Faculty Bibliography

The dual role of nitric oxide in cancer biology is discussed here through the perspective of our work on nitric oxide-mediated signaling events. The nitric oxide-stimulated Src-FAK and Ras-ERK1/2 mitogen-activated protein kinases (MAPKs) oncogenic signaling pathways are discussed, highlighting the cross-talk between 2 major posttranslational modifications: protein phosphorylation and protein S-nitrosylation. In addition, we discuss the importance of nitric oxide synthases in cancer biology, focusing on the roles of endothelial nitric oxide synthase and arginase 2 in human thyroid tumor progression. A direct relationship between the expression levels of both enzymes was found in human follicular thyroid carcinoma. Finally, the antioncogenic, proapoptotic actions of nitric oxide based on its antiadhesive properties are presented and discussed. 2012 by Begell House, Inc

The role of NO in regulating the focal adhesion proteins, Src, FAK, p130 Cas, and PTP-alpha, was investigated. Fibroblasts expressing PTP-alpha (PTP-alpha(WT) cells), fibroblasts "knockout" for PTP-alpha (PTP-alpha(-/-) cells), and "rescued" "knockout" fibroblasts (PTP-alpha A5/3 cells) were stimulated with either S-nitroso-N-acetylpenicillamine (SNAP) or fetal bovine serum (FBS). FBS increased inducible NO synthase in both cell lines. Activation of Src mediated either by SNAP or by FBS occurred independent of dephosphorylation of Tyr527 in PTP-alpha(-/-) cells. Both stimuli promoted dephosphorylation of Tyr527 and activation of Src kinase in PTP-alpha(WT) cells. NO-mediated activation of Src kinase affected the activities of FAK and p130Cas and was dependent on the expression of PTP-alpha. Analogous to tyrosine phosphorylation, SNAP and FBS stimulated differential generation of NO and S-nitrosylation of Src kinase in both cell lines. Incubation with SNAP resulted in higher levels of NO and S-nitrosylation of immunoprecipitated Src in PTP-alpha(-/-) cells (oxidizing redox environment) as compared with the levels of NO and S-nitrosylated Src in PTP-alpha(WT) cells (reducing redox environment). SNAP differentially stimulated cell proliferation of both cell lines is dependent on the intracellular redox environment, Src activity, and PTP-alpha expression. This dependence also is observed with FBS-stimulated cell migration.

Abnormalities of platelet functions have been linked to reelin-impaired neuronal disorders. However, little attention has been given to understanding the interplay between reelin and platelet. In this study, reelin was found to present in the human platelets and megakaryocyte-like leukemic cells. Reelin-binding assays revealed that extracellular reelin can interact with platelets through the receptor belonging to the low density lipoprotein receptor gene family. The reelin-to-platelet interactions enhance platelet spreading on fibrinogen concomitant with the augmentation of lamellipodia formation and F-actin bundling. In contrast, reelin has no effect on integrin alphaIIbbeta3 activation and agonist-induced platelet aggregation. Molecular analysis revealed that the up-regulation of Rac1 activity and the inhibition of protein kinase C delta-Thr505 phosphorylation are important for reelin-mediated enhancement of platelet spreading on fibrinogen. These findings demonstrate for the first time that reelin is present in platelets and the reelin-to-platelet interactions play a novel role in platelet signaling and functions

BACKGROUND: Relatively few studies have rigorously assessed the effectiveness of computer-based self-assessment in medical education. AIM: To assess whether an online self-assessment tool can be an effective adjunct to a traditional curriculum for second-year medical students. METHODS: The NYU School of Medicine Online Self-Assessment Tool (SOMOSAT) consists of >450 multiple-choice questions spanning disciplines of internal medicine, administered as separate modules focused on individual organ systems. Questions are coded on multiple dimensions, permitting second-year medical students to receive low-stakes, highly specific feedback regarding their knowledge and performance. Students can also review their answers to guide future study. We employed data collected during SOMOSAT operation to assess its utility and effectiveness. RESULTS: Overall, SOMOSAT accurately predicted student performance on future exams. SOMOSAT participants generally performed better than non-participants on subsequent graded course examinations (p < 0.05). Students using SOMOSAT subsequently experienced greater improvement in areas in which they initially performed poorly, compared with those in which they initially performed well. Students reported that SOMOSAT was most helpful in filling knowledge gaps, and providing opportunities to practice exam-style questions. CONCLUSION: The ability of SOMOSAT to enhance learning and exam performance suggests that web-based self-assessment tools can be effective adjuncts to traditional educational methods

Colorectal cancer (CRC), is the second-leading cause of cancer-related deaths in the USA, affecting both men and women. Current projections show little or no change since the publication of a morbidity and mortality study in 2005. The projected number of new cases for 2008 is 154,000, and the projected number of CRC cancer deaths for 2008 is 53,000. The standard diagnostic paradigm is based on histopathology of either biopsy or surgical specimens. This article suggests a new paradigm for colon cancer diagnosis and staging using matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS or IMS). IMS may identify potential tumors in normal tissue of cancer patients and predict those cancer patients who are at risk for recurrent cancer

Accumulating evidence indicates that post-translational protein modifications by nitric oxide and its derived species are critical effectors of redox signaling in cells. These protein modifications are most likely controlled by intracellular reductants. Among them, the importance of the 12 kDa dithiol protein thioredoxin-1 (TRX-1) has been increasingly recognized. However, the effects of TRX-1 in cells exposed to exogenous nitrosothiols remain little understood. We investigated the levels of intracellular nitrosothiols and survival signaling in HeLa cells over-expressing TRX-1 and exposed to S-nitrosoglutahione (GSNO). A role for TRX-1 expression on GSNO catabolism and cell viability was demonstrated by the concentration-dependent effects of GSNO on decreasing TRX-1 expression, activation of caspase-3, and increasing cell death. The over-expression of TRX-1 in HeLa cells partially attenuated caspase-3 activation and enhanced cell viability upon GSNO treatment. This was correlated with reduction of intracellular levels of nitrosothiols and increasing levels of nitrite and nitrotyrosine. The involvement of ERK, p38 and JNK pathways were investigated in parental cells treated with GSNO. Activation of ERK1/2 MAP kinases was shown to be critical for survival signaling. In cells over-expressing TRX-1, basal phosphorylation levels of ERK1/2 MAP kinases were higher and further increased after GSNO treatment. These results indicate that the enhanced cell viability promoted by TRX-1 correlates with its capacity to regulate the levels of intracellular nitrosothiols and to up-regulate the survival signaling pathway mediated by the ERK1/2 MAP kinases