A Mechanistic Study of Thioester Hydrolysis with Heavy Atom Kinetic Isotope Effects

The carbonyl-C, carbonyl-O, and leaving-S kinetic isotope effects (KIEs) were determined for the hydrolysis of formylthiocholine. Under acidic conditions, ¹³<i>k</i>_obs = 1.0312, ¹⁸<i>k</i>_obs = 0.997, and ³⁴<i>k</i>_obs = 0.995; for neutral conditions, ¹³<i>k</i>_obs = 1.022, ¹⁸<i>k</i>_obs = 1.010, and ³⁴<i>k</i>_obs = 0.996; and for alkaline conditions, ¹³<i>k</i>_obs = 1.0263, ¹⁸<i>k</i>_obs = 0.992, and ³⁴<i>k</i>_obs = 1.000. The observed KIEs provided helpful insights into a qualitative description of the bond orders in the transition state structure

Cytotoxic T cell depletion with increasing epithelial abnormality in women with benign breast disease.

PURPOSE: We quantified cytotoxic T cells in nonmalignant breast tissues from women with and without subsequent breast cancer to assess evidence of whether immunosurveillance may be suppressed prior to tumor development. METHODS: We used an age-matched set of breast tissues from women with benign breast disease (BBD) who subsequently developed breast cancer (BBD with later BC), women with BBD who remained cancer free (BBD cancer-free), and normal Komen Tissue Bank (KTB) tissue donors (KTB controls). We evaluated terminal duct lobular units (lobules) for degree of epithelial abnormality and density of dual-positive CD8/CD103 T cells, as CD103+ cells are thought to be a subset of CD8+ cytotoxic T cells located primarily in the intraepithelial compartment. RESULTS: In 10 sets of age-matched women, 256 breast lobules were studied: 85 in BBD women with later BC, 85 in BBD cancer-free women, and 86 in KTB donors. The majority of all lobules were histologically normal (N = 143, 56%), with 65 (25%) nonproliferative fibrocystic change, and 48 (19%) proliferative epithelial change (with or without atypia). In BBD women with later BC, median CD8+/CD103+ cell density was 39.6, 31.7, and 10.5 cells/mm CONCLUSION: In women with BBD, breast lobules with increasing epithelial abnormality show significant decreases in cytotoxic T cells as measured by CD8/CD103 staining, suggesting that impaired immunosurveillance may be a component of the earliest stages of breast cancer development