Design, synthesis and evaluation of 2-(2-oxoethyl)pyrimidine-5-carboxamide derivatives as acetylcholinesterase inhibitors.

A novel series of 2-(2- oxoethyl)pyrimidine-5-carboxamide derivatives were designed, synthesized and evaluated as acetylcholinesterase inhibitors (AChEIs) for the treatment of Alzheimer's disease (AD). Biological activity results demonstrated that compound 10q showed the best inhibitory activity against AChE (IC50 = 0.88 ± 0.78 µM), which was better than that of Huperzine-A, and its inhibitory effect on BuChE was weak (IC50 = 10.0 ± 1.30 µM), which indicated that compound 10q was a dominant AChE inhibitor. In addition, the result of molecular docking study displayed that 10q could simultaneously bind to CAS and PAS sites of AChE, which was consistent with the mixed inhibition mode shown by the enzymatic kinetics study of 10q. Furthermore, the molecular properties of the target compounds were predicted online using the molinspiration server and pkCSM, The results exhibited that compound 10q had drug-like properties that satisfied the Lipinski's rule of five. Based on the bioactivity and molecular properties, compound 10q for further development was valuable.

Accuracy of the spontaneous breathing trial using a combined CPAP + PSV model to predict extubation outcomes in very preterm infants.

BACKGROUND: Very preterm infants often require mechanical ventilation. However, objective criteria to predict the outcomes of extubation in very premature neonates remain lacking. The aim of this study was to investigate the accuracy of the spontaneous breathing trial (SBT) using a combined model of continuous positive airway pressure (CPAP) and low-level pressure support ventilation (PSV) to predict the extubation outcomes of preterm infants with gestational age < 32 weeks. METHODS: Preterm infants with gestational age < 32 weeks, birth weight < 1500 g and requiring mechanical ventilation were selected for the study. All infants underwent a 10-minute SBT using CPAP combined with low-level PSV prior to the planned extubation. Then, the infants were extubated within 1 h after SBT. The outcomes of extubation were considered successful if the neonates did not require reintubation 72 h after extubation. RESULTS: A total of 119 eligible preterm infants were enrolled in the study, with a median gestational age of 28.9 (27.1-30.3) weeks and a median birth weight of 1100 (900-1350) g. In total, 101 of all infants had successful extubation, 18 of whom failed and eventually had to be reintubated. Of the 102 infants who achieved SBT, 99 were successfully extubated, and 15 of the 17 infants who did not pass SBT had failed extubation. Finally, the diagnostic value for SBT could be assessed with a sensitivity of 98%, a specificity of 83.3%, a positive predictive value of 97.1% and a negative predictive value of 88.2%. CONCLUSION: SBT using a combined CPAP + low-level PSV model can predict the outcomes of extubation in very preterm infants with high sensitivity and specificity.

Self-assembly of peptide nanomaterials at biointerfaces: molecular design and biomedical applications.

Self-assembly is an important strategy for constructing ordered structures and complex functions in nature. Based on this, people can imitate nature and artificially construct functional materials with novel structures through the supermolecular self-assembly pathway of biological interfaces. Among the many assembly units, peptide molecular self-assembly has received widespread attention in recent years. In this review, we introduce the interactions (hydrophobic interaction, hydrogen bond, and electrostatic interaction) between peptide nanomaterials and biological interfaces, summarizing the latest advancements in multifunctional self-assembling peptide materials. We systematically demonstrate the assembly mechanisms of peptides at biological interfaces, such as proteins and cell membranes, while highlighting their application potential and challenges in fields like drug delivery, antibacterial strategies, and cancer therapy.

Effect of postmastectomy radiotherapy on pT1-2N1 breast cancer patients with different molecular subtypes.

OBJECTIVE: To clarify the effect of postmastectomy radiotherapy (PMRT) on pT1-2N1 breast cancer patients with different molecular subtypes. METHODS: We retrospectively analyzed the data of 5442 patients with pT1-2N1 breast cancer treated using modified radical mastectomy in 11 hospitals in China. Univariate, multivariate, and propensity score matching (PSM) analyses were used to evaluate the effect of PMRT on locoregional recurrence (LRR). RESULTS: With a median follow-up duration of 63.8 months, the 5-year LRR rates were 4.0% and 7.7% among patients treated with and without PMRT, respectively (p < 0.001). PMRT was independently associated with reduced LRR after adjustments for confounders (p < 0.001). After grouping the patients according to the molecular subtype of cancer and conducting PSM, we found that the 5-year LRR rates among patients treated with and without PMRT (in that order) were as follows: luminal HER2-negative cancer, 1.9% and 6.5% (p < 0.001); luminal HER2-positive cancer, 3.8% and 13.7% (p = 0.041); HER2-overexpressing cancer, 10.2% and 15.5% (p = 0.236); and triple-negative cancer, 4.6% and 15.9% (p = 0.002). Among patients with HER2-overexpressing and triple-negative cancers, the LRR hazard rate displayed a dominant early peak, and was extremely low after 5 years. However, patients with luminal cancer continued to have a long-lasting high annual LRR hazard rate during follow-up. CONCLUSION: PMRT significantly reduced the LRR risk in patients with pT1-2N1 luminal and triple-negative breast cancers, but had no effect on the LRR risk in patients with HER2-overexpressing cancer. Patients with different molecular subtypes displayed different annual LRR patterns, and the late recurrence of the luminal subtype suggests the necessity of long-term follow-up to evaluate the efficacy of PMRT.

Clinical Evaluation and Gait Characteristics before and after Total Knee Arthroplasty Based on a Portable Gait Analyzer.

OBJECTIVE: To evaluate the effects of surgery and rehabilitation on patients undergoing total knee arthroplasty (TKA). METHODS: Twelve patients and 12 healthy controls were enrolled and their clinical scores evaluated by a doctor. Gait data, including walking velocity, stride length, single support time, foot fall and swing power, were collected using a portable gait analyzer from 12 patients before and 6 weeks and 6 months after surgery and from 12 healthy controls. The gait data and clinical scores at selected time points were compared and correlations between gait characteristics and clinical scores assessed. RESULTS: Clinical knee and knee function scores increased significantly from before surgery to 6 weeks to 6 months after surgery (P < 0.001). The only significant differences identified were for single support time on the diseased side between before surgery and 6 months after surgery (P = 0.031) and for foot fall with the diseased side between 6 weeks and 6 months after surgery (P = 0.016). Foot fall and speed of the healthy or diseased sides were significantly different in patients at all time points from those of the healthy subjects (P < 0.05). Single support time on the diseased side was significantly different 6 months after surgery (P = 0.035) in patients than in healthy controls. Single support time on the healthy side before surgery was significantly different from that of healthy controls (P = 0.048) and 6 weeks after surgery (P = 0.042). Stride lengths differed significantly between patients and healthy subjects before surgery (healthy side: P = 0.007; diseased side: P = 0.008) and 6 weeks after surgery (healthy side: P = 0.001; diseased side: P = 0.001), but were not different at 6 months after surgery (healthy side: P = 0.088; diseased side: P = 0.077). The only significant correlations identified were between single support time with the diseased side of patients and their knee (r = 0.43, P = 0.032) and knee function scores (r = 0.493, P = 0.012). CONCLUSIONS: A portable gait analyzer appears to be suitable for evaluating the effects of TKA. Single support time on the diseased side may be a sensitive quantitative index for determining the effect of TKA and rehabilitation.