Eightly-four novel thioheterocyclic nucleoside derivatives were designed, synthesized, and evaluated for antitumor activity in vitro and in vivo. Most of the compounds inhibited the growth of HCT116 and HeLa cancer cells in vitro, among them 33a and 36b exhibited potent activity against HCT116 cells (IC₅₀ = 0.27 and 0.49 μmol/L, respectively). Both compounds 33a and 36b inhibited cell metastasis, arrested the cell cycle in the G₂/M phase, and induced apoptosis in vitro. Mechanistic studies revealed that 33a and 36b increased ROS levels, led to DNA damage, ER stress, and mitochondrial dysfunction, and inhibited autophagy in HCT116 cells. Biological information analysis, RNA-sequencing, Gene Set Enrichment Analysis (GSEA), drug affinity responsive target stability (DARTS) assay, cellular thermal shift assay (CETSA), and SPR experiments identified that compounds 33a and 36b showed antitumor activity by suppressing the c-MYC pathway. c-MYC silencing assays indicated that c-MYC proteins participated in 33a-mediated anticancer activities in HCT116 cells. More importantly, compound 33a presented favorable pharmacokinetic properties in mice (T _1/2 = 6.8 h) and showed significant antitumor efficacy in vivo without obvious toxicity, showing promising potential for further clinical development.

Azvudine and nirmatrelvir/ritonavir (Paxlovid) are recommended for COVID-19 treatment in China, but their safety and efficacy in the elderly population are not fully known. In this multicenter, retrospective, cohort study, we identified 5131 elderly hospitalized COVID-19 patients from 32,864 COVID-19 patients admitted to nine hospitals in Henan Province, China, from December 5, 2022, to January 31, 2023. The primary outcome was all-cause death, and the secondary outcome was composite disease progression. Propensity score matching (PSM) was performed to control for confounding factors, including demographics, vaccination status, comorbidities, and laboratory tests. After 2:1 PSM, 1786 elderly patients receiving azvudine and 893 elderly patients receiving Paxlovid were included. Kaplan-Meier and Cox regression analyses revealed that compared with Paxlovid group, azvudine could significantly reduce the risk of all-cause death (log-rank P = 0.002; HR: 0.71, 95% CI: 0.573-0.883, P = 0.002), but there was no difference in composite disease progression (log-rank P = 0.52; HR: 1.05, 95% CI: 0.877-1.260, P = 0.588). Four sensitivity analyses verified the robustness of above results. Subgroup analysis suggested that a greater benefit of azvudine over Paxlovid was observed in elderly patients with primary malignant tumors (P for interaction = 0.005, HR: 0.32, 95% CI: 0.18-0.57) compared to patients without primary malignant tumors. Safety analysis revealed that azvudine treatment had a lower incidence of adverse events and higher lymphocyte levels than Paxlovid treatment. In conclusion, azvudine treatment is not inferior to Paxlovid treatment in terms of all-cause death, composite disease progression and adverse events in elderly hospitalized COVID-19 patients.

Molecular editing around privileged scaffolds, also known as periphery editing, is a commonly used strategy in contemporary drug discovery and development. Tranylcypromine (TCP) is a widely acknowledged scaffold with diverse pharmacological activities. TCP-derived compounds target different enzymes and cellular receptors such as amine oxidase, platelet P2Y₁₂ receptor, and cytochrome P450 superfamily. These compounds have demonstrated various effects including antidepressant, anticancer, antiviral properties, involvement in prostaglandin synthesis, and mediation of drug metabolism. Notably, the first reversible oral P2Y₁₂ receptor antagonist, ticagrelor, is currently used to prevent future myocardial infarction, stroke, and cardiovascular death. Several TCP-based lysine demethylase 1 (LSD1) inhibitors are currently undergoing clinical assessment. MIV-150, a third-generation non-nucleoside reverse transcriptase inhibitor, has progressed to the clinical stage for treating human immunodeficiency virus type 1 (HIV-1) seronegative patients suffering from acute coronary syndrome. This review aims to explore the target landscape of TCPs, highlight key structure-activity relationships (SARs), and emphasize the therapeutic potential of TCPs for treating various diseases. Finally, the lessons learned from our medicinal chemistry practice, challenges and future directions of TCP-based drug discovery are briefly discussed.

Objective:To assess the safety and feasibility of selectively preserving the first branch of the right gastro-omental artery using bidirectional dissection in laparoscopic pylorus-preserving gastrectomy (LPPG).Methods:In this retrospective analysis, we studied preoperative, intraoperative, postoperative, and follow-up data of 30 patients with early gastric cancer treated in the Department of Gastric Cancer in Zhejiang Cancer Hospital (28 patients), Department of Gastrointestinal Surgery in Jiaxing Second Hospital (one patient) and Department of Gastrointestinal Surgery in Hangzhou Red Cross Hospital (one patient) who had undergone selective preservation of the first branch of the right gastro-omental artery during LPPG. The main variables studied were as follows: (1) intraoperative preservation of the first branch of the right gastro-omental artery; (2) the overall surgical situation; and (3) postoperative small bowel follow-through and endoscopy findings.Results:LPPG with selective preservation of the right gastro-omental artery vascular branch was achieved in all 30 of the study patients. The mean operation time was (244.3±29.3) minutes and the median intraoperative blood loss 50 (20–200) mL. The median tumor diameter was 1.2 (0.5–3.6) cm and an average of 32.3±11.6 lymph nodes were dissected. The overall median number of positive lymph nodes was 0 (0–6), and of No. 6 lymph nodes 5.1±1.5. Postoperative feeding resumed at an average of 5.2±0.5 days and the postoperative hospital stay averaged 8.4±3.4 days. Pathological stages were as follows: T1a (14 cases), T1b (10 cases), and T2 (6 cases). Small bowel follow-through imaging showed good results in 28 patients 5 days post-surgery, the remaining two exhibiting good results 9 days post-surgery. There were no instances of delayed gastric emptying, and only one patient (3.3%) developed intra-abdominal infection (resolved with conservative treatment).Conclusion:Selective preservation of the right gastro-omental artery during laparoscopic early gastric cancer surgery is a safe and feasible procedure for treating early mid-gastric body cancer with pyloric preservation.

Objective:To assess the safety and feasibility of selectively preserving the first branch of the right gastro-omental artery using bidirectional dissection in laparoscopic pylorus-preserving gastrectomy (LPPG).Methods:In this retrospective analysis, we studied preoperative, intraoperative, postoperative, and follow-up data of 30 patients with early gastric cancer treated in the Department of Gastric Cancer in Zhejiang Cancer Hospital (28 patients), Department of Gastrointestinal Surgery in Jiaxing Second Hospital (one patient) and Department of Gastrointestinal Surgery in Hangzhou Red Cross Hospital (one patient) who had undergone selective preservation of the first branch of the right gastro-omental artery during LPPG. The main variables studied were as follows: (1) intraoperative preservation of the first branch of the right gastro-omental artery; (2) the overall surgical situation; and (3) postoperative small bowel follow-through and endoscopy findings.Results:LPPG with selective preservation of the right gastro-omental artery vascular branch was achieved in all 30 of the study patients. The mean operation time was (244.3±29.3) minutes and the median intraoperative blood loss 50 (20–200) mL. The median tumor diameter was 1.2 (0.5–3.6) cm and an average of 32.3±11.6 lymph nodes were dissected. The overall median number of positive lymph nodes was 0 (0–6), and of No. 6 lymph nodes 5.1±1.5. Postoperative feeding resumed at an average of 5.2±0.5 days and the postoperative hospital stay averaged 8.4±3.4 days. Pathological stages were as follows: T1a (14 cases), T1b (10 cases), and T2 (6 cases). Small bowel follow-through imaging showed good results in 28 patients 5 days post-surgery, the remaining two exhibiting good results 9 days post-surgery. There were no instances of delayed gastric emptying, and only one patient (3.3%) developed intra-abdominal infection (resolved with conservative treatment).Conclusion:Selective preservation of the right gastro-omental artery during laparoscopic early gastric cancer surgery is a safe and feasible procedure for treating early mid-gastric body cancer with pyloric preservation.

Low-density lipoprotein receptor-related protein 1B (LRP1B) is defined as a potential cancer suppressor since it was discovered, and it has been found to be silencing in multiple tumors, and its main pathogenic mechanisms include gene mutations, epigenetic modifications in the promoter region and regulation by microRNA (miRNA). Recent studies showed that LRP1B played an important role in the occurrence and development of digestive system tumors. Combined with domestic and international research advances, this review summarizes the structure and function of LRP1B and its effect on digestive system tumors, further reveals its potential value as a marker of immunotherapy, and explores its transition from cancer inhibitor to cancer promotor in different tumors, with the aim of helping the subsequent research on the mechanism.

Ubiquitin-Protein Ligases/metabolism* ; Proteolysis ; Biological Products ; Ligands