The role of TNF-α, Fas/Fas ligand system and NT-proBNP in the early detection of asymptomatic left ventricular dysfunction in cancer patients treated with anthracyclines

Background: Anthracycline-induced cardiotoxicity typically presents as congestive heart failure (CHF). As immuno-inflammatory activation and apoptosis are important mechanisms in the process of heart failure, the use of biomarkers that could detect cardiovascular toxicity before the clinical presentation is of great importance. We studied whether sTNF-a, sTNF-RI, sTNF-RII, Fas/FasLigand system and NT-proBNP associate with early cardiac dysfunction in patients receiving cardiotoxic drugs. Methods: Two groups of breast cancer patients-group A with metastatic disease under chemotherapy with epirubicin and group B with no residual disease under a less cardiotoxic regimen-as well as healthy women were included in this prosprective study. NT-proBNP, sTNF-a, sTNF-RI, sTNF-RII, sFas, sFas-Ligand and left ventricular ejection fraction (LVEF) were determined in all patients before and after the completion of chemotherapy. Results: In Group A, an increase in sFas levels (p< 0.001), a decrease in the sFasL levels (p= 0.010), an NT-proBNP increase (p < 0.001) and a significant reduction of LVEF (p< 0.001) was recorded post-chemotherapy. The decrease in LVEF correlated significantly with the increase in sFas, the decrease in sFasL and the rise in NT-proBNP levels. In Group B, TNF-RI levels were higher (p= 0.024) and mean sFas-L levels lower (p= 0.021) post chemotherapy with no LVEF drop. Two of group A (7.6%) patients developed symptomatic CHF 12 and 14. months respectively after the end of chemotherapy. Conclusion: SFas, sFas-L and NT-proBNP correlate with reductions in LVEF and could be used as sensitive biochemical indices for the detection of asymptomatic left ventricular dysfunction in cancer patients under cardiotoxic chemotherapy. © 2015 The Authors. Published by Elsevier Ireland Ltd

CRISPR-Cas9-mediated knockout of CYP79D1 and CYP79D2 in cassava attenuates toxic cyanogen production

Cassava (Manihot esculenta) is a starchy root crop that supports over a billion people in tropical and subtropical regions of the world. This staple, however, produces the neurotoxin cyanide and requires processing for safe consumption. Excessive consumption of insufficiently processed cassava, in combination with protein-poor diets, can have neurodegenerative impacts. This problem is further exacerbated by drought conditions which increase this toxin in the plant. To reduce cyanide levels in cassava, we used CRISPR-mediated mutagenesis to disrupt the cytochrome P450 genes CYP79D1 and CYP79D2 whose protein products catalyze the first step in cyanogenic glucoside biosynthesis. Knockout of both genes eliminated cyanide in leaves and storage roots of cassava accession 60444; the West African, farmer-preferred cultivar TME 419; and the improved variety TMS 91/02324. Although knockout of CYP79D2 alone resulted in significant reduction of cyanide, mutagenesis of CYP79D1 did not, indicating these paralogs have diverged in their function. The congruence of results across accessions indicates that our approach could readily be extended to other preferred or improved cultivars. This work demonstrates cassava genome editing for enhanced food safety and reduced processing burden, against the backdrop of a changing climate

Clinical Pharmacology of Endothelin Receptor Antagonists Used in the Treatment of Pulmonary Arterial Hypertension

International audiencePulmonary arterial hypertension (PAH) is a devastating life-threatening disorder characterized by elevated pulmonary vascular resistance leading to elevated pulmonary arterial pressures, right ventricular failure and ultimately death. Vascular endothelial cells mainly produce and secrete endothelin (ET-1) in vessels that lead to a potent and long-lasting vasoconstrictive effect in pulmonary arterial smooth muscle cells. Along with its strong vasoconstrictive action, ET-1 can promote smooth muscle cell proliferation. Thus, ET-1 blockers have attracted attention as an antihypertensive drug and the ET-1 signaling system has paved a new therapeutic avenue for the treatment of PAH. The present chapter outlines not only the current understanding of the pathogenic role played by ET-1 signaling systems in the pathogenesis of PH, but also on the clinical pharmacology of endothelin receptor antagonists (ERA) used in the treatment of PAH