Analysis For Identification Of Biomarkers Research Articles

Association of progression free survival with the timing of genomic testing in non-small cell lung cancer: Evidence from the GuardantInform clinic-genomic database.

e21143 Background: The clinical utility of ctDNA analysis for biomarker identification in advanced non-small cell lung cancer (NSCLC) has been established, supporting clinical adoption of this testing modality. All FDA-approved, immune-checkpoint inhibitor (ICI) immunotherapies require the prerequisite of negativity for ALK rearrangement and EGFR mutation, or prior toxicity or progression on oral therapies targeting mutations in these genes. Despite these recommendations and support from the American Society of Clinical Oncology and National Comprehensive Cancer Network, broad-panel marker testing for targeted therapy options in NSCLC continues to be underperformed. Data are even limited on when those tests are typically conducted and the effects of timing on the treatment outcomes. Methods: The GuardantINFORM™ clinic-genomic database was interrogated for patients over the age of 18 having a Guardant360 test positive for EGFR mutations of L858R or exon 19 after 2016 and known to have a confirmed diagnosis of lung cancer one year prior to testing. Patients had to have at least three claims prior to, and 90 days of follow-up after, their test. Patients were stratified into three groups by pre- and post-test treatment: 1) patients treated with an EGFR tyrosine kinase inhibitor (TKI) as a first-line treatment after the test, with no other chemotherapy, ICI immunotherapy (IO), or targeted therapy before the test; 2) patients with other first-line treatments prior to the test and then EGFR TKI immediately following the test; and 3) patients treated with ICI or chemotherapy after the test and before EGFR TKI or patients not treated after the test. Real-world time to next treatment (rwTTN) was defined as the index date to the treatment different than the index therapy. Progression free survival (PFS) time was defined as rwTTN or time to death, whichever came earlier. Patients who experienced adverse events (AEs) associated with chemotherapy or IO were reported as a percentage (p-value<0.001). Results: Among the 3 cohorts of patients (384 in each group who were matched on age with difference < 3, gender, and follow-up time with difference < 4 months) identified, a statistically significant difference in PFS was discovered between group 1 ( EGFR TKI as first-line treatment) and the other two groups based on the Cox proportional hazard model [hazard ratio=1.8, p-value<0.001, median survival time for group 1= 26 months (95% CI 23-29) vs. 17 months (95% CI 14-19)]. No difference existed in PFS between groups 2 and 3. The proportion of patients experiencing treatment-associated AEs was lowest in group 1 (13.5% vs 15.9% in group 2 vs 30.2% in group 3 for ICI-related AEs, 16.9% vs 23.2% vs 38.5% for chemo-related AEs, p-value<0.001). Conclusions: Performing genomic testing sooner, as early as first-line treatment, may improve the treatment response for patients with NSCLC.

Computational Approaches towards Micro-RNA Expression Analysis for Identification of Biomarkers in Inflammatory Bowel Disease Subtypes

Background and Aim: The potential biomarkers of inflammatory bowel diseases (IBDs) were analyzed from GSE53867 dataset. The current study aimed to identify miRNAs as potential diagnostic and prognostic biomarkers to delineate the IBD subtypes. Methods: Differentially expressed microRNAs (DEMs)-genes and protein-protein interaction networks were constructed and hub genes were selected using Cytoscape. Differentially expressed genes were analyzed for GO (Gene Ontology) and Reactome-pathway. Results: Seven DEMs were upregulated in Crohn’s disease (CD), 4 downregulated in ulcerative colitis (UC), 8 upregulated and 2 downregulated in IBD. A 620, 2377 and 1821 target-genes were in CD, UC and IBD, respectively. SOCS3, upregulated by miR-650, was hub gene in CD, induced by cytokines, through NFKB-signalling pathway to mediate ubiquitin-proteasomal degradation. CIRH1A, downregulated by miR-16, was hub gene of UC, acted by impairing ribosomebiogenesis. SKP2 and ASB1, up- and downregulated, by miR-142 and miR-665, respectively, were hub genes of IBD, induced cytokines through activation of TLR- and TNF-signalling pathways to mediate ubiquitin-proteasomal degradation. Conclusion: The SOCS3, CIRH1A, SKP2 and ASB1 genes might serve as valuable biomarkers to differentiate CD, UC and IBD.

Tumor genomic analysis for biomarker identification in a phase I trial of the Wee 1 inhibitor adavosertib (AZD1775).

3624 Background: Adavosertib, a first-in-class Wee1 kinase inhibitor, abrogates G2/M cell cycle arrest causing premature mitosis and DNA replication stress, yielding enhanced DNA damage. Here we report on potential biomarkers of response from tumor genomic analysis in patients (pts) with solid tumors treated with adavosertib. Methods: Adavosertib was administered once daily on days 1-5 and 8-12 of a 21-day cycle. RECIST 1.1 was used to evaluate clinical response. Paired tumor biopsies were obtained for RNASeq gene expression profiling (GEP) and for whole-exome sequencing (WES) to evaluate gene mutation and copy number amplification (CNA). Fold change (FC) was calculated to define gene overexpression. To identify the frequency of CNA and mRNA overexpression for the genomic biomarkers of interest, cBioPortal analysis using TCGA and MSK-IMPACT datasets was performed. Differential GEP analysis of tumor and paired normal tissue was performed using the gene expression profiling interactive analysis (GEPIA) interface (Tang et al. 2017). Results: Out of 35 pts evaluable for response, 6 (17%) had partial response (PR; 4 ovarian carcinoma [OVC], 2 endometrial carcinoma [EC]). The median duration of response was 5.2 months (range 4.0-23.1). Eighteen pts (51.4%) had stable disease. Genomic analysis of tumor biopsies was available for 9 pts; 7 of these pts were evaluable for response, and 3 had PR (2 OVC, 1 EC). WES revealed TP53 mutations in 6 pts (66.6%; 3 pts with PR, 2 with progressive disease,1 not evaluable). On WES, tumor Cyclin E1 ( CCNE1) CNA was present in 1 of 3 PR pts while tumors from all 3 PR samples showed relatively high CCNE1 expression by RNAseq (FC = 4.07). In the MSK-IMPACT 2017 dataset, CCNE1 CNA was identified in 1.8% of pts (194 of 10336); of which, OVC (10.3%) and EC (8.7%) had the highest incidence of CCNE1 CNAs. In separate tumor-specific (OVC, EC) TCGA datasets having CCNE1 overexpression and/or CNA, overlap in CCNE1 overexpression with CCNE1 CNA was 35.5% (OVC) and 25.2% (EC). Compared to normal ovarian/ endometrial tissues, GEPIA analysis revealed significantly higher CCNE1 mRNA expression in OVC (FC = 3.5) and EC (FC = 3.8). Conclusions: CCNE1alterations (overexpression and/or CNA) tend to be enriched in OVC and EC with a limited fraction showing both overexpression and CNA. Tumor genomic analysis of additional OVC and EC pts treated with adavosertib is required to determine whether CCNE1 mRNA overexpression, regardless of CCNE1 CNA, is a potential biomarker of response to this drug in these tumor types. Funded by NCI contract No. HHSN261200800001E. Clinical trial information: NCT01748825 .

Correction: iTRAQ-based quantitative proteomic analysis for identification of biomarkers associated with emodin against severe acute pancreatitis in rats

Correction for ‘iTRAQ-based quantitative proteomic analysis for identification of biomarkers associated with emodin against severe acute pancreatitis in rats’ by Hong Xiang et al., RSC Adv., 2016, 6, 72447–72457.

ITRAQ-based quantitative proteomic analysis for identification of biomarkers associated with emodin against severe acute pancreatitis in rats

Emodin has potent actions against SAP injury by inhibiting the HTRA1/TGF-β1 signaling pathway and subsequent inflammatory responses.

Isolation of Chlamydia trachomatis and membrane vesicles derived from host and bacteria

The study of intracellular bacteria and nanometer-size membrane vesicles within infected host cells poses an important challenge as it is difficult to identify each distinct population in the context of the complex populations generated from active host-pathogen interactions. Here, suspension cultures of L929 cells infected with the prevalent obligate intracellular bacterium Chlamydia trachomatis strain F/Cal-IC-13 are utilized for the large scale preparation and isolation of natural membrane vesicles and bacterial forms. Cell lysis with nitrogen cavitation in combination with differential centrifugation, OptiPrep™ density gradient separation, and immunoenrichment using anti-chlamydial lipopolysaccharide antibodies and MagnaBind beads allows for the isolation of both productive and persistent bacterial forms, as well as membrane vesicles derived from the host and pathogen. We have evaluated these populations by electron microscopy and Western blot analysis for identification of biomarkers. In addition, purified persistent forms of C. trachomatis induced by ampicillin display adenosine-5′-triphosphate (ATP) transport activity, suggesting that ampicillin-induced persistent C. trachomatis organisms, at least in part, rely upon host ATP as an energy source. Importantly, several chlamydial cytotoxic and/or secreted proteins are demonstrated to be associated with these vesicles, supporting the idea that membrane vesicles are generated by Chlamydia as a means of carrying and delivering virulence factors necessary for pathogenesis. The ability to produce large-scale infections and generate distinct bacteria and host-derived populations for biochemical analysis, while reducing the burdens of time and cost have implications in all areas of chlamydiology. These protocols can be applied to other strains of C. trachomatis or other intracellular bacteria.