Control of lysozyme gene expression in differentiating HL-60 cells

We have investigated the control of lysozyme gene expression in HL-60 cells induced to differentiate into macrophage-like cells with phorbol myristate acetate (PMA). Differentiation, as evidenced by cellular adherence, and morphological changes corresponded temporally to an increase in nonspecific esterase activity. The lysozyme concentration in the medium of uninduced HL-60 cells was 10 Μg/10 7 cells. increasing to a maximum of 46 Μg/10 7 cells after 48 h incubation with PMA (16 nm). At 72 h the lysozyme concentration decreased to 16 Μg/10 7 cells. Intracellular lysozyme activity remained constant throughout differentiation. If HL-60 cells were exposed to PMA for 24 h, washed, then maintained in normal medium, they differentiated normally, confirming their irreversible commitment to differentiate. The increase in lysozyme secretion by these cells, however, is markedly blunted suggesting that continued PMA treatment of differentiated cells is required for their secretion of lysozyme. There is no change in the rate of extracellular degradation of lysozyme during differentiation. The level of lysozyme mRNA does not correlate directly with the amount of lysozyme secreted into the medium. Hybridization of uninduced HL-60 cell RNA with a chicken lysozyme cDNA probe demonstrates moderate hybridization. There is a modest (five-fold) increase in lysozyme mRNA between 0 and 36 h of exposure to PMA, corresponding to the burst of lysozyme secretion by these cells. The lysozyme mRNA decreases to a level which is lower than the original baseline by 72 h, when the cells are still secreting substantial amounts of lysozyme. These data suggest that both transcriptional and post-transcriptional controls are operative in the control of lysozyme gene expression during the differentiation of HL-60 cells. They also imply that lysozyme secretion is not a necessary component in the macrophage-monocyte differentiation of these cells.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/71582/1/j.1365-2141.1985.tb07380.x.pd

Heat flow and calculus on metric measure spaces with Ricci curvature bounded below - the compact case

We provide a quick overview of various calculus tools and of the main results concerning the heat flow on compact metric measure spaces, with applications to spaces with lower Ricci curvature bounds. Topics include the Hopf-Lax semigroup and the Hamilton-Jacobi equation in metric spaces, a new approach to differentiation and to the theory of Sobolev spaces over metric measure spaces, the equivalence of the L^2-gradient flow of a suitably defined "Dirichlet energy" and the Wasserstein gradient flow of the relative entropy functional, a metric version of Brenier's Theorem, and a new (stronger) definition of Ricci curvature bound from below for metric measure spaces. This new notion is stable w.r.t. measured Gromov-Hausdorff convergence and it is strictly connected with the linearity of the heat flow.Comment: To the memory of Enrico Magenes, whose exemplar life, research and teaching shaped generations of mathematician

Generalized reduced basis methods and n-width estimates for the approximation of the solution manifold of parametric PDEs

The set of solutions of a parameter-dependent linear partial differential equation with smooth coefficients typically forms a compact manifold in a Hilbert space. In this paper we review the generalized reduced basis method as a fast computational tool for the uniform approximation of the solution manifold. We focus on operators showing an affine parametric dependence, expressed as a linear combination of parameter-independent operators through some smooth, parameter-dependent scalar functions. In the case that the parameter-dependent operator has a dominant term in its affine expansion, one can prove the existence of exponentially convergent uniform approximation spaces for the entire solution manifold. These spaces can be constructed without any assumptions on the parametric regularity of the manifold -- only spatial regularity of the solutions is required. The exponential convergence rate is then inherited by the generalized reduced basis method. We provide a numerical example related to parametrized elliptic equations confirming the predicted convergence rate

Immunohistochemical markers associated with brain metastases in patients with nonsmall cell lung carcinoma

BACKGROUND: There are no reliable markers able to identify patients with non-small cell lung cancer (NSCLC) likely to metastasize to the brain. We investigated associations between immunohistochemical markers and development of brain metastases in patients with NSCLC. METHODS: We performed a hospital-based, case-control study of patients with newly diagnosed NSCLC between 1989 and 2003 that developed brain metastases who had available pathology material from both primary NSCLC and brain metastases. The control patients had NSCLC and no evidence of brain metastases. We examined NSCLC for expression of Ki-67, caspase-3, VEGF-A, VEGF-C, E-cadherin and EGFR in 54 surgical pathology specimens using immunohistochemistry and evaluated associations with development of brain metastases. RESULTS: Brain metastases developed after a median time of 12.5 months (range 1.7-89.4 months) from the diagnosis of NSCLC. A significantly increased risk of developing brain metastases was associated with patients who had high Ki-67 (adjusted odds ratio 12.2, 95% CI, 2.4 to 70.4, P<0.001), low caspase-3 (adjusted odds ratio 43.0, 95% CI, 5.3 to >100, P<0.001), high VEGF-C (adjusted odds ratio 14.6, 95% CI, 2.0 to >100, P<0.001), and low E-cadherin (adjusted odds ratio 3.6, 95% CI, 0.9 to 16.4, P=0.05), in the primary NSCLC. No significant risk was observed with VEGF-A and EGFR. A high Ki-67 was also associated with a shorter overall survival (P=0.04). CONCLUSIONS: Patients with NSCLC and high Ki-67, low caspase-3, high VEGF-C, and low E-cadherin in their tumors may benefit from close surveillance since they may have an increased risk of developing brain metastases