Training Grant Faculty Research Interests

GI TRAINING GRANT

My laboratory studies the mechanisms that switch-on and switch-off inflammation and pain. Inflammation protects against infection, and the sensation of pain allows organisms to avoid stimuli that would otherwise cause injury. However, inflammation must be tightly controlled since dysregulated, exaggerated inflammation causes disease and pain. The mechanisms that initiate and terminate inflammation and pain are poorly understood, and consequently the therapies are inadequate and often associated with detrimental side effects. Our work focuses on the role of proteolytic enzymes as “molecular switches” that initiate and terminate signaling by mediators of inflammation and pain. Proteases that act at the cell-surface and in endosomes, lysosomes and proteasomes cleave neuropeptides, G-protein coupled receptors and ion channels and thereby control signaling by major mediators of inflammation and pain transmission.

Selected Publications

• Amadesi S, Nie J, Vergnolle N, Cottrell GS, Grady EF, Trevisani M, Manni C, Geppetti P, McRoberts JA, Ennes H, Davis JB, Mayer EA & Bunnett NW. (2004). Protease-activated receptor 2 sensitizes the capsaicin receptor transient receptor potential vanilloid receptor 1 to induce hyperalgesia. J Neurosci 24, 4300-4312.
• Grant AD, Cottrell GS, Amadesi S, Trevisani M, Nicoletti P, Materazzi S, Altier C, Cenac N, Zamponi GW, Bautista-Cruz F, Barajjas Lopez C, Joseph E, Levine JD, Liedtke W, Vanner S, Vergnolle N, Geppetti P & Bunnett NW. (2006). Protease-Activated Receptor 2 Sensitizes the Transient Receptor Potential Vanilloid 4 Ion Channel to Cause Mechanical Hyperalgesia. J Physiol.
• Jacob C, Cottrell GS, Gehringer D, Schmidlin F, Grady EF & Bunnett NW. (2005). c-Cbl mediates ubiquitination, degradation, and down-regulation of human protease-activated receptor 2. J Biol Chem 280, 16076-16087.
• Steinhoff M, Vergnolle N, Young SH, Tognetto M, Amadesi S, Ennes HS, Trevisani M, Hollenberg MD, Wallace JL, Caughey GH, Mitchell SE, Williams LM, Geppetti P, Mayer EA & Bunnett NW. (2000). Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism. Nat Med 6, 151-158.
• Vergnolle N, Bunnett NW, Sharkey KA, Brussee V, Compton SJ, Grady EF, Cirino G, Gerard N, Basbaum AI, Andrade-Gordon P, Hollenberg MD & Wallace JL. (2001). Proteinase-activated receptor-2 and hyperalgesia: A novel pain pathway. Nat Med 7, 821-826.

The main focus of my laboratory is on increasing our understanding of the biology of the liver and enterohepatic circulation in health and disease, through the application of genetic approaches. Studies of several liver diseases are ongoing in my laboratory, and each at a different stage. These projects include:

1. Genetic studies of Familial hypercholanemia (FHCA).
2. Study of disease caused by mutation in FIC1(ATP8B1), and characterization of mouse models of ATP8B1 disease.
3. Genetic studies of lymphedema-cholestasis syndrome (LCS, Aagenaes syndrome).
4. Evaluation of genetic factors influencing susceptibility to 'secondary' liver diseases, including drug-induced cholestasis.

Selected Publications

• Carlton VE, Harris BZ, Puffenberger EG, Batta AK, Knisely AS, Robinson DL, Strauss KA, Shneider BL, Lim WA, Salen G, Morton DH, Bull LN. (2003) Complex inheritance of familial hypercholanemia with associated mutations in TJP2 and BAAT. Nature Genetics, vol 34, pp. 91-96.
• Bull, L.N., Roche, E., Song, E.J., Pedersen, J., Knisely, A.S., van der Hagen, C.B., Eiklid, K., Aagenaes, O., Freimer, N.B. (2000) Mapping of the locus for Cholestasis-Lymphedema Syndrome (Aagenaes Syndrome) to a 6.6.cM interval on chromosome 15q. American Journal of Human Genetics, vol 67, pp. 994-999.
• Bull, L.N., Juijn, J.A., Liao, M., van Eijk, M.J.T., Sinke, R.J., Stricker, N.L., DeYoung, J.A., Carlton, V.E.H., Baharloo, S., Klomp, L.W.J., Abukawa, D., Barton, D.E., Bass, N.M., Bourke, B., Drumm, B., Jankowska, I., Lovisetto, P., McQuaid, S., Pawlowska, J., Tazawa, Y., Villa, E., Tygstrup, N., Berger, R., Knisely, A.S., Houwen, R.H.J., Freimer, N.B. (1999) Fine-resolution mapping by haplotype evaluation: the examples of PFIC1 and BRIC. Human Genetics, vol 104, #3, pp 241-248.
• Strautnieks, S.S., Bull, L.N., Knisely, A.S., Kocoshis, S.A., Dahl, N., Arnell, H., Sokal, E., Dahan, K., Childs, S., Ling, V., Tanner, M.S., Kagalwalla, A.F., Németh, A., Pawlowska, J., Baker, A., Mieli-Vergani, G., Freimer, N.B., Gardiner, R.M., Thompson, R.J. (1998). A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis. Nature Genetics, vol. 20, #3, pp.233-238.
• Bull, L.N., van Eijk, M.J.T., Pawlikowska, L., DeYoung, J.A., Juijn, J.A., Liao, M., Klomp, L.W.J., Lomri, N., Berger, R., Scharschmidt, B.F., Knisely, A.K., Houwen, R.H.J., Freimer, N.B. (1998). A gene encoding a P-type ATPase is mutated in two forms of hereditary cholestasis. Nature Genetics, vol. 18, #3, pp. 219-224.

Gastrointestinal cancers, drug safety, and reflux disease.

Selected Publications

• Corley DA. Chemoprevention in Barrett's Esophagus: Are we There yet, Are we There yet...? Clin Gastroenterol Hepatol. 2009 Sep 16.
• He T, Corley DA, Lu M, Di Spigna NH, He J, Nackashi DP, Franzon PD, Tour JM. Controllable molecular modulation of conductivity in silicon-based devices. J Am Chem Soc. 2009 Jul 29;131(29):10023-30.
• Corley DA, Kubo A, DeBoer J, Rumore GJ. Diagnosing Barrett's esophagus: reliability of clinical and pathologic diagnoses. Gastrointest Endosc. 2009 May;69(6):1004-10.
• Wong RJ, Corley DA. Survival differences by race/ethnicity and treatment for localized hepatocellular carcinoma within the United States. Dig Dis Sci. 2009 Sep;54(9):2031-9.
• Kubo A, Levin TR, Block G, Rumore GJ, Quesenberry CP Jr, Buffler P, Corley DA. Alcohol types and sociodemographic characteristics
• as risk factors for Barrett's esophagus. Gastroenterology. 2009 Mar;136(3):806-15. Kubo A, Levin TR, Block G, Rumore GJ, Quesenberry CP Jr, Buffler P, Corley DA. Dietary antioxidants, fruits, and vegetables and the risk of Barrett's esophagus. Am J Gastroenterol. 2008 Jul;103(7):1614-23.
• Mahadevan U, Sandborn WJ, Li DK, Hakimian S, Kane S, Corley DA. Pregnancy outcomes in women with inflammatory bowel disease: a large community-based study from Northern California. Gastroenterology. 2007 Oct;133(4):1106-12.

The rapid induction of protective antibodies is critical for host defense against pathogens. Reciprocally, unwanted antibody responses against self-components (antigens) are a cause of autoimmune disease. To mount antibody responses, antigen-specific B and T cells that may be as rare as 1 in 100,000 cells must first encounter the antigen and then interact with each other. These encounters occur within peripheral lymphoid organs - lymph nodes, spleen, and mucosal lymphoid tissues - but the mechanisms that control lymphoid cell migration and that promote interactions between rare antigen-specific cells are far from understood. Major goals: (i) define the molecular cues that guide B and T cell migration and interactions in lymphoid organs during the immune response; (ii) characterize selection events required for induction of high affinity antibody responses; (iii) determine how autoreactive B cells are regulated.

Selected Publications

• Allen CDC, Okada T, Tang HL, Cyster JG. Imaging of Germinal Center Selection Eventds During Affinity Maturation. Science 2007;315, 528-31.
• Lesley R, Kelly LM, Xu Y, Cyster JG. Naïve CD4 T cells constitutively express CD40L and augment autoreactive B cell survival. Proc Natl Acad Sci 2006;103, 10717-22.
• Schwab S, Pereira JP, Matloubian M, Xu Y, Huang Y, Cyster JG. Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients. Science 2005;309, 1735-1739.
• Matloubian M, Lo CG, Cinamon G, Lesneski MJ, Xu Y, Brinkmann V, Allende ML, Proia RL, Cyster JG. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 2004;427, 355-360

For 20 years, she has studied the epidemiology of cancer. Dr. Holly is PI of large NCI grants to study the Molecular Epidemiology of non-Hodgkin Lymphoma and the Molecular Epidemiology of Pancreatic Cancer, and the PI of other NCI grants. She is an author of more than 170 scientific reports and a co-author of the text, Designing Clinical Research, now in its second edition. Principal research interests include the epidemiology of: non-Hodgkin lymphoma, pancreatic cancer, anal cancer precursor lesions/HPV, melanoma, and of childhood brain tumors.

Selected Publications

• Tranah GJ, Bracci PM, Holly EA. Domestic and farm-animal exposures and risk of non-Hodgkin's lymphoma in a population-based study in the San Francisco Bay Area. Cancer Epidemiol Biomarkers Prev. 2008 Sep;17(9):2382-7.
• Duell EJ, Bracci PM, Moore JH, Burk RD, Kelsey KT, Holly EA. Detecting pathway-based gene-gene and gene-environment interactions in pancreatic cancer. Cancer Epidemiol Biomarkers Prev. 2008 Jun;17(6):1470-9.
• Lee JS, Bracci PM, Holly EA. Non-Hodgkin lymphoma in women: reproductive factors and exogenous hormone use. Am J Epidemiol. 2008 Aug 1;168(3):278-88. Epub 2008 Jun 10.

• The impact of adherence on the cost-effectiveness of screening for colorectal cancer
• Socio-economic variation in patient-borne costs of cancer screening
• Evaluation of new techniques to decrease mortality from esophageal adenocarcinoma.

Selected Publications

• Somsouk M, Gralnek I, Inadomi JM. Management of obscure occult gastrointestinal bleeding: a cost-minimization analysis. Clinical Gastroenterology and Hepatology 2008;6:661-670.
• Rubenstein JH, Dahlkemper A, Kao JY, Zhang M, Morgenstern H, McMahon L, Inadomi JM. A Pilot study of the association of low plasma adiponectin and Barrett’s esophagus. American Journal of Gastroenterology 2008;103:1358-1364.
• Inadomi JM. Fear of loss, not promise of gain, drivees practice patterns in Barrett’s esophagus. Gastroenterology 2008;134:1258-1260.
• Rubenstein JH, Sonnenberg A, Davis J, McMahon L, Inadomi JM. Effect of a prior endoscopy on outcomes of esophageal adenocarcinoma among United States veterans. Gastrointestinal Endoscopy 2008; June 9: epub ahead of print.
• Inadomi JM, Somsouk M, Madanick RD, Thomas JP, Shaheen NJ. A Cost-utility analysis of ablative therapy for Barrett’s esophagus. Gastroenterology 2009; epub ahead of print.
• Sorrell MF, Belongia EA, Costa J, Gareen IF, Grem JL, Inadomi JM, Kern ER, McHugh JA, Petersen GM, Rein MF, Strader DB, Trotter HT. National Institutes of Health Consensus Development Conference Statement: Management of Hepatitis B. Annals of Internal Medicine 2009;150:104-110.
• Rex DK, Johnson DA, Anderson JC, Schoenfeld PS, Burke CA, Inadomi JM. American College of Gastroenterology Guidelines for Colorectal Cancer Screening 2008. American Journal of Gastroenterology 2009;104:739-750.

Major aim of our work is the rational design of targeted combination therapies for GI cancer. The projects exploring the systems biology of cancer and have a strongly translational angle. We utilize cutting edge technologies and collaborate with leading scientists to design novel cancer therapies based on an in-depth understanding of cancer signal transduction networks. There are currently two main research tracks:

• Analysis and prediction of pathway responses to targeted inhibition of the EGF- receptor pathway in esophageal and breast cancer. Computer models of signaling networks are being developed and the anti-tumor efficacy of inhibition of critical molecules within these networks is being explored.
• Regulation and function of the human coxsackie-adenovirus receptor CAR. We discovered novel mechanisms of regulation of CAR, which is mission- critical for the success of adenovirus-based cancer treatments. We are investigating the possibility of pharmacological receptor restoration on cancer cells in order to increase the therapeutic efficacy of these viral agents.

Selected Publications

• Korn WM, Macal M, Christian C, Ding R-X, Rauen KA, Warren RS, Ferrell L., Expression of the Coxsackievirus and Adenovirus Receptor in gastrointestinal tumors correlates with tumor differentiation. Cancer Gene Therapy, 2006; 13:792-7
• Lacher M, Anders M, Oft M, Balmain A, Korn WM, TGF? receptor inhibition enhances adenoviral infectivity of carcinoma cells via up-regulation of CAR consequent to mesenchymal-epithelial-transition. Cancer Research, Cancer Res. 2006;66:1648-57.
• Au T, Thorne S, Korn WM, Sze D, Kirn D, Reid TR. Minimal hepatic toxicity pf ONYX-015: spatial restriction of CAR receptor in normal liver. Cancer Gene Therapy, 2007;14:139-150.

Since my advancement in July 2005 to Associate Professor of Clinical Medicine, the major change in my clinical activities has been the launching of the Intestinal Rehabilitation Program. My outpatient and inpatient clinical activity continues to involve general gastroenterology and specialized consultation in motility and functional gastrointestinal disorders, as well as endoscopy.

Selected Publications

• Ladabaum U, McGonigle DJ, Roberts TP. Gastric Fundic Distension Activates Fronto- Limbic Structures but not Primary Somatosensory Cortex: A Functional Magnetic Resonance Imaging Study. Neuroimage 2007 Jan 15;34(2):724-32.
• Ladabaum U, When even people at high risk do not take up colorectal cancer screening. Gut 2007 Dec;56(12):1648-50
• Yen EF, Ladabaum U, Muthusamy VR, Cello JP, McQuaid KR, Shah JN, Colonoscopic Treatment of Acute Diverticular Hemorrhage Using Endoclips. Dig Dis Sci 2007 Dec 20
• Parekh M, Fendrick AM, Ladabaum U, As tests evolve and costs of cancer care rise: reappraising stool-based screening for colorectal neoplasia. Aliment Pharmacol Ther 2008 Apr;27(8):697-712

Liver-related work in the Lanier lab focuses on the activating NKG2D-DAP10 receptor and its ligands. Previously, our group has shown that NKG2D ligands are constitutively expressed in the liver, and expression is increased during chemically- or virally-induced hepatitis. Studies are underway to explore whether NKG2D activation of NK cells or T cells contributes to the pathogenesis of viral hepatitis. This is being accomplished by experiments involving antibody blockade of NKG2D and by use of DAP10-deficient and DAP12-deficient mice. In addition, we are collaborating with Dr. Averil Ma to examine the effects of IL-15 on NKG2D expression and signaling in T cells.

Selected Publications

• Vilarinho S, K Ogasawara, S Nishimura, LL Lanier, JL Baron. Blockade of NKG2D on NKT cells prevents hepatitis and the acute immune response to hepatitis B virus. Proc Natl Acad Sci USA, 2007;104:18187-18192.
• Lanier LL. Evolutionary struggles between NK cells and viruses. Nat Rev Immunol 2008;8:259-268.
• Rosen DB, W Cao, DT Avery, SG Tangye, Y-J Liu, JP Houchins, LL Lanier. Expression and function of LLT1, a ligand of human NKR-P1A, on activated B cells and dendritic cells. J Immunol 2008;180:6508-6517.
• Sun, J.C. and L.L. Lanier. 2008. Tolerance of NK cells encountering their viral ligand during development. J. Exp. Med. 205:1819-1828.
• Sun, J.C. and L.L. Lanier. 2008. Cutting Edge: Viral infection breaks NK cell tolerance to "Missing Self". J. Immunol. 181:7453-7457.
• Orr, M.T., J.C. Sun, D.G.T Hesslein, H. Arase, J.H. Phillips, T. Takai, and L.L. Lanier. 2009. Ly49H signaling through both DAP10 and DAP12 is required for optimal NK cell responses to mouse cytomegalovirus infection. J. Exp. Med. 206:807-817.
• Sun, J.C., J.N. Beilke, and L.L. Lanier. 2009. Adaptive immune features of Natural Killer cells. Nature 457:557-561.

The immune system is a complex organization of many cell types whose activities are orchestrated through controlled expression and secretion of cytokines and other mediators. We have produced cytokine reporter mice that allow the visualization of immune system function during a variety of infectious and inflammatory diseases. Our primary interests involve efforts to understand allergic and anti-helminth immunity, which constitute major public health issues in both developed and developing countries. The major goals of the laboratory involve identification of molecular processes that drive eosinophil and basophil responses in tissues; that activate macrophages to the ‘alternatively activated’ state associated with allergic inflammation; that promote the differentiation of Th2 cells in lymph nodes; and that promote T cell help for the induction of the immunoglobulin isotypes IgG1 and IgE associated with allergy.

Selected Publications

• Mohrs K, AE Wakil, N Killeen, RM Locksley, M Mohrs.  2005.  A two-step process for cytokine production revealed by IL-4 dual-reporter mice.   Immunity 23:419-29.
• Veldhoen M, RJ Hocking, CJ Atkins, RM Locksley, B Stockinger. 2006.  TGF- B in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells.   Immunity 24:179-89.
• Scheu S, DB Stetson, RL Reinhardt, JH Leber, M Mohrs, RM Locksley.  2006.  Activation of the integrated stress response during T helper cell differentiation.   Nature Immunol 7:644-651.
• Voehringer D, TA Reese, X Huang, K Shinkai, RM Locksley.  2006.  Type 2 immunity is controlled by IL-4/IL-13 expression in hematopoietic non-eosinophil cells of the innate immune system. J Exp Med 203:1435-1446.
• Scheu S, DB Stetson, RL Reinhardt, *JH Leber, M Mohrs, RM Locksley. 2006. Activation of the integrated stress response during T helper cell differentiation. Nature Immunol 7:644-651.
• Reese TA, H-E Liang, AM Tager, AD Luster, N van Rooijen, D Voehringer, RM Locksley. 2007. Chitin induces accumulation in tissue of innate immune cells associated with allergy. Nature 447:92-96.
• Reinhardt RL, H-E Liang, RM Locksley. 2009. Cytokine-secreting follicular T cells shape the antibody repertoire. Nature Immunol 10:385-93.
• Sullivan BM, RM Locksley. 2009. Basophils: a nonredundant contributor to host immunity. Immunity 30:12-20.
• Seibold MA, *TA Reese, S Choudhry, MT Salam, K Beckman, C Egn, A Atakilit, K Meade, M Lenoir, HG Watson, S Thyne, R Kumar, KB Weiss, LC Grammar, P Avila, RP Schleimer, JV Fahy, J Rodriguez-Santana, W Rodriguez-Cintron, RG Boot, D Sheppard, FD Gilliland, RM Locksley, EG Burchard. 2009. Differential enzymatic activity of common haplotypic versions of the human acidic mammalian chitinase protein. J Biol Chem (in press).

The proper regulation of immune signals is critical for preventing autoimmune diseases such as inflammatory bowel disease. Our laboratory’s interest in this area has focused on the intracellular mechanisms by which immune signals such as TNF- and TLR-induced signal transduction events are regulated. By targeting the A20 gene in mice, we found that a A20 is essential for restricting TNF, TLR and NOD induced activation signals in macrophages and dendritic cells (Lee et al, Science 2000, Boone et al, Nature Immunology 2004; Turer et al, J Exp Med 2008; Hitotsumatsu et al, Immunity 2008). We have further found that A20 is a unique ubiquitin modifying enzyme that regulates both the activity and stability of signaling proteins such as RIP and TRAF6 (Wertz et al, Nature 2004; Boone et al, Nature Immunology 2004). A20 appears to work with other ubiquitin dependent proteins, such as ABIN-1, and ABIN-1 deficiency is independently critical for regulating TNF signals (Oshima et al, Nature 2009).

In addition to being biologically and biochemically potent molecules, these proteins are extraordinarily important for human diseases. Recent genetic studies suggest that A20 and ABIN-1 are important for regulating multiple autoimmune diseases in human patients (e.g., Musone et al, Nature Genetics 2008). In addition, loss of A20 function is pathogenetic in a large percentage of human B cell malignancies. Ongoing studies focus on the mechanisms by which A20, ABIN-1, and related proteins function, on the cell signaling cascades and cellular functions impacted by these proteins, and on the roles of the roles of these ubiquitin dependent proteins in regulating immune responses and autoimmunity.

Selected Publications

• Lee EG, Boone DL, Chai S, Libby S, Chien M, Lodolce JP, and Ma A. 2000. Failure to regulate TNF induced NF-kB and cell death responses in A20 deficient mice. Science 289;2350-54.
• Ma A. 2007. T-bet sends host-microbe mutualism awry. Cell 131;33-35.
• Oshima S, Turer EE, Callahan JA, Advincula R, Chai S, Barrera J, Shifrin N, Lee B, Woo T, Malynn BA, and Ma A. 2009. ABIN-1 is a ubiquitin sensor that restricts TNF induced cell death and sustains embryonic development. Nature 457;906-910.
• Malynn BA and Ma A. 2009. A20 takes on tumors: tumor suppression by a ubiquitin editing enzyme. Journal of Experimental Medicine 206;977-980.
• Mortier E, Advincula R, Kim L, Chmura S, Barrera J, Reizis B, Malynn BA, and Ma A. Macrophage and dendritic cell derived IL-15Ra support distinct CD8+ T cell subsets. Immunity (in press).

Dr. Phillips’ research focuses on how health care is organized, delivered, and financed in the US. She focuses on personalized medicine – specifically, targeting health care interventions to patients based on their genetics – and the impact of personalized medicine on clinical care, health economics, and health policy, particularly in the area of cancer screening and treatment. ??Dr. Phillips conducts cross-disciplinary research across the basic, clinical, and social sciences and also across academia, industry, and government. She is serving as the Prinicipal Investigator on several NIH and foundation grants, has led or participated in approximately 35 funded research grants, and has had continuous funding from the NIH throughout her career.

Selected Publications

• Phillips KA, Van Bebber S, Liang SY, and the CANPERS Research Group. Challenges to the translation of personalized medicine: Utilization, preferences, and economic value (in press,   Current Opinions in Molecular Therapeutics)
• Van Bebber SL, Liang SY, Phillips KA, Marshall D, Johnson FR, Walsh JW, Kulin N. Valuing risk information: Willingness to pay for genetic testing for colorectal cancer risk. Personalized Medicine 2007, 4(3): 342-350.
• Marshall D, Johnson FR, Phillips KA, Marshall JK, Thabane L, Ozdemir S, Kulin N. Measuring preferences for colorectal cancer screening using choice-format stated preferences. Value in Health 2007, 10(5): 415-430.
• Haas J, Phillips KA, Fitzmaurice G, Brawarsky P, Liang SY, Klabunde CN, Brown ML. Association of regional variation in physicians' colorectal cancer screening recommendations with individual use of colorectal cancer screening. Preventing Chronic Diseases 2007, 4(4): www.cdc.gov/pcd.

The Pancreas Cancer Program is comprised of a multi-disciplinary group of investigators focused on pancreatic cancer. These investigators include a team of clinicians and clinical scientists in endocrinology, epidemiology, gastroenterology, medical oncology, radiation oncology and surgical oncology who are qualified to address critical issues in pancreatic cancer, with full integration of faculty in basic and population sciences. The investigators in the program are not only interested in identifying better treatments but also in identifying persons at high risk for the disease and methods for screening and prevention.

Selected Publications

• Hruban RH, Rustgi AK, Brentnall TA, Tempero MA, Wright CV, Tuveson DA. Pancreatic Cancer in Mice and Man: The Penn Workshop 2004. Cancer Res 66:(1): 14-7), January 2006.
• Ko AH, Dito E, Schillinger B, Venook AP, Bergsland EK, Tempero MA. Phase II study of fixed dose rate gemcitabine with cisplatin for metastatic adenocarcinoma of the pancreas. J Clin Oncol, January 2006.
• Jhawer M, Rosen L, Dancey J, Hochster H, Hamburg S, Tempero MA, Clendeninn N, Mani S. Phase II Trial of Nolatrexed Dihydrochloride [Thymitaq, AG 337] in Patients with Advanced Hepatocellular Carcinoma. Invest New Drugs, June 2006.

I perform clinical and translation research in the areas of colorectal cancer prevention, especially among individuals at high risk for cancer, such as those with hereditary cancer syndromes or those with longstanding inflammatory bowel disease. Particular areas of interest include the optimal provision of genetic counseling and testing, cancer risk factor identification and risk mitigation by interventions such as drugs (chemoprevention) and colonoscopy. I also study the use of genetic and genomic markers to determine cancer risk and prognosis and prediction of response to therapy among those already diagnosed with cancer. I also am interested in projects related to biomarkers of prognosis and prediction of response to therapies in patients with inflammatory bowel disease. My research is performed in collaboration with basic science investigators in the UCSF Cancer Center (Fred Waldman, MD, PhD), UCSF Center for Colitis and Crohn’s Disease (Averil Ma, MD), and investigators at outside institutions including the Division of Research of Kaiser Permanente-northern California, the Dana Farber and MD Anderson Cancer Center, the Mayo Clinic in Rochester, MN and others.

Selected Publications

• Shergill AK, Terdiman JP. Refining colorectal cancer screening recommendations based on gender. Gastroenterology 2007;132:2605-6.
• Terdiman JP. Hereditary diffuse gastric cancer: surveillance endoscopy is not enough to save lives. Gastroenterology 2007;133:1730-2.
• Shergill AK, Terdiman JP. Controversies in the treatment of Crohn's disease: The case for an accelerated step-up treatment approach. World J Gastroenterol 2008;14:2670-77.
• Li D, Terdiman JP. “Did you check my colon for flat polyps?" Should patients and colonoscopists really be concerned? Gastroenterology. 2008.
• Shergill AK, Terdiman JP. The Early Use of Immunosuppression Reduces Morbidity in Patients with Moderately Severe or Severe Crohn's Disease. Gastroenterology, 2008;135:1417-20.
• Nguyen SP, Bent S, Chen YH, Terdiman JP. Gender as a risk factor for advanced neoplasia and colorectal cancer: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2009 Jun;7(6):676-81.
• Wang JY, Terdiman JP, Vittinghoff E, Minichiello T, Varma MG. Hospitalized ulcerative colitis patients have an elevated risk of thromboembolic events. World J Gastroenterol. 2009 Feb 28;15(8):927-35.
• Li D, Jin C, McCulloch C, Kakar S, Berger BM, Imperiale TF, Terdiman JP. Association of Large Serrated Polyps With Synchronous Advanced Colorectal Neoplasia. Am J Gastroenterol. 2009;104:695-702.

The response of T lymphocytes to antigen presents a unique opportunity to study how complex molecular interactions between cells can lead to cell differentiation and proliferation. We are interested in understanding how T and B cell receptors involved in antigen recognition initiate signal transduction events that regulate cell responses. We know that such receptors functionally interact with tyrosine kinases and phosphatases, enzymes that regulate protein phosphorylation, to induce signaling pathways that regulate gene expression. By studying the mechanisms by which these molecules are regulated and how they control cellular responses in development, we hope to understand how signaling pathways in normal immune responses and how perturbations in these pathways can lead to immune deficiency or autoimmunity.

Selected Publications

• Roose J, M Mollenauer, M Ho, T Kurosaki, A Weiss. Unusual interplay of two types of Ras activators, RasGRP and SOS, establishes sensitive and robust Ras activation in lymphocytes. Mol Cell Biol 27 2007:2732-2745.
• Deindl S, TA Kadlecek, T Brdicka, X Cao, A Weiss, J Kuriyan. Structural basis for the inhibition of tyrosine kinase activity of ZAP-70. Cell 129 2007:735-746.
• Zhu JW, T Brdicka, TR Katsumoto, J Lin, A Weiss. Structurally distinct phosphatases CD45 and CD148 regulate B cell and macrophage immunoreceptor signaling. Immunity 28 2008:183-196.
• Levin SE, C Zhang, TA Kadlecek, K Shokat, A Weiss, A. Inhibition of ZAP-70 kinase activity via an analog-sensitive allele blocks T cell receptor and CD28 superagonist signaling. J Biol Chem 283 2008:15419-15430.

HEPATOLOGY TRAINING GRANT

Our research group studies basic mechanisms involved in immunopathogenesis of acute and chronic hepatitis B virus (HBV) infection, as well as basic principles in both innate and adaptive immunity to viral pathogens. By identifying the role of both innate and adaptive immunity in HBV clearance and virus-induced liver damage, we hope to develop strategies for therapeutic intervention. Our approach is to model hepatitis B pathogenesis in mice, to explore candidate mechanisms, and to test their applicability to human disease. Such inter-species experimental transitions are crucial to definitively understanding human disease pathogenesis. New results from our mouse models have revealed disease mechanisms that we believe are likely involved in human HBV immunopathogenesis. The hypotheses formulated from these results have recently provided our laboratory the exciting opportunity to launch our first human studies in pursuit of our goals.

Selected Publications

• Baron JL, Gardiner L, Nishimura S, Locksley R, Ganem D. Activation of a non-classical NKT cell subset in a transgenic mouse model of hepatitis B virus infection. Immunity 2002;16:583-594.
• Matsuda JL, Gapin L, Baron JL, Sidobre S, Stetson DB, Mohrs M, Locksley RM, Kronenberg M. Mouse V alpha 14i natural killer T cells are resistant to cytokine polarization in vivo. Proc Natl Acad Sci U S A 2003;100:8395-400.
• Stetson DB, Mohrs M, Reinhardt RL, Baron JL, Wang ZE, Gapin L, Kronenberg M, Locksley RM. Constitutive Cytokine mRNAs Mark Natural Killer (NK) and NK T cells Poised for Rapid Effector Function. J Exp Med 2003;198:1069-1076.
• Villarinho S, Ogasawara K, Nishimura S, Lanier LL, Baron JL. Blockade of NKG2D on NKT cells prevents hepatitis and the acute immune response to Hepatitis B Virus. Proc Natl Acad Sci USA, 2007;104 :18187-92.

My research focuses on clinical and translational studies of portal hypertension, fatty liver disease, cholestatic liver disease and drug-induced liver disease. I am site director for the NIH-funded NASH Clinical Research Network, in which one local project addresses the genomic basis of nonalcoholic fatty liver disease. In concert with other multi-center groups, we are conducting therapeutic trials of pharmacological agents and blood products in chronic liver disease and portal hypertension. We are also testing novel therapies for acute liver failure.

Selected Publications

• Merriman RB, Ferrell LD, Patti MG, Weston SR, Pabst MS, Aouizerat BE, Bass NM. Correlation of paired liver biopsies in morbidly obese patients with suspected nonalcoholic fatty liver disease. Hepatology 2006t;44:874-880.
• Kadayifci A, Merriman RB, Bass NM. Medical treatment of non-alcoholic steatohepatitis. Clin Liver Dis 2007;11:119-140.
• Krasnoff JB, Painter PL, Wallace JP, Bass NM, Merriman RB. Health-related fitness and physical activity in patients with nonalcoholic fatty liver disease. Hepatology. 2008;47:1158-1166.
• Campos GM, Bambha K, Vittinghoff E, Rabl C, Posselt AM, Ciovica R, Tiwari U, Ferrell L, Pabst M, Bass NM, Merriman RB. A clinical scoring system for predicting nonalcoholic steatohepatitis in morbidly obese patients. Hepatology 2008;47:1916-1923.

My laboratory investigates tissue remodeling in liver injury. We have been focusing recently on oval cells, which are liver progenitor cells and proliferate in several forms of liver injury. Oval cells, can be isolated and, with expansion in culture, hold promise for cell-based therapy of a variety of liver diseases. We have recently defined a member of the TNF-alpha family of cytokines that appears to be a specific growth factor for a subset of oval cells. We are interested also in mechanisms of the fibrotic response to biliary injury. We have found that TGF? and the integrin ?v?6 have key roles.

Selected Publications

• Chang ML, Chen JC, Alonso CR, Kornblihtt AR, Bissell DM. Regulation of fibronectin splicing in sinusoidal endothelial cells from normal or injured liver. Proc Natl Acad Sci USA 2004;101:18093-98.
• Kikuchi S, Griffin CT, Wang SS, Bissell DM. Role of cd44 in epithelial wound repair: migration of rat hepatic stellate cells utilizes hyaluronic acid and cd44v6. J Biol Chem 2005;280:15398-404.
• Jakubowski A, Ambrose C, Parr M, Lincecum JM, Wang MZ, Zheng TS, Browning B, Michaelson JS, Baestcher M, Wang B, Bissell DM, Burkly LC. Tweak induces liver progenitor cell proliferation. J Clin Invest 2005;115:2330-40.
• Wang B, Dolinski B, Kikuchi N, Leone DR, Peters MG, Weinreb PH, Violette SM., Bissell DM. Role of ?v?6 in acute biliary fibrosis. Hepatology 2007;46:1404-12.
• Okayama T, Kikuchi S, Ochiai T, Ikoma H, Kubota T, Ichikawa D, Fujiwara H, Okamoto K, Sakakura C, Sonoyama T, Kokuba Y, Doi Y, Tsukita S, Bissell DM, Otsuji E. Attenuated response to liver injury in moesin- deficient mice: Impaired stellate cell migration and decreased fibrosis. Biochem Biophys Acta 2008.

Research in my laboratory is aimed at understanding the mechanisms underlying the development of cholestasis, through study of patients and animal models. Currently, our studies are focused on the following: (1) characterization of the differences between FIC1 disease (due to mutation in ATP8B1) and B.S.EP disease (due to mutation in ABCB11), (2) identification of genetic factors underlying intrahepatic cholestasis of pregnancy and lymphedema-cholestasis syndrome, (3) identification of factors that may influence the phenotype of patients with FIC1 disease through genetic studies to identify loci that modify phenotypes in the Fic1 mutant mouse and (4) participation in the CLiC (Cholestatic Liver Disease in Children) consortium.

Selected Publications

• Knisely AS, Strautnieks SS, Meier Y, Stieger B, Byrne JA, Portmann BC, Bull LN, et al. Hepatocellular Carcinoma in ten children under five years old with bile salt export pump deficiency. Hepatology, 2006;44:478-486.
• Groen A, Kunne C, Paulusma CC, Kramer W, Agellon LB, Bull LN, Oude-Elferink RPJ. Intestinal bile salt absorption in Atp8b1 deficient mice. J Hepatol 2007;47:114-22.
• Strautnieks S, Byrne J, Pawlikowska L, Cebecauerov· D, Rayner A, Dutton L, Meier Y, et al. Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families. Gastroenterology 2008;134:1203-1214.
• Hussaini H, Bassas A, Verkade H, Groen A, Kunne C, Jongsma G, van den Oever K, Petruzelli M, Vrins C, Bull L, Paulusma C, Oude-Elferink R. Enhanced biliary cholesterol output in Atp8b1 mutant mice is Abcg5/Abcg8-independent. Gut 2008, in press.

My research interests include acute liver failure (ALF) and hepatocellular carcinoma (HCC). I am a part of the multicenter Acute Liver Failure Study Group, which has been gathering clinical data, serum, and tissue as part of an ongoing registry, and conducting clinical trials to learn how to manage patients with ALF. I am also interested in HCC and trying to find ways to reduce the number of patients who drop off the liver transplant waiting list because of tumor progression. We are about to begin an open-label study of sorafenib, an oral multikinase inhibitor, in patients on the liver transplant waiting list undergoing chemoembolization.

Selected Publications

• Oren K. Fix, Nathan M. Bass, Teresa De Marco, Raphael B. Merriman. Long-term follow-up of portopulmonary hypertension: effect of treatment with epoprostenol. Liver Transplantation 2007;13(6):875-885.
• Oren K. Fix. Does a latte a day keep the hepatologist away? Hepatology 2008;47(1):348- 351.
• Edie Y. Chan, Anne M. Larson, Oren K. Fix, Matthew M. Yeh, Adam E. Levy, Ramasamy Bakthavatsalam, Jeffrey B. Halldorson, Jorge D. Reyes, James D. Perkins. Identifying risk patient recurrent hepatocellular carcinoma after liver transplantation: implications for surveillance studies and new adjuvant therapies. Liver Transplantation 2008. 14(7):956- 965.
• Jeffrey B. Halldorson, Ramasamy Bakthavatsalam, Oren Fix, Jorge D. Reyes, James D. Perkins. D-MELD, a simple predictor of post liver transplant mortality for optimization of donor/recipient matching. American Journal of Transplantation 2009;9(2):318-326.
• James D. Perkins, Jeffrey B. Halldorson, Ramasamy Bakthvatsalam, Oren K. Fix, Robert L. Carithers, Jr., Jorge D. Reyes. Should liver transplantation in patients with model for end- stage liver disease scores Edwin J. Lai, Audrey H. Calderwood, Gheorge Doros, Oren K. Fix, Brian C. Jacobson. The Boston Bowel Preparation Scale: A valid and reliable instrument for colonoscopy-oriented research. Gastrointestinal Endoscopy 2008;69:620-625.

My research involves both clinical and translational research components. My clinical research focuses on epidemiology of hepatitis C and hepatitis B disease as well as optimal treatment strategies for these viruses. We are also evaluating liver cancer screening practices in hepatitis B infected Asians. The focus of my translational research is better defining the mechanisms of glucose intolerance and diabetes in HCV infected individuals. My group previously evaluated mechanisms of insulin resistance and secretion in a large cohort of hepatitis C patients, and is now examining how HCV affects insulin action among the high risk Latino population. We are studying insulin action over time, with and without HCV treatment, using direct measures of insulin secretion and insulin action.

Selected Publications

• Khalili M, Watson J, Bass N, Ascher N, Roberts J, Terrault N. New Onset Diabetes Mellitus After Liver Transplantation: The Critical Role of Hepatitis C Infection. Liver Transplantation 2004;10:349-355.
• Khalili M, Fisher E, Bernstein D, Lentz E, Barylski C, Hoffman-Terry M. Peginterferon alfa-2a With or Without Ribavirin in HCV/HIV Coinfected Patients: Partially-Blinded and Randomized Multicenter Trial. Dig Dis Sci 2005;50:1148-55.
• Khalili M, Vardanian AJ, Hamerski CM, Wang R, Bacchetti P, Roberts JP, Terrault NA. Management of hepatitis C-infected liver transplant recipients at large North-American centres: changes in recent years. Clin Transplant 2006;20:1-9.
• Kuo A, Lan B, Tan V, Khalili M, Feng S, Roberts JP, Terrault NA. Long-Term Histological Effects of Preemptive Antiviral Therapy in Liver Transplant Recipients with Hepatitis C Virus Infection. American Journal of Liver Transplantation 2008 Oct;14(10):1491-7.
• Terrault N, Khalili M. A Glimpse of Future HCV Treatment Paradigms. Hepatology 2009, In Press.

Liver-related work in the Lanier lab focuses on the activating NKG2D-DAP10 receptor and its ligands. Previously, our group has shown that NKG2D ligands are constitutively expressed in the liver, and expression is increased during chemically- or virally-induced hepatitis. Studies are underway to explore whether NKG2D activation of NK cells or T cells contributes to the pathogenesis of viral hepatitis. This is being accomplished by experiments involving antibody blockade of NKG2D and by use of DAP10-deficient and DAP12-deficient mice. In addition, we are collaborating with Dr. Averil Ma to examine the effects of IL-15 on NKG2D expression and signaling in T cells.

Selected Publications

• Vilarinho S, K Ogasawara, S Nishimura, LL Lanier, JL Baron. Blockade of NKG2D on NKT cells prevents hepatitis and the acute immune response to hepatitis B virus. Proc Natl Acad Sci USA, 2007;104:18187-18192.
• Lanier LL. Evolutionary struggles between NK cells and viruses. Nat Rev Immunol 2008;8:259-268.
• Rosen DB, W Cao, DT Avery, SG Tangye, Y-J Liu, JP Houchins, LL Lanier. Expression and function of LLT1, a ligand of human NKR-P1A, on activated B cells and dendritic cells. J Immunol 2008;180:6508-6517.
• Sun JC, LL Lanier. Tolerance of NK cells encountering their viral ligand during development. J Exp Med, 2008, In press.

My laboratory studies basic mechanisms of hepatotoxicity, with a focus on clinically relevant diseases such as drug-induced liver injury and nonalcoholic steatohepatitis (NASH). One important goal is to identify hepatoprotective compounds that are therapeutic in the setting of acute liver failure or liver transplantation. In the setting of fatty liver, we are interested in the ability of specific fatty acids to cause liver cell death (“lipotoxicity”). We use cell culture and animal models to investigate how fat causes liver injury, and how the accumulation of toxic fatty acids in the liver might be avoided by dietary modifications such as lowering sugar consumption.

Selected Publications

• Hanson JC, Bostick MK, Campe CB, Kodali P, Lee G, Yan J, Maher JJ. Transgenic overexpression of interleukin-8 in mouse liver protects against galactosamine/endotoxin toxicity. J Hepatol 2006;44:359-367.
• Rizki G, Arnaboldi L, Gabrielli B, Lee G, Yan J, Ng R, Turner S, Badger TM, Pitas RE, Maher JJ. Mice fed a lipogenic diet lacking methionine and choline develop hypermetabolism and weight loss coincident with hepatic suppression of stearoyl-CoA desaturase-1. J Lipid Res 2006;47:2280-2290.
• Lee G, Yan J, Ng RK, Kakar S, Maher JJ. Polyunsaturated fat in the methionine-choline-deficient diet influences hepatic inflammation but not hepatocellular injury. J Lipid Res 2007;48:1885-1896.
• Maher JJ, Leon P, Ryan JC. Beyond Insulin Resistance: Innate Immunity in NASH. Hepatology 2008; 48:670-678.
• Pickens MK, Yan JS, Ng RK, Ogata H, Grenert JP, Beysen C, Turner SM, Maher JJ. Dietary sucrose is essential to the development of liver injury in the MCD model of steatohepatitis. J Lipid Res 2009; 50:2072-2082.

My research interest is in hepatitis C virus (HCV) variants and immune responses in injection drug users. We are examining rates of re-infection or genotype switching over time, describing rates and predictors of liver disease progression and examining causes of death. We are also comparing hematological and virological changes during interferon-based therapy in subjects with HCV alone to those with HIV-HCV co-infection.

Selected Publications

• Currie SL, Ryan JC, Tracy D, Wright TL, George S, McQuaid R, Kim M, Shen H, Monto A. A prospective study to examine persistent HCV reinfection in injection drug users who have previously cleared the virus. Drug Alcohol Depend 2008;93:148-154.
• Shah T, Lampiris H, Vu M, Monto A, Tien PC. Resolution of hepatitis C virus-induced steatosis improves tolerability of antiretroviral drugs associated with hepatotoxicity in an HIV-infected individual. J Infect Dis 2008;197:932-933.
• Bonkovsky HL, Tice AD, Yapp RG, Bodenheimer HC, Monto A, Rossi SJ, Sulkowski MS. Efficacy and safety of peginterferon alfa-2a/ribavirin in methadone maintenance patients: randomized comparison of direct observed therapy and self-administration. American Journal of Gastroenterology 2008;103:2757-2765.
• Sewell JL, Stick KM, Monto A. Hepatocellular carcinoma after sustained virologic response in hepatitis C patients without cirrhosis on a pre-treatment liver biopsy. Eur J Gastroenterol Hepatol. 2009;21:225-229.
• Garcia-Tsao G, Lim J, Monto A, Yee H, Durfee J, Dieperink E, Dominitz J, Ross D, Valdiserri R. Management and treatment of patients with cirrhosis and portal hypertension: recommendations from the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program. American Journal of Gastroenterology 2009;104:1802-1829.

My major interest is in viral hepatitis and the role of the host immune response. My work focuses on interactions among alcohol use, cannabis use and HIV co-infection on outcomes of HCV infection. We are currently evaluating the effect of light and moderate alcohol use, alone or in combination with cannabis, on the severity and rate of progression of liver disease in women co-infected with HCV and HIV. We are also studying adherence to antiretroviral therapy in HIV/HCV co-infected women and on HCV-specific and innate immune responses in persons co-infected with HCV and HIV. I work within the AIDS Clinical Trial Group to develop clinical trials in viral hepatitis and HIV and within the Women’s Interagency HIV Study (WIHS) to examine predictors of liver-related morbidity and mortality in a cohort of women with HIV/HCV infection.

Selected Publications

• Julie H. Ishida, Marion G. Peters, Chengshi Jin, Karly Louie, Vivian Tan, Peter Bacchetti, Norah A. Terrault. Influence of Cannabis Use on Severity of Hepatitis C Disease. Clin Gastroenterol Hepatol 2008:6(1):69-75
• Margaret Koziel and Marion Peters. Viral Hepatitis in HIV Infection. New Eng J Med, 2007: 356; 1445-54.
• David J. Quan and Marion G. Peters. Tenofovir disoproxil fumarate for the treatment of hepatitis B virus infection: pharmacokinetics and clinical efficacy. Therapy 2007; 4; 141-151.
• Marion Peters. Hepatobiliary Complications. American Academy of HIV Medicine Study Guide, Fundamentals of HIV Medicine 2007. John Stansell Editor. In press 2008.
• Oren K Fix, Stephen A. Locarnini and Marion G. Peters. Virology and clinical management of Heptitis B and HIV co-infection. PRN notebook 2007 in press
• George Lau, Patrick Marcellin and Marion Peters. Chronic hepatitis B – a global health problem requiring coherent worldwide treatment strategies. Hepatology International In press 2007.
• Marion Peters: HIV and Hepatitis B Virus Coinfection, Top HIV Med. 2007;15:163-6.
• Peters MG. Special populations with hepatitis B virus infection. Hepatology. 2009 May;49(5 Suppl):S146-55.

My research uses the power of forward genetics in zebrafish to investigate the cellular and molecular mechanisms underlying liver development. Since liver development has not been characterized in zebrafish, an initial goal has been to establish the details of the process in wild-type organisms. Experiments make use of a transgenic line that expresses GFP in the developing gut and associated organs including the liver. This makes it possible to track the cellular movements leading to liver development, along with the expression pattern of relevant genes of interest. Our lab recently demonstrated that Wnt2b, Bmp and Fgf signaling are each important in the early stages of liver development in zebrafish. More recently, the lab has used single cell lineage tracing in zebrafish to investigate the origin of hepatic progenitors in vivo and to analyze cell fate decisions that lead to development of liver vs. pancreas.

Selected Publications

• Ober EA, Verkade H, Field HA, Stainier DY. Mesodermal Wnt2b signalling positive regulates liver specification. Nature 2006;442:688-691.
• Shin D, Shin CH, Tucker J, Ober EA, Rentzsch F, Poss KD, Hammerschmidt M, Mullins MC, Stainier DY. Bmp and Fgf signaling are essential for liver specification in zebrafish. Development 2007;134:2041-2050.
• Dong PD, Munson CA, Norton W, Crosnier C, Pan X, Gong Z, Neumann CJ, Stainier DY. Fgf10 regulates hepatopancreatic ductal system patterning and differentiation. Nat Genet 2007;39:397-402.
• Schlegel A, Stainier DY. Microsomal triglyceride transfer protein is required for yolk lipid utilization and bsorption of dietary lipids in zebrafish larvae. Biochemistry 2006;45:15179-15187.
• Chung, W-S., Shin, C.H. and Stainier D.Y.R. Bmp2 signaling regulates the hepatic vs pancreatic fate decision. Developmental Cell 2008;15: 738-748.
• Sakaguchi, T.F., Sadler, K.C., Crosnier, C. and Stainier, D.Y.R. Endothelial signals modulate hepatocyte apico-basal polarization in zebrafish. Current Biology 2008;18: 1565-1571.

My research focuses on the natural history and treatment of hepatitis C virus (HCV) and hepatitis B virus (HBV), particularly in special populations, including those undergoing liver transplantation. Work in progress addresses the natural history of post-transplant disease and specific therapies to prevent infection or modify HCV and HBV disease progression and loss of grafts from recurrent disease. Our virological analyses are focused on characterization of viral mutations that occur in liver transplant recipients receiving antiviral therapies and assessment of the effect of these variant viruses on the natural history and severity of disease post-transplantation. Knowledge of these factors may allow improved organ allocation by identifying subsets of patients with HCV recurrence in liver grafts who would be favorable or unfavorable candidates for retransplantation.

Selected Publications

• Conjeevaram HS, Fried MW, Jeffers LJ, Terrault NA, et al. for the Virahep-C Study Group. Peginterferon and ribavirin treatment in African American and Caucasian American patients with hepatitis C genotype 1. Gastroenterology. 2006;131:470-477.
• Terrault NA, Shiffman ML, Lok AS, Saab S, Tong L, Brown RS, Everson GT, Reddy KR, Fair JH, Kulik LM, Pruett TL, Seeff LB; A2ALL Study Group. Outcomes in hepatitis C virus-infected recipients of living donor vs. deceased donor liver transplantation. Liver Transpl. 2007;13:122-129.
• Galun E, Terrault NA, Eren R, Zauberman A, Nussbaum O, Terkieltaub D, Zohar M, et al. Clinical evaluation (Phase I) of a human monoclonal antibody against hepatitis C virus: safety and antiviral activity. J Hepatol 2007;46:37-44.
• Ishida JH, Peters MG, Jin C, Louie K, Tan V, Bacchetti P, Terrault NA. Influence of cannabis use on severity of hepatitis C disease. Clin Gastroenterol Hepatol 2008;6:69-77.

The liver has the capacity to regenerate, but this ability is lost in chronic liver disease. Because donor organs for liver transplantation are sparse, our goal is to establish novel means to promote liver regeneration. For example, we are investigating ways to induce bone marrow or pluripotent stem cells to differentiate into hepatocytes that can be transplanted into patients with end-stage liver disease. To this end, we are studying the origin of liver stem or progenitor cells and are working to understand the signals that direct their expansion and differentiation. In addition to losing its regenerative capacity, the diseased liver undergoes scarring and often develops cancer. Another goal of our laboratory is to understand the mechanisms that lead to this unfortunate chain of events, in particular with regard to the role of immature liver cells in the process of liver cancer initiation and promotion.

Selected Publications

• Irwin J, Terrault NA. Cognitive Impairment in hepatitis C patients on antiviral therapy. Gastroenterol Hepatol 2008;4:65-67
• Terrault NA, Jacobson IM. Treating chronic hepatitis B infection in patients who are pregnant or are undergoing immunosuppressive chemotherapy. Semin Liver Dis. 2007;27 Suppl 1:18-24.
• Coffin CS, Terrault NA. Management of hepatitis B in liver transplant recipients. J Viral Hepat. 2007;14 Suppl 1:37-44.
• Terrault NA, Adey DB.The kidney transplant recipient with hepatitis C infection: pre- and posttransplantation treatment. Clin J Am Soc Nephrol. 2007;2(3):563-75.
• Samuel D, Weber R, Stock P, Duclos-Vallée JC, Terrault N. Are HIV-infected patients candidates for liver transplantation? J Hepatol. 2008;48(5):697-707.
• Terrault NA, Tran TT, Schiff E, McGuire BM, Brown RS Jr, Tupper R, Ramanathan S, Enejosa J, Zhong L, Zong J; Study 531 Team. Pharmacokinetics of tacrolimus co-administered with adefovir dipivoxil to liver transplant recipients. Liver Int. 2009 Sep;29(8):1178-83.
• Terrault NA. Benefits and risks of combination therapy for hepatitis B. Hepatology. 2009 May;49(5 Suppl):S122-8.
• Terrault NA, Im K, Boylan R, Bacchetti P, Kleiner DE, Fontana RJ, Hoofnagle JH, Belle SH; VIRAHEP- C Study Group. Fibrosis progression in African Americans and Caucasian Americans with chronic hepatitis C. Clin Gastroenterol Hepatol. 2008 Dec;6(12):1403-11.
• Terrault NA. Hepatitis C therapy before and after liver transplantation. Liver Transpl. 2008 Oct;14 Suppl 2:S58-66.

Our research seeks to create, implement, test, and disseminate strategies for improving the quality of and access to specialty healthcare, especially in hepatology and gastroenterology. Our investigations focus in particular on (1) integrating health information technology with specialty care delivery, (2) facilitating communication between primary care and specialty care providers, and (3) enhancing the efficiency of specialty service provision. Much of our work employs San Francisco’s safety net healthcare system, which is distinguished by universal access to primary and specialty care and a horizontally and vertically integrated healthcare system.

Selected Publications

• Melton, AC, Datta, A, Yee, Jr HF, [Ca2+]i-independent contractile force generation by rat hepatic stellate cells in response to endothelin-1, Am J Physiol, 290: G7-G13, 2006.
• Melton, AC, Yee, Jr HF, Hepatic stellate cell protrusions couple platelet-derived growth factor BB to chemotaxis, Hepatology, 45: 1446-53, 2007.
• Melton, AC, Soon, R, Park, JG, Martinez, L, DeHart, G, Yee, Jr HF, Focal adhesion disassembly is an essential early event in hepatic stellate cell chemotaxis, Am J Physiol, 293: G1272-80, 2007.
• Somsouk, M, Inadomi, JM, Yee, Jr HF, A cost-decision analysis comparing two strategies for confirming hepatitis C infection in dialysis patients, Digestive Diseases and Science, 53: 1093-99, 2008.
• Flores, YN, Yee, Jr HF, Leng, M, Escarce, J, Bastani, R, Salmeron, J, Morales, LS, Risk factors for chronic liver disease in Blacks, Mexican-Americans and Whites in the U.S.: Results from NHANES IV, 1999-2004, Am J Gastro, 103:2231-8, 2008.
• Sewell, JL, Kushel, MB, Inadomi, JM, Yee, Jr HF, Non-English speakers attend subspecialty clinic appointments at higher rates than English speakers in a vulnerable patient population, J Clin Gastro, 43:652-60, 2009.
• Somsouk, M, Yee, Jr HF, Biggins, SW, Understanding liver health using the National Center for Health Statistics, Digestive Diseases and Science, Epub DOI 10.1007/s10620-009-0823-3, 2009.
• Guy, J, Yee, Jr HF, Health disparities in liver disease: Time to take notice and take action, Hepatology, 50:309-13, 2009.
• Chen, A Hm, and Yee, Jr HF, Improving the primary-specialty care interface: getting from here to there, Arch Intern Med, 169:1024-1026, 2009.