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PD-1+ IFN-γ+ subset of CD8+ T cell in circulation predicts response to anti–PD-1 therapy in NSCLC

BackgroundTreatment with programmed cell death protein-1 (PD-1) antibodies has minimal response rates in patients with non–small cell lung cancer (NSCLC), and, actually, they are treated with chemotherapy combined with anti–PD-1 therapy clinically. Reliable markers based on circulating immune cell subsets to predict curative effect are still scarce.MethodsWe included 30 patients with NSCLC treated with nivolumab or atezolizumab plus platinum drugs between 2021 and 2022. Whole blood was collected at baseline (before treatment with nivolumab or atezolizumab). The percentage of circulating PD-1+ Interferon-γ (IFN-γ+) subset of CD8+ T cell was determined by flow cytometry. The proportion of PD-1+ IFN-γ+ was calculated after gating on CD8+ T cells. Neutrophil/lymphocyte ratio (NLR), relative eosinophil count (%), and Lactate dehydrogenase (LDH) concentration at baseline of included patients were extracted from electronic medical records.ResultsThe percentage of circulating PD-1+ IFN-γ+ subset of CD8+ T cell at baseline in responders was significantly higher than those in non-responders (P < 0.05). Relative eosinophil count (%) and LDH concentration in responders showed no significance between non-responders and responders. NLR in responders was significantly lower than those in non-responders (P < 0.05). Receiver operation characteristic (ROC) analysis found that the areas under the ROC curve for PD-1+ IFN-γ+ subset of CD8+ T cell and NLR were 0.7781 (95% CI, 0.5937–0.9526) and 0.7315 (95% CI, 0.5169–0.9461). Moreover, high percentage of PD-1+ IFN-γ+ subset in CD8+ T cells was relevant to long progression-free survival in patients with NSCLC treated with chemotherapy combined with anti–PD-1 therapy.ConclusionThe percentage of circulating PD-1+ IFN-γ+ subset of CD8+ T cell could be a potential marker at baseline to predict early response or progression in patients with NSCLC receiving chemotherapy combined with anti–PD-1 therapy

The analysis of barriers to bim implementation for industrialized building construction: a China study

The emerging Building Information Modeling (BIM) can better promote the development of building industrialization, with data integration between information-rich building models and business processes. However, the practical implementation of BIM still faces barriers. Existing studies have discussed these barriers extensively, but the research on the barriers to the implementation of BIM amid building industrialization in China is inadequate. In this study, 23 barriers were identified through literature review. A questionnaire survey approach was used to collect data from various parties. Factor analysis methods were used to process and rank barrier factors for BIM applications in the context of industrialized building. Based on the analysis of each factor, analytic hierarchy process was adopted to identify the key barriers to the implementation of BIM for industrialized building construction. The study concluded that the main barriers for BIM implementation for industrialized building were capital-related factors and the lack of support from owners. This study proposes that in addition to governmental policy support for BIM and multi-stakeholder engagement, companies should also organize experts to effectively evaluate the risks of applying BIM. Overall, this study provides suggestions on construction organizational transformations in the roadmap of moving towards digital-driven building industrialization

The Protective Effect of Magnesium Lithospermate B on Hepatic Ischemia/Reperfusion via Inhibiting the Jak2/Stat3 Signaling Pathway

Acute inflammation is an important component of the pathogenesis of hepatic ischemia/reperfusion injury (HIRI). Magnesium lithospermate B (MLB) has strong neuroprotective and cardioprotective effects. The purpose of this study was to determine whether MLB had underlying protective effects against hepatic I/R injury and to reveal the potential mechanisms related to the hepatoprotective effects. In this study, we first examined the protective effect of MLB on HIRI in mice that underwent 1 h ischemia followed by 6 h reperfusion. MLB pretreatment alleviated the abnormal liver function and hepatocyte damage induced by I/R injury. We found that serum inflammatory cytokines, including IL-6, IL-1β, and TNF-α, were significantly decreased by MLB during hepatic ischemia/reperfusion (I/R) injury, suggesting that MLB may alleviate hepatic I/R injury via inhibiting inflammatory signaling pathways. Second, we investigated the protein level of p-Jak2/Jak2 and p-Stat3/Stat3 using Western blotting and found that MLB could significantly inhibit the activation of the Jak2/Stat3 signaling pathway, which was further verified by AG490 in a mouse model. Finally, the effect of MLB on the Jak2/Stat3 pathway was further assessed in an in vitro model of RAW 264.7 cells; 1 µg/ml LPS induced the secretion of inflammatory mediators, including IL-6, TNF-α, and activation of the Jak2/Stat3 signaling pathway. MLB significantly inhibited the abnormal secretion of inflammatory factors and the activation of the Jak2/Stat3 signaling pathway in RAW264.7 cells. In conclusion, MLB was found for the first time to reduce inflammation induced by hepatic I/R via suppressing the Jak2/Stat3 pathway

Practice of pharmaceutical services and prescription analysis in internet-based psychiatric hospitals during COVID-19 pandemic in Wuxi, China

ObjectiveTo study the practice of pharmaceutical services in internet-based psychiatric hospitals, and to analyze the prescriptions to ensure the safety and efficacy of internet-based medication in Wuxi, China.MethodsAll 1,259 internet-based prescriptions from our hospital in 2022 were collected, and data on patients’ age, gender, diagnosis, medications used, medication types, dosage forms, rationality of medication use, and reasons for irrationality were analyzed through descriptive statistics.ResultsIn the electronic prescriptions of internet-based psychiatric hospitals, females accounted for the majority (64.50%), with a female-to-male ratio of 1.82:1. Middle-aged and young adults accounted for the majority of patients (57.50%). There were 47 diagnosed diseases involved, with 89 types of medications used and 1,938prescriptions issued. Among them, there were 78 types of western medicine with 1,876 prescriptions (96.80%), and 11 types of traditional Chinese medicine with 62 prescriptions (3.20%). The main medications used were anti-anxiety and antidepressant medications (44.94%) and psychiatric medications (42.21%). The dosage forms were all oral, with tablets (78.53%), capsules (17.54%), and solution preparations (2.17%) being the top three in frequency. According to the prescription review results, the initial pass rate of internet-based system review was 64.26%. After intervention by the internet-based system and manual review by pharmacist reviewers, the final pass rate of internet-based prescriptions reached 99.76%.ConclusionThe practice of pharmaceutical services and prescription analysis in internet-based psychiatric hospitals could significantly improve medication rationality, which fills the research gap in this field. In addition, it promotes the transformation of pharmaceutical service models

Cellular crosstalk of macrophages and therapeutic implications in non-small cell lung cancer revealed by integrative inference of single-cell transcriptomics

Introduction: Non-small cell lung cancer (NSCLC) exhibits heterogeneity with diverse immune cell infiltration patterns that can influence tumor cell behavior and immunotherapy. A comprehensive characterization of the tumor microenvironment can guide precision medicine.Methods: Here, we generated a single-cell atlas of 398170 cells from 52 NSCLC patients, and investigated the imprinted genes and cellular crosstalk for macrophages. Subsequently, we evaluated the effect of tumor cells on macrophages and verified the expression of marker genes using co-culture experiments, flow cytometry and RT-qPCR assays.Results: Remarkable macrophage adaptability to NSCLC environment was observed, which contributed to generating tumor-associated macrophages (TAMs). We identified 5 distinct functional TAM subtypes, of which the majority were SELENOP-positive macrophages, with high levels of SLC40A1 and CCL13. The TAMs were also involved in mediating CD8+ T cell activity and form intercellular interaction with cancer cells, as indicated by receptor-ligand binding. Indirect coculture of tumor cells SPC-A1 and THP-1 monocytes, produced M2-like TAMs that highly expressed several markers of SELENOP-positive macrophages. The abundance of this type TAMs seemed to be associated with poorer overall survival rates [hazard ratio (HR) = 1.34, 95% confidence interval (CI) = 0.98-1.83, p = 0.068] based on deconvolution of TCGA-LUAD dataset.Discussion: In summary, we provided a high-resolution molecular resource of TAMs, and displayed the acquired properties in the tumor microenvironment. Dynamic crosstalk between TAMs and tumor cells via multiple ligand-receptor pairs were revealed, emphasizing its role in sustaining the pro-tumoral microenvironment and its implications for cancer therapy

Wip1-dependent modulation of macrophage migration and phagocytosis

Macrophage accumulation within the vascular wall is a hallmark of atherosclerosis. Controlling macrophage conversion into foam cells remains a major challenge for treatment of atherosclerotic diseases. Here, we show that Wip1, a member of the PP2C family of Ser/Thr protein phosphatases, modulates macrophage migration and phagocytosis associated with atherosclerotic plaque formation. Wip1 deficiency increases migratory and phagocytic activities of the macrophage under stress conditions. Enhanced migration of Wip1-/- macrophages is mediated by Rac1-GTPase and PI3K/AKT signalling pathways. Elevated phagocytic ability of Wip1-/- macrophages is linked to CD36 plasma membrane recruitment that is regulated by AMPK activity. Our study identifies Wip1 as an intrinsic negative regulator of macrophage chemotaxis. We propose that Wip1-dependent control of macrophage function may provide avenues for preventing or eliminating plaque formation in atherosclerosis

NtMYB4 and NtCHS1 Are Critical Factors in the Regulation of Flavonoid Biosynthesis and Are Involved in Salinity Responsiveness

High levels of salinity induce serious oxidative damage in plants. Flavonoids, as antioxidants, have important roles in reactive oxygen species (ROS) scavenging. In the present study, the tobacco R2R3 MYB type repressor, NtMYB4, was isolated and characterized. The expression of NtMYB4 was suppressed by salinity. Overexpression of NtMYB4 reduced the salt tolerance in transgenic tobacco plants. NtMYB4 repressed the promoter activity of NtCHS1 and negatively regulated its expression. Rutin accumulation was significantly decreased in NtMYB4 overexpressing transgenic plants and NtCHS1 RNAi silenced transgenic plants. Moreover, high H2O2 and O2− contents were detected in both types of rutin-reduced transgenic plants under high salt stress. In addition, exogenous rutin supplementation effectively scavenged ROS (H2O2 and O2−) and improved the salt tolerance of the rutin-reduced transgenic plants. In contrast, NtCHS1 overexpressing plants had increased rutin accumulation, lower H2O2 and O2− contents, and higher tolerance to salinity. These results suggested that tobacco NtMYB4 acts as a salinity response repressor and negatively regulates NtCHS1 expression, which results in the reduced flavonoid accumulation and weakened ROS-scavenging ability under salt stress

Enhanced Anti-diabetic Effect of Berberine Combined With Timosaponin B2 in Goto-Kakizaki Rats, Associated With Increased Variety and Exposure of Effective Substances Through Intestinal Absorption

Objective: Inspired by the traditionally clinical application of herb pair Zhimu-Huangbo to treat diabetes, a combination of plant ingredients, timosaponin B2 (TB-2) and berberine (BBR), was evaluated for their anti-diabetic efficacy and cooperative mechanisms.Methods: The efficacy and pharmacokinetics of orally administered TB-2 (33.3 mg/kg/day), BBR (66.7 mg/kg/day), and TB-2+BBR (100 mg/kg/day) were evaluated in spontaneously non-obese diabetic Goto-Kakizaki (GK) rats, and metformin (200 mg/kg/day) was used as a positive control. The comparative exposure of the parent drugs, timosaponin A3 (TB-2 metabolite), and M1–M5 (BBR metabolites) was quantified in the portal vein plasma (before hepatic disposition), liver, and systemic plasma (after hepatic disposition) of normal rats on single and combination treatments. Cooperative mechanism of TB-2 and BBR on intestinal absorption and hepatic metabolism was investigated in Caco-2 cells and primary hepatocytes, respectively.Results: After a 6-week experiment, non-fasting and fasting blood glucose levels and oral glucose tolerance test results showed that TB-2+BBR treatments (100 mg/kg/day) displayed significantly anti-diabetic efficacy in GK rats, comparable to that on metformin treatments. However, no significant improvement was observed on TB-2 or BBR treatments alone. Compared to single treatments, combination treatments led to the increased circulating levels of BBR by 107% in GK rats. In normal rats, the hepatic exposure of BBR, timosaponin A3, and M1–M5 was several hundred folds higher than their circulating levels. Co-administration also improved the levels in the plasma and liver by 41–114% for BBR, 141–230% for TB-2, and 12–282% for M1–M5. In vitro, the interaction between TB-2 and BBR was mediated by intestinal absorption, rather than hepatic metabolism.Conclusion: Combining TB-2 and BBR enhanced the anti-diabetic efficacy by increasing the in vivo variety of effective substances, including the parent compounds and active metabolites, and improving the levels of those substances through intestinal absorption. This study is a new attempt to assess the effects of combined plant ingredients on diabetes by scientifically utilizing clinical experience of an herb pair