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.     

HC gp-39 gene is upregulated in glioblastomas

Public databases of the Cancer Genome Anatomy Project were used to quantify the relative gene expression levels in glioblastoma multiforme (GBM) and normal brain by Serial Analysis of Gene Expression (SAGE). Analysis revealed HC gp-39 among the genes with the most pronounced changes of expression in tumor cells. Northern hybridization confirmed the results of computer analysis and showed that enhanced expression of the HC gp-39 gene was mainly in GBMs and occasionally in anaplastic astrocytomas. Neither SAGE nor Northern analysis revealed the presence of HC gp-39 mRNA in the glioblastoma cell line, thus the detection of increased quantities of this mRNA in GBMs may be associated with activated macrophages. Since the numbers of infiltrating macrophages and small vessel density are higher in glioblastomas than in anaplastic astrocytomas or astrocytomas, the HC gp-39 gene can be used as a molecular marker in the analysis of malignant progression of astrocytic gliomas.     

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.     

Structural and optical properties of langbeinite-related red-emitting K2Sc2(MoO4)(PO4)2:Eu phosphors

The concentration series of langbeinite-related solid solutions K₂Sc₂(MoO₄)(PO₄)₂:xEu (x = 0.1, 0.2, 0.6, 0.8, and 1.0 mol%) has been prepared via a solid state route and the effects of europium content on the phase composition, morphology, crystal structure and luminescence properties have been studied by scanning electron microscopy, X-ray powder diffraction, UV-vis, IR and luminescence spectroscopy. The band gap values have been estimated from UV-vis spectra and are in the range of 3.7–3.8 eV for all concentrations studied. The electronic band structure calculations have shown that Sc d, Mo d and O^phos p states dominate in the band edge region and determine the optical transitions in the K₂Sc₂(MoO₄)(PO₄)₂ host. The photoluminescence (PL) spectra, intensity and decay time dependences on the Eu³⁺ concentration revealed complex behavior of europium-containing emitting centers. The PL characteristics indicated the presence of at least two types of luminescence centers. One of them (Eu_K) is shown to be formed by the Eu³⁺ ion located within K sites, while the other one is formed by the Eu³⁺ ions that reside in Sc sites (Eu_Sc). The luminescence color coordinates calculated for K₂Sc₂(MoO₄)(PO₄)₂:xEu indicated that these ceramics can be potential candidates for UV-based lighting applications as efficient red phosphors.

The luminescence properties of K₂Sc₂(MoO₄)(PO₄)₂:Eu indicate that these ceramics can be potential candidates for UV-based lighting applications as red phosphors.