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Background: This study was conducted to find out CD10 expression in premalignant and epithelial malignant lesions of the colon and rectum with clinicopathological correlation. Methods: This was a hospital-based cross-sectional study conducted 50 biopsy/resected specimens of adenomas (20 cases) and adenocarcinomas (30 cases) who were selected randomly. They underwent H&E staining and IHC for CD10, with the exclusion of non-epithelial tumor samples and submitted to the Department of Surgical Gastroenterology, Department of Surgery, Hi-Tech Medical College and Hospital, from August 2020 to August 2023, after obtaining clearance from the institutional ethics committee and written informed consent from the study participants. Results: Among the 50 cases, 35 (70%) >50 years and 15 (30%) <50 years, 28 (56%) were males, and 22 (44%) were females. Location-wise tumours comprise rectum 16 (32%), followed by descending colon 13 (26%), ascending colon 10 (20%), rectosigmoid junction 7 (14%), and transverse colon 4 (8%). The level of CD10 expression slowly rose from adenomas (<10%) to well-differentiated (G1)-adenocarcinomas (10–25%), with the highest level of expression seen in poorly differentiated (G3)-adenocarcinomas (>50%). Conclusion: At every step of the adenomacarcinoma cascade, CD10 is crucial. Association of CD10 expression with malignant behaviour of colorectal adenocarcinomas and CD10 could be a new biomarker for aggressiveness and prognostic information. When used as a therapeutic target, CD10 will allow for the greatest possible targeting of malignant areas. [ABSTRACT FROM AUTHOR]

Dual modifications (base and sugar) in siRNA have the potential to overcome off‐target effects and impart nuclease resistance. Here we present the synthesis and detailed structural analysis of N3‐methyluridine and 2'‐alkoxy/fluoro‐N3‐methyluridine modifications, the rationally designed modifications for oligonucleotide therapeutics. Using X‐ray crystallography and 1H NMR spectral data, it is clear that the C2'‐endo conformation of N3‐methyluridine switches to the C3'‐endo pucker state preferentially due to the introduction of electron‐withdrawing 2'‐alkoxy or fluoro substituents. DFT study confirms that the modifications preferentially acquire the C3'‐endo conformation. NBO analysis indicates that in the presence of the 2'‐alkoxy/fluoro substituents, the C3'‐endo conformation is stabilized due to nO4'→σ*C1'‐N1 anomeric as well as σC3'‐H→σ*C2'‐R and σC1'‐C2'→σ*C3'‐OH hyperconjugation effects. The W−C hydrogen bond energies of the modified nucleosides were calculated using the DFT and SAPT methods at the modified base pair regions, and it was observed that one of the hydrogen bonds gets disrupted due to the presence of the N3‐methyl group, causing significant decline in hydrogen bond energy. These detailed structural studies will help to expand the scope of these destabilizing modifications in the rational design of RNAi‐based therapeutics. [ABSTRACT FROM AUTHOR]

Carbocyclic carbenes (CCCs) are a class of nucleophilic carbenes which are very similar to N‐heterocyclic carbenes (NHCs) in terms of their reactivity, but they do not contain a stabilizing heteroatom in their cyclic ring system. In this study, 17 representative known CCCs and 34 newly designed CCCs are evaluated using quantum chemical methods, and the results are compared in terms of their stability, nucleophilicity, and proton affinity (PA) parameters. The results are divided on the basis of ring size of the known and reported CCCs. The stability, nucleophilicity, PA, complexation energy, and bond strength–related parameters were estimated using M06/6‐311++G(d,p) method. The results indicated that the CCCs known in the literature are strong σ‐electron donating species and have considerable π‐accepting properties. This study led to the design and identification of a few new CCCs with dimethylamine and diaminomethynyl substituents which can be singlet stable and are substantially nucleophilic. © 2018 Wiley Periodicals, Inc. Carbocyclic carbenes are interesting species but still lack thorough investigation based on their stability and reactivity. This is a systematic effort to understand different properties of CCCs with variable ring sizes. This work also exploits some promising substitutions to establish a balance between the nucleophilic properties and stability. [ABSTRACT FROM AUTHOR]

Over the last few decades, chemically modified sugars have been incorporated into nucleic acid-based therapeutics to improve their pharmacological potential. Chemical modification can influence the sugar conformation, Watson-Crick hydrogen (W-C) bonding, and nucleobase stacking interactions, which play major roles in the structural integrity and dynamic properties of nucleic acid duplexes. In this study, we categorized 33 uridine (U*) and cytidine (C*) sugar modifications and calculated their sugar conformational parameters. We also calculated the Watson-Crick hydrogen bond energies of the modified RNA-type base pairs (U*:A and C*:G) using DFT and sSAPT0 methods. The W-C base pairing energy calculations suggested that the South -type modified sugar strengthens the C*:G base pair and weakens the U*:A base pair compared to the unmodified one. In contrast, the North -type sugar modifications form weaker C*:G base pair and marginally stronger U*:A base pair compared to the South -type modified sugars. Moreover, intrastrand base stacking energies were calculated for 15 modifications incorporated at the fourth position in 7-mer non-self-complementary RNA duplexes [(GCAU*GAC) 2 and (GCAC*GAC) 2 ], utilizing molecular dynamics simulation and quantum mechanical (DFT and sSAPT0) methods. The sugar modifications were found to have minimal effect on the intrastrand base-stacking interactions. However, the glycol nucleic acid modification disturbs the intrastrand base-stacking significantly, corroborating the experimental data.

Herein, we have demonstrated that the siRNA activity could be enhanced by incorporating the guide strand in the RISC complex through thermodynamic asymmetry caused by m 3 U-based destabilizing modifications. A nuclease stability study revealed that 2'-OMe-m 3 U and 2'-OEt-m 3 U modifications slightly improved the half-lives of siRNA strands in human serum. In the in vitro gene silencing assay, 2'-OMe-m 3 U modification at the 3'-overhang and cleavage site of the passenger strand in anti-renilla and anti-Bcl-2 siRNA duplexes were well-tolerated and exhibited improved gene silencing activity. However, gene silencing activity was attenuated when these modifications were incorporated at position 3 in the seed region of the antisense strand. The molecular modeling studies using these modifications at the seed region with the MID domain of hAGO2 explained that the 2'-alkoxy group makes steric interactions with the amino acid residues of the hAGO2 protein., Competing Interests: The authors declare no competing financial interest., (© 2024 American Chemical Society.)