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PurposeTo identify and clarify the roles of inflammatory markers in prognosis for advanced non-small cell lung cancer (NSCLC) patients treated with EGFR tyrosine kinase inhibitor (TKI).Patients and methodsOne hundred and twelve adenocarcinoma, clinical stage IV, NSCLC patients with either EGFR exon 19 deletion (E19del) or EGFR exon 21 L858R substitution mutation (L858R) were selected for this study. The blood cell count at different stages of treatment was used to calculate the inflammatory markers. The Kaplan–Meier statistics and Cox regression model were used to test the differences of progression-free survival (PFS) between groups by the optimal cutoff point of biomarkers.ResultsThe median values of white blood cell (WBC), neutrophil to lymphocyte ratio (NLR), monocyte to lymphocyte ratio (MLR) and platelet to lymphocyte ratio (PLR) in NSCLC patients tended to be reduced after 3 months treated with EGFR TKI and increased conversely when the disease develops progression (P<0.001). With an optimal cutoff point of 2.96, NLR is the best prognostic marker in prediction of clinical response among the investigated markers (area under the curve [AUC]=0.873, 95% CI: 0.821–0.926, P<0.001), and it is an independent predictive marker (OR=3.52, 95% CI: 1.42–8.71, P<0.001). With optimal cutoff point of 0.38, MLR is also a predictive marker in response evaluation (AUC=0.762, 95% CI: 0.691–0.832). Univariate analyses have shown that the larger tumor size (>3cm) and the high level of pretreatment NLR were associated with the shortening of PFS (HR=2.24, 95% CI: 1.04–4.83, P=0.039 and HR=2.67, 95% CI: 1.41–5.03, P=0.006, respectively). Multivariate analysis has shown that the elevated NLR is an independent prognostic marker for worse PFS of NSCLC patients treated with EGFR TKI (HR=2.15, 95% CI: 1.15–3.99, P=0.016).ConclusionNLR and MLR are valuable markers in response evaluation for NSCLC patients treated with EGFR TKI. The elevated NLR is also an independent prognostic factor for worse survival.

Streptomyces sp. VN1 was isolated from the coastal region of Phu Yen Province (central Viet Nam). Morphological, physiological, and whole genome phylogenetic analyses suggested that strain Streptomyces sp. VN1 belonged to genus Streptomyces. Whole genome sequencing analysis showed its genome was 8,341,703 base pairs in length with GC content of 72.5%. Diverse metabolites, including cinnamamide, spirotetronate antibiotic lobophorin A, diketopiperazines cyclo-L-proline-L-tyrosine, and a unique furan-type compound were isolated from Streptomyces sp. VN1. Structures of these compounds were studied by HR-Q-TOF ESI/MS/MS and 2D NMR analyses. Bioassay-guided purification yielded a furan-type compound which exhibited in vitro anticancer activity against AGS, HCT116, A375M, U87MG, and A549 cell lines with IC 50 values of 40.5, 123.7, 84.67, 50, and 58.64 µM, respectively. In silico genome analysis of the isolated Streptomyces sp. VN1 contained 34 gene clusters responsible for the biosynthesis of known and/or novel secondary metabolites, including different types of terpene, T1PKS, T2PKS, T3PKS, NRPS, and hybrid PKS-NRPS. Genome mining with HR-Q-TOF ESI/MS/MS analysis of the crude extract confirmed the biosynthesis of lobophorin analogs. This study indicates that Streptomyces sp. VN1 is a promising strain for biosynthesis of novel natural products. Natural products (NPs) have been starting points of drug discovery for several decades. Major antimicrobials and chemotherapeutics entering clinical trials are often based on NPs 1,2. Drugs with a natural origin can be produced as primary or secondary metabolites from versatile living organisms. Different microorganisms such as Streptomyces, myxobacteria and uncultured bacteria are major sources of such beneficial NPs 3,4. Moreover, different metabolic engineering approaches and sophisticated techniques employing systems biology or synthetic biology can assist in harnessing the full potential of these bacteria in terms of productivity or creating diverse products 5,6. Hence, there is renewed interest in mining microorganisms for new leads owing to the remarkable success of microbial metabolites as starting points for developing effective antibiotics, anticancer agents, and agrochemicals 7. Streptomyces are Gram-positive, aerobic bacteria in the order of Actinomycetales within the class of Actinobacteria. Genus Streptomyces was first proposed by Waksman and Henrici in 1943. It was classified into the family of Streptomycetaceae based on its morphology and cell wall chemotype 8. Previous studies have shown that more than 74% of current antibiotics are derived from the genus Streptomyces 9. Using integrated approaches of compound screening and drug development, Streptomyces arsenal has been found to be able to combat antibiotic resistance 5. Multiple approaches such as ribosome engineering 10 and genome mining 11 have been used to find new secondary metabolites in old Streptomyces strains. Besides the effort to work on old strains to explore novel biosynthetic gene clusters (BGCs),...

Streptomyces spp. are prolific sources of valuable natural products (NPs) that are of great interest in pharmaceutical industries such as antibiotics, anticancer chemotherapeutics, immunosuppressants, etc. Approximately two-thirds of all known antibiotics are produced by actinomycetes, most predominantly by Streptomyces. Nevertheless, in recent years, the chances of the discovery of novel and bioactive compounds from Streptomyces have significantly declined. The major hindrance for obtaining such bioactive compounds from Streptomyces is that most of the compounds are not produced in significant titers, or the biosynthetic gene clusters (BGCs) are cryptic. The rapid development of genome sequencing has provided access to a tremendous number of NP-BGCs embedded in the microbial genomes. In addition, the studies of metabolomics provide a portfolio of entire metabolites produced from the strain of interest. Therefore, through the integrated approaches of different-omics techniques, the connection between gene expression and metabolism can be established. Hence, in this review we summarized recent advancements in strategies for activating cryptic BGCs in Streptomyces by utilizing diverse state-of-the-art techniques.

BACKGROUND. A significant number of thyroid fine‐needle aspiration cytology (FNAC) cases yield inconclusive results. The recent National Cancer Institute guidelines and those published by other societies are important contributions to standardizing the diagnostic approach. Nevertheless, there are significant issues in the application of guidelines and the evaluation of their clinical efficacy. Data from individual departments can be useful in demonstrating the role of standardized reporting. METHODS. The authors followed 529 consecutive cases with inconclusive thyroid FNA results that were analyzed in a single laboratory in Western Australia. In that laboratory, standardized reporting in categories has been in place for a decade, and inconclusive cases have been subdivided into indeterminate and atypical groups. Follow‐up data was obtained for 341 indeterminate cases (17.2% of total thyroid FNA accessions) and for 188 atypical cases (9.5% of accessions). RESULTS. In total, 127 nodules with atypical results (67.6%) underwent surgical excision compared with 131 nodules with indeterminate results (38.4%; P < .0001). In 96 excised nodules with atypical results (75.6%), the excised specimens were identified as neoplastic compared with 61 excised nodules with indeterminate results (46.6%; P < .0001). In addition, 31 excised nodules with atypical results (24.4%) had a malignancy proven compared with 17 excised nodules with indeterminate results (13%; P < .05). In addition, 51 of 82 repeat FNAs (62.2%) among patients who had indeterminate results yielded a more specific diagnosis compared with 2 of 9 repeat FNAs (22.2%) among patients who had atypical results (P < .05). CONCLUSIONS. The routine subcategorization of patients who had inconclusive thyroid FNA reports into indeterminate and atypical groups resulted in statistically significant differences in the likelihood of neoplasia and malignancy. Patients who had indeterminate results were more likely to benefit from repeat FNAC than patients who had atypical results. The current results indicated that patients who fall into these 2 categories are likely to benefit from different clinical management protocols. Cancer Cancer Cytopathol 2010. © 2010 American Cancer Society.