The overactivated CDK6/Cyclin D3 complex is considered to be associated with poor prognosis in patients with NSCLC, thus developing CDK6/Cyclin D3 inhibitors is expected to provide new options for NSCLC patients. This study successfully utilized a mixed virtual screening workflow based on artificial intelligence, pharmacophores, and docking to rapidly identify multiple CDK6/Cyclin D3 inhibitors from a compound library consisting of 12,563 compounds, achieving a hit rate of over 40% (2 out of 5 selected candidate compounds). Among these, compound 2 exhibited the most potent CDK6/Cyclin D3 inhibitory activity, with an IC50 value of 38.6 nM, comparable to CDK6 inhibitors in clinical trial phases. In vitro antitumor activity indicated that compound 2 has strong proliferation-inhibitory activity against NSCLC, with IC50 values below 78 nM for two NSCLC cell lines, showing promise for further exploration. Kinetic simulation results revealed that compound 2 binds to the ATP-binding pocket of CDK6, stabilizing its conformation through hydrogen bond interaction with Val101 and ionic interaction with Asp104, providing new insights for the development of subsequent CDK6 inhibitors.

Evidence for rivaroxaban during the early postoperative period after surgical bioprosthetic valve replacement remains limited, particularly in Asian patients receiving low-dose rivaroxaban. We compared the effectiveness and safety of low-dose rivaroxaban versus dose-adjusted warfarin within the initial 3 months after surgery. In this single-center retrospective cohort study, we included consecutive adults who underwent surgical bioprosthetic valve replacement between August 2021 and December 2023 and received postoperative oral anticoagulation with low-dose rivaroxaban (15 or 10 mg once daily) or warfarin. Propensity score matching was used as the primary analysis, and inverse probability of treatment weighting was performed as a sensitivity analysis. The primary effectiveness outcome was thromboembolic events; the primary safety outcome was clinically relevant bleeding. Time-to-event outcomes were analyzed using Cox proportional hazards models, and absolute risk differences were reported descriptively. A total of 367 patients were included (178 rivaroxaban, 189 warfarin). After 1:1 PSM, 125 pairs were analyzed. During the 3-month follow-up, thromboembolic events occurred in 1/125 patients (0.8

This study aims to evaluate the effects of low-dose rivaroxaban in patients during the initial three months following bioprosthetic valve replacement. In this retrospective study, we compared low-dose rivaroxaban (15 mg once daily) with dose-adjusted warfarin (target international normalized ratio of 2.0 to 3.0) in patients who received a bioprosthetic valve replacement within the first three months. Primary efficacy outcome was the incidence of thromboembolic complications, while primary safety outcome was the incidence of bleeding within three months post-surgery. A total of 380 patients were enrolled at a large teaching hospital. The primary efficacy outcome occurred in 1 patient in both the warfarin and the rivaroxaban groups (p < 0.001 for noninferiority). There were no deaths in either group. 19 patients experienced the primary safety outcome; specifically, bleeding events occurred in 7 patients in the rivaroxaban group and in 12 patients in the warfarin group (7/178 vs. 12/189, p < 0.001 for noninferiority). After propensity score matching, the prevalence of clinical thromboembolic events was comparable between the two groups (1/130 vs. 0/130, p < 0.001 for noninferiority). The incidence of bleeding events in the rivaroxaban group was found to be noninferior to that in the warfarin group (6/130 vs. 6/130, p < 0.001 for noninferiority). In the early three months following bioprosthetic valve replacement, low-dose rivaroxaban demonstrated noninferiority to warfarin with respect to the incidence of primary outcomes (death, major cardiovascular events, or major bleeding).

The distinct redox imbalance in malignant cells, characterized by elevated reactive oxygen species and glutathione levels compared to normal tissues, establishes a therapeutic window for chemotherapeutic intervention through exploitation of the tumor microenvironment. Group 16 elements (sulfur, selenium, and tellurium) exhibit redox-modulating capabilities and engage in diverse biological processes, render them strategic candidates for developing tumor-selective nano-prodrugs that minimizing off-target toxicity. This review specifically focused on sulfur- (thioether, disulfide, and polysulfide), selenium, and tellurium-based nano-prodrugs constructed by linking small molecules-rather than polymeric or proteinaceous frameworks. We systematically examined structural determinants (chains length, substituent type, functional group composition) governing colloidal stability, chemical stability, and in vivo antitumor efficacy of these supramolecular assemblies. The strategic molecular engineering of linker motifs and side-chain architectures enhances drug delivery precision and therapeutic indices were also highlighted. Furthermore, we evaluate current translational progress in redox-responsive nano-prodrug platforms and propose rational design principles to advance their clinical translation, emphasizing structure-activity relationships and microenvironment-responsive drug release mechanisms.

Purpose The incidence of linezolid-induced thrombocytopenia (LIT) has been reported to vary widely across studies. We performed a meta-analysis to identify the risk factors for thrombocytopenia among patients who received linezolid treatment. Methods The PubMed, Embase and Cochrane Library databases were searched from inception to November 2022 to identify eligible studies. Data on the potential predictors of incidence in LIT were pooled using a random effects model. Sensitivity analyses were performed to determine the robustness of the results when significant heterogeneity was observed. Results Forty observational studies involving 6454 patients treated with linezolid were included in the analysis. LIT was estimated to occur in 37% of patients. The following important factors were associated with the incidence of LIT: advanced age, body mass index, concurrent renal impairment or liver disease, abnormal laboratory parameters (including white blood cell count, serum creatinine, baseline platelet count, albumin, creatinine clearance rate, and estimated glomerular filtration rate), treatment duration and renal replacement therapy. Conclusions A variety of risk factors related to the occurrence of LIT were revealed in our analysis. Early identification of these factors could help patients improve clinical outcomes.

目的 探讨2017年-2019年某三甲医院老年艰难梭菌感染患者的毒素基因分型及耐药性.方法 选择2017年-2019年反复性腹泻老年患者154例作为研究对象,采集患者粪便标本,采用酶联免疫荧光法鉴定标本内艰难梭菌,探究艰难梭菌感染患者的毒素基因分型及耐药特征.结果 154例粪便标本中,检测出艰难梭菌定植的48例,占比为31.17％.艰难梭菌对红霉素、头孢曲松、阿奇霉素、四环素存在较高耐药性,耐药率均＞88％;艰难梭菌对静脉用青霉素、甲硝唑、万古霉素均无耐药性.结论 2017年-2019年三甲医院老年艰难梭菌感染定植率高,艰难梭菌对红霉素、头孢曲松、阿奇霉素、四环素存在较高耐药性;艰难梭菌对静脉用青霉素、甲硝唑、万古霉素均无耐药性,抗感染效果更佳.

FGFR1 is well known as a molecular target in anticancer drug design. TKI258 plays an important role in RTK inhibitors. Utilizing TKI258 as a lead compound that contains a quinazolinone nucleus, we synthesized four series of 3-vinyl-quinoxalin-2(1H)-one derivatives, a total of 27 compounds. We further evaluated these compounds for FGFR1 inhibition ability as well as cytotoxicity against four cancer cell lines (H460, B16-F10, Hela229, and Hct116) in vitro. Some compounds displayed good-to-excellent potency against the four tested cancer cell lines compared with TKI258. Structure-activity relationship analyses indicated that small substituents at the side chain of the 3-vinyl-quinoxalin-2(1H)-one were more effective than large substituents. Lastly, we used molecular docking to obtain further insight into the interactions between the compounds and FGFR1.

-Aminopropylsilatrane has been reported to possess biological activity against tumor cancer cells with low cytotoxicity in many kinds of silatranes. So some N-substituted -aminopropylsilatrane derivatives were synthesized and assayed by a primary anticancer screening against HT-29, Hela, and MDAMB435 cells by the use of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) method. The structures of these derivatives were confirmed by H-1 NMR, electrospray ionization-mass spectrometry, and elemental analysis. The structure-activity relationship showed that the N-substituted derivatives exhibit better activity in which the -amino group of the silatrane is connected with stronger electron-withdrawing groups.

Hepatitis B virus (HBV) infection causes major public health problems worldwide. Acyclovir (ACV) is mainly used to inhibit herpes simplex virus (HSV) rather than HBV. In this study, we used the combination principle to design and synthesize nucleoside analogues that contain silatrane on the basis of the structure of ACV. We found that the compounds were effective inhibitors of HBV, both in vitro and in vivo. All of the compounds showed suppressive activity on the expression of HBV surface antigen (HBsAg) and HBV e antigen (HBeAg) in the HepG2.2.15 cell line with low cytotoxicity. One of compounds was studied in HBV transgenic mice model, and the test results showed its ability to reduce the levels of HBsAg, HBeAg and HBV DNA by ELASE and qPCR. Furthermore, significant improvement of T lymphocyte was observed after treatment, as evaluated by flow cytometry (FCM).