Showing papers by "Dale C. Snover published in 1993"

Reducing Mortality from Colorectal Cancer by Screening for Fecal Occult Blood

Abstract: Background Although tests for occult blood in the feces are widely used to screen for colorectal cancers, there is no conclusive evidence that they reduce mortality from this cause. We evaluated a fecal occult-blood test in a randomized trial and documented its effectiveness. Methods We randomly assigned 46,551 participants 50 to 80 years of age to screening for colorectal cancer once a year, to screening every two years, or to a control group. Participants who were screened submitted six guaiac-impregnated paper slides with two smears from each of three consecutive stools. About 83 percent of the slides were rehydrated. Participants who tested positive underwent a diagnostic evaluation that included colonoscopy. Vital status was ascertained for all participants over 13 years of follow-up. A committee determined causes of death. A single pathologist determined the stage of cancer for each tissue specimen. Differences in mortality from colorectal cancer, the primary study end point, were monitored with the...

Role of mesenchymal cell death in lung remodeling after injury.

Abstract: Repair after acute lung injury requires elimination of granulation tissue from the alveolar airspace. We hypothesized that during lung repair, signals capable of inducing the death of the two principal cellular elements of granulation tissue, fibroblasts and endothelial cells, would be present at the air-lung interface. Bronchoalveolar lavage fluid obtained from patients during lung repair induced both fibroblast and endothelial cell death, while fluid obtained at the time of injury or from patient controls did not. The mode of cell death for endothelial cells was apoptosis. Fibroblast death, while morphologically distinct from necrosis, also differed from typical apoptosis. Only proliferating cells were susceptible to the bioactivities in lavage fluid, which were trypsin sensitive and lipid insoluble. Histological examination of lung tissue from patients after lung injury revealed evidence of apoptotic cells within airspace granulation tissue. Our results suggest that cell death induced by peptide(s) present at the air-lung interface may participate in the remodeling process that accompanies tissue repair after injury.

Murine recipients of fully mismatched donor marrow are protected from lethal graft-versus-host disease by the in vivo administration of rapamycin but develop an autoimmune-like syndrome.

Abstract: We investigated the ability of the macrolide antifungal agent rapamycin (RAPA) to inhibit murine graft-vs-host disease induced across the MHC barrier. An optimum dose (1.5 mg/kg) given for 14 days beginning on the day of transplant (and then three times weekly until 1 mo) effectively and significantly (p < 0.001) protected 80% of irradiated B10.BR recipients of C57Bl/6 bone marrow/spleen grafts for over 90 days, whereas 80% of control mice died by day 37. Using a congenic model in which a mixture of Ly5.1+ bone marrow (T cell-depleted) and Ly5.2+ spleen cells allowed us to distinguish mature and immature cells, we found that RAPA inhibits the splenic expansion of mature donor-derived T cells in B10.BR recipients after bone marrow transplantation. In addition, phenotyping studies revealed that RAPA causes a massive reduction of immature CD4+CD8+ T cells in the thymus, indicating that RAPA probably interferes with maturation of immature CD3-CD4-CD8- T cells to CD4+CD8+ T cells. There was also a predilection toward development or intrathymic retention of the more mature CD3+CD4-CD8+ or CD3+CD4+CD8- cells in the thymus of long term survivors. These same observations were made in different experiments with mice given syngeneic bone marrow transplantation and RAPA. However, RAPA administration was associated with the occurrence of an autoimmune-like syndrome, consisting of ulcerative dermatitis, hepatic bile duct proliferation, and nondestructive lymphoid peribronchiolar infiltration of the lung. RAPA interfered with the deletion of potentially self-reactive T cells that occurs in thymic development. The failure of clonal deletion was observed in allogeneic and syngeneic transplants given RAPA, although only the allografted mice experienced an autoimmune-like syndrome. Some, but not all, of the nondeleted V beta populations were functionally active. These new findings bear certain dissimilarities to the syndrome and lesions observed with cyclosporin A treatment, particularly in the observation of bile duct proliferation and ulcerative skin lesions. Nonetheless, because of the potent effect of RAPA in preventing lethal graft-vs-host induced across the MHC, further investigation of the immune consequences of this highly effective compound is warranted.

Nonmitogenic anti-CD3F(ab')2 fragments inhibit lethal murine graft-versus-host disease induced across the major histocompatibility barrier.

Abstract: We have investigated the in vivo administration of nonmitogenic anti-CD3F(ab')2 fragments for the prevention of lethal graft-vs-host disease (GVHD) in irradiated recipients of fully allogeneic bone marrow cells plus splenocyte (BMS) inocula. Recipients of anti-CD3F(ab')2 fragments administered for 1 mo post-bone marrow transplantation (BMT) had 100% survival without clinical or histopathological evidence of GVHD. Controls given saline injections succumbed by 39 days post-BMT. Similar results were obtained in groups of recipient mice given BMS in which T cells were depleted by in vitro anti-Thy-1.2 plus C' treatment. Further studies were undertaken to define mechanistic differences in the two approaches. Using Ly-5 congenic sources of donor bone marrow and spleen, we determined that anti-CD3F(ab')2 fragments induced TCR modulation and T cell depletion. Mature splenic-derived CD4+ cells were depleted to a greater extent than CD8+ cells. Early post-BMT, recipients receiving injections with control saline had the highest number of CD4+ and CD8+ cells (which may cause GVHD) followed by recipients of anti-CD3F(ab')2 fragments, with the fewest CD8+ cells observed in the anti-Thy-1.2 + C' treated group. CD3+CD4-CD8- cells (which may suppress GVHD generation) were present in higher numbers early post-BMT in recipients given anti-CD3F(ab')2 fragments as compared to recipients given anti-Thy-1.2 + C'-treated BMS. In long term survivors, a mononuclear T cell containing infiltrate without evidence of destruction was observed in sites of GVHD (lung and liver), consistent with a "Quilty" effect, which was not observed in either of the other two groups. Although survivors were tolerant of donor skin grafts and rejected third party grafts, recipients given anti-CD3F(ab')2 fragments but not anti-Thy-1.2 + C'-treated BMS had vigorous anti-host proliferative responses. These results demonstrate that although in vitro anti-Thy-1.2 + C' treatment of BMS (which is highly depletionary) and in vivo administration of anti-CD3F(ab')2 fragments (which is modulatory and less depletionary) are both effective strategies for GVHD, the cellular events involved in achieving GVHD prevention are indeed different.

Histochemical and immunohistochemical characterization of cells constituting the giant cell tumor of bone

Abstract: Enzymatic activity and cell membrane proteins were characterized in cells from five giant cell tumors of bone (GCTs). Naphthyl alpha esterase (NAE) and acid phosphatase (AP) activity was noted within both the mononuclear and multinucleated cells of each tumor. In each tumor, all mononucleated cell populations displayed tartrate-sensitive AP activity, whereas the multinucleated cell populations demonstrated variable expression of tartrate-sensitive and tartrate-resistant AP activity. Analysis of cell membrane proteins included attempts at immunodetection of mannose receptor, OKM-1 antigen (OKM-1a), colony-stimulating factor-1 receptor (CSF-1r), and platelet-derived growth factor receptor (PDGFr). None of these membrane antigens were elicited on multinucleated cells. In contrast, the mannose receptor, OKM-1a, and PDGFr all were detected on the mononucleated cells within each tumor. These data demonstrate that a population of mononucleated, not multinucleated cells, expresses features unique to mature mononuclear phagocytes and establishes the presence of a membrane receptor, PDGFr, associated with mitogenesis of mesenchymal cells.