Alzheimer's disease amyloid-β (Aβ) oligomers are synaptotoxic, inappropriately increasing extracellular glutamate concentration and glutamate receptor activation to thereby rapidly disrupt synaptic plasticity. Thus, acutely promoting brain glutamate homeostasis with a blood-based scavenging system, glutamate-oxaloacetate transaminase (GOT), and blocking metabotropic glutamate 5 (mGlu5) receptor or its co-receptor cellular prion protein (PrP), prevent the acute inhibition of long-term potentiation (LTP) by exogenous Aβ. Here, we evaluated the time course of the effects of such interventions in the persistent disruptive effects of Aβ oligomers, either exogenously injected in wild type rats or endogenously generated in transgenic rats that model Alzheimer's disease amyloidosis. We report that repeated, but not acute, systemic administration of recombinant GOT type 1, with or without the glutamate co-substrate oxaloacetate, reversed the persistent deleterious effect of exogenous Aβ on synaptic plasticity. Moreover, similar repetitive treatment reversibly abrogated the inhibition of LTP monitored longitudinally in freely behaving transgenic rats. Remarkably, brief repeated treatment with an mGlu5 receptor antagonist, basimglurant, or an antibody that prevents Aβ oligomer binding to PrP, ICSM35, also had similar reversible ameliorative effects in the transgenic rat model. Overall, the present findings support the ongoing development of therapeutics for early Alzheimer's disease based on these complementary approaches.

Purpose: We developed and validated an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for simultaneous therapeutic drug monitoring (TDM) and clinical pharmacokinetic antipsychotic drugs: clozapine (CLP), chlorpromazine (CPZ), risperidone (RPD), paliperidone (PLD), quetiapine (QTP;), aripiprazole (APZ), dehydroaripiprazole (DAP), olanzapine (OZP), ziprasidone (ZRD), and amisulpride (ASP). Methods: Analytes and internal standards (ISs) were separated using a Phenomenex phenyl-hexyl column (50.0 × 2.1 mm, 1.7 μm) with water containing 0.1% formic acid and 2 mM ammonium acetate, and methanol containing 0.1% formic acid and 2 mM ammonium acetate as the mobile phase. The antipsychotic drugs and ISs were extracted from 50 μL of plasma using acetonitrile. Results: The calibration ranges were 25.0– 1500.0 ng/mL for CLP, CPZ, DAP, and QTP, 10.0– 600.0 ng/mL for CPZ and ZRD, 2.5– 150.0 ng/mL for RPD, 5.0– 300.0 ng/mL for PLD and OZP, and 20.0– 1200.0 ng/mL for ASP. Validation was carried out according to the guidelines for bioanalytical validation, including assessment of calibration curves, specificity, accuracy, precision, recovery, stability, dilution integrity, and matrix effect. All the results satisfied the requirements. Conclusion: The results provided significant information to support future clinical TDM and rational drug use research. The proposed method also provided a simple, reliable, specific, and suitable technique for TDM and pharmacokinetic studies.

10-HCPT is a topoisomerase I inhibitor effective in the treatment of liver cancer but its use is hampered by its resistance. The expression of hypoxia-inducible factor-1α (HIF-1α) is reportedly upregulated in liver cancer tissues, which is directly linked to the resistance of 10-HCPT. While BBR can significantly decrease the level of HIF-1α according to the literature report. Thus, the aim of this study was to prepare a novel intravenous 10-HCPT-BBR-loaded lipid microsphere (LM) and evaluate their synergistic effect on liver cancer treatment. The optimal preparation mainly included 10.0% oil phase (medium-chain triglyceride:long-chain triglyceride = 1:1), emulsifier (egg lecithin E80 and pluronic F68), antioxidant (0.02% NaHSO₃), and pH regulator (0.1 mol/L Hcl). Then, the behaviors of BBR-10-HCPT loaded LM in vitro and in vivo were systematically investigated. In vitro, it showed an obvious sustained-release effect in different release mediums, good physicochemical stability at accelerated and long-term storage conditions, and great anti-proliferative capability toward human liver cancer Hep-3B cells. In vivo, the prepared LM exhibited a longer half-life and higher AUC compared to BBR injection and 10-HCPT injection. More importantly, it was found that The LM was distributed more in the liver, spleen, and tumors, but less in the lungs and heart, especially in the lung. And then, it showed significant inhibition of tumor growth against nude mouse with Hep-3B tumor, and the tumor inhibition rate reached 91.55%. Thus, the data obtained in our study suggested that BBR combined with 10-HCPT can raise curative effect and reduce the toxicity of 10-HCPT.

Background: Immune checkpoint inhibitors (ICIs) have been an emerging treatment strategy for advanced triple-negative breast cancer (TNBC). Some studies have shown that high expression of programmed death-ligand 1 (PD-L1) can achieve a better response of clinical efficacy. However, the efficacy of ICIs in advanced TNBC remains controversial. In this meta-analysis, we evaluated the correlation of PD-L1 expression with the efficacy of ICIs in patients with advanced TNBC.Methods: We conducted a systematic search using four databases until March 2022 to obtain eligible randomized controlled trials (RCTs). The quality of the studies was assessed by the Cochrane risk of bias tool. Hazard ratio (HR) was extracted to evaluate the relationship between PD-L1 expression and progression-free survival (PFS) or overall survival (OS) in patients with advanced TNBC.Results: Five randomized controlled clinical trials (RCTs) with 3104 patients were included in this meta-analysis. The results demonstrated that ICIs could significantly improve the OS (HR 0.77, 95% CI 0.60–0.98, p = 0.03) in PD-L1 positive TNBC group. In the subgroup analysis, longer OS was observed (HR: 0.70, 95% CI: 0.60–0.82, p = 0.00001) in PD-L1 positive TNBC patients receiving ICIs alone or ICIs combined with nab-paclitaxel. In terms of PFS, PFS was significantly improved (HR: 0.68, 95% CI: 0.58–0.79, p < 0.00001) in PD-L1 positive patients receiving first-line ICIs and chemotherapy compared to those with ICIs alone. No significant improvement was observed for OS or PFS in PD-L1 negative group.Conclusion: Our study indicated significant improvement for OS in advanced TNBC with ICIs therapy in the PD-L1 positive status, and ICIs alone or ICIs combined with nab-paclitaxel might be a excellent choice in terms of OS. Although PFS has no significant benefit in PD-L1 positive patients, the subgroup analysis showed that ICIs combined with chemotherapy could achieve the PFS benefit in the first-line treatment. However, further clinical studies are needed to validate our conclusions due to limited relevant research.