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Background: Poor survival in pancreatic adenocarcinoma is associated with African-American race and also with low socioeconomic status (SES). However, it is not known whether the observed poor survival of African-American pancreatic adenocarcinoma cases is due to SES itself and/or treatment disparities. We set out to determine this using the large, population-based California Cancer Registry (CCR) database as a model. Methods: We conducted a case-only analysis of CCR data (1989)(1990)(1991)(1992)(1993)(1994)(1995)(1996)(1997)(1998)(1999)(2000)(2001)(2002)(2003), including descriptive analysis of relevant clinical variables and SES. The SES variable used has been derived from principle component analysis of census block level CCR data linked to census data to address seven major indicators of SES. Overall survival univariate analyses were conducted using the Kaplan-Meier method. Multivariate survival analyses were done using Cox proportional hazards ratios (HR).

To elucidate signal transduction pathways leading to neuronal differentiation, we have investigated a conditionally immortalized cell line from rat hippocampal neurons (H19-7) that expresses a temperaturesensitive simian virus 40 large T antigen. Treatment of H19-7 cells with the differentiating agent basic fibroblast growth factor at 39؇C, the nonpermissive temperature for T function, resulted in the activation of c-Raf-1, MEK, and mitogen-activated protein (MAP) kinases (ERK1 and -2). To evaluate the role of Raf-1 in neuronal cell differentiation, we stably transfected H19-7 cells with v-raf or an oncogenic human Raf-1-estrogen receptor fusion gene (⌬Raf-1:ER). ⌬Raf-1:ER transfectants in the presence of estradiol for 1 to 2 days expressed a differentiation phenotype only at the nonpermissive temperature. However, extended exposure of the ⌬Raf-1:ER transfectants to estradiol or stable expression of the v-raf construct yielded cells that extended processes at the permissive as well as the nonpermissive temperature, suggesting that cells expressing the large T antigen are capable of responding to the Raf differentiation signal. ⌬Raf-1:ER, MEK, and MAP kinase activities in the ⌬Raf-1:ER cells were elevated constitutively for up to 36 h of estradiol treatment at the permissive temperature. At the nonpermissive temperature, MEK and ERKs were activated to a significantly lesser extent, suggesting that prolonged MAP kinase activation may not be sufficient for differentiation. To test this possibility, H19-7 cells were transfected or microinjected with constitutively activated MEK. The results indicate that prolonged activation of MEK or MAP kinases (ERK1 and -2) is not sufficient for differentiation of H19-7 neuronal cells and raise the possibility that an alternative signaling pathway is required for differentiation of H19-7 cells by Raf.Biochemical and genetic studies of cells from a wide variety of species have demonstrated that the signals leading to differentiation are highly conserved and that in many cases, the same compounds are involved in both cell growth and transformation. Two general hypotheses have been suggested to explain why common signaling pathways can lead to different endpoints. First, it has been suggested that both the amplitude and the duration of a particular signal can influence the final biological endpoint (reviewed in reference 18). Alternatively, differences in phenotypes have been attributed to differences in specific cellular environments (both internal and external). While it is likely that both factors contribute to the final biological endpoint, it is important to investigate a number of differentiation systems in order to identify their relative contributions.One major problem, particularly with respect to neuronal cell differentiation, has been the limited availability of appropriate model systems. The best-characterized system to date is the pheochromocytoma cell line PC12, which is derived from a transplantable rat adrenal pheochromocytoma (13). One problem that potentially compl...

We tested whether activation of mitogen-activated protein kinase/ extracellular signal-regulated kinase kinase-1 (MEK1) is required and sufficient for extracellular signal-regulated kinase (ERK) activation in airway smooth muscle cells. First, we transiently cotransfected bovine tracheal myocytes with an epitope-tagged ERK2 and a dominant-negative or a constitutively active form of the gene encoding MEK1 and assessed ERK2 activation by in vitro phosphorylation assay. Expression of the dominant-negative MEK1 inhibited platelet-derived growth factor (PDGF)-induced ERK2 activation, whereas expression of the constitutively active MEK1 induced ERK2 activation, suggesting that MEK1 is required and sufficient for ERK activation in these cells. Next, we assessed the effect of PD-98059, a synthetic MEK inhibitor, on PDGF-induced MEK1 and ERK activation. PD-98059 (10 microM) inhibited MEK1 and ERK activation, confirming that MEK1 is required for ERK activation in bovine tracheal myocytes. PD-98059 had no effect on Src or Raf-1 activity, evidence that PD-98059 is a specific inhibitor of MEK in this system. Finally, PD-98059 reduced PDGF-induced [(3)H]thymidine incorporation in a concentration-dependent manner, suggesting that catalytic activation of MEK1 and ERKs is required for DNA synthesis. We conclude that MEK1 is required for PDGF-induced ERK activation in bovine tracheal myocytes and that MEK1 and ERKs are required for PDGF-induced DNA synthesis in these cells.