Key words: omega-3 fatty acid; fish oil; soybean oil; immunonutrition; inflammation; acute-phase response; parenteral nutritionEpidemiologic studies have indicated that high intake of saturated fat and/or animal fat increases the risk of colon and breast cancers. 1 Further laboratory experiments showed reduced risk of colon carcinogenesis after omega-3 PUFA supplementation. In a phase II clinical trial of patients with colonic polyps, dietary FO supplements inhibited cell proliferation. Mechanisms accounting for the antitumour effects in animal models are reduced levels of PGE 2 and inducible NO synthase as well as increased lipid peroxidation or translation inhibition and subsequent cell-cycle arrest. 2 In patients with advanced cancer, weight loss is a major cause of morbidity and mortality. While it is possible to increase energy and protein intake on the enteral or parenteral route, this appears to have little impact on patients' progressive weight loss. 3 Clinical studies in the last few years have provided evidence for beneficial effects of FO administration in cancer cachexia 4 and during radioand chemotherapy. 5 Omega-3 EPA is capable of downregulating the production and action of a number of mediators of cachexia, e.g., IL-1, IL-6, TNF-␣ and proteolysis-inducing factor. 6,7 However, SO (omega-6) emulsions appear to impede tumoricidal activity compared to EPA. 8 Beyond the beneficial effects of long-term intake of omega-3 PUFA in cancer patients, we likewise observed rapid-onset effects in previous experimental studies. Compared to SO emulsion, we found decreased inflammatory pulmonary vascular response in isolated rabbit lungs after omega-3 PUFA infusion. 9 Lung edema formation was blunted because proinflammatory 4-series leukotrienes were shifted to less inflammatory 5-series leukotrienes and, consequently, pulmonary vascular resistance and permeability were reduced. 9 These rapid effects of omega-3 PUFA were confirmed in patients with acute respiratory distress syndrome, showing improved pulmonary function within a few days on an omega-3 fatty acid-enriched diet. 10 The background of these beneficial effects was reduced release of proinflammatory AA derivatives. 11 Following major abdominal nonliver surgery, increases in ALAT were observed and correlated with ultrastructural damage of the liver. 12 In the postoperative course after major abdominal surgery, intact liver function is crucial not only for energy balance (glucose and lactate metabolism) but also for providing several humoral factors, which induce, support and ultimately terminate regenerative mechanisms. This APR of the liver sets off immediately after the (surgical) trauma and upregulates coagulation factors and proteinase inhibitors for wound healing and complement components and opsonins (e.g., CRP) for early bactericidal activity at the site of trauma. 13
We propose incorporation of metabolome data into the diagnostics algorithm in PPGLs to guide genetic testing and variant interpretation and to help identify rare cases with PV in FH and IDHx.
Pheochromocytomas and paragangliomas (PPGLs) are catecholamine-producing chromaffin cell tumors with diverse phenotypic features reflecting mutations in numerous genes, including MYC-associated factor X (MAX). To explore whether phenotypic differences among PPGLs reflect a MAX-mediated mechanism and opposing influences of hypoxia-inducible factor (HIF)s HIF2a and HIF1a, we combined observational investigations in PPGLs and gene-manipulation studies in two pheochromocytoma cell lines. Among PPGLs from 140 patients, tumors due to MAX mutations were characterized by gene expression profiles and intermediate phenotypic features that distinguished these tumors from other PPGLs, all of which fell into two expression clusters: one cluster with low expression of HIF2a and mature phenotypic features and the other with high expression of HIF2a and immature phenotypic features due to mutations stabilizing HIFs. Max-mutated tumors distributed to a distinct subcluster of the former group. In cell lines lacking Max, re-expression of the gene resulted in maturation of phenotypic features and decreased cell cycle progression. In cell lines lacking Hif2a, overexpression of the gene led to immature phenotypic features, failure of dexamethasone to induce differentiation and increased proliferation. HIF1a had opposing actions to HIF2a in both cell lines, supporting evolving evidence of their differential actions on tumorigenic processes via a MYC/MAX-related pathway. Requirement of a fully functional MYC/MAX complex to facilitate differentiation explains the intermediate phenotypic features in tumors due to MAX mutations. Overexpression of HIF2a in chromaffin cell tumors due to mutations affecting HIF stabilization explains their proliferative features and why the tumors fail to differentiate even when exposed locally to adrenal steroids.
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