scholarly journals Urinary Neuropilin-1: A Predictive Biomarker for Renal Outcome in Lupus Nephritis

2019 ◽  
Vol 20 (18) ◽  
pp. 4601 ◽  
Author(s):  
Torres-Salido ◽  
Sanchis ◽  
Solé ◽  
Moliné ◽  
Vidal ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Clinical Response ◽  
Mesangial Cells ◽  
Characteristic Curve ◽  
Predictive Biomarker ◽  
Renal Outcome ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Neuropilin 1

At present, Lupus Nephritis (LN) is still awaiting a biomarker to better monitor disease activity, guide clinical treatment, and predict a patient’s long-term outcome. In the last decade, novel biomarkers have been identified to monitor the disease, but none have been incorporated into clinical practice. The transmembrane receptor neuropilin-1 (NRP-1) is highly expressed by mesangial cells and its genetic deletion results in proteinuric disease and glomerulosclerosis. NRP-1 is increased in kidney biopsies of LN. In this work we were interested in determining whether urinary NRP-1 levels could be a biomarker of clinical response in LN. Our results show that patients with active LN have increased levels of urinary NRP-1. When patients were divided according to clinical response, responders displayed higher urinary and tissue NRP-1 levels at the time of renal biopsy. Areas under the receiver operating characteristic curve, comparing baseline creatinine, proteinuria, urinary NRP-1, and VEGFA protein levels, showed NRP-1 to be an independent predictor for clinical response. In addition, in vitro studies suggest that NRP-1could promote renal recovery through endothelial proliferation and migration, mesangial migration and local T cell cytotoxicity. Based on these results, NRP-1 may be used as an early prognostic biomarker in LN.

scholarly journals The Urinary Exosomal miRNA Expression Profile is Predictive of Clinical Response in Lupus Nephritis

2020 ◽  
Vol 21 (4) ◽  
pp. 1372 ◽  
Author(s):  
Eloi Garcia-Vives ◽  
Cristina Solé ◽  
Teresa Moliné ◽  
Marta Vidal ◽  
Irene Agraz ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Clinical Response ◽  
Mesangial Cells ◽  
Area Under The Curve ◽  
Mirna Expression Profile ◽  
Renal Tissue ◽  
Renal Outcome ◽  
Protein Levels ◽  
Urinary Exosomes

Data on exosomal-derived urinary miRNAs have identified several miRNAs associated with disease activity and fibrosis formation, but studies on prognosis are lacking. We conducted a qPCR array screening on urinary exosomes from 14 patients with biopsy-proven proliferative lupus glomerulonephritis with a renal outcome of clinical response (n = 7) and non-response (n = 7) following therapy. Validation studies were performed by qRT-PCR in a new lupus nephritis (LN) cohort (responders = 22 and non-responders = 21). Responder patients expressed significantly increased levels of miR-31, miR-107, and miR-135b-5p in urine and renal tissue compared to non-responders. MiR-135b exhibited the best predictive value to discriminate responder patients (area under the curve = 0.783). In vitro studies showed exosome-derived miR-31, miR-107, and miR-135b-5p expression to be mainly produced by tubular renal cells stimulated with inflammatory cytokines (e.g IL1, TNFα, IFNα and IL6). Uptake of urinary exosomes from responders by mesangial cells was superior compared to that from non-responders (90% vs. 50%, p < 0.0001). HIF1A was identified as a potential common target, and low protein levels were found in non-responder renal biopsies. HIF1A inhibition reduced mesangial proliferation and IL-8, CCL2, CCL3, and CXCL1 mesangial cell production and IL-6/VCAM-1 in endothelial cells. Urinary exosomal miR-135b-5p, miR-107, and miR-31 are promising novel markers for clinical outcomes, regulating LN renal recovery by HIF1A inhibition.

scholarly journals Neuraminidase activity mediates IL-6 production by activated lupus-prone mesangial cells

2018 ◽  
Vol 314 (4) ◽  
pp. F630-F642 ◽  
Author(s):  
Kamala Sundararaj ◽  
Jessalyn I. Rodgers ◽  
Subathra Marimuthu ◽  
Leah J. Siskind ◽  
Evelyn Bruner ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Signaling Pathway ◽  
Mesangial Cells ◽  
Morbidity And Mortality ◽  
Receptor Complex ◽  
Catabolic Pathway ◽  
Neuraminidase Activity ◽  
Complex Signaling

The development of nephritis is a leading cause of morbidity and mortality in lupus patients. Although the general pathophysiological progression of lupus nephritis is known, the molecular mediators and mechanisms are incompletely understood. Previously, we demonstrated that the glycosphingolipid (GSL) catabolic pathway is elevated in the kidneys of MRL/lpr lupus mice and human lupus patients with nephritis. Specifically, the activity of neuraminidase (NEU) and expression of Neu1, an enzyme in the GSL catabolic pathway is significantly increased. To better understand the role and mechanisms by which this pathway contributes to the progression of LN, we analyzed the expression and effects of NEU activity on the function of MRL/lpr lupus-prone mesangial cells (MCs). We demonstrate that NEU1 and NEU3 promote IL-6 production in MES13 MCs. Neu1 expression, NEU activity, and IL-6 production are significantly increased in stimulated primary MRL/lpr lupus-prone MCs, and blocking NEU activity inhibits IL-6 production. NEU1 and NEU3 expression overlaps IgG deposits in MCs in vitro and in renal sections from nephritic MRL/lpr mice. Together, our results suggest that NEU activity mediates IL-6 production in lupus-prone MCs possibly through an IgG-receptor complex signaling pathway.

scholarly journals Superiority of temozolomide over radiotherapy for elderly patients with RTK II methylation class, MGMT promoter methylated malignant astrocytoma

2020 ◽  
Vol 22 (8) ◽  
pp. 1162-1172 ◽  
Author(s):  
Antje Wick ◽  
Tobias Kessler ◽  
Michael Platten ◽  
Christoph Meisner ◽  
Michael Bamberg ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Methylation Status ◽  
Predictive Biomarker ◽  
Copy Number Variations ◽  
Mgmt Promoter Methylation ◽  
Prognostic Impact ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Mgmt Promoter

Abstract Background O6-methylguanine DNA-methyl transferase (MGMT) promoter methylation status is predictive for alkylating chemotherapy, but there are non-benefiting subgroups. Methods This is the long-term update of NOA-08 (NCT01502241), which compared efficacy and safety of radiotherapy (RT, n = 176) and temozolomide (TMZ, n = 193) at 7/14 days in patients &gt;65 years old with anaplastic astrocytoma or glioblastoma. DNA methylation patterns and copy number variations were assessed in the biomarker cohort of 104 patients and in an independent cohort of 188 patients treated with RT+TMZ-containing regimens in Heidelberg. Results In the full NOA-08 cohort, median overall survival (OS) was 8.2 [7.0–10.0] months for TMZ treatment versus 9.4 [8.1–10.4] months for RT; hazard ratio (HR) = 0.93 (95% CI: 0.76–1.15) of TMZ versus RT. Median event-free survival (EFS) [3.4 (3.2–4.1) months vs 4.6 (4.2–5.0) months] did not differ, with HR = 1.02 (0.83–1.25). Patients with MGMT methylated tumors had markedly longer OS and EFS when treated with TMZ (18.4 [13.9–24.4] mo and 8.5 [6.9–13.3] mo) versus RT (9.6 [6.4–13.7] mo and 4.8 [4.3–6.2] mo, HR 0.44 [0.27–0.70], P &lt; 0.001 for OS and 0.46 [0.29–0.73], P = 0.001 for EFS). Patients with glioblastomas of the methylation classes receptor tyrosine kinase I (RTK I) and mesenchymal subgroups lacked a prognostic impact of MGMT in both cohorts. Conclusion MGMT promoter methylation is a strong predictive biomarker for the choice between RT and TMZ. It indicates favorable long-term outcome with initial TMZ monotherapy in patients with MGMT promoter-methylated tumors primarily in the RTK II subgroup.

Response, Survival, and Long-Term Toxicity After Therapy With the Radiolabeled Somatostatin Analogue [90Y-DOTA]-TOC in Metastasized Neuroendocrine Cancers

2011 ◽  
Vol 29 (17) ◽  
pp. 2416-2423 ◽  
Author(s):  
Anna Imhof ◽  
Philippe Brunner ◽  
Nicolas Marincek ◽  
Matthias Briel ◽  
Christian Schindler ◽  
...  
Keyword(s):  
Clinical Response ◽  
Renal Toxicity ◽  
Somatostatin Receptor ◽  
Somatostatin Analogue ◽  
Receptor Imaging ◽  
Open Label ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Neuroendocrine Cancers

Purpose To investigate response, survival, and safety profile of the somatostatin-based radiopeptide 90yttrium-labeled tetraazacyclododecane-tetraacetic acid modified Tyr-octreotide ([90Y-DOTA]-TOC) in neuroendocrine cancers. Patients and Methods In a clinical phase II single-center open-label trial, patients with neuroendocrine cancers were treated with repeated cycles of [90Y-DOTA]-TOC. Each cycle consisted of a single intravenous injection of 3.7GBq/m2 body-surface [90Y-DOTA]-TOC. Additional cycles were withheld in case of tumor progression and/or permanent toxicity. Results Overall, 1,109 patients received 2,472 cycles of [90Y-DOTA]-TOC (median, two; range, one to 10 cycles per patient). Of the 1,109 patients, 378 (34.1%) experienced morphologic response; 172 (15.5%), biochemical response; and 329 (29.7%), clinical response. During a median follow-up of 23 months, 491 patients (44.3%) died. Longer survival was correlated with each: morphologic (hazard ratio [HR], 0.46; 95% CI, 0.38 to 0.56; median survival, 44.7 v 18.3 months; P < .001), biochemical (HR, 0.75; 95% CI, 0.59 to 0.96; 35.3 v 25.7 months; P = .023), and clinical response (HR, 0.68; 95% CI, 0.56 to 0.82; 36.8 v 23.5 months; P < .001). Overall, 142 patients (12.8%) developed grade 3 to 4 transient hematologic toxicities, and 103 patients (9.2%) experienced grade 4 to 5 permanent renal toxicity. Multivariable regression revealed that tumoral uptake in the initial imaging study was predictive for overall survival (HR, 0.45; 95% CI, 0.29 to 0.69; P < .001), whereas the initial kidney uptake was predictive for severe renal toxicity (HR, 1.59; 95% CI, 1.17 to 2.17; P = .003). Conclusion This study documents the long-term outcome of [90Y-DOTA]-TOC treatment in a large cohort. Response to [90Y-DOTA]-TOC is associated with longer survival. Somatostatin receptor imaging is predictive for both survival after [90Y-DOTA]-TOC treatment and occurrence of renal toxicity.

scholarly journals Tirosin Kinase Inhibitors in Chronic Graft versus Host Disease: From Bench to Bedside

2011 ◽  
Vol 11 ◽  
pp. 1908-1931 ◽  
Author(s):  
Jacopo Olivieri ◽  
Sabrina Coluzzi ◽  
Imma Attolico ◽  
Attilio Olivieri
Keyword(s):  
Growth Factor ◽  
Graft Versus Host Disease ◽  
Kinase Inhibitors ◽  
Transforming Growth Factor ◽  
Toxicity Profile ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Host Disease ◽  
Graft Versus Host

Chronic Graft Versus Host Disease (cGVHD) is a major complication of allogeneic stem-cell transplantation (SCT). In many inflammatory fibrotic diseases, such as Systemic Scleroderma (SSc) and cGVHD with fibrotic features, an abnormal activation of transforming growth factor (TGFβ) and platelet-derived growth factor receptor (PDGF-R) pathways have been observed. Tyrosin Kinase Inhibitors (TKIs), which are currently used for treatment of patients with Chronic Myeloid Leukemia (CML), share potent antifibrotic and antiinflammatory properties, being powerful dual inhibitors of both PDGF-R and TGFβpathways. Moreover accumulating in vitro data confirm that TKIs, interacting with the TCR and other signalling molecules, carry potent immunomodulatory effects, being involved in both T-cell and B-cell response. Translation to the clinical setting revealed that treatment with Imatinib can achieve encouraging responses in patients with autoimmune diseases and steroid-refractory cGVHD, showing a favourable toxicity profile. While the exact mechanisms leading to such efficacy are still under investigation, use of TKIs in the context of clinical trials should be promoted, aiming to evaluate the biological changes induced in vivo by TKIs and to assess the long term outcome of these patients. Second-generation TKIs, with more favourable toxicity profile are under evaluation in the same setting.

SAT0401 Antiphospholipid Antibodies in Lupus Nephritis and Their Role in Long-Term Outcome

2015 ◽  
Vol 74 (Suppl 2) ◽  
pp. 804.2-804
Author(s):  
I. Parodis ◽  
E. Svenungsson ◽  
J. Gerhardsson ◽  
A. Zickert ◽  
V. Malmström ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Antiphospholipid Antibodies ◽  
Term Outcome ◽  
Long Term Outcome
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