Dermcidin expression in hepatic cells improves survival without N-glycosylation, but requires asparagine residues

Proteolysis-inducing factor, a cachexia-inducing tumour product, is an N-glycosylated peptide with homology to the unglycosylated neuronal survival peptide Y-P30 and a predicted product of the dermcidin gene, a pro-survival oncogene in breast cancer. We aimed to investigate whether dermcidin is pro-survival in liver cells, in which proteolysis-inducing factor induces catabolism, and to determine the role of potentially glycosylated asparagine residues in this function. Reverse cloning of proteolysis-inducing factor demonstrated ∼100% homology with the dermcidin cDNA. This cDNA was cloned into pcDNA3.1+ and both asparagine residues removed using site-directed mutagenesis. In vitro translation demonstrated signal peptide production, but no difference in molecular weight between the products of native and mutant vectors. Immunocytochemistry of HuH7 cells transiently transfected with V5-His-tagged dermcidin confirmed targeting to the secretory pathway. Stable transfection conferred protection against oxidative stress. This was abrogated by mutation of both asparagines in combination, but not by mutation of either asparagine alone. These findings suggest that dermcidin may function as an oncogene in hepatic as well as breast cells. Glycosylation does not appear to be required, but the importance of asparagine residues suggests a role for the proteolysis-inducing factor core peptide domain

Plasma and neutrophil fatty acid composition in advanced cancer patients and response to fish oil supplementation

Metabolic demand and altered supply of essential nutrients is poorly characterised in patients with advanced cancer. A possible imbalance or deficiency of essential fatty acids is suggested by reported beneficial effects of fish oil supplementation. To assess fatty acid status (composition of plasma and neutrophil phospholipids) in advanced cancer patients before and after 14 days of supplementation (12±1 g day−1) with fish (eicosapentaenoic acid, and docosahexaenoic acid) or placebo (olive) oil. Blood was drawn from cancer patients experiencing weight loss of >5% body weight (n=23). Fatty acid composition of plasma phospholipids and the major phospholipid classes of isolated neutrophils were determined using gas liquid chromatography. At baseline, patients with advanced cancer exhibited low levels (<30% of normal values) of plasma phospholipids and constituent fatty acids and elevated 20 : 4 n-6 content in neutrophil phospholipids. High n-6/n-3 fatty acid ratios in neutrophil and plasma phospholipids were inversely related to body mass index. Fish oil supplementation raised eicosapentaenoic acid and docosahexaenoic acid content in plasma but not neutrophil phospholipids. 20 : 4 n-6 content was reduced in neutrophil PI following supplementation with fish oil. Change in body weight during the supplementation period related directly to increases in eicosapentaenoic acid in plasma. Advanced cancer patients have alterations in lipid metabolism potentially due to nutritional status and/or chemotherapy. Potential obstacles in fatty acid utilisation must be addressed in future trials aiming to improve outcomes using nutritional intervention with fish oils

Use of Renal Replacement Therapy May Influence Graft Outcomes following Liver Transplantation for Acute Liver Failure:A Propensity-Score Matched Population-Based Retrospective Cohort Study

INTRODUCTION:Acute kidney injury is associated with a poor prognosis in acute liver failure but little is known of outcomes in patients undergoing transplantation for acute liver failure who require renal replacement therapy. METHODS:A retrospective analysis of the United Kingdom Transplant Registry was performed (1 January 2001-31 December 2011) with patient and graft survival determined using Kaplan-Meier methods. Cox proportional hazards models were used together with propensity-score based full matching on renal replacement therapy use. RESULTS:Three-year patient and graft survival for patients receiving renal replacement therapy were 77.7% and 72.6% compared with 85.1% and 79.4% for those not requiring renal replacement therapy (P<0.001 and P = 0.009 respectively, n = 725). In a Cox proportional hazards model, renal replacement therapy was a predictor of both patient death (hazard ratio (HR) 1.59, 95% CI 1.01-2.50, P = 0.044) but not graft loss (HR 1.39, 95% CI 0.92-2.10, P = 0.114). In groups fully matched on baseline covariates, those not receiving renal replacement therapy with a serum creatinine greater than 175 μmol/L had a significantly worse risk of graft failure than those receiving renal replacement therapy. CONCLUSION:In patients being transplanted for acute liver failure, use of renal replacement therapy is a strong predictor of patient death and graft loss. Those not receiving renal replacement therapy with an elevated serum creatinine may be at greater risk of early graft failure than those receiving renal replacement therapy. A low threshold for instituting renal replacement therapy may therefore be beneficial

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

Perioperative events influence cancer recurrence risk after surgery.

Surgery is a mainstay treatment for patients with solid tumours. However, despite surgical resection with a curative intent and numerous advances in the effectiveness of (neo)adjuvant therapies, metastatic disease remains common and carries a high risk of mortality. The biological perturbations that accompany the surgical stress response and the pharmacological effects of anaesthetic drugs, paradoxically, might also promote disease recurrence or the progression of metastatic disease. When cancer cells persist after surgery, either locally or at undiagnosed distant sites, neuroendocrine, immune, and metabolic pathways activated in response to surgery and/or anaesthesia might promote their survival and proliferation. A consequence of this effect is that minimal residual disease might then escape equilibrium and progress to metastatic disease. Herein, we discuss the most promising proposals for the refinement of perioperative care that might address these challenges. We outline the rationale and early evidence for the adaptation of anaesthetic techniques and the strategic use of anti-adrenergic, anti-inflammatory, and/or antithrombotic therapies. Many of these strategies are currently under evaluation in large-cohort trials and hold promise as affordable, readily available interventions that will improve the postoperative recurrence-free survival of patients with cancer

EMISSION AND ABSORPTION OF PHONONS BY THE 2-DIMENSIONAL ELECTRON-GAS IN A GAAS MODFET STRUCTURE

We have observed both emission and absorption of phonons by the two-dimensional electron gas in a GaAs modulation-doped field effect transistor (MODFET). For the first time in this system directly emitted LA phonons were seen, in addition to the TA products of LO down-conversion. The angular dependence of the LA feature suggested that its origin was piezoelectric not deformation potential coupling. Direct absorption of phonons by the 2DEG was found to have a response time approximately ns, so that the transmission stop bands of a superlattice phonon filter could be used as a dispersive spectrometer