Multigene Panel Sequencing Reveals Cancer-Specific and Common Somatic Mutations in Colorectal Cancer Patients: An Egyptian Experience.

This study aims at identifying common pathogenic somatic mutations at different stages of colorectal carcinogenesis in Egyptian patients. Our cohort included colonoscopic biopsies collected from 120 patients: 20 biopsies from patients with inflammatory bowel disease, 38 from colonic polyp patients, and 62 from patients with colorectal cancer. On top of this, the cohort included 20 biopsies from patients with non-specific mild to moderated colitis. Targeted DNA sequencing using a customized gene panel of 96 colorectal related genes running on the Ion Torrent NGS technology was used to process the samples. Our results revealed that 69% of all cases harbored at least one somatic mutation. Fifty-seven genes were found to carry 232 somatic non-synonymous variants. The most frequently pathogenic somatic mutations were localized in TP53, APC, KRAS, and PIK3CA. In total, 16 somatic mutations were detected in the CRC group and in either the IBD or CP group. In addition, our data showed that 51% of total somatic variants were CRC-specific variants. The average number of CRC-specific variants per sample is 2.4. The top genes carrying CRC-specific mutations are APC, TP53, PIK3CA, FBXW7, ATM, and SMAD4. It seems obvious that TP53 and APC genes were the most affected genes with somatic mutations in all groups. Of interest, 85% and 28% of the APC and TP53 deleterious somatic mutations were located in Exon 14 and Exon 3, respectively. Besides, 37% and 28% of the total somatic mutations identified in APC and TP53 were CRC-specific variants, respectively. Moreover, we identified that, in 29 somatic mutations in 21 genes, their association with CRC patients was unprecedented. Ten detected variants were likely to be novel: six in PIK3CA and four variants in FBXW7. The detected P53, Wnt/ßcatenin, Angiogenesis, EGFR, TGF-ß and Interleukin signaling pathways were the most altered pathways in 22%, 16%, 12%, 10%, 9% and 9% of the CRC patients, respectively. These results would contribute to a better understanding of the colorectal cancer and in introducing personalized therapies for Egyptian CRC patients.

An interactive SAR approach to discover novel hybrid thieno probes as ligands for D2-like receptors with affinities in the subnanomolar range.

A series of [(phenylpiperazinyl)alkyl]-isoindole-1,3-dione derivatives was synthesized to serve as probes for dopaminergic receptors. Among this series, compound 6a showed the highest affinity towards D4 and D3 receptors with Ki values in the low nanomolar range, and D2/D4- and D2/D3-selectivity indices of 72 and 20, respectively. Optimization rounds were adopted and led to the D4-selective ligand thiophene-2-carboxamide 9a with a Ki (D4) value of 0.62 nM, and to its butyl analog, 10a, with Ki (D4) and Ki (D3) values of 0.03 and 0.26 nM, respectively. Docking experiments revealed the importance of the unique D4 residue Arg186 in manipulating the ligands' D4-subtype-receptor selectivity.

In Silico Characterization of Toxin-Antitoxin Systems in Campylobacter Isolates Recovered from Food Sources and Sporadic Human Illness.

Campylobacter spp. represents the most common cause of gastroenteritis worldwide with the potential to cause serious sequelae. The ability of Campylobacter to survive stressful environmental conditions has been directly linked with food-borne illness. Toxin-antitoxin (TA) modules play an important role as defense systems against antimicrobial agents and are considered an invaluable strategy harnessed by bacterial pathogens to survive in stressful environments. Although TA modules have been extensively studied in model organisms such as Escherichia coli K12, the TA landscape in Campylobacter remains largely unexplored. Therefore, in this study, a comprehensive in silico screen of 111 Campylobacter (90 C.jejuni and 21 C.coli) isolates recovered from different food and clinical sources was performed. We identified 10 type II TA systems belonging to four TA families predicted in Campylobacter genomes. Furthermore, there was a significant association between the clonal population structure and distribution of TA modules; more specifically, most (12/13) of the Campylobacter isolates belonging to ST-21 isolates possess HicB-HicA TA modules. Finally, we observed a high degree of shared synteny among isolates bearing certain TA systems or even coexisting pairs of TA systems. Collectively, these findings provide useful insights about the distribution of TA modules in a heterogeneous pool of Campylobacter isolates from different sources, thus developing a better understanding regarding the mechanisms by which these pathogens survive stressful environmental conditions, which will further aid in the future designing of more targeted antimicrobials.

Four-component synthesis of 1,2-dihydropyridine derivatives and their evaluation as anticancer agents.

Two series of compounds with the general formula of 4,6-diaryl-2-oxo-1,2 dihydropyridine-3-carbonitriles and their isosteric imino derivatives were synthesized through a one pot reaction of acetophenone, aldehyde and ammonium acetate with ethyl cyanoacetate or malononitrile, respectively. The synthesized compounds were evaluated for tumor cell growth inhibitory using the human HT-29 colon and MDA-MB-231 breast tumor cell lines. Compound 4-(2- Ethoxyphenyl)-2-imino-6-(4-fluorophenyl)-1,2-dihydropyridine-3 carbonitrile (6) showed IC50 value of 0.70 µM versus HT-29. Meanwhile, compound 4-(2-Hydroxyphenyl)-2-imino-6-(4-fluorophenyl)-1,2-dihydropyridine-3-carbonitrile (4) showed IC50 value of 4.6 µM versus MDA-MB-231. Docking compound 10 to possible molecular targets, survivin and PIM1 kinase showed appreciable interactions with both, which suggest possible targets for the antitumor activity of this novel class of anticancer compounds.

CoMFA and CoMSIA studies of 1,2-dihydropyridine derivatives as anticancer agents.

Taking advantage of our in-house experimental data on 3-cyano-2-imino-1, 2-dihydropyridine and 3-cyano-2- oxo-1,2-dihydropyridine derivatives as inhibitors of the growth of the human HT-29 colon adenocarcinoma tumor cell line, we have established a highly significant CoMFA and CoMSIA models (q2cv=0.70/0.639). The models were investigated to assure their stability and predictivity (r2pred=0.65/0.61) and successfully applied to design two new potential cell growth inhibitory agents with IC50s in the submicromolar range.