Citations

Abstract Microvesicles (MVs) released by malignant cancer cells constitute an important part of the tumor microenvironment. They can transfer various messages to target cells and may be critical to disease progression. Here, we demonstrate that MVs circulating in plasma of B-cell chronic lymphocytic leukemia (CLL) patients exhibit a phenotypic shift from predominantly platelet derived in early stage to leukemic B-cell derived at advanced stage. Furthermore, the total MV level in CLL was significantly greater compared with healthy subjects. To understand the functional implication, we examined whether MVs can interact and modulate CLL bone marrow stromal cells (BMSCs) known to provide a “homing and nurturing” environment for CLL B cells. We found that CLL-MV can activate the AKT/mammalian target of rapamycin/p70S6K/hypoxia-inducible factor-1α axis in CLL-BMSCs with production of vascular endothelial growth factor, a survival factor for CLL B cells. Moreover, MV-mediated AKT activation led to modulation of the β-catenin pathway and increased expression of cyclin D1 and c-myc in BMSCs. We found MV delivered phospho-receptor tyrosine kinase Axl directly to the BMSCs in association with AKT activation. This study demonstrates the existence of separate MV phenotypes during leukemic disease progression and underscores the important role of MVs in activation of the tumor microenvironment.

Background A "teachable moment" is an event that motivates spontaneous behavior change. Some evidence suggests that major surgery for a smoking-related illness can serve as a teachable moment for smoking cessation. This study tested the hypotheses that surgery increases the likelihood of smoking cessation and that cessation is more likely after major surgical procedures compared with outpatient surgery. Methods Secondary analyses were performed of longitudinal biennial survey data (1992-2004) from the nationally representative Health and Retirement Study of U.S. adults older than 50 yr, determining the relationship between the incidence of smoking cessation and the occurrence of surgery. Results Five thousand four hundred ninety-eight individuals reported current smoking at enrollment, and 2,444 of them (44.5%) quit smoking during the period of examination. The incidence of quitting in smokers undergoing major surgery was 20.6/100 person-years of follow-up and 10.2/100 person-years in those undergoing outpatient surgery. In a multivariate negative binomial regression model, the incidence rate ratio of quitting associated with major surgery was 2.02 (95% CI: 1.67-2.44) and that of those associated with outpatient surgery was 1.28 (95% CI: 1.09-1.50). Estimates derived from national surgical utilization data show that approximately 8% of all quit events in the United States annually can be attributed to the surgical procedures analyzed. Conclusions Undergoing surgery is associated with an increased likelihood of smoking cessation in the older U.S. population. Cessation is more likely in association with major procedures compared with outpatient surgery. These data support the concept that surgery is a teachable moment for smoking cessation.

Cigarette smoking and/or nicotine administration have been shown to transiently ameliorate several psychophysiological deficits in patients with schizophrenia such as indicators of deficient sensory gating and attention, but acute effects of smoking on positive and negative symptoms in schizophrenia have not been evaluated in experimental paradigms. The current study assessed whether smoking of cigarettes, after 6–12 h abstinence, transiently alters the expression of negative and/or positive symptoms in patients with schizophrenia who have a history of regular smoking. In a double–blind, placebo controlled study patients with schizophrenia participated in two sessions in which they smoked either cigarettes moderately high in nicotine content or denicotinized cigarettes. They were interviewed pre–and postsmoking to obtain ratings of PANSS and SANS scales, and had blood pressure and pulse serially recorded before and after smoking. Pulse rate and blood pressure were slightly higher after smoking in the high nicotine cigarette session. Negative symptom scores on both scales were significantly lower after cigarette smoking compared to same–day predrug baseline, but there were no differences in active versus denicotinized cigarette drug effects. These results suggest that acute smoking of cigarettes reduces negative symptoms in patients with schizophrenia in this experimental paradigm. Future work needs to identify the mechanism responsible for this behavioral effect.

Abstract Purpose: The eukaryotic translation initiation factor complex 4E (eIF4E) is downstream in the mammalian target of rapamycin (mTOR) pathway. This study explored expression of eIF4E and its relationship with the PTEN/AKT and RAS/MEK/ERK pathways in non–small cell lung carcinoma (NSCLC). Experimental Design: The status of phosphorylated eIF4E (p-eIF4E), phosphorylated AKT (p-AKT), PTEN, phosphorylated tuberin (p-TSC2), phosphorylated mTOR (p-mTOR), phosphorylated S6 (p-S6), and phosphorylated Erk1/2 (p-Erk1/2) was studied using immunohistochemical analysis applied to a tissue microarray containing 300 NSCLCs. Staining results for each antibody were compared with clinical and pathologic features, and the relationship between staining results was explored. Results: Overexpression of p-eIF4E, p-AKT, p-TSC2, p-mTOR, p-S6, and p-Erk1/2 in NSCLC was found in 39.9%, 78.8%, 5.1%, 46.7%, 27.1%, and 16.6% of tumors, respectively. The phenotype of p-eIF4E correlated positively with that of p-AKT, p-TSC2, and p-S6 (P < 0.001). Overall survival in NSCLC patients was significantly shorter in cases with overexpression of p-eIF4E and p-AKT alone and in combination (log-rank P < 0.001, each). Cases with underexpression of PTEN were limited (6.4%), and this phenotype did not correlate with any clinical variable. In cluster analysis, the p-AKT/p-mTOR/p-eIF4E/p-S6–positive group had significantly shorter survival compared with the survival of all cases (P < 0.001). Multivariate analysis showed that p-eIF4E overexpression is an independent prognostic factor for NSCLC (P = 0.004). Conclusions: This study shows that p-eIF4E expression in addition to p-AKT predicts poor prognosis in NSCLC. Moreover, the correlation between expression of p-eIF4E with p-AKT, as well as p-TSC2 and p-S6, indicates that eIF4E activation through the AKT pathway plays an important role in the progression of NSCLC. Clin Cancer Res; 16(1); OF1–9