Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Reporte de Guatemala

1 p.La comisión nacional de la mosca blanca se formó a finales de 1993, según acuerdo ministerial 238-93 del 1 de diciembre de 1993. La comisión inicialmente estuvo integrada por autoridades del sector público agrícola, sector privado, asociaciones y gremios. Surgió como una necesidad de productores de cultivos no tradicionales, tradicionales de exportación y cultivos alimenticios de consumo local. Se integra por un equipo multiinstitucional para llevar acciones contra la plaga denominada mosca blanca (Bemisia tabaci, biotipo B)

Building Bonds: Cancer Stem Cells Depend on Their Progeny to Drive Tumor Progression

Little is currently known about how cancer stem-like cells (CSCs) interact with their more restricted progeny. In this issue of Cell Stem Cell, Wang et&nbsp;al. (2018) demonstrate a novel bidirectional signaling axis between CSCs and their progeny that is mediated by brain-derived neurotrophic factor and VGF accelerating glioma progression

Building Bonds: Cancer Stem Cells Depend on Their Progeny to Drive Tumor Progression

Little is currently known about how cancer stem-like cells (CSCs) interact with their more restricted progeny. In this issue of Cell Stem Cell, Wang et&nbsp;al. (2018) demonstrate a novel bidirectional signaling axis between CSCs and their progeny that is mediated by brain-derived neurotrophic factor and VGF accelerating glioma progression

A 4-miRNA signature to predict survival in glioblastomas

<div><p>Glioblastomas are among the most lethal cancers; however, recent advances in survival have increased the need for better prognostic markers. microRNAs (miRNAs) hold great prognostic potential being deregulated in glioblastomas and highly stable in stored tissue specimens. Moreover, miRNAs control multiple genes representing an additional level of gene regulation possibly more prognostically powerful than a single gene. The aim of the study was to identify a novel miRNA signature with the ability to separate patients into prognostic subgroups. Samples from 40 glioblastoma patients were included retrospectively; patients were comparable on all clinical aspects except overall survival enabling patients to be categorized as short-term or long-term survivors based on median survival. A miRNome screening was employed, and a prognostic profile was developed using leave-one-out cross-validation. We found that expression patterns of miRNAs; particularly the four miRNAs: hsa-miR-107_st, hsa-miR-548x_st, hsa-miR-3125_st and hsa-miR-331-3p_st could determine short- and long-term survival with a predicted accuracy of 78%. Heatmap dendrograms dichotomized glioblastomas into prognostic subgroups with a significant association to survival in univariate (HR 8.50; 95% CI 3.06–23.62; p<0.001) and multivariate analysis (HR 9.84; 95% CI 2.93–33.06; p<0.001). Similar tendency was seen in The Cancer Genome Atlas (TCGA) using a 2-miRNA signature of miR-107 and miR-331 (miR sum score), which were the only miRNAs available in TCGA. In TCGA, patients with O6-methylguanine-DNA-methyltransferase (MGMT) unmethylated tumors and low miR sum score had the shortest survival. Adjusting for age and MGMT status, low miR sum score was associated with a poorer prognosis (HR 0.66; 95% CI 0.45–0.97; p = 0.033). A Kyoto Encyclopedia of Genes and Genomes analysis predicted the identified miRNAs to regulate genes involved in cell cycle regulation and survival. In conclusion, the biology of miRNAs is complex, but the identified 4-miRNA expression pattern could comprise promising biomarkers in glioblastoma stratifying patients into short- and long-term survivors.</p></div

The two miRNA patterns and multivariate analysis.

<p>The two miRNA patterns and multivariate analysis.</p

KEGG pathway enriched for mRNAs predicted to be targeted by miRNAs in the 4-miRNA signature.

<p>KEGG pathway enriched for mRNAs predicted to be targeted by miRNAs in the 4-miRNA signature.</p

TCGA and multivariate analysis.

<p>TCGA and multivariate analysis.</p

Glioblastoma patient characteristics.

<p>Glioblastoma patient characteristics.</p

Short-(STS) and long-term (LTS) glioblastoma survivors have different microRNA (miRNA) profiles.

<p><b>(A)</b> Heatmap of the ten most deregulated miRNAs in STS and LTS. STS and LTS are grouped into two overall patterns as shown by the dendrograms. Pattern one (red bar) was characterized by STS whereas pattern two (green bar) mostly characterized LTS (18 LTS and 7 STS). In the heatmap, red represents upregulated miRNAs and green represents downregulated miRNAs. <b>(B)</b> Kaplan Meier plot showing a significant separation in overall survival between the two patterns. <b>(C)</b> Volcano plot illustrating that no miRNAs were significantly deregulated above the two-fold threshold. Blue represent normal fold changes and p-values while red represent permutated values. The four miRNAs included in the signature are indicated with arrows.</p