Citations

Abstract Purpose: Here, we describe a novel interplay between NAD synthesis and degradation involved in pancreatic tumor growth. Experimental Design: We used human pancreatic cancer cells, both in vitro (cell culture experiments) and in vivo (xenograft experiments), to demonstrate the role of NAD synthesis and degradation in tumor cell metabolism and growth. Results: We demonstrated that pharmacologic and genetic targeting of Nampt, the key enzyme in the NAD salvage synthesis pathway, inhibits cell growth and survival of pancreatic cancer cells. These changes were accompanied by a reduction of NAD levels, glycolytic flux, lactate production, mitochondrial function, and levels of ATP. The massive reduction in overall metabolic activity induced by Nampt inhibition was accompanied by a dramatic decrease in pancreatic tumor growth. The results of the mechanistic experiments showed that neither the NAD-dependent enzymes PARP-1 nor SIRT1 play a significant role on the effect of Nampt inhibition on pancreatic cancer cells. However, we identified a role for the NAD degradation pathway mediated by the NADase CD38 on the sensitivity to Nampt inhibition. The responsiveness to Nampt inhibition is modulated by the expression of CD38; low levels of this enzyme decrease the sensitivity to Nampt inhibition. In contrast, its overexpression decreased cell growth in vitro and in vivo, and further increased the sensitivity to Nampt inhibition. Conclusions: Our study demonstrates that NAD metabolism is essential for pancreatic cancer cell survival and proliferation and that targeting NAD synthesis via the Nampt pathway could lead to novel therapeutic treatments for pancreatic cancer. Clin Cancer Res; 20(1); 120–30. ©2013 AACR.

Although the etiology of bipolar disorder remains uncertain, multiple studies examining neuroimaging, peripheral markers and genetics have provided important insights into the pathophysiologic processes underlying bipolar disorder. Neuroimaging studies have consistently demonstrated loss of gray matter, as well as altered activation of subcortical, anterior temporal and ventral prefrontal regions in response to emotional stimuli in bipolar disorder. Genetics studies have identified several potential candidate genes associated with increased risk for developing bipolar disorder that involve circadian rhythm, neuronal development and calcium metabolism. Notably, several groups have found decreased levels of neurotrophic factors and increased pro-inflammatory cytokines and oxidative stress markers. Together these findings provide the background for the identification of potential biomarkers for vulnerability, disease expression and to help understand the course of illness and treatment response. In other areas of medicine, validated biomarkers now inform clinical decision-making. Although the findings reviewed herein hold promise, further research involving large collaborative studies is needed to validate these potential biomarkers prior to employing them for clinical purposes. Therefore, in this positional paper from the ISBD-BIONET (biomarkers network from the International Society for Bipolar Disorders), we will discuss our view of biomarkers for these three areas: neuroimaging, peripheral measurements and genetics; and conclude the paper with our position for the next steps in the search for biomarkers for bipolar disorder.

SummaryObjectivesTo describe the experience of a single, tertiary care institution in the care of patients with Fontan physiology undergoing anesthesia for noncardiac surgery.BackgroundThe Fontan procedure was developed in 1971 to palliate patients with univentricular cardiac physiology leading to long‐term survival of these patients, who may now present as adults for noncardiac surgery.MethodsWe retrospectively reviewed the medical records of Fontan patients 16 years and older who underwent general anesthesia for noncardiac surgery at Mayo Clinic in Rochester, Minnesota. Preoperative data, perioperative course, intraoperative and postoperative hemodynamic, pulmonary, cardiovascular, and renal complications were described.ResultsThirty‐nine general anesthetics were administered to 31 patients for noncardiac surgery after Fontan palliation. Perioperative complications occurred in 12 of the 39 (31%) noncardiac surgeries, and there was one postoperative death that occurred on day 13 after ventral hernia repair. The two patients who had complications that did not resolve (long‐term dialysis and death) had ejection fractions well below the mean for the group (22% and 28%).ConclusionIt may be more appropriate for Fontan patients to undergo anesthesia for noncardiac surgery in a tertiary institution, particularly patients with an ejection fraction of <30%. Intraoperative arterial blood pressure monitoring and overnight admission are likely appropriate for most cases.