Perioperative Toripalimab Plus Chemotherapy for Patients With Resectable Non-Small Cell Lung Cancer: The Neotorch Randomized Clinical Trial

IMPORTANCE: Adjuvant and neoadjuvant immunotherapy have improved clinical outcomes for patients with early-stage non-small cell lung cancer (NSCLC). However, the optimal combination of checkpoint inhibition with chemotherapy remains unknown. OBJECTIVE: To determine whether toripalimab in combination with platinum-based chemotherapy will improve event-free survival and major pathological response in patients with stage II or III resectable NSCLC compared with chemotherapy alone. DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial enrolled patients with stage II or III resectable NSCLC (without EGFR or ALK alterations for nonsquamous NSCLC) from March 12, 2020, to June 19, 2023, at 50 participating hospitals in China. The data cutoff date for this interim analysis was November 30, 2022. INTERVENTIONS: Patients were randomized in a 1:1 ratio to receive 240 mg of toripalimab or placebo once every 3 weeks combined with platinum-based chemotherapy for 3 cycles before surgery and 1 cycle after surgery, followed by toripalimab only (240 mg) or placebo once every 3 weeks for up to 13 cycles. MAIN OUTCOMES AND MEASURES: The primary outcomes were event-free survival (assessed by the investigators) and the major pathological response rate (assessed by blinded, independent pathological review). The secondary outcomes included the pathological complete response rate (assessed by blinded, independent pathological review) and adverse events. RESULTS: Of the 501 patients randomized, 404 had stage III NSCLC (202 in the toripalimab + chemotherapy group and 202 in the placebo + chemotherapy group) and 97 had stage II NSCLC and were excluded from this interim analysis. The median age was 62 years (IQR, 56-65 years), 92% of patients were male, and the median follow-up was 18.3 months (IQR, 12.7-22.5 months). For the primary outcome of event-free survival, the median length was not estimable (95% CI, 24.4 months-not estimable) in the toripalimab group compared with 15.1 months (95% CI, 10.6-21.9 months) in the placebo group (hazard ratio, 0.40 [95% CI, 0.28-0.57], P \u3c .001). The major pathological response rate (another primary outcome) was 48.5% (95% CI, 41.4%-55.6%) in the toripalimab group compared with 8.4% (95% CI, 5.0%-13.1%) in the placebo group (between-group difference, 40.2% [95% CI, 32.2%-48.1%], P \u3c .001). The pathological complete response rate (secondary outcome) was 24.8% (95% CI, 19.0%-31.3%) in the toripalimab group compared with 1.0% (95% CI, 0.1%-3.5%) in the placebo group (between-group difference, 23.7% [95% CI, 17.6%-29.8%]). The incidence of immune-related adverse events occurred more frequently in the toripalimab group. No unexpected treatment-related toxic effects were identified. The incidence of grade 3 or higher adverse events, fatal adverse events, and adverse events leading to discontinuation of treatment were comparable between the groups. CONCLUSIONS AND RELEVANCE: The addition of toripalimab to perioperative chemotherapy led to a significant improvement in event-free survival for patients with resectable stage III NSCLC and this treatment strategy had a manageable safety profile. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04158440

Disaster Chain Analysis of Landfill Landslide: Scenario Simulation and Chain-Cutting Modeling

Landfill landslide is a man-made event that occurs when poorly managed garbage mounds at landfills collapse. It has become common in recent decades due to the rising waste volumes in cities. Normally, it is a complex process involving many disaster-causing factors and composed by many sequential sub-events. However, most current studies treat the landslide as a single and independent event and cannot give a full picture of the disaster. We propose a disaster chain analysis framework for landfill landslide in terms of scenario simulation and chain-cutting modeling. Each stage of the landfill landslide is modeled by taking advantage of various advanced techniques, e.g., remote sensing, 3DGIS, non-Newtonian fluid model, central finite difference scheme, and agent-base steering model. The 2015 Shenzhen “1220” landslide was firstly reviewed to summarize the general disaster chain model for landfill landslide. Guided by this model, we then proposed the specific steps for landfill landslide disaster chain analysis and applied them to another undergoing landfill, i.e., Xinwuwei landfill in Shenzhen, China. The scenario simulation in this landfill provides suggestions on potential hazardous risks and some applicable treatments. Through chain-cutting modeling, we further validated the effectiveness and feasibility of these treatments. The most optimized solution is subsequently deduced, which can provide support for disaster prevention and mitigation for this landfill

Multiple delivery strategies of nanocarriers for myocardial ischemia-reperfusion injury: current strategies and future prospective

AbstractAcute myocardial infarction, characterized by high morbidity and mortality, has now become a serious health hazard for human beings. Conventional surgical interventions to restore blood flow can rapidly relieve acute myocardial ischemia, but the ensuing myocardial ischemia-reperfusion injury (MI/RI) and subsequent heart failure have become medical challenges that researchers have been trying to overcome. The pathogenesis of MI/RI involves several mechanisms, including overproduction of reactive oxygen species, abnormal mitochondrial function, calcium overload, and other factors that induce cell death and inflammatory responses. These mechanisms have led to the exploration of antioxidant and inflammation-modulating therapies, as well as the development of myocardial protective factors and stem cell therapies. However, the short half-life, low bioavailability, and lack of targeting of these drugs that modulate these pathological mechanisms, combined with liver and spleen sequestration and continuous washout of blood flow from myocardial sites, severely compromise the expected efficacy of clinical drugs. To address these issues, employing conventional nanocarriers and integrating them with contemporary biomimetic nanocarriers, which rely on passive targeting and active targeting through precise modifications, can effectively prolong the duration of therapeutic agents within the body, enhance their bioavailability, and augment their retention at the injured myocardium. Consequently, these approaches significantly enhance therapeutic effectiveness while minimizing toxic side effects. This article reviews current drug delivery systems used for MI/RI, aiming to offer a fresh perspective on treating this disease

Integrating Network Pharmacology with Molecular Docking to Unravel the Active Compounds and Potential Mechanism of Simiao Pill Treating Rheumatoid Arthritis

Objective. To explore the main components and unravel the potential mechanism of simiao pill (SM) on rheumatoid arthritis (RA) based on network pharmacological analysis and molecular docking. Methods. Related compounds were obtained from TCMSP and BATMAN-TCM database. Oral bioavailability and drug-likeness were then screened by using absorption, distribution, metabolism, and excretion (ADME) criteria. Additionally, target genes related to RA were acquired from GeneCards and OMIM database. Correlations about SM-RA, compounds-targets, and pathways-targets-compounds were visualized through Cytoscape 3.7.1. The protein-protein interaction (PPI) network was constructed by STRING. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed via R packages. Molecular docking analysis was constructed by the Molecular Operating Environment (MOE). Results. A total of 72 potential compounds and 77 associated targets of SM were identified. The compounds-targets network analysis indicated that the 6 compounds, including quercetin, kaempferol, baicalein, wogonin, beta-sitosterol, and eugenol, were linked to ≥10 target genes, and the 10 target genes (PTGS1, ESR1, AR, PGR, CHRM3, PPARG, CHRM2, BCL2, CASP3, and RELA) were core target genes in the network. Enrichment analysis indicated that PI3K-Akt, TNF, and IL-17 signaling pathway may be a critical signaling pathway in the network pharmacology. Molecular docking showed that quercetin, kaempferol, baicalein, and wogonin have good binding activity with IL6, VEGFA, EGFR, and NFKBIA targets. Conclusion. The integrative investigation based on bioinformatics/network topology strategy may elaborate on the multicomponent synergy mechanisms of SM against RA and provide the way out to develop new combination medicines for RA

DAPR-tree: a distributed spatial data indexing scheme with data access patterns to support Digital Earth initiatives

This paper proposes a novel data indexing scheme, the distributed access pattern R-tree (DAPR-tree), for spatial data retrieval in a distributed computing environment. As compared to traditional distributed indexing schemes, the DAPR-tree introduces the data access patterns during the indexing utilization stage so that a more balanced indexing structure can be provided for spatial applications (e.g. Digital Earth data warehouse). In this new indexing scheme, (a) an indexing penalty matrix is proposed by considering the balance of data number, topology and access load between different indexing nodes; (b) an ‘access possibility’ element is integrated to a classic ‘Master-Client’ structure for a distributed indexing environment; and (c) indexing algorithm for the DAPR-tree is provided for index implementations. By using a duplication of official GEOSS Clearinghouse system as a case study, the DAPR-tree was evaluated in a number of scenarios. The results show that our indexing schemes generally outperform (around 9%) traditional distributed indices with the utilization of data access patterns. Finally, we discuss the applicability of the DARP-tree and document DARP-tree shortcomings to encourage researchers pursuing related topics in Big Data indexing for Digital Earth and other geospatial initiatives

Noctua 12. évf. 4. szám

Puerarin (PUE) is the most abundant isoflavonoid in kudzu root. It is widely used as a therapeutic agent for the treatment of cardiovascular diseases. However, the short elimination half-life, poor-bioavailability, and acute intravascular hemolysis of PUE are the main obstacles to its widespread clinical applications. Whereas PEG-PE micelles possess the ability to release medicine slowly, enhance the cellular uptake of drugs and improve their biocompatibility. Therefore, it was aim to fabricate puerarin-loaded PEG-PE (PUE@PEG-PE) micelles to improve the pharmaceutical properties of drugs. It can be observed from the TEM images that PUE@PEG-PE micelles appeared obvious core-shell structure and remained well-dispersed without aggregation and adhesion. PUE was successfully embedded in the core of PEG-PE micelles, which was confirmed by FT-IR and 1H NMR spectra. In vitro studies showed that PUE@PEG-PE micelles exhibited a sustained release behavior in pH 7.4 PBS buffer and decreased hemolysis rate of PUE. Compared with PUE, PUE@PEG-PE micelles showed a 3.2-fold increase in the half-life of PUE and a 1.58-fold increase in bioavailability. In addition, the PUE@PEG-PE micelles exerted enhanced protective effect against isoprenaline-induced H9c2 cells apoptosis compared with PUE, as evident by decreased percentage of Hoechst-positive cells, Caspase 3 activity, Bax expression, and increased Bcl-2 expression. Notably, the PEG-PE micelles exhibited favorable cellular uptake efficiency on H9c2 cells, and this may account for their enhanced anti-apoptotic effect of the incorporated drug. Altogether, the PUE@PEG-PE micelles were not only able to control the drug release but also offered promise to enhance the pharmacokinetic and pharmacodynamic potential of PUE

Localization and Extraction of Road Poles in Urban Areas from Mobile Laser Scanning Data

Lampposts, traffic lights, traffic signs, utility poles and so forth are important road furniture in urban areas. The fast and accurate localization and extraction of this type of furniture is urgent for the construction and updating of infrastructure databases in cities. This paper proposes a pipeline for mobile laser scanning data processing to locate and extract road poles. The proposed method is based on the vertical continuity with isolation feature of the pole part and the overall roughness feature of the attachment part of road poles. The isolation feature of the pole part is analysed by constructing two concentric cylinders from bottom to top and there should be no or a limited number of, points between these two cylinders. After splitting up the pole part and the attachment part of a road pole, the roughness of the candidate attachment points is computed and the attachment is obtained by performing region growing method based on roughness values. By applying the proposed pipeline to different situations in two datasets, the proposed method proves to be efficient not only in simple scenes but also in cluttered scenes

Mutagenesis of seed storage protein genes in Soybean using CRISPR/Cas9

Abstract Objective Soybean seeds are an important source of vegetable proteins for both food and industry worldwide. Conglycinins (7S) and glycinins (11S), which are two major families of storage proteins encoded by a small family of genes, account for about 70% of total soy seed protein. Mutant alleles of these genes are often necessary in certain breeding programs, as the relative abundance of these protein subunits affect amino acid composition and soy food properties. In this study, we set out to test the efficiency of the CRISPR/Cas9 system in editing soybean storage protein genes using Agrobacterium rhizogenes-mediated hairy root transformation system. Results We designed and tested sgRNAs to target nine different major storage protein genes and detected DNA mutations in three storage protein genes in soybean hairy roots, at a ratio ranging from 3.8 to 43.7%. Our work provides a useful resource for future soybean breeders to engineer/develop varieties with mutations in seed storage proteins

Polygonatum sibiricum Polysaccharides Protect against MPP-Induced Neurotoxicity via the Akt/mTOR and Nrf2 Pathways

Polygonatum sibiricum, a well-known life-prolonging tonic in Chinese medicine, has been widely used for nourishing nerves in the orient, but the underlying molecular mechanisms remain unclear. In this study, we found that P. sibiricum polysaccharides (PSP) ameliorated 1-methyl-4-phenyl-1,2.3,6-tetrahydropyridine- (MPTP-) induced locomotor activity deficiency and dopaminergic neuronal loss in an in vivo Parkinson’s disease (PD) mouse model. Additionally, PSP pretreatment inhibited N-methyl-4-phenylpyridine (MPP+) induced the production of reactive oxygen species, increasing the ratio of reduced glutathione/oxidized glutathione. In vitro experiments showed that PSP promoted the proliferation of N2a cells in a dose-dependent manner, while exhibiting effects against oxidative stress and neuronal apoptosis elicited by MPP+. These effects were found to be associated with the activation of Akt/mTOR-mediated p70S6K and 4E-BP1 signaling pathways, as well as nuclear factor erythroid 2-related factor 2- (Nrf2-) mediated NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1), glutamate-cysteine ligase catalytic subunit (Gclc), and glutamate-cysteine ligase modulatory subunit (Gclm), resulting in antiapoptotic and antioxidative effects. Meanwhile, PSP exhibited no chronic toxicity in C57BJ/6 mice. Together, our results suggest that PSP can serve as a promising therapeutic candidate with neuroprotective properties in preventing PD