A comprehensive signature based on endoplasmic reticulum stress-related genes in predicting prognosis and immunotherapy response in melanoma.

Melanoma is considered as one of the most invasion types of skin cancer with high mortality rates. Although combination of immune checkpoint therapy with local surgical excision provide a novel promising therapeutic strategies, the overall prognosis of melanoma patients remains unsatisfactory. Endoplasmic reticulum (ER) stress, a process of protein misfolding and undue accumulation, has been proven to play an indispensable regulatory role in tumor progression and tumor immunity. However, whether the signature based ER genes has predictive value for the prognosis and immunotherapy of melanoma has not been systematically manifested. In this study, the LASSO regression and multivariate Cox regression were applied to construct a novel signature for predicting melanoma prognosis both in the training and testing set. Intriguingly, we found that patients endowed with high- and low-risk scores displayed differences in clinicopathologic classification, immune cell infiltration level, tumor microenvironment, and immune checkpoint treatment response. Subsequently, based on molecular biology experiments, we validated that silencing the expression of RAC1, an ERG composed of the risk signature, could restrain the proliferation and migration, promote apoptosis, as well as increase the expression of PD-1/PD-L1 and CTLA4 in melanoma cells. Taken together, the risk signature was regarded as promising predictors for melanoma prognosis and might provide prospective strategies to ameliorate patients' response to immunotherapy.

lncRNA EGFEM1P promotes thyroid cancer progression by acting as an miR-369-3p sponge and upregulating TCF4.

Thyroid cancer is the most commonly diagnosed endocrine cancer, with the incidence of 14.42 per 100,000 person-years in 2010-2013. It is important to conduct an in-depth exploration into the molecular mechanisms of thyroid cancer, providing insights into the improvements of therapy. Long non-coding RNAs (lncRNAs) act as oncogenes or tumor suppressors in thyroid cancer by sponging microRNAs (miRNAs), however, the functions of numerous lncRNAs are still unknown. In the present study, via the comprehensive analysis of microarray data derived from papillary thyroid tumors and the RNA sequencing of thyroid tumors from The Cancer Genome Atlas database, EGF like and EMI domain containing 1 (EGFEM1P) expression levels in papillary thyroid tumors and normal adjacent tissues were explored. Reverse transcription-quantitative PCR was used to detect EGFEM1P, microRNA (miR)-369-3p and T cell factor 4 (TCF4) expression levels. Western blotting was used to detect TCF4 protein and cleaved caspase-3/8 expression levels. Cell proliferative ability and apoptosis were assessed using the Cell Counting Kit-8 assay and flow cytometry, respectively. The interactions between EGFEM1P and miR-369-3p, and miR-369-3p and TCF4, were determined using the dual-luciferase reporter assay. The results demonstrated that EGFEM1P was upregulated in papillary thyroid tumors and thyroid cancer cells compared with normal adjacent tissues and human normal thyroid epithelial Nthy-ori 3-1 cell line. In the examined thyroid cancer cells, EGFEM1P was demonstrated to interact with miR-369-3p and decreased miR-369-3p expression levels. Thereafter, TCF4 was determined to be a target gene of miR-369-3p and EGFEM1P promoted TCF4 expression via regulating miR-369-3p expression levels. At last, it was found that EGFEM1P expression promoted rapid cell proliferation and inhibited cell apoptosis in thyroid cancer cells via acting as a miR-369-3p sponge. In conclusion EGFEM1P promoted thyroid cancer progression via acting as a sponge of the miR-369-3p/TCF4 axis.

Inhibition Mechanism of PinX1 Gene on Cancer Stem Cells of Nasopharyngeal Carcinoma.

The recurrence and long-term metastasis of these tumors are important causes of treatment failure and death. On the other hand, PinX1 is a nucleolar protein found in recent years that can interact with telomere/telomerase simultaneously, and it is highly conserved in human and yeast. Some studies have shown that the PinX1 gene can inhibit the tumor stem cells of NPC. Therefore, the mechanism of inhibition of the PinX1 gene on the tumor stem cells of NPC has been studied in this paper. In this paper, CNE2 cells of NPC were used as experimental materials, CD133 as a marker, PinX1 overexpression plasmids and their corresponding empty plasmids were respectively transfected in CD133+ cells, PinX1 siRNA and their corresponding NC siRNA were respectively transfected in CD133- cells for control experiments. In this study, we found that the telomerase activity of the CD133 - + NC group was 1.001 ± 0.086, the CD133 - + pinx1sirna group was 0.974 ± 0.046, CD133+ + vector group was 0.928 ± 0.102, CD133+ + over PinX1 group was 0.703 ± 0.086. Therefore, the PinX1 gene can inhibit NPC stem cells by inhibiting telomerase activity.

Discovery of N-((3R,4R)-4-Fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidine-3-yl)acrylamide (PF-06747775) through Structure-Based Drug Design: A High Affinity Irreversible Inhibitor Targeting Oncogenic EGFR Mutants with Selectivity over Wild-Type EGFR.

Mutant epidermal growth factor receptor (EGFR) is a major driver of non-small-cell lung cancer (NSCLC). Marketed first generation inhibitors, such as erlotinib, effect a transient beneficial response in EGFR mutant NSCLC patients before resistance mechanisms render these inhibitors ineffective. Secondary oncogenic EGFR mutations account for approximately 50% of relapses, the most common being the gatekeeper T790M substitution that renders existing therapies ineffective. The discovery of PF-06459988 (1), an irreversible pyrrolopyrimidine inhibitor of EGFR T790M mutants, was recently disclosed.1 Herein, we describe our continued efforts to achieve potency across EGFR oncogenic mutations and improved kinome selectivity, resulting in the discovery of clinical candidate PF-06747775 (21), which provides potent EGFR activity against the four common mutants (exon 19 deletion (Del), L858R, and double mutants T790M/L858R and T790M/Del), selectivity over wild-type EGFR, and desirable ADME properties. Compound 21 is currently being evaluated in phase-I clinical trials of mutant EGFR driven NSCLC.

A trigonal prismatic ligand in the metal-mediated self-assembly of one- and two-dimensional metallosupramolecular polymers.

A novel trispyrazine-pillared prismatic bicycooxacalixaromatic ligand L is synthesized, and its application in metal-mediated self-assembly is described. Under self-assembly conditions, single chain, double-stranded cross-linked coordination polymer and two-dimensional (2D) coordination polymeric networks were formed via M-L (Ag(+), Cu(2+), and Zn(2+)) coordinative interactions. Structural analyses revealed that the antiparallelly arranged one-dimensional coordination polymers (Cu(2+) and Zn(2+)) are arranged to generate well-defined voids to host aromatic guests (benzene) via C-H···π and π···π interactions, while the double-stranded cross-linked coordination polymer (Ag(+)) contains a rhomboidal [Ag2(L(3))2] (L(3): tridentate ligand) cage motif to include a benzene guest; the "thicker" (thickness: ac 5 Å) 2D coordination polymeric networks (Ag(+), Cu(2+), and Zn(2+)), however, are all formed by connection of one or two kinds of topologically different metallomacrocyclic cage units. These unique metallomacrocyclic cage units in the 2D coordination polymeric networks are capable of hosting different guest species. For instance, the rhomboidal [M2(L(3))2] (M = Ag(+), Cu(2+)) cage units were found to host a benzene or a nitrate anion; a hexahedral [M3(L(3))3] (M = Ag(+)) cage was found to host a ligand L or a DMF molecule; the hexahedral [M4(L(3))4] (M = Cu(2+)) cage was found to host four solvent molecules of benzene; and the rectangular [M3(L(3))3] (M = Cu(2+), Zn(2+)) cage units, however, were found to host two THF molecules. The results highlight the potential of ligand L for applications in the construction of "thicker" 2D coordination polymeric networks with well-defined metallomacrocyclic cage units capable of hosting various guest species.

[Study for lung sound acquisition module based on ARM and Linux].

A acquisition module with ARM and Linux as a core was developed. This paper presents the hardware configuration and the software design. It is shown that the module can extract human lung sound reliably and effectively.

Coordination-driven self-assembly of discrete and polymeric copper(ii) and dicopper(ii) supramolecular structures based on oxacalix[2]benzene[2]pyrazines.

The reaction of oxacalix[2]benzene[2]pyrazines and with copper(ii) nitrate, as well as dimeric copper(ii) tetraacetate are presented. Ligands and , both adopt 1,3-alternate conformation, with the two exo-Lewis basic sites spatially oriented outwards. Ligand reacts with copper(ii) ions generated a discrete molecular cage by bridging two ligands via two Cu(2+) ions in the equatorial region. While the reaction of with dicopper(ii) tetraacetate unit resulted in the formation of a discrete supramolecular complex with 1 : 2 stoichiometry between the dicopper(ii) unit and ligand , due to the larger size and axial coordination mode of the dicopper(ii) unit. The conformationally flexible nature of ligand facilitated the formation of coordination polymers and upon interaction with copper(ii) and dicopper(ii) units, respectively. Coordination polymer featured a zigzag structure of alternating ligand and Cu(2+) ion, while in coordination polymer , ligand serves as an axial 2-connected node, propagating the "paddlewheel" dicopper(ii) unit along the polymeric chain.