Citations

Abstract The central importance of the ERBB/RAS signal transduction cascade has been well established in human cancer. As such, novel approaches to counteract activated ERBB/RAS signals constitute important measures to reverse tumorigenesis and metastasis in human cancers. Instead of targeting an upstream signaling module such as ERBB/RAS/MEK/MAPK/AKT/mTOR, we targeted the most downstream signaling module in the ERBB/RAS pathway called the SIAH-dependent proteolytic machinery. SIAHs are the human homologs of Seven-In-Absentia (SINA), an evolutionarily conserved RING E3 ligase, an essential downstream signaling module and a critical “gatekeeper” required for proper Drosophila RAS signal transduction. Guided by the insights and principles learned from Drosophila RAS signaling pathway, we conducted preclinical studies to examine SIAH function in the context of RAS-mediated tumorigenesis and metastasis in human cancer cells.We found that (1) SIAH is a novel biomarker for human cancer, i.e. it specifically decorates proliferating tumor cells (not stromal cells in the tumor microenvironment). SIAH expression is progressively and markedly upregulated as human cancer progresses to the advanced stages in human pancreatic, lung, breast and prostate cancers; and (2) inhibiting the proteolytic function of SIAH is highly effective to abolish tumorigenesis and metastasis in eight of the most aggressive human cancer cell lines known in the literature that include pancreatic cancer cells (MiaPaCa and Panc-1), lung cancer cells (A549), invasive breast cancer cells (MDA-MB-231, MDA-MB-468 and MDA-MB-435) and hormonal-refractory prostate cancer cells (PC-3 and DU-145) in soft agar as well as in athymic nude mice. These findings suggest that SIAH may be an attractive new therapeutic target for novel anti-RAS and anti-cancer therapy in human cancer. As a highly evolutionarily conserved E3 ligase and consistent with its “gatekeeper” function identified in the ERBB/RAS signaling pathway, SIAH is well positioned to become a next-generation and potent anticancer drug target to block the tumor-promoting RAS pathway and to treat the most aggressive types of human cancers. “Using anti-SIAH molecules to block active RAS signaling in human cancer” may be another example of “from the bench [basic science from fruitflies (model organism) to human cancers] to the bedside story [translational medicine in the near future]”. Anti-SIAH-based anticancer strategy may aid in expanding our arsenal of novel anticancer therapies. By attacking the oncogenic ERBB/RAS pathway using multi-pronged synergistic inhibitions at upstream (EGFR/HER2 membrane receptors), midstream (RAS/RAF/MEK/mTOR) and downstream (SIAH E3 ligase) signaling modules in parallel, we may be in a great position to halt the genesis, progression and metastasis of the most aggressive and lethal types of human cancers. If successful, we hope to translate our findings to the cancer clinics to treat many cancer patients with metastatic diseases in the future. Citation Information: Cancer Res 2009;69(23 Suppl):A1.

AbstractAdvanced cirrhosis is often complicated by a multi organ failure syndrome which involves many different organs besides the liver. The high morbidity and mortality secondary to this clinical setting is often related to renal dysfunction, either alone or, more frequently, in combination with other organ dysfunction. A clear defintion of renal dysfunction, an accurate differential diagnostic process of its different phenotypes as well as of full understanding of its pathophysiological mechanisms are crucial to the development of strategies for the management of this complication. This article is based either on the more recent knowledge on renal dysfunction in advanced cirrhosis or current opinions among the members of the International Club of Ascites (ICA) on the management of this complication, obtained through a survey and discussed during the EASL‐ICA Joint Meeting in Berlin in March 2011. It reviews critically our current knowledge and it outlines future perspectives, on the management of renal dysfunction in patients with cirrhosis.

Abstract Aims For patients with refractory atrial fibrillation (AF) undergoing atrioventricular nodal ablation (AVNA), initial single-chamber right ventricular (RV)-only pacing is standard. Given the deleterious effects of chronic RV-only pacing, the impact of an initial biventricular (BiV) pacing strategy post-ablation is of interest. Methods and results We conducted a meta-analysis to determine the effect of BiV vs. RV-only pacing in patients undergoing AVNA for refractory atrial fibrillation. A search of multiple electronic databases identified 921 reports, which included four randomized controlled trials (n = 534). Mean New York Heart Association (NYHA) class was 2.3 and mean left ventricular ejection fraction (LVEF) was 44%. When compared with RV-only pacing, BiV pacing was not associated with reduced mortality [risk ratio 0.85, 95% confidence interval (CI) 0.40–1.82, P = 0.68]. In three studies comprised of patients with left ventricular systolic dysfunction (mean EF 41 ± 3%), BiV pacing demonstrated a non-significant reduction in cardiac mortality (risk ratio 0.59, 95% CI 0.25–1.39; P = 0.23). Compared with RV-only pacing, BiV pacing was associated with significant improvement in symptoms [Minnesota Living with Heart Failure Questionnaire (MLWHFQ) 2.72 points fewer, 95% CI 1.45–3.99] and increased LVEF (+2.6%, 95% CI 1.69–3.44), but no significant change in 6 min walk distance (6MWD) (5.02 ms more, 95% CI −1.56 to 11.59; P = 0.13). Conclusions In patients with refractory AF undergoing AVNA, BiV pacing was not associated with significantly improved survival when compared with RV-only pacing. A modest, but significant improvement in structural and functional response to BiV pacing was observed.