Patients with high-risk resected colon cancer obtain benefit from FU-based therapy across subsets of age, sex, location, T stage, nodal status, and grade. Model estimates of survival stratified by T stage, nodal status, grade, and age are available at http://www.mayoclinic.com/calcs. This information may improve patients' and physicians' understanding of the potential benefits of adjuvant therapy.

Background-Insulin resistance predisposes to cardiovascular disease and shortens human lifespan. We therefore tested the hypothesis that a rise in insulin resistance in concert with gain in body mass is associated with accelerated white blood cell telomere attrition. Methods and Results-We measured white blood cell telomere dynamics and age-related changes in insulin resistance and body mass index in young adults of the Bogalusa Heart Study.

To examine whether the hexosamine biosynthetic pathway might play a role in fat-induced insulin resistance, we monitored the effects of prolonged elevations in FFA availability both on skeletal muscle levels of UDP-N -acetyl-hexosamines and on peripheral glucose disposal during 7-h euglycemichyperinsulinemic ( ‫ف‬ 500 U/ml) clamp studies. When the insulin-induced decrease in the plasma FFA levels (to ‫ف‬ 0.3 mM) was prevented by infusion of a lipid emulsion in 15 conscious rats (plasma FFA ‫ف‬ 1.4 mM), glucose uptake (5-7 h ϭ 32.5 Ϯ 1.7 vs 0-2 h ϭ 45.2 Ϯ 2.8 mg/kg per min; P Ͻ 0.01) and glycogen synthesis ( P Ͻ 0.01) were markedly decreased. During lipid infusion, muscle UDP-N -acetyl-glucosamine (UDP-GlcNAc) increased by twofold (to 53.4 Ϯ 1.1 at 3 h and to 55.5 Ϯ 1.1 nmol/gram at 7 h vs 20.4 Ϯ 1.7 at 0 h, P Ͻ 0.01) while glucose-6-phosphate (Glc-6-P) levels were increased at 3 h (475 Ϯ 49 nmol/gram) and decreased at 7 h (133 Ϯ 7 vs 337 Ϯ 28 nmol/gram at 0 h, P Ͻ 0.01).To discern whether such an increase in the skeletal muscle UDP-GlcNAc concentration could account for the development of insulin resistance, we generated similar increases in muscle UDP-GlcNAc using three alternate experimental approaches. Euglycemic clamps were performed after prolonged hyperglycemia (18 mM, n ϭ 10), or increased availability of either glucosamine (3 mol/kg per min; n ϭ 10) or uridine (30 mol/kg per min; n ϭ 4). These conditions all resulted in very similar increases in the skeletal muscle UDP-GlcNAc (to ‫ف‬ 55 nmol/gram) and markedly impaired glucose uptake and glycogen synthesis.Thus, fat-induced insulin resistance is associated with: ( a ) decreased skeletal muscle Glc-6-P levels indicating defective transport/phosphorylation of glucose; ( b ) marked accumulation of the endproducts of the hexosamine biosynthetic pathway preceding the onset of insulin resistance. Most important, the same degree of insulin resistance can be reproduced in the absence of increased FFA availability by a similar increase in skeletal muscle UDP-N -acetyl-hexosamines.

The emergence of castrate-resistant prostate cancer (CRPC) contributes to the high mortality of patients diagnosed with prostate cancer (PCa), which in part could be attributed to the existence and the emergence of cancer stem cells (CSCs). Recent studies have shown that deregulated expression of microRNAs (miRNAs) contributes to the initiation and progression of PCa. Among several known miRNAs, let-7 family appears to play a key role in the recurrence and progression of PCa by regulating CSCs; however, the mechanism by which let-7 family contributes to PCa aggressiveness is unclear. Enhancer of Zeste homolog 2 (EZH2), a putative target of let-7 family, was demonstrated to control stem cell function. In this study, we found loss of let-7 family with corresponding over-expression of EZH2 in human PCa tissue specimens, especially in higher Gleason grade tumors. Overexpression of let-7 by transfection of let-7 precursors decreased EZH2 expression and repressed clonogenic ability and sphere-forming capacity of PCa cells, which was consistent with inhibition of EZH2 3′UTR luciferase activity. We also found that the treatment of PCa cells with BR-DIM (formulated DIM: 3,3′-diindolylmethane by Bio Response, Boulder, CO, abbreviated as BR-DIM) up-regulated let-7 and down-regulated EZH2 expression, consistent with inhibition of self-renewal and clonogenic capacity. Moreover, BR-DIM intervention in our on-going phase II clinical trial in patients prior to radical prostatectomy showed upregulation of let-7 consistent with down-regulation of EZH2 expression in PCa tissue specimens after BR-DIM intervention. These results suggest that the loss of let-7 mediated increased expression of EZH2 contributes to PCa aggressiveness, which could be attenuated by BR-DIM treatment, and thus BR-DIM is likely to have clinical impact.