Tumorigenic Progression (Cancer Development) Model
Developed a model that represent different stages of tumorigenic progression (cancer development). The cells are 1) normal NIH Swiss embryonic cells (mortal); 2) non-tumorigenic NIH 3T3 cells (immortal); 3) tumorigenic ras oncogenic-transformed NIH 3T3 cells; 4) cancer cells (from injection of ras oncogene-transformed NIH 3T3 cells into NIH Swiss mouse; and 5) Metastatic cancer cells (from injection of cancer cells into NIH Swiss mouse).
Study respiratory metabolism and Mitochondrial DNA structure in tumorigenic progression.
A tumor progression model derived from a new T24 HRAS transformed NIH/3T3 cell line.
T1-A, T2-A, T3-HA, T4PA lines derived from GhrasT-NIH/3T3, T1-A, T2-A, T3-HA tumors.
PCR detected the human HRAS oncogene in T2-A and T4-PA metastatic tumors.
These five new cell lines showed a progressive increase in tumorigenic potential.
New method obtained doubling times using daily photomicrographs of gridded plates.
Our lab used six polymorphic loci, DXS369, DXS297, DXS296, DXS304, IDS and DXS374 to map the fragile X FRAXA chromosome. We report the results of genetic linkage analysis of 32 fragile X [fra(X)] families using 12 polymorphic loci including these new markers. Cytogenetic and molecular data were combined in two-point linkage analysis for the estimation of lod scores and carrier probabilities in potential carriers. Use of these six new marker loci substantially changed the carrier risk estimates for members of 7 of the 32 families from the risk estimates previously calculated on the basis of less closely linked probes available prior to 1989.
The ability of IFN-gamma to increase the expression of MHC class I gene products is likely to enhance cytolytic T lymphocyte recognition of viral pathogens and tumor cells. The murine lymphoma AKR SL3 cells responds aberrantly to treatment with interferon-gamma such that H-2Dk surface expression is augmented, but H-2Kk expression remains at constitutive levels.
Virology: Cancer and AIDS
The primary interests of the lab focus on cell-mediated immunity to mouse retroviruses that cause either leukemia or immunodeficiency. We have been studying resistance to endogenous AKR/Gross virus-induced leukemia mediated by cytotoxic T lymphocyte (CTL) responses. By use of "low leukemia" mouse strains, CTL that readily lyse AKR/Gross retrovirus-induced tumors have been generated. The CTL recognize "type-specific" viral determinants with the major immunodominant viral peptide located in the transmembrane anchor protein encoded by the envelope gene. Other mouse strains of higher leukemia incidence are unable to generate such CTL responses. The mechanism of unresponsiveness include both MHC-dependent mechanisms and apoptosis of effector CTL following interaction with FasL-expressing virus infected cells.
Another area of emphasis is the study of both immunity to the mouse acquired immunodeficiency syndrome (MAIDS) retroviral isolate and the mechanism of retroviral pathogenesis. In this model of HIV induced AIDS, we have raised unique protective CTL to the causative virus. Interestingly, the immunodominant determinant recognized by the CTL is encoded by a previously unrecognized alternative viral translational reading frame. Moreover, this alternative reading frame is extended, and mutagenesis experiments have shown that it exists because its protein product is necessary for viral pathogenesis. . We are also interested in the retroviral induction of myeloid-derived suppressor cells (MDSC) in this system: especially their unique inhibition of B-cell immune responsiveness (as well as of T-cell responses), and the first report in any system of involvement of the new checkpoint regulator VISTA in MDSC suppression of B-cell activity.
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