Background: Cancer cells rely on energy metabolism that requires increased glucose uptake and constitutive NF-B activity for survival. Results: Pancreatic cancer cells display elevated O-GlcNAcylation, reduction of which inhibits cell survival and oncogenic NF-B signaling. Conclusion: Hyper-O-GlcNAcylation is anti-apoptotic and contributes to NF-B activation in pancreatic cancer. Significance: Targeting hyper-O-GlcNAcylation may serve as a novel therapeutic intervention in pancreatic cancer.

The Hexosamine Biosynthetic Pathway (HBP) is highly dependent on multiple metabolic nutrients including glucose, glutamine and acetyl-CoA. Increased flux through HBP leads to elevated post-translational addition of β-D-N-acetylglucosamine sugars to nuclear and cytoplasmic proteins. Increased total O-GlcNAcylation is emerging as a general characteristic of cancer cells and recent studies suggest that O-GlcNAcylation is a central communicator of nutritional status to control key signaling and metabolic pathways that regulate multiple cancer cell phenotypes. This review summarizes our current understanding of changes of O-GlcNAc cycling enzymes in cancer, the role of O-GlcNAcylation in tumorigenesis and the current challenges in targeting this pathway therapeutically.

O-Linked ␤-N-acetylglucosamine (O-GlcNAc) is a carbohydrate post-translational modification on hydroxyl groups of serine and/or threonine residues of cytosolic and nuclear proteins. Analogous to phosphorylation, O-GlcNAcylation plays crucial regulatory roles in cellular signaling. Recent work indicates that increased O-GlcNAcylation is a general feature of cancer and contributes to transformed phenotypes. In this minireview, we discuss how hyper-O-GlcNAcylation may be linked to various hallmarks of cancer, including cancer cell proliferation, survival, invasion, and metastasis; energy metabolism; and epigenetics. We also discuss potential therapeutic modulation of O-GlcNAc levels in cancer treatment.

It has been reported that sleeve lobectomy (SL) concomitant with or without pulmonary artery reconstruction (PAR) might be an alternative procedure for pneumonectomy (PN) in non-small cell lung cancer (NSCLC). The aim of this study was to assess whether SL or PN offers a low morbidity and mortality and better long-term survival. We performed a meta-analysis of studies published in English between 1996 and 2006 to comprehensively compare the postoperative mortality, morbidity, locoregional recurrences, and time-to-event outcomes of SL and PN in NSCLC, and reviewed the recent literatures on PAR in the corresponding period as well. Twelve studies met the defined criteria including a total of 2984 subjects, and five studies for PAR. The odds ratio for postoperative mortality (SL vs PN) was 0.65 (95% confidence interval (CI): 0.42-1.01), 1.01 (95% CI: 0.70-1.44) for postoperative complications, and 0.91 (95% CI: 0.45-1.82) for locoregional recurrences. The weighted mean operative mortality for PAR was 3.3%, and 32.4% for complications. The estimated combined hazard ratio for overall survival in 10 studies was 0.70 (95% CI: 0.62-0.79) in favor of SL group. The median overall survival was 60 months for the SL group, 26 months for the PN group, and 30 months for PAR group. Survival difference in patients with pN0 or pN1 at 1 year demonstrated a pooled risk difference (SL vs PN) of 0.03 (95% CI: -0.08-0.13), 0.13 (95% CI: 0.00-0.25) in patients with pN2 at 1 year, 0.21 (95% CI: 0.07-0.36) in patients with pN0 or pN1 at 5 years, and 0.06 (95% CI: -0.10-0.21) in patients with pN2 at 5 years. Our results suggests that SL with or without PAR can be accomplished safely in selected patients without increasing the morbidity and mortality as compared to PN, that SL even with PAR offers better long-term survival than does PN, and that a more radical operation such as PN is not a more appropriate procedure, even in higher stage tumors.

Warfarin dosing remains challenging due to narrow therapeutic index and highly individual variability. Incorrect warfarin dosing is associated with devastating adverse events. Remarkable efforts have been made to develop the machine learning based warfarin dosing algorithms incorporating clinical factors and genetic variants such as polymorphisms in CYP2C9 and VKORC1. The most widely validated pharmacogenetic algorithm is the IWPC algorithm based on multivariate linear regression (MLR). However, with only a single algorithm, the prediction performance may reach an upper limit even with optimal parameters. Here, we present novel algorithms using stacked generalization frameworks to estimate the warfarin dose, within which different types of machine learning algorithms function together through a meta-machine learning model to maximize the prediction accuracy. Compared to the IWPC-derived MLR algorithm, Stack 1 and 2 based on stacked generalization frameworks performed significantly better overall. Subgroup analysis revealed that the mean of the percentage of patients whose predicted dose of warfarin within 20% of the actual stable therapeutic dose (mean percentage within 20%) for Stack 1 was improved by 12.7% (from 42.47% to 47.86%) in Asians and by 13.5% (from 22.08% to 25.05%) in the low-dose group compared to that for MLR, respectively. These data suggest that our algorithms would especially benefit patients requiring low warfarin maintenance dose, as subtle changes in warfarin dose could lead to adverse clinical events (thrombosis or bleeding) in patients with low dose. Our study offers novel pharmacogenetic algorithms for clinical trials and practice.

-GlcNAcylation is the covalent addition of an -linked β--acetylglucosamine (-GlcNAc) sugar moiety to hydroxyl groups of serine/threonine residues of cytosolic and nuclear proteins. -GlcNAcylation, analogous to phosphorylation, plays critical roles in gene expression through direct modification of transcription factors, such as NF-κB. Aberrantly increased NF-κB-GlcNAcylation has been linked to NF-κB constitutive activation and cancer development. Therefore, it is of a great biological and clinical significance to dissect the molecular mechanisms that tune NF-κB activity. Recently, we and others have shown that -GlcNAcylation affects the phosphorylation and acetylation of NF-κB subunit p65/RelA. However, the mechanism of how-GlcNAcylation activates NF-κB signaling through phosphorylation and acetylation is not fully understood. In this study, we mapped -GlcNAcylation sites of p65 at Thr-305, Ser-319, Ser-337, Thr-352, and Ser-374.-GlcNAcylation of p65 at Thr-305 and Ser-319 increased CREB-binding protein (CBP)/p300-dependent activating acetylation of p65 at Lys-310, contributing to NF-κB transcriptional activation. Moreover, elevation of -GlcNAcylation by overexpression of OGT increased the expression of p300, IKKα, and IKKβ and promoted IKK-mediated activating phosphorylation of p65 at Ser-536, contributing to NF-κB activation. In addition, we also identified phosphorylation of p65 at Thr-308, which might impair the-GlcNAcylation of p65 at Thr-305. These results indicate mechanisms through which both non-pathological and oncogenic -GlcNAcylation regulate NF-κB signaling through interplay with phosphorylation and acetylation.

Background-Receptor signaling is central to vascular endothelial function and is dysregulated in vascular diseases such as atherosclerosis and pulmonary arterial hypertension (PAH). Signaling pathways involved in endothelial function include vascular endothelial growth factor receptors (VEGFRs) and G protein-coupled receptors (GPCRs), which classically activate distinct intracellular signaling pathways and responses. The mechanisms that regulate these signaling pathways have not been fully elucidated and it is unclear what nodes for crosstalk exist between these diverse signaling pathways. For example, multifunctional β-arrestin (ARRB) adapter proteins are best known as regulators of GPCR signaling but their role at other receptors and their physiological importance in the setting of vascular disease is unclear.

Warfarin is a widely used anticoagulant with a narrow therapeutic index and large interpatient variability in the therapeutic dose. Complications from inappropriate warfarin dosing are one of the most common reasons for emergency room visits. Approximately one third of warfarin dose variability results from common genetic variants. Therefore, it is very necessary to recognize warfarin sensitivity in individuals caused by genetic variants. Based on combined polymorphisms in CYP2C9 and VKORC1 , we established a clinical classification for warfarin sensitivity. In the International Warfarin Pharmacogenetic Consortium (IWPC) with 5542 patients, we found that 95.1% of the Black in the IWPC cohort were normal warfarin responders, while 74.8% of the Asian were warfarin sensitive (P < 0.001). Moreover, we created a clinical algorithm to predict warfarin sensitivity in individual patients using logistic regression. Compared to a fixed-dose approach, the clinical algorithm provided significantly better performance. In addition, we validated the derived clinical algorithm using the external Easton cohort with 106 chronic warfarin users. The AUC was 0.836 vs. 0.867 for the Easton cohort and the IWPC cohort, respectively. With the use of this algorithm, it is very likely to facilitate patient care regarding warfarin therapy, thereby improving clinical outcomes.