Identification of plasma lipid biomarkers for prostate cancer by lipidomics and bioinformatics

Background: Lipids have critical functions in cellular energy storage, structure and signaling. Many individual lipid molecules have been associated with the evolution of prostate cancer; however, none of them has been approved to be used as a biomarker. The aim of this study is to identify lipid molecules from hundreds plasma apparent lipid species as biomarkers for diagnosis of prostate cancer. Methodology/Principal Findings: Using lipidomics, lipid profiling of 390 individual apparent lipid species was performed on 141 plasma samples from 105 patients with prostate cancer and 36 male controls. High throughput data generated from lipidomics were analyzed using bioinformatic and statistical methods. From 390 apparent lipid species, 35 species were demonstrated to have potential in differentiation of prostate cancer. Within the 35 species, 12 were identified as individual plasma lipid biomarkers for diagnosis of prostate cancer with a sensitivity above 80%, specificity above 50% and accuracy above 80%. Using top 15 of 35 potential biomarkers together increased predictive power dramatically in diagnosis of prostate cancer with a sensitivity of 93.6%, specificity of 90.1% and accuracy of 97.3%. Principal component analysis (PCA) and hierarchical clustering analysis (HCA) demonstrated that patient and control populations were visually separated by identified lipid biomarkers. RandomForest and 10-fold cross validation analyses demonstrated that the identified lipid biomarkers were able to predict unknown populations accurately, and this was not influenced by patient's age and race. Three out of 13 lipid classes, phosphatidylethanolamine (PE), ether-linked phosphatidylethanolamine (ePE) and ether-linked phosphatidylcholine (ePC) could be considered as biomarkers in diagnosis of prostate cancer. Conclusions/Significance: Using lipidomics and bioinformatic and statistical methods, we have identified a few out of hundreds plasma apparent lipid molecular species as biomarkers for diagnosis of prostate cancer with a high sensitivity, specificity and accuracy

Is the Peritoneum a Significant Transport Barrier in Peritoneal Dialysis?

Objectives The anatomic peritoneum is often considered equivalent to the barrier between the dialysate and the blood, and is also called “the peritoneal membrane.” Our hypothesis is that the normal peritoneum is not a significant barrier to solute or water flow. The goal of this study was to explore the effects of alteration of the anatomic peritoneum on the transperitoneal transport of water and solute. Design In vivo transport experiments were carried out in control and treated rats. Treatments consisted of frequent mixing of the peritoneal solution versus no mixing, drying the peritoneum prior to the experiment, or selective removal of the entire peritoneum. Transport experiments were carried out via a plastic chamber affixed to the parietal peritoneum. After measuring solute transport or osmotically induced filtration, the tissue underlying the chamber was collected and stained for histology. Results Mixing the chamber solution every 5 minutes versus no mixing over 90 minutes did not result in a significant change in the mass transfer coefficient for mannitol (MTCmannitol, n = 14, p &gt; 0.25). Drying the peritoneum prior to the transport experiment did not significantly alter the MTC of albumin or mannitol ( n = 17, p &gt; 0.6; n = 19, p &gt; 0.1, respectively). Manual drying did not remove or significantly alter the apparent peritoneal coating on the surface of the mesothelium. Removal of the entire peritoneum did not significantly alter the osmotically induced volume flux from the tissue, nor did it change the MTCmannitol ( n = 9, p &gt; 0.9; n = 9, p &gt; 0.4, respectively). Conclusions Mixing of the solution directly over the tissue, manual drying of the peritoneum, or removal of the entire peritoneum does not result in significant alterations in transport. We conclude that the anatomic peritoneum is relatively unimportant as a physical transport barrier in peritoneal dialysis. </jats:sec

Cardiovascular and renal responses to a high-fat diet in Osborne-Mendel rats

This study examined the cardiovascular, renal, and hormonal responses of dietary-induced obesity in Osborne-Mendel (OM) rats. Male OM rats were fed either a low (LF; n = 10)- or high-fat (HF; n = 11) diet for 17 wk. During week 15 of the study, arterial pressure was measured directly, 24 h/day, from chronically indwelling catheters. Body and kidney weights were 46 ± 5 and 33 ± 5% greater, respectively, in rats fed HF vs. LF diet. Left and right ventricular weights were also greater in rats fed HF diet (21 ± 7 and 36 ± 6%, respectively). Direct measurement of arterial pressure revealed only a slight increase in mean arterial pressure (88 ± 1 in rats fed HF diet vs. 85 ± 1 mmHg in rats fed LF diet), whereas there was no difference in resting heart rate between the two groups. Consumption of HF diet was also associated with a 3.5-fold increase in plasma insulin, a 16 ± 4% higher blood glucose, and a 40 ± 6% reduction in plasma renin activity compared with LF-fed rats. Thus feeding OM rats HF diet led to obesity, cardiac and renal hypertrophy, and hyperinsulinemia but only a slight increase in mean arterial pressure. </jats:p

Alveolar Hemorrhage and Renal Microangiopathy in Systemic Lupus Erythematosus

AbstractContext.—Acute alveolar hemorrhage in systemic lupus erythematosus usually occurs as a pulmonary-renal syndrome. In most cases, the lungs show “bland” alveolar hemorrhage with little or no inflammation. Whether this alveolar injury is similar to the better-defined noninflammatory renal lupus vasculopathy is unresolved.Objectives.—To investigate the relationships and the mechanisms of small vascular injury in the lung and kidney of 2 lupus patients who died of diffuse AH.Methods.—We investigated the relationship of AH to immune complex deposition in the lungs of 6 patients with systemic lupus erythematosus and correlated the findings with glomerular and vascular disease in the kidney. Lung and kidney were studied by light, immunofluorescence, and/or electron microscopy; apoptosis was investigated using in situ nick-end labeling.Results.—The clinical course of 2 patients was complicated by alveolar hemorrhage, and the lungs of these patients revealed alveolar wall immune complex deposits and bland alveolar hemorrhage. These 2 patients had World Health Organization class IV lupus nephritis and renal arterioles involved by a noninflammatory lupus vasculopathy. Apoptosis was identified in the lupus microangiopathy and in alveolar walls within areas of alveolar hemorrhage. Alveolar wall immune complex deposits were not found in 4 patients who had a lupus glomerulonephritis but did not have renal lupus vasculopathy. Apoptosis was not seen in renal arterioles or lungs of these 4 cases, except in areas of diffuse alveolar damage or herpesvirus pneumonia.Conclusions.—Our findings indicate that alveolar hemorrhage in systemic lupus erythematosus, characterized by bland alveolar wall changes, is pathogenetically similar to the lupus microangiopathy of the kidney. In both lung and kidney, the pathogenesis of the microvascular injury appears to be related to immune complex deposition and the induction of apoptosis.</jats:p

ANG II-related myocardial damage: role of cardiac sympathetic catecholamines and β-receptor regulation

The objectives of this study were 1) to determine whether ANG II-induced myocardial damage (ANG Dam) is mediated via the β1-adrenergic receptor, 2) to elucidate whether adrenal medulla or cardiac sympathetic neuron catecholamines are responsible for ANG Dam, and 3) to determine whether the lack of damage after 3 days of elevated ANG II levels is due to β1-receptor downregulation. To this end, ANG II was administered to rats 1) that were treated with a β-receptor blocker, 2) after adrenal medullectomy and/or cardiac sympathectomy, and 3) for 3 or 8 days. ANG II caused both myocyte necrosis and coronary vascular damage after adrenal medullectomy but not after cardiac sympathectomy. There was a 38 and 55% decrease in β-receptor density after 3 and 8 days, respectively, of ANG II infusion, and an upregulation to control levels 5 days after a 3-day ANG II infusion was stopped. We conclude that cardiac sympathetic neuron catecholamines are responsible for ANG Dam and that the acute nature of this damage is associated with a downregulation of β1-adrenergic receptors.</jats:p

Cytochrome P450 2B1 mediates oxidant injury in puromycin-induced nephrotic syndrome

Cytochrome P450 2B1 mediates oxidant injury in puromycin-induced nephrotic syndrome.BackgroundReactive oxygen metabolites (ROM) are important mediators of puromycin aminonucleoside (PAN) induced minimal change nephrotic syndrome (NS) in rats. We have recently shown that cytochrome P450 (CYP) is a significant source of catalytic iron in this model of glomerular injury. The current study was designed to identify the CYP isozyme(s) in the rat glomeruli and explore the role of the specific isozyme(s) in PAN-induced minimal change NS.MethodsNS was induced in rats by a single intravenous injection of PAN. Animals were sacrificed at different time points for variety of biochemical assays including Western blot, immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR). Ultrastructural histochemistry was utilized to study hydrogen peroxide (H2O2) generation in the kidney.ResultsSeveral CYP isozymes were tested and CYP2B1 was localized exclusively in the rat glomeruli but not in the tubules. Treatment with PAN resulted in the generation of H2O2 in the glomerular basement membrane with significant loss of CYP2B1 content accompanied by a marked increase in the catalytic iron. CYP2B1 inhibitors cimetidine and piperine significantly reduced H2O2 generation, and prevented the loss of CYP2B1 content and the increase in the catalytic iron. CYP2B1 inhibitors also provided significant protection against PAN induced proteinuria. The induction of heme oxygenase and ferritin also was observed in the glomeruli in PAN-treated rats. Both cimetidine and piperine reduced the up-regulation of these proteins.ConclusionOur data indicate that CYP2B1 plays an important role in PAN induced NS by serving as a site for ROM generation and a significant source of catalytic iron