or other complications of transplantation. The Postmortem Pathology Section serves as a diagnostic and education resource for the clinical staff as well as a source of research material for the study of diseases under protocol at the NIH Clinical Center. Dr. Carl C. Baker conducts research on human papillomaviruses and cervical cancer, including the molecular characterization of HPVs and their interaction with the host cell. Current interests include: 1) molecular characterization of cervical cancer progression, including microarray expression profiling; 2) alternative splicing of cellular and viral pre-mRNAs; 3) development of anti-HPV and anti-cervical cancer therapeutics using RNA trans-splicing. Dr. Stephen M. Hewitt supervises the Tissue Array Research Program (TARP). The TARP produces tissue arrays for both the extramural and intramural communities. The intramural tissue arrays are constructed on a collaborative basis, and have included model systems for osteosarcoma, esophageal cancer, non-small cell lung cancer, lymphoma, mesothelioma, prostate cancer, and renal tumors as well as cell line arrays. Dr. Hewitt's interests focus on improving array technology, including automated arraying, data collection, quantitative methodologies for immunohistochemistry, and tissue-immunoblotting. Dr. Alexander Vortmeyer is studying the molecular pathogenesis of CNS- and neural crest-derived neoplasms.
o. Surgical Pathology Section: Dr. Maria Merino, in collaboration with other members of the Surgical Pathology staff, is investigating the role of different tumor markers (e.g., Ki 67, collagenases and GCDFP-15) as prognostic tools in the diagnosis of breast, ovarian and thyroid cancer, as well as soft tissue sarcomas. The Section is also investigating the use of antibodies against P-glycoprotein, which has been associated with a multidrug-resistant phenotype.
Further information about the Laboratory of Pathology (LP) can be found on our public Web site. This site contains the detailed Specimen Collection Guide and LP Staff Directory. The LP Web site is a useful supplement to this manual.