Pathology Research Brochure

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Division of Clinical Chemistry

Email dchan@jhmi.edu

Phone (410) 955-2674

Daniel W. Chan, Ph.D.
Director, Division of Clinical Chemistry
Primary Appointment in Pathology; Secondary Appointments in Urology, Radiology, Oncology

The focus of my research is cancer proteomics. We identify cancer biomarkers using high throughput approaches, such as SELDI-TOF (surface-enhanced laser desorption ionization - time of flight) mass spectrometry. Once protein markers are identified, we develop antibodies and immunoassays for clinical studies. Bioinformatics is used to analyze and enhance the clinical usefulness of these biomarkers for the early detection of cancer. Studies are being conducted on patient specimens from prostate, breast, colorectal, and ovarian cancer. Our laboratory is involved in the Human Proteome Project (HUPO). This research will lead to a greater understanding of the importance of human proteome in the diagnosis and management of human cancer.

Publications

Diamandis E.P., Fritsche H.A., Lilja H., Chan D.W., Schwartz M.K., eds. Tumor Markers: Physiology, Pathobiology, Technology, and Clinical Applications. AACC Press, Washington, DC, 2002.
Clarke W., Zhang Z., Chan D.W. The application of clinical proteomics to cancer and other diseases. Clin. Chem. Lab. Med. 41:1562-1570, 2003.
Li J., White N., Zhang Z., Rosenzweig J., Mangold L.A., Partin A.W., Chan D.W. Detection of prostate cancer using serum proteomics pattern in a histologically confirmed population. J. Urol. 171:1782-1787, 2004.
Rai A.J., Chan D.W. Cancer Proteomics: Serum Diagnostics for Tumor Marker Discovery. Ann. N.Y. Acad. Sci. 1022:286-294, 2004.
Zhang Z., Bast Jr. R.C., Yu Y., Li J., Sokoll L.J., Rai A.J., Rosenzweig J.M., Cameron B., Wang Y.Y., Meng X.-Y., Berchuck A., van Haaften-Day C., Hacker N.F., de Bruijn H.W.A., van der Zee A.G.J., Jacobs I.J., Fung E.T., and Chan D.W. Three biomarkers identified from serum proteomics analysis for the detection of early stage ovarian cancer. Cancer Research 64:5882-5890, 2004.

Email	wclarke@jhmi.edu
Phone	(410) 502-7692

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William Clarke, Ph.D.

Primary Appointment in Pathology
Member, Graduate Program in Biochemistry, Cellular and Molecular Biology

My research interests involve the development of analytical methods for drug analysis. This includes the development and implementation of tandem mass spectrometric methods for measurement of multiple drugs in a single sample and investigation of alternative matrices for drug testing. Additionally, I am interested in investigation of techniques for measurement of free drug concentrations, and the applicability of these measurements in the clinical environment. Our other focus involves the proteomic characterization of renal transplant rejection. Studies are primarily aimed at discovery of biomarkers for early detection of acute rejection leading to the development of minimally invasive methods for transplant monitoring. We are also investigating renal ischemic injury using urine proteomic analysis.

Publications

William Clarke and David S. Hage. Development of Sandwich HPLC Microcolumns for Analyte Absorption on the Millisecond Time Scale. Anal.Chem. 73 (2001) 1366.
William Clarke and David S. Hage. Analysis for Free Drug Fractions byUltra Fast Immunoaffinity Chromatography. Anal. Chem. 73 (2001) 2157.
William Clarke and James H. Nichols. Bedside Glucose Testing:Applications in the Home and Hospital. Clin. Lab. Medicine. 21 (2001) 305.
William Clarke, Benjamin C. Silverman, Zhen Zhang, Daniel W. Chan, Andrew S. Klein, and Ernesto P. Molmenti. Characterization of Renal Allograft Rejection by Urinary Proteomic Analysis. Ann Surg, 237 (2003) 660.
William Clarke, Zhen Zhang, and Daniel W. Chan. The Application of Clinical Proteomics to Cancer and Other Diseases. Clin Chem Lab Med, 41 (2003) 1562.

Email	ladenson@jhmi.edu
Phone	(410) 955-3663

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Paul W. Ladenson, M.D.

Director, Division of Endocrinology, Department of Medicine
Primary Appointment in Medicine; Secondary Appointments in Pathology, Oncology

High prevalence of thyroid dysfunction and neoplasia, particularly in women, mandate development of new, accurate, and cost-effective approaches to clinical laboratory and cytological diagnosis of thyroid disorders. Our clinical studies and laboratory have included development and assessment of new analytical procedures, decision and cost-effectiveness analyses of thyroid function screening and testing strategies, and clinical-pathological correlation studies. Other work includes trials of recombinant thyrotropin in the long-term monitoring treated thyroid cancer patients, and investigations of adrenal dysfunction in patients with adrenomyeloneuropathy.

Publications

Ladenson PW, Singer PA, Levy EG, Ain KB, Bagchi M, Bigos ST, Smith SA, Daniels GH. American Thyroid Association guidelines for detection of thyroid dysfunction. Arch Int Med 2000;160:1573-1575.
Chin BB, Patel P, Cohade C, Ewertz ME, Wahl RL, Ladenson PW. Recombinant human TSH stimulation of FDG PET uptake in well-differentiated thyroid carcinoma. J Clin Endocrinol Metab 2004;89:91-5.
Xing M, Tufano RP, Tufaro AP, Basaria S, Byrne PJ, Wang J, Sidransky D, Ladenson PW. Detection of BRAF mutation on fine needle aspiration biopsy specimens: a new diagnostic tool for papillary thyroid cancer. J Clin Endocrinol Metab. 2004;89:2867-72.
Belin RM, Astor B, Powe NR, Ladenson PW. Smoke exposure and thyroid disease: complex associations in the third National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab, in press.

Email	lsokoll@jhmi.edu
Phone	(410) 955-2673

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Lori Sokoll, Ph.D.

Primary Appointment in Pathology; Secondary Appointments in Oncology and Urology

My primary research interest is the investigation of serum tumor markers for the early detection, diagnosis, staging, and monitoring of cancer. Our focus is to develop new tumor markers and to develop new applications for existing markers in order to increase their clinical utility. We are primarily studying markers for prostate cancer and breast cancer. Other research interests include immunoassay automation and intraoperative hormone measurements.

Publications

Sokoll LJ, Mangold LA, Partin AW, Epstein JI, Bruzek DJ, Dunn W, Mohr P, Wallerson G, Chan DW. cPSA as a staging tool for prostate cancer: a prospective study in 420 men. Urology 2002;60:18-23.
Wians FH, Cheli CD, Balko JA, Bruzek DJ, Chan DW, Sokoll LJ. Evaluation of the clinical performance of equimolar- and skewed-response total prostate-specific antigen assays versus complexed and free PSA assays and their ratios in discriminating between benign prostatic hyperplasia and prostate cancer. Clin Chim Acta 2002;326:81-95.
Sokoll LJ, Chan DW, Mikolajczyk SD, Rittenhouse HG, Evans CL, Linton HJ, Mangold LA, Mohr P, Bartsch G, Klocker H, Horninger W, Partin AW. Proenzyme PSA for the early detection of prostate cancer in the 2.5-4.0 ng/mL total PSA range: preliminary analysis. Urology 2003;61:274-6.
Sokoll LJ, Wians FH, Remaley AT. Rapid intraoperative immunoassay of PTH and other hormones: a new paradigm for point-of-care testing. Clin Chem 2004;50:1126-35.

Email	hzhang32@jhmi.edu
Phone	(410) 502-8149
Related Websites
UniPep

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Hui Zhang, Ph.D.

Primary Appointment in Pathology

Protein modification is one of the key mechanisms that governs the diverse protein structure and function, and plays a significant role in the development of many diseases such as cancer. Unfortunately, the dynamic nature of protein modification remains uncharacterized, which is one of the major bottlenecks to biochemical research.

My primary research goal is to study protein modification on the proteome scale and the effects of modification on protein function and disease progression. For the past few years, my research has been focused on developing high-throughput technologies to isolate and identify two of the most abundant protein modifications - phosphorylation and glycosylation. One technology enables capturing and identification of modified peptides using affinity chromatography. To do so, I have developed a group of antibodies reactive against a variety of protein modification sites, such as phosphorylation, nitration, acetylation, and substrates of a specific modification enzyme, etc. Among those, phospho-specific antibodies have enabled isolation of a large number of phosphorylated peptides that can be subsequently identified by tandem mass spectrometry. The second technology enables capturing glycopeptides using solid phase extraction, which has become a powerful tool to analyze glycoproteins on cell surface and in body fluids. Thus far, thousands of novel glycosylation sites have been identified from different tissues using this novel glycopeptide capture technology; this significantly expends the limited number of experimentally identified glycosylation sites prior to the new technology. These methods are highly sensitive, holding a strong promise for discovering low abundance disease marker proteins in tissue, plasma or other body fluids.

Currently, we are applying these proteomics technologies to determine protein modifications associated with cancer for early detection and monitoring therapeutic effects as well as developing novel methods to study protein modifications that will have major implications for human health.

Publications

Tian, Y., Zhou, Y., Elliott, S., Aebersold, R., and Zhang. H. Solid-phase extraction of N-linked glycopeptides. Nature Protocols (2007) 2: 334.
Zhang, H., Liu, A. Y., Loriaux, P., Wollscheid, B., Zhou, Y., Watts, J. D., and Aebersold, R. Mass spectrometric detection of tissue-derived proteins in blood. Molecular & Cellular Proteomics (2007) 6: 64.
Zhang, H., Loriaux, P., Eng, J., Campbell, D., Keller, A., Moss, P., Bonneau, R., Zhang, N., Zhou, Y., Wollscheid, B., Cooke, K., Yi, E. C, Lee, H, Peskind, E. R., Zhang, J., Smith, R. D., and Aebersold, R. UniPep, a database for human N-linked glycosites: A Resource for Biomarker Discovery. Genome Biology (2006) 7: R73.
Zhang, H., Li, X. J., Martin, D. B., and Aebersold, R. Identification and quantification of N-linked glycoproteins using hydrazide chemistry, stable isotope labeling and mass spectrometry. Nature Biotechnology (2003) 21:660.
Zhang, H., Zha, X., Tan, Y., Hornbeck, P. V., Mastrangelo, A. J., Alessi, D. R., Polakiewicz, R. D., and Comb, M. J. Phosphoprotein analysis using antibodies broadly reactive against phosphorylated motifs. Journal of Biological Chemistry (2002) 277:39379.

Email	zzhang7@jhmi.edu
Phone	(410) 502-7871

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Zhen Zhang, Ph.D.

Primary Appointment in Pathology

My research interests are in the development and application of bioinformatics tools for clinical diagnosis. What used to be considered as a single diagnosis may actually consist of a number of different phenotypes with distinguished disease pathways and varying genomic and proteomics expression patterns. I am interested in deriving new mathematical and computational algorithms to identify such patterns for biomarker discovery and use them to establish predictive models for the diagnosis and management of diseases. Currently, our effort is focused on tumor marker discovery using high throughput proteomics approaches.

Publications

Zhang Z., Barnhill S.D., Zhang H., Xu F., Yu Y., Jacobs I., Woolas R.P., Berchuck A., Madyastha K.R., Bast R.C. Jr. Combination of multiple serum markers using an artificial neural network to improve specificity in discriminating malignant from benign pelvic masses. Gynecol Oncol. 1999; 73(1):56-61.
Li J, Zhang Z., Rosenzweig J., Wang Y., Chan D.W. Proteomics and bioinformatics approaches for identification of serum biomarkers to detect breast cancer. Clin. Chem., 2002 Aug;48(8):1296-1304.
Zhang Z. Combining Multiple Biomarkers in Clinical Diagnostics - A review of Methods and Issues. In: Diamandis E.P., Fritsche H.A., Lilja H.,Chan D.W., Schwartz M.K., eds. Tumor Markers: Physiology, Pathobiology, Technology and Clinical Applications. AACC Press, Washington, DC, 2002.
Buckhaults P., Zhang Z., Chen Y.C., Wang T.L., St Croix B., Saha S., Bardelli A., Morin P.J., Polyak K., Hruban R.H., Velculescu V.E., Shih IeM. Identifying tumor origin using a gene expression-based classification map. Cancer Res. 2003; 63(14):4144-9.
Zhang Z., Bast R.C. Jr, Yu Y., Li J., Sokoll L.J., Rai A.J., Rosenzweig J.M., Cameron B., Wang Y.Y., Meng X.Y., Berchuck A., Van Haaften-Day C., Hacker N.F., de Bruijn H.W., van der Zee A.G., Jacobs I.J., Fung E.T., Chan D.W. Three biomarkers identified from serum proteomic analysis for the detection of early stage ovarian cancer. Cancer Res. 2004; 64(16):5882-90.