Alterations of the p53 and pRB pathways in human astrocytoma

Human astrocytomas are characterized by a number of molecular changes affecting two critical tumor suppressor pathways: the pRB and the p53 pathways. Genetic alterations functionally eliminate pRB and p53 themselves or upstream and/or downstream molecules such as products of theInk4a/ARF locus, p16^Ink4a and p14^ARF. As a result, malignant cells are defective in critical cell cycle and apoptosis regulatory elements contributing to unrelenting tumour growth and invasion. Current research aims to discover effective means of reconstituting p53 and pRB pathway components in an effort to attenuate the aggressive phenotype of astrocytoma.     

NGS‐based liquid biopsy profiling identifies mechanisms of resistance to ALK inhibitors: a step toward personalized NSCLC treatment

Despite impressive and durable responses, nonsmall cell lung cancer (NSCLC) patients treated with anaplastic lymphoma kinase (ALK) inhibitors (ALK‐Is) ultimately progress due to development of resistance. Here, we have evaluated the clinical utility of circulating tumor DNA (ctDNA) profiling by next‐generation sequencing (NGS) upon disease progression. We collected 26 plasma and two cerebrospinal fluid samples from 24 advanced ALK‐positive NSCLC patients at disease progression to an ALK‐I. These samples were analyzed by NGS and digital PCR. A tool to retrieve variants at the ALK locus was developed (VALK tool). We identified at least one resistance mutation in the ALK locus in ten (38.5%) plasma samples; the G1269A and G1202R mutations were the most prevalent among patients progressing to first‐ and second‐generation ALK‐Is, respectively. Overall, 61 somatic mutations were detected in 14 genes: TP53, ALK, PIK3CA, SMAD4, MAP2K1 (MEK1), FGFR2, FGFR3, BRAF, EGFR, IDH2, MYC, MET, CCND3, and CCND1. Specifically, a deletion in exon 19 in EGFR, a non‐V600 BRAF mutation (G466V), and the F129L mutation in MAP2K1 were identified in four patients who showed no objective survival benefit from ALK‐Is. Potential ALK‐I‐resistance mutations were also found in PIK3CA and IDH2. Finally, a c‐MYC gain, along with a loss of CCND1 and FGFR3, was detected in a patient progressing on a first‐line treatment with crizotinib. We conclude that NGS analysis of liquid biopsies upon disease progression identified different putative ALK‐I‐resistance mutations in most cases and could be a valuable approach for therapy decision making.     

Role of cannabinoid receptors in the regulation of cardiac contractility during ischemia/reperfusion

We studied the effect of selective ligands of cannabinoid (CB) receptors on contractility of isolated Langendorff-perfused rat heart under conditions of 45-min total ischemia and 30-min reperfusion. Perfusion with a solution containing selective CB receptor agonist HU-210 for 10 min before ischemia increased the severity of reperfusion contractile dysfunction. This drug decreased left ventricular developed pressure and maximum rates of contraction and relaxation, but had no effect on heart rate and end-diastolic pressure. The negative inotropic effect of the drug was transitory and disappeared after 5-min reperfusion. Pretreatment with selective CB1 receptor antagonist SR141716A and selective CB2 receptor antagonist SR144528 had no effect on heart rate and myocardial contractility during reperfusion. Our results indicate that stimulation of CB receptors can increase the degree of reperfusion-induced cardiac contractile dysfunction. However, endogenous cannabinoids are not involved in the development of myocardial contractile dysfunction during ischemia/reperfusion of the isolated heart. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 142, No. 11, pp. 500–504, November, 2006