Response to "Alternative models for carcinogenicity testing: weight of evidence across models" Sam Cohen, Toxicologic Pathology (2001) 29(suppl.): 183-190.
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HACS1 is a Src homology 3 and sterile alpha motif domain-containing adaptor that is preferentially expressed in normal hematopoietic tissues and malignancies including myeloid leukemia, lymphoma, and myeloma. Microarray data showed HACS1 expression is up-regulated in activated human B cells treated with interleukin (IL)-4, CD40L, and anti-immunoglobulin (Ig)M and clustered with genes involved in signaling, including TNF receptor-associated protein 1, signaling lymphocytic activation molecule, IL-6, and DEC205. Immunoblot analysis demonstrated that HACS1 is up-regulated by IL-4, IL-13, anti-IgM, and anti-CD40 in human peripheral blood B cells. In murine spleen B cells, Hacs1 can also be up-regulated by lipopolysaccharide but not IL-13. Induction of Hacs1 by IL-4 is dependent on Stat6 signaling and can also be impaired by inhibitors of phosphatidylinositol 3-kinase, protein kinase C, and nuclear factor kappaB. HACS1 associates with tyrosine-phosphorylated proteins after B cell activation and binds in vitro to the inhibitory molecule paired Ig-like receptor B. Overexpression of HACS1 in murine spleen B cells resulted in a down-regulation of the activation marker CD23 and enhancement of CD138 expression, IgM secretion, and Xbp-1 expression. Knock down of HACS1 in a human B lymphoma cell line by small interfering ribonucleic acid did not significantly change IL-4-stimulated B cell proliferation. Our study demonstrates that HACS1 is up-regulated by B cell activation signals and is a participant in B cell activation and differentiation.
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Accelerated changes in the DNA ploidy associated with in vitro aging were examined in fibroblast-like cells isolated from the dorsal dermis of newborn SAMP11 (accelerated senescence-prone, short-lived) mice, and were compared to changes observed in cell lines from SAMR1 (accelerated senescence-resistant, long-lived) mice. Flow cytometric analysis of the DNA content in confluent cells and chromosome analysis in mitoses revealed that the diploid cells were being replaced with tetraploid cells until a growth crisis; thereafter, hypotetraploid cells became predominant, accompanied by immortalization. The number of mitoses decreased as the crisis ensued, then increased. Although these changes were observed in the cell lines from both strains of mice, the changes occurred more rapidly and at earlier population doublings in the cell lines from the SAMP11 mice. These results suggest that the cell lines from SAMP11 mice might have higher susceptibility to factors that cause polyploidization, including oxidative stress.
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During his house staff training before World War II, Dr. W. Proctor Harvey encountered Dr. Samuel A. Levine at the Peter Bent Brigham Hospital in Boston. Following military service, Harvey returned to Boston and became Levine's first cardiology fellow. The book Clinical Auscultation of the Heart--the Little Green Book by Levine and Harvey in 1949 combined Levine's clinical wisdom with Harvey's objective phonocardiographic methods and brought an important objective dimension to the art of cardiac auscultation. Both Levine and Harvey shared experiences and friendship with Henry Christian, the first Physician-in-Chief when the new Brigham Hospital Opened in 1913. Christian, appointed Dean of the Harvard Medical School in 1908 at the age of 32, was referred to as the "Boy Dean." He held the Hersey Chair of Theory and Practice of Physic from 1908 until 1939, was one of the founding group of the American Society for Clinical Investigation, and a major force in academic medicine. Levine served as intern to Christian and then joined the Brigham medical staff in 1915. Proctor Harvey followed Henry Christian's path from their mutual hometown of Lyunchburg, VA to the Peter Bent Brigham Hospital. A series of illuminating and respectful professional interactions--initially between Christian and Levine, between Levine and Harvey in the early 1940s, and between Harvey and Christian in the 1950s--provide the background for the genesis of the Little Green Book and a remarkable example of academic heritage.