Circulating tumor cell clusters (CTCcl) have a higher metastatic potential compared to single CTCs and predict long-term outcomes in breast cancer (BC) patients. Because of the rarity of CTCcls, molecular characterization of primary tumors that give rise to CTCcl hold significant promise for better diagnosis and target discovery to combat metastatic BC. In our study, we utilized the reverse-phase protein array (RPPA) and transcriptomic (RNA-Seq) data of 10 triple-negative BC patient-derived xenograft (TNBC PDX) transplantable models with CTCs and evaluated expression of upregulated candidate protein Bcl2 (B-cell lymphoma 2) by immunohistochemistry (IHC). The sample-set consisted of six CTCcl-negative (CTCcl−) and four CTCcl-positive (CTCcl+) models. We analyzed the RPPA and transcriptomic profiles of CTCcl− and CTCcl+ TNBC PDX models. In addition, we derived a CTCcl-specific gene signature for testing if it predicted outcomes using a publicly available dataset from 360 patients with basal-like BC. The RPPA analysis of CTCcl+ vs. CTCcl− TNBC PDX tumors revealed elevated expression of Bcl2 (false discovery rate (FDR) < 0.0001, fold change (FC) = 3.5) and reduced acetyl coenzyme A carboxylase-1 (ACC1) (FDR = 0.0005, FC = 0.3) in CTCcl+ compared to CTCcl− tumors. Genome-wide transcriptomic analysis of CTCcl+ vs. CTCcl− tumors revealed 549 differentially expressed genes associated with the presence of CTCcls. Apoptosis was one of the significantly downregulated pathways (normalized enrichment score (NES) = −1.69; FDR < 0.05) in TNBC PDX tumors associated with CTCcl positivity. Two out of four CTCcl+ TNBC PDX primary tumors had high Bcl2 expression by IHC (H-score > 34); whereas, only one of six CTCcl− TNBC PDX primary tumors met this criterion. Evaluation of epithelial-mesenchymal transition (EMT)-specific signature did not show significant differences between CTCcl+ and CTCcl− tumors. However, a gene signature associated with the presence of CTCcls in TNBC PDX models was associated with worse relapse-free survival in the publicly available dataset from 360 patients with basal-like BC. In summary, we identified the multigene signature of primary PDX tumors associated with the presence of CTCcls. Evaluation of additional TNBC PDX models and patients can further illuminate cellular and molecular pathways facilitating CTCcl formation.
ABSTRACT. The study focused on the molecular docking of GC-MS isolated compounds from the Sargassum wightii against inflammatory marker Cycloxigenase-2 (COX2). Seven compounds isolated by GC-MS were tested for their anti-inflammatory action using insilico analysis. The crystal structure obtained from the protein data bank was docked against seven compounds and the glide score as well as glide energy were determined using Schrödinger Maestro software (version 2013.1). The results of molecular docking showed that out of the seven bioactive compounds tested, methyl salicylate, benzoic acid, 2-hydroxy-,ethyl ester, diethyl phthalate, hexadecanoic acid, ethyl ester and (E) -9-octadecenoic acid ethyl ester were effectively inhibited the COX2 protein. The ADME properties of the compounds analyzed using Qikprop version 3.6 software of Schrodinger suite and the results showed that all the compounds were biologically active and the scores were within the acceptable range. This study revealed that the possibility of using these compounds against COX2 to treat inflammation.
The aim of this study was to design, synthesize, and investigate the in vivo anti-inß ammatory activity of some novel 2, 5-disubstituted -1, 3, 4-oxadiazole derivatives. Ethyl-4-acetamido phenoxy acetate (I) was prepared by the condensation of ethyl chloroacetate with starting material p-acetamidophenol in the presence of dry acetone and anhydrous potassium carbonate. Hydrazinolysis of (I) with hydrazine hydrate results in the formation of 4-acetamidophenoxy acetyl hydrazide (II), which on cyclisation with various substituted aromatic carboxylic acids in the presence of phosphorous oxychloride affords various 2, 5-disubstituted -1, 3, 4-oxadiazole derivatives (IIIa-IIIi). The newly synthesized compounds were characterized by IR, 1 HNMR, and MS spectral data. The titled compounds were screened for in vivo anti-inß ammatory activity using the carrageenan-induced paw edema method. A few of them manifested promising activity when compared with the standard drug Diclofenac sodium.
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