Alterations of immune response of non-small lung cancer with azacytidine

Innovative therapies are needed for advanced Non-Small Cell Lung Cancer (NSCLC). We have undertaken a genomics based, hypothesis driving, approach to query an emerging potential that epigenetic therapy may sensitize to immune checkpoint therapy targeting PD-L1/PD-1 interaction. NSCLC cell lines were treated with the DNA hypomethylating agent azacytidine (AZA - Vidaza) and genes and pathways altered were mapped by genome-wide expression and DNA methylation analyses. AZA-induced pathways were analyzed in The Cancer Genome Atlas (TCGA) project by mapping the derived gene signatures in hundreds of lung adeno (LUAD) and squamous cell carcinoma (LUSC) samples. AZA up-regulates genes and pathways related to both innate and adaptive immunity and genes related to immune evasion in a several NSCLC lines. DNA hypermethylation and low expression of IRF7, an interferon transcription factor, tracks with this signature particularly in LUSC. In concert with these events, AZA up-regulates PD-L1 transcripts and protein, a key ligand-mediator of immune tolerance. Analysis of TCGA samples demonstrates that a significant proportion of primary NSCLC have low expression of AZA-induced immune genes, including PD-L1. We hypothesize that epigenetic therapy combined with blockade of immune checkpoints - in particular the PD-1/PD-L1 pathway - may augment response of NSCLC by shifting the balance between immune activation and immune inhibition, particularly in a subset of NSCLC with low expression of these pathways. Our studies define a biomarker strategy for response in a recently initiated trial to examine the potential of epigenetic therapy to sensitize patients with NSCLC to PD-1 immune checkpoint blockade

Epidermal Growth Factor Receptor and K-RAS status in two cohorts of squamous cell carcinomas

With the availability of effective anti-EGFR therapies for various solid malignancies, such as non-cell small lung cancer, colorectal cancer and squamous cell carcinoma of the head and neck, the knowledge of EGFR and K-RAS status becomes clinically important. The aim of this study was to analyse EGFR expression, EGFR gene copy number and EGFR and K-RAS mutations in two cohorts of squamous cell carcinomas, specifically anal canal and tonsil carcinomas.Journal ArticleMulticenter StudyResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Biological Evaluation of Cyclooxygenase-2 Inhibitor Nimesulide Derivatives as Anti-agents

Cyclooxygenase-2 (COX-2) inhibitor nimesulide inhibits the proliferation of various types of cancer cells mainly via COX-2 independent mechanisms, which makes it a good lead compound for anti-cancer drug development. A series of new nimesulide analogs were evaluated with cell proliferation assay based on a non-small lung cancer cell line H292. The results showed that several derivatives were very active to against H292 cell growth with IC50s of sub nano mole. These results suggest the possibility of using these nimesulide derivatives as chemo preventive agents.https://engagedscholarship.csuohio.edu/u_poster_2012/1036/thumbnail.jp

The Total Syntheses of JBIR-94 and Two Synthetic Analogs and Their Cytotoxicities Against A549 (CCL-185) Human Small Lung Cancer Cells

We here disclose the total syntheses of the natural polyphenol JBIR-94 and two nonnatural analogs, whose structures are of interest for their bioactivity potential as radical scavengers. Although we initially attempted this by dually acylating both of putrecine’s amine nitrogens in a single pot, our endeavors with this method (which has been successfully reported by other groups) proved ineffectual. We accordingly opted for the lengthier approach of acylating each amine individually, which gratuitously prevailed and also aligns with separate literature precedent. Moreover, we here share our analysis of these target compounds’ cytotoxicities and IC50 values against A549 (CCL-185) human small lung cancer cells

The Total Syntheses of JBIR-94 and Two Synthetic Analogs and Their Cytotoxicities Against A549 (CCL-185) Human Small Lung Cancer Cells

We here disclose the total syntheses of the natural polyphenol JBIR-94 and two nonnatural analogs, whose structures are of interest for their bioactivity potential as radical scavengers. Although we initially attempted this by dually acylating both of putrecine’s amine nitrogens in a single pot, our endeavors with this method (which has been successfully reported by other groups) proved ineffectual. We accordingly opted for the lengthier approach of acylating each amine individually, which gratuitously prevailed and also aligns with separate literature precedent. Moreover, we here share our analysis of these target compounds’ cytotoxicities and IC50 values against A549 (CCL-185) human small lung cancer cells

Nonomuraea monospora sp. nov., an actinomycete isolated from cave soil in Thailand, and emended description of the genus Nonomuraea

A novel actinomycete, designated strain PT708T, was isolated from cave soil collected in Pha Tup Cave Forest Park, Nan province, Thailand. It produced compounds with antimicrobial and anticancer activities. Its chemotaxonomic properties were consistent with those of members of the genus Nonomuraea . The major menaquinone was MK-9(H4), with minor amounts of MK-9(H6), MK-9(H2), MK-10(H2) and MK-8(H4). The polar lipid profile contained phosphatidylmonomethylethanolamine, diphosphatidylglycerol, hydroxy-phosphatidylmonomethylethanolamine, hydroxy-phosphatidylethanolamine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol mannoside and phosphatidylinositol. The major fatty acids were iso-C16 : 0, 10-methyl C17 : 0, C16 : 0 and C17 : 1ω6c. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain PT708T belonged to the genus Nonomuraea and was most closely related to Nonomuraea rhizophila YIM 67092T (98.50 % sequence similarity) and Nonomuraea rosea GW 12687T (98.30 %). The genomic DNA G+C content of strain PT708T was 73.3 mol%. Unlike the recognized members of the genus Nonomuraea , the novel strain formed single spores at the tips of aerial hyphae. Based on the phenotypic, phylogenetic and genotypic evidence, strain PT708T represents a novel species of the genus Nonomuraea , for which the name Nonomuraea monospora sp. nov. is proposed. The type strain is PT708T ( = TISTR 1910T = JCM 16114T)

FoxO regulates epithelial-mesenchymal transition reprogramming in non-small lung cancer cell through epigenetic modification

FoxO是Forkhead转录因子O亚家族成员，它能通过调控一系列下游靶基因的表达参与调控细胞周期停滞、细胞凋亡、新陈代谢和抗氧化应激等多个生物学过程，研究表明FoxO作为一个肿瘤抑制因子参与调控肿瘤形成和转移过程。上皮细胞-间质细胞转变(EMT)作为肿瘤形成和转移过程中的关键环节，最近的研究发现FoxO能参与调控EMT过程，然而具体的机制还未得到全面的阐述。本论文以人非小细胞肺癌细胞株A549为研究体系，探索FoxO与EMT之间的关系，实验结果表明在A549细胞中敲低FoxO能诱导EMT的发生，在此过程中上皮细胞标记蛋白E-cadherin表达下降而间质细胞标记蛋白Vimentin表达上升；...FoxO belongs to the O subfamily of forkhead box proteins, and is involved in the regulation of metabolism, oxidative stress resistance, cell cycle arrest and apoptosis by regulating diverse gene expression programmes. Recent studies have shown that the tumor suppressor FoxO participates in the regulation of tumor progression and metastasis. Epithelial-mesenchymal transition (EMT) plays a key role ...学位：理学硕士院系专业：生命科学学院_细胞生物学学号：2162012115239

Microstructural Characterization of Silver Nanoparticles for Bioimaging Applications

Junta de Andalucía FQM-6615, PI0070, FQM31

Osteopontin induces growth of metastatic tumors in a preclinical model of non-small lung cancer

Osteopontin (OPN), also known as SPP1 (secreted phosphoprotein), is an integrin binding glyco-phosphoprotein produced by a variety of tissues. In cancer patients expression of OPN has been associated with poor prognosis in several tumor types including breast, lung, and colorectal cancers. Despite wide expression in tumor cells and stroma, there is limited evidence supporting role of OPN in tumor progression and metastasis. Using phage display technology we identified a high affinity anti-OPN monoclonal antibody (hereafter AOM1). The binding site for AOM1 was identified as SVVYGLRSKS sequence which is immediately adjacent to the RGD motif and also spans the thrombin cleavage site of the human OPN. AOM1 efficiently inhibited OPNa binding to recombinant integrin αvβ3 with an IC50 of 65 nM. Due to its unique binding site, AOM1 is capable of inhibiting OPN cleavage by thrombin which has been shown to produce an OPN fragment that is biologically more active than the full length OPN. Screening of human cell lines identified tumor cells with increased expression of OPN receptors (αvβ3 and CD44v6) such as mesothelioma, hepatocellular carcinoma, breast, and non-small cell lung adenocarcinoma (NSCLC). CD44v6 and αvβ3 were also found to be highly enriched in the monocyte, but not lymphocyte, subset of human peripheral blood mononuclear cells (hPBMCs). In vitro, OPNa induced migration of both tumor and hPBMCs in a transwell migration assay. AOM1 significantly blocked cell migration further validating its specificity for the ligand. OPN was found to be enriched in mouse plasma in a number of pre-clinical tumor model of non-small cell lung cancers. To assess the role of OPN in tumor growth and metastasis and to evaluate a potential therapeutic indication for AOM1, we employed a KrasG12D-LSLp53fl/fl subcutaneously implanted in vivo model of NSCLC which possesses a high capacity to metastasize into the lung. Our data indicated that treatment of tumor bearing mice with AOM1 as a single agent or in combination with Carboplatin significantly inhibited growth of large metastatic tumors in the lung further supporting a role for OPN in tumor metastasis and progression