Plasma sRAGE is independently associated with increased mortality in ARDS: a meta-analysis of individual patient data

Purpose

The soluble receptor for advanced glycation end-products (sRAGE) is a marker of lung epithelial injury and alveolar fluid clearance (AFC), with promising values for assessing prognosis and lung injury severity in acute respiratory distress syndrome (ARDS). Because AFC is impaired in most patients with ARDS and is associated with higher mortality, we hypothesized that baseline plasma sRAGE would predict mortality, independently of two key mediators of ventilator-induced lung injury.

Methods

We conducted a meta-analysis of individual data from 746 patients enrolled in eight prospective randomized and observational studies in which plasma sRAGE was measured in ARDS articles published through March 2016. The primary outcome was 90-day mortality. Using multivariate and mediation analyses, we tested the association between baseline plasma sRAGE and mortality, independently of driving pressure and tidal volume.

Results

Higher baseline plasma sRAGE [odds ratio (OR) for each one-log increment, 1.18; 95% confidence interval (CI) 1.01–1.38; P?=?0.04], driving pressure (OR for each one-point increment, 1.04; 95% CI 1.02–1.07; P?=?0.002), and tidal volume (OR for each one-log increment, 1.98; 95% CI 1.07–3.64; P?=?0.03) were independently associated with higher 90-day mortality in multivariate analysis. Baseline plasma sRAGE mediated a small fraction of the effect of higher ΔP on mortality but not that of higher V_T.

Conclusions

Higher baseline plasma sRAGE was associated with higher 90-day mortality in patients with ARDS, independently of driving pressure and tidal volume, thus reinforcing the likely contribution of alveolar epithelial injury as an important prognostic factor in ARDS. Registration: PROSPERO (ID: CRD42018100241).

     

Immune reconstitution and associated infections following axicabtagene ciloleucel in relapsed or refractory large B-cell lymphoma

CD19 chimeric antigen receptor T (CAR T)-cell therapy with axicabtagene ciloleucel (axi-cel) for relapsed or refractory (R/R) large B-cell lymphoma (LBCL) may lead to durable remissions, however, prolonged cytopenias and infections may occur. In this single center retrospective study of 85 patients, we characterized immune reconstitution and infections for patients remaining in remission after axi-cel for LBCL. Prolonged cytopenias (those occurring at or after day 30 following infusion) were common with ≥grade 3 neutropenia seen in 21 of 70 (30%) patients at day 30 and persisting in 3 of 31 (9.7%) patients at 1 year. B cells were undetectable in 30 of 34 (88.2%) patients at day 30, but were detected in 11 of 19 (57.9%) at 1 year. Median immunoglobulin G levels levels reached a nadir at day 180. By contrast, CD4 T cells decreased from baseline and were persistently low with a median CD4 count of 155 cells/mL at 1 year after axi-cel (n=19, range: 33– 269). In total, 23 of 85 (27.1%) patients received intravenous immunoglobulins after axi-cel, and 34 of 85 (40%) received granulocyte-colony stimulating factor. Infections in the first 30 days occurred in 31 of 85 (36.5%) patients, of which 11 of 85 (12.9%) required intravenous antibiotics or hospitalization (“severe”) and were associated with cytokine release syndrome, neurotoxicity, tocilizumab use, corticosteroid use, and bridging therapy on univariate analyses. After day 30, seven severe infections occurred, with no late deaths due to infection. Prolonged cytopenias are common following axi-cel therapy for LBCL and typically recover with time. Most patients experience profound and prolonged CD4 T-cell immunosuppression without severe infection.     

A subset of anti-rotavirus antibodies directed against the viral protein VP7 predicts the onset of celiac disease and induces typical features of the disease in the intestinal epithelial cell line T84

Celiac disease (CD) is an autoimmune disorder of the small intestine triggered by environmental factors in genetically predisposed individuals. A strong association between type 1 diabetes (T1DM) and CD has been reported. We have previously shown that rotavirus infection may be involved in the pathogenesis of CD through a mechanism of molecular mimicry. Indeed, we identified a subset of anti-transglutaminase IgA antibodies that recognize the rotavirus viral protein VP7. In this study, we aimed at evaluating whether such antibodies may predict the onset of CD in children affected by T1DM. Moreover, to further analyze the link between rotavirus infection and pathogenesis of CD, we analyzed the effect of anti-rotavirus VP7 antibodies on T84 intestinal epithelial cells using the gene-array technique, complemented by the analysis of molecules secreted in the supernatant of stimulated cells. We found that anti-rotavirus VP7 antibodies are present in the vast majority (81 %) of T1DM-CD tested sera, but are detectable also in a fraction (27 %) of T1DM children without CD. Moreover, we found that anti-rotavirus VP7 antibodies are present before the CD onset, preceding the detection of anti-tTG and anti-endomysium antibodies. The gene-array analysis showed that purified anti-rotavirus VP7 antibodies modulate genes that are involved in apoptosis, inflammation, and alteration of the epithelial barrier integrity in intestinal epithelial cells, all typical features of CD. Taken together, these new data further support the involvement of rotavirus infection in the pathogenesis of CD and suggest a predictive role of anti-rotavirus VP7 antibodies.     

Long pentraxin‐3 as an epithelial–stromal fibroblast growth factor‐targeting inhibitor in prostate cancer

Fibroblast growth factors (FGFs) exert autocrine/paracrine functions in prostate cancer by stimulating angiogenesis and tumour growth. Here dihydrotestosterone (DHT) up‐regulates FGF2 and FGF8b production in murine TRAMP‐C2 prostate cancer cells, activating a FGF‐dependent autocrine loop of stimulation. The soluble pattern recognition receptor long pentraxin‐3 (PTX3) acts as a natural FGF antagonist that binds FGF2 and FGF8b via its N‐terminal domain. We demonstrate that recombinant PTX3 protein and the PTX3‐derived pentapeptide Ac‐ARPCA‐NH₂ abolish the mitogenic response of murine TRAMP‐C2 cells and human LNCaP prostate cancer cells to DHT and FGFs. Also, PTX3 hampers the angiogenic activity of DHT‐activated TRAMP‐C2 cells on the chick embryo chorioallantoic membrane (CAM). Accordingly, human PTX3 overexpression inhibits the mitogenic activity exerted by DHT or FGFs on hPTX3_TRAMP‐C2 cell transfectants and their angiogenic activity. Also, hPTX3_TRAMP‐C2 cells show a dramatic decrease of their angiogenic and tumourigenic potential when grafted in syngeneic or immunodeficient athymic male mice. A similar inhibitory effect is observed when TRAMP‐C2 cells overexpress only the FGF‐binding N‐terminal PTX3 domain. In keeping with the anti‐tumour activity of PTX3 in experimental prostate cancer, immunohistochemical analysis of prostate needle biopsies from primary prostate adenocarcinoma patients shows that parenchymal PTX3 expression, abundant in basal cells of normal glands, is lost in high‐grade prostatic intraepithelial neoplasia and in invasive tumour areas. These results identify PTX3 as a potent FGF antagonist endowed with anti‐angiogenic and anti‐neoplastic activity in prostate cancer. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Development of a hollow fibre-based renal module for active transport studies

Journal of Artificial Organs - Understanding the active transport of substrates by the kidney in the renal proximal convoluted tubule is crucial for drug development and for studying kidney...