Effect of aliskiren on post-discharge outcomes among diabetic and non-diabetic patients hospitalized for heart failure: insights from the ASTRONAUT trial

Aims The objective of the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) was to determine whether aliskiren, a direct renin inhibitor, would improve post-discharge outcomes in patients with hospitalization for heart failure (HHF) with reduced ejection fraction. Pre-specified subgroup analyses suggested potential heterogeneity in post-discharge outcomes with aliskiren in patients with and without baseline diabetes mellitus (DM). Methods and results ASTRONAUT included 953 patients without DM (aliskiren 489; placebo 464) and 662 patients with DM (aliskiren 319; placebo 343) (as reported by study investigators). Study endpoints included the first occurrence of cardiovascular death or HHF within 6 and 12 months, all-cause death within 6 and 12 months, and change from baseline in N-terminal pro-B-type natriuretic peptide (NT-proBNP) at 1, 6, and 12 months. Data regarding risk of hyperkalaemia, renal impairment, and hypotension, and changes in additional serum biomarkers were collected. The effect of aliskiren on cardiovascular death or HHF within 6 months (primary endpoint) did not significantly differ by baseline DM status (P = 0.08 for interaction), but reached statistical significance at 12 months (non-DM: HR: 0.80, 95% CI: 0.64-0.99; DM: HR: 1.16, 95% CI: 0.91-1.47; P = 0.03 for interaction). Risk of 12-month all-cause death with aliskiren significantly differed by the presence of baseline DM (non-DM: HR: 0.69, 95% CI: 0.50-0.94; DM: HR: 1.64, 95% CI: 1.15-2.33; P < 0.01 for interaction). Among non-diabetics, aliskiren significantly reduced NT-proBNP through 6 months and plasma troponin I and aldosterone through 12 months, as compared to placebo. Among diabetic patients, aliskiren reduced plasma troponin I and aldosterone relative to placebo through 1 month only. There was a trend towards differing risk of post-baseline potassium ≥6 mmol/L with aliskiren by underlying DM status (non-DM: HR: 1.17, 95% CI: 0.71-1.93; DM: HR: 2.39, 95% CI: 1.30-4.42; P = 0.07 for interaction). Conclusion This pre-specified subgroup analysis from the ASTRONAUT trial generates the hypothesis that the addition of aliskiren to standard HHF therapy in non-diabetic patients is generally well-tolerated and improves post-discharge outcomes and biomarker profiles. In contrast, diabetic patients receiving aliskiren appear to have worse post-discharge outcomes. Future prospective investigations are needed to confirm potential benefits of renin inhibition in a large cohort of HHF patients without D

Proteomic-Based Analysis of Hypoxia- and Physioxia-Responsive Proteins and Pathways in Diffuse Large B-Cell Lymphoma

Hypoxia is a common feature in most tumors, including hematological malignancies. There is a lack of studies on hypoxia- and physioxia-induced global proteome changes in lymphoma. Here, we sought to explore how the proteome of diffuse large B-cell lymphoma (DLBCL) changes when cells are exposed to acute hypoxic stress (1% of O-2) and physioxia (5% of O-2) for a long-time. A total of 8239 proteins were identified by LC-MS/MS, of which 718, 513, and 486 had significant changes, in abundance, in the Ri-1, U2904, and U2932 cell lines, respectively. We observed that changes in B-NHL proteome profiles induced by hypoxia and physioxia were quantitatively similar in each cell line; however, differentially abundant proteins (DAPs) were specific to a certain cell line. A significant downregulation of several ribosome proteins indicated a translational inhibition of new ribosome protein synthesis in hypoxia, what was confirmed in a pathway enrichment analysis. In addition, downregulated proteins highlighted the altered cell cycle, metabolism, and interferon signaling. As expected, the enrichment of upregulated proteins revealed terms related to metabolism, HIF1 signaling, and response to oxidative stress. In accordance to our results, physioxia induced weaker changes in the protein abundance when compared to those induced by hypoxia. Our data provide new evidence for understanding mechanisms by which DLBCL cells respond to a variable oxygen level. Furthermore, this study reveals multiple hypoxia-responsive proteins showing an altered abundance in hypoxic and physioxic DLBCL. It remains to be investigated whether changes in the proteomes of DLBCL under normoxia and physioxia have functional consequences on lymphoma development and progression

Large-Scale Proteomic Analysis of Follicular Lymphoma Reveals Extensive Remodeling of Cell Adhesion Pathway and Identifies Hub Proteins Related to the Lymphomagenesis

Simple Summary Follicular lymphoma represents the major subtype of indolent B-cell non-Hodgkin lymphomas, ranging from about 20 to 30% of all B-NHLs cases in western countries. Yet, the global proteome profile of follicular lymphoma remains largely undocumented; thus, we aimed to employ for the first time a comprehensive proteomic analysis to outline its molecular landscape. A total of 15 lymphoma fine-needle aspiration biopsy samples and 14 controls were evaluated by label-free quantitative proteomics. Among the 7673 proteins identified in our dataset, 1186 proteins were differentially expressed between lymphoma and control samples. Importantly, dysregulated proteins were enriched in biological processes such as B-cell receptor signaling pathway, cellular adhesion molecules pathway, or membrane trafficking. Additionally, we identified several novel hub proteins related to lymphomagenesis. To summarize, we have determined the molecular characteristics of follicular lymphoma and discovered proteins which may hold potential for biomarkers or therapeutic targets. Follicular lymphoma (FL) represents the major subtype of indolent B-cell non-Hodgkin lymphomas (B-NHLs) and results from the malignant transformation of mature B-cells in lymphoid organs. Although gene expression and genomic studies have identified multiple disease driving gene aberrations, only a few proteomic studies focused on the protein level. The present work aimed to examine the proteomic profiles of follicular lymphoma vs. normal B-cells obtained by fine-needle aspiration biopsy (FNAB) to gain deep insight into the most perturbed pathway of FL. The cells of interest were purified by magnetic-activated cell sorting (MACS). High-throughput proteomic profiling was performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and allowed to identify of 6724 proteins in at least 75% of each group of samples. The 'Total Protein Approach' (TPA) was applied to the absolute quantification of proteins in this study. We identified 1186 differentially abundant proteins (DAPs) between FL and control samples, causing an extensive remodeling of several molecular pathways, including the B-cell receptor signaling pathway, cellular adhesion molecules, and PPAR pathway. Additionally, the construction of protein-protein interactions networks (PPINs) and identification of hub proteins allowed us to indicate the key player proteins for FL pathology. Finally, ICAM1, CD9, and CD79B protein expression was validated in an independent cohort by flow cytometry (FCM), and the results were consistent with the mass spectrometry (MS) data

Pattern of Melanotransferrin Expression in Human Colorectal Tissues: An Immunohistochemical Study on Potential Clinical Application

Background: Our previous liquid chromatographytandem mass spectrometry (LC-MS/MS) study on colorectal cancer proteome resulted in identification of 10,000 differentially expressed proteins. We observed a significantly changed expression of 25% of all identified proteins between patient and matched adjacent normal mucosa, carcinoma and colorectal adenoma, including melanotransferrin. Herein, we consider this protein as a potential biomarker of colorectal cancer. Materials and Methods: Immunohistochemical detection of melanotransferrin was carried-out to localize its expression pattern within the colorectal tissues by tissue microarray. The diagnostic utility of melanotransferrin was evaluated in patient serum by enzyme-linked immunosorbent assay (ELISA). Results: Strong melanotransferrin expression was found to be related to clinicopathological characteristics, lymph node involvement (p=0.008), tumor localization in colon (p=0.001), presence of mucin (p<0.013) and increasing tumor grade (p<0.001). Melanotransferrin level in serum from patients with colorectal cancer was significantly higher than that in healthy controls (p<0.001). Conclusion: We provide novel evidence that melanotransferrin may be involved in transformation from benign tumor to malignancy and is a marker of an invasive tumor phenotype

Anaemia is an independent predictor of poor outcome in patients with chronic heart failure

Background: Mild anaemia frequently occurs in patients with chronic heart failure (CHF), particularly in the advanced stages of the disease. The correction of anaemia with erythropoietin is a therapeutic possibility. The aim of this study was to assess prospectively the relationship between the prevalence of anaemia (haemoglobin level≤120 g/l) and prognosis in an unselected CHF population. Methods: All consecutive patients with a diagnosis of CHF admitted to our department between January 2000 and April 2000 were considered for the present study. Those with secondary causes of anaemia were excluded. Patients were followed up until November 2001 (>18 months in all survivors), and the end-point of the study was all-cause mortality. Results: A total of 176 patients were enrolled (mean age: 63 years, New York Heart Association (NYHA) classification I/II/III/IV: 15/81/51/29; left ventricular ejection fraction (LVEF): 42%, ischaemic aetiology in 62%). In the whole population the mean haemoglobin level was 140±15 g/l. Anaemia was found in 18 (10%) patients, and was significantly more common in women than in men (18 vs. 7%, respectively, P=0.02) and in those with most severe CHF symptoms (frequency in NYHA I/II/III/IV: 0/9/10/21%, respectively; NYHA IV vs. I-III, P=0.03), but not related to the other clinical indices. Univariate analysis revealed NYHA class III-IV (hazard ratio 3.8, 95% CI: 1.6-8.9, P=0.003), low LVEF <35% (hazard ratio 2.3, 95% CI: 1.0-4.9, P=0.04) and anaemia (hazard ratio 2.9, 95% CI: 1.2-7.2, P=0.02) as predictors of 18-month mortality. In multivariate analysis, anaemia remained an independent predictor of death when adjusted for NYHA class and LVEF (hazard ratio: 2.6, 95% CI: 1.0-6.5, P=0.04). In anaemic patients, 18-month survival was 67% (95% CI: 45-89%) compared to 87% (81-92%) in patients with a normal haemoglobin level (P=0.016). Conclusions: Mild anaemia is a significant and independent predictor of poor outcome in unselected patients with CHF. Correction of low haemoglobin level may become an interesting therapeutic option for CHF patients

Effect of darbepoetin alfa on exercise tolerance in anemic patients with symptomatic chronic heart failure: a randomized, double-blind, placebo-controlled trial

ObjectivesThis study sought to investigate whether darbepoetin alfa, an erythropoiesis-stimulating protein (ESP), improves exercise capacity in patients with symptomatic chronic heart failure (CHF) and anemia.BackgroundAnemia is common in patients with CHF.MethodsIn a multicenter, randomized, double-blind, placebo-controlled study, CHF patients with anemia (hemoglobin ≥9.0 to ≤12.0 g/dl) received subcutaneous placebo (n = 22) or darbepoetin alfa (n = 19) at a starting dose of 0.75 μg/kg every 2 weeks for 26 weeks. The primary end point was change in exercise tolerance from baseline to week 27 as measured by peak oxygen uptake (ml/min/kg body weight). Other end points included changes in absolute peak Vo2(ml/min), exercise duration, and health-related quality of life.ResultsDifferences (95% confidence interval) in mean changes from baseline to week 27 between treatment groups were 1.5 g/dl (0.5 to 2.4) for hemoglobin concentration (p = 0.005), 0.5 ml/kg/min (−0.7 to 1.7) for peak Vo2(p = 0.40), 45 ml/min (−35 to 127) for absolute peak Vo2(p = 0.27), and 108 s (−11 to 228) for exercise duration (p = 0.075). Patients receiving darbepoetin alfa compared with placebo had an improvement in self-reported Patient’s Global Assessment of Change (79% vs. 41%, p = 0.01) but no significant differences in the Kansas City Cardiomyopathy and Minnesota Living with Heart Failure Questionnaire scores. Darbepoetin alfa was well tolerated.ConclusionsIn patients with symptomatic CHF and anemia, darbepoetin alfa increased and maintained hemoglobin concentrations and improved health-related quality of life. A trend toward increased exercise time but not peak Vo2was observed. (Impact of Darbepoetin Alfa on Exercise Tolerance and Left Ventricular Structure in Subjects With Symptomatic Congestive Heart Failure (CHF) and Anemia; http://clinicaltrials.gov/ct/show/NCT00117234?order = 1; NCT00117234)