Evaluation of matrix metalloproteinase 7 in plasma and pancreatic juice as a biomarker for pancreatic cancer

Differentiating between periampullary carcinoma and chronic pancreatitis with an inflammatory mass is difficult. Consequently, 6% to 9% of pancreatic resections for suspected carcinoma are done inappropriately for chronic pancreatitis. Here, we test if matrix metalloproteinase 7 (MMP-7), a secreted protease frequently expressed in pancreatic carcinoma, can be measured in plasma, pancreatic, and duodenal juice, and if it can distinguish between periampullary carcinoma and chronic pancreatitis. Ninety-four patients who underwent pancreatic surgery for a (peri)pancreatic neoplasm (n = 63) or chronic pancreatitis (n = 31) were analyzed. Median plasma MMP-7 levels were significantly higher in carcinoma (1.95 ng/mL; interquartile range, 0.81-3.22 ng/mL) compared with chronic pancreatitis and benign disease (0.83 ng/mL; interquartile range, 0.25-1.21 ng/mL; P < 0.01). MMP-7 levels in pancreatic juice were higher, although not significantly, in carcinoma (62 ng/mg protein; interquartile range, 18-241 ng/mg protein) compared with chronic pancreatitis and benign disease (23 ng/mg protein; interquartile range, 8.5-99 ng/mg protein; P = 0.17). MMP-7 levels in duodenal juice were universally low. At an arbitrary cutoff of 1.5 ng/mL in plasma, positive and negative predictive values were 83% and 57%, respectively, values comparable to those of today's most common pancreatic tumor marker, carbohydrate antigen 19-9 (CA19-9; 83% and 53%, respectively). Positive and negative likelihood ratios for plasma MMP-7 were 3.35 and 0.52, respectively. The area under the receiver operating characteristic curve for MMP-7 was 0.73 (95% confidence interval, 0.63-0.84) and for CA19-9, 0.75 (95% confidence interval, 0.64-0.85). Combined MMP-7 and CA19-9 assessment gave a positive predictive value of 100%. Thus, plasma MMP-7 levels discriminated between patients with carcinoma and those with chronic pancreatitis or benign disease. The diagnostic accuracy of plasma MMP-7 alone is not sufficient to determine treatment strategy in patients with a periampullary mass, but combined evaluation of plasma MMP-7 with CA19-9 and other markers may be clinically usefu

Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity

Oligodendrocytes, the myelin-forming glial cells of the central nervous system, maintain long-term axonal integrity. However, the underlying support mechanisms are not understood. Here we identify a metabolic component of axon–glia interactions by generating conditional Cox10 (protoheme IX farnesyltransferase) mutant mice, in which oligodendrocytes and Schwann cells fail to assemble stable mitochondrial cytochrome c oxidase (COX, also known as mitochondrial complex IV). In the peripheral nervous system, Cox10 conditional mutants exhibit severe neuropathy with dysmyelination, abnormal Remak bundles, muscle atrophy and paralysis. Notably, perturbing mitochondrial respiration did not cause glial cell death. In the adult central nervous system, we found no signs of demyelination, axonal degeneration or secondary inflammation. Unlike cultured oligodendrocytes, which are sensitive to COX inhibitors, post-myelination oligodendrocytes survive well in the absence of COX activity. More importantly, by in vivo magnetic resonance spectroscopy, brain lactate concentrations in mutants were increased compared with controls, but were detectable only in mice exposed to volatile anaesthetics. This indicates that aerobic glycolysis products derived from oligodendrocytes are rapidly metabolized within white matter tracts. Because myelinated axons can use lactate when energy-deprived, our findings suggest a model in which axon–glia metabolic coupling serves a physiological function