IL-3 receptor signaling is dispensable for BCR-ABL-induced myeloproliferative disease

BCR-ABL expression led to a dramatic up-regulation of the IL-3, IL-5, and granulocyte-macrophage colony-stimulating factor receptor beta common (IL-3Rbetac) and IL-3 receptor beta (IL-3Rbeta) chains in murine embryonic stem cell-derived hematopoietic cells coincident with an expansion of multipotent progenitors and myeloid elements. This up-regulation required BCR-ABL tyrosine kinase activity and led to IL-3Rbetac/beta chain tyrosine phosphorylation in the absence of detectable IL-3 production. These results suggested that cytokine-independent IL-3 receptor activation could be a dominant signaling component in BCR-ABL-induced leukemogenesis. To unambiguously define the significance of IL-3 receptor-dependent signaling in BCR-ABL-induced leukemogenesis, BCR-ABL-transduced bone marrow cells deficient in either IL-3Rbetac chain or both IL-3Rbetac/beta chain expression were examined for their ability in generating myeloproliferative disease (MPD). These BCR-ABL-expressing knockout cells were capable of generating MPD similar to control cells, demonstrating that IL-3 receptor activation is not essential for BCR-ABL-induced MPD. However, the IL-3Rbetac/beta chain could act as a cofactor in BCR-ABL-induced leukemogenesis by activation of its many known oncogenic signaling pathways.     

Estrogen inhibits systemic T cell expression of TNF-alpha and recruitment of TNF-alpha(+) T cells and macrophages into the CNS of mice developing experimental encephalomyelitis

Estrogen treatment has been found to have suppressive activity in several models of autoimmunity. To investigate the mechanism of 17 beta-estradiol (E2) suppression of experimental autoimmune encephalomyelitis, we evaluated E2 effects on TNF-alpha expression in the central nervous system (CNS) and spleen of C57BL/6 mice immunized with MOG 35-55/CFA. Kinetic analysis demonstrated that E2 treatment drastically decreased the recruitment of total inflammatory cells as well as TNF-alpha(+) macrophages and T cells into the CNS at disease onset. In contrast, E2 had only moderate effects on the relatively high constitutive TNF-alpha expression by resident CNS microglial cells. E2 treatment also had profound inhibitory effects on expression of TNF-alpha by splenic CD4(+) T cells, including those responsive to MOG 35-55 peptide. We propose that the mechanism of E2 protection may involve both systemic inhibition of TNF-alpha expression and local (CNS) recruitment of inflammatory cells, with modest effects on TNF-alpha expression by resident CNS microglial cells.     

Induction of antigen-specific T cell anergy: An early event in the course of tumor progression

The priming of tumor-antigen-specific T cells is critical for the initiation of successful anti-tumor immune responses, yet the fate of such cells during tumor progression is unknown. Naive CD4⁺ T cells specific for an antigen expressed by tumor cells were transferred into tumor-bearing mice. Transient clonal expansion occurred early after transfer, accompanied by phenotypic changes associated with antigen recognition. Nevertheless, these cells had a diminished response to peptide antigen in vitro and were unable to be primed in vivo. The development of antigen-specific T cell anergy is an early event in the tumor-bearing host, and it suggests that tolerance to tumor antigens may impose a significant barrier to therapeutic vaccination.     

Acceleration of type 1 diabetes mellitus in proinsulin 2-deficient NOD mice

Accumulating evidence favors a role for proinsulin as a key autoantigen in diabetes. In the mouse, two proinsulin isoforms coexist. Most studies point to proinsulin 2 as the major isoform recognized by T cells in the NOD mouse. We studied mice in which a null proinsulin 2 mutation was transferred from proinsulin 2-deficient 129 mice onto the NOD background along with 16 genetic markers (including I-A(g7) MHC molecule) associated with diabetes. Intercross mice from the fourth backcross generation showed that proinsulin 2(-/-) mice develop accelerated insulitis and diabetes. The high prevalence of anti-insulin autoantibodies in proinsulin 2(-/-) mice indicates that diabetes acceleration relates to altered recognition of proinsulin. The prevalence of anti-glutamic acid decarboxylase autoantibodies and of sialitis is not increased in proinsulin 2(-/-) mice. We give evidence that proinsulin 2 expression leads to silencing of T cells specific for an epitope shared by proinsulin 1 and proinsulin 2. In the human, alleles located in the VNTR region flanking the insulin gene control beta cell response to glucose and proinsulin expression in the thymus and are key determinants of diabetes susceptibility. Proinsulin 2(-/-) NOD mice provide a model to study the role of thymic expression of insulin in susceptibility to diabetes.     

Glycodelin in ovarian serous carcinoma: association with differentiation and survival

Ovarian cancer consists of many subtypes, serous carcinoma being the most common of them. In addition to the histopathological subtype, grading, clinical staging, and the amount of residual tumor, a great number of putative prognostic markers have been introduced. This study addresses in ovarian serous carcinoma the role of glycodelin, the major progesterone-regulated lipocalin protein of the reproductive axis with diverse actions in cell recognition and differentiation. Glycodelin expression was determined by immunohistochemistry of tissue microarrays in ovarian serous carcinomas from 460 patients, and the results were analyzed with respect to progesterone receptor subtype A (PRA) and progesterone receptor subtype B (PRB), clinical parameters, and survival. Glycodelin was localized to the cytoplasm of tumor cells, whereas vascular endothelium in tumor tissue was glycodelin-negative. Glycodelin expression was more frequent in well-differentiated (grade I, 79%) than in poorly differentiated carcinomas (grade III, 51%; P < 0.0001), and it was also more frequent in early-stage compared with advanced-stage carcinomas (P = 0.002). Nuclear PRA and PRB were often coexpressed with cytoplasmic glycodelin. Although this was not consistent in all tumors, there was a positive correlation between the presence of glycodelin and PRs in the tumor (P < 0.02), but not between the presence of, or the absence of, glycodelin in tumor and the CA-125 serum concentration. Although in multivariate analysis glycodelin was not an independent variable, the patients with glycodelin-expressing tumors showed a higher 5-year overall survival compared with those with glycodelin-negative tumors (55 versus 39%; P < 0.0001; hazard ratio in univariate analysis, 0.57; confidence interval, 0.44-0.74). This difference was notable in patients with grade I tumors and stage III disease. In the latter group, the 10-year survival probability of patients with glycodelin-positive tumors was more than twice as high as that in women with glycodelin-negative tumors. This was also found within well-defined clinical categories, e.g., stage III/grade II and stage III/grade III carcinomas, in which patients with glycodelin-positive tumors carried significantly better 10-year overall survival compared with those with glycodelin-negative tumors. It is concluded that, in ovarian serous carcinoma, glycodelin expression portends better prognosis, probably because of its differentiation-related disposition.     

Computer skills for the next generation of healthcare executives

Students beginning a career in healthcare administration must possess an array of professional and management skills in addition to a strong fundamental understanding of the field of healthcare administration. Proficient computer skills are a prime example of an essential management tool for healthcare administrators. However, it is unclear which computer skills are absolutely necessary for healthcare administrators and the extent of congruency between the computer skills possessed by new graduates and the needs of senior healthcare professionals. Our objectives in this research are to assess which computer skills are the most important to senior healthcare executives and recent healthcare administration graduates and examine the level of agreement between the two groups. Based on a survey of senior healthcare executives and graduate healthcare administration students, we identify a comprehensive and pragmatic array of computer skills and categorize them into four groups, according to their importance, for making recent health administration graduates valuable in the healthcare administration workplace. Traditional parametric hypothesis tests are used to assess congruency between responses of senior executives and of recent healthcare administration graduates. For each skill, responses of the two groups are averaged to create an overall ranking of the computer skills. Not surprisingly, both groups agreed on the importance of computer skills for recent healthcare administration graduates. In particular, computer skills such as word processing, graphics and presentation, using operating systems, creating and editing databases, spreadsheet analysis, using imported data, e-mail, using electronic bulletin boards, and downloading information were among the highest ranked computer skills necessary for recent graduates. However, there were statistically significant differences in perceptions between senior executives and healthcare administration students as to the extent of computer skills required in areas such as word processing, graphics and presentation, spreadsheet analysis, using imported data, and working with local area networks (LANs).