作者: Zhao, Jie ; Wen, Shidi ; Zhou, Anda ; Wan, Rui ; Duan, Jianchun ; Sun, Boyang ; Cui, Lina ; Bai, Hua ; Wang, Jie ; He, Danming ; Lin, Yiwen ; Wang, Zhijie ; Wang, Lu ; Fang, Wenfeng ; Zhang, Li ; Zhong, Jia ; Zhuang, Wei

BACKGROUNDPredictive biomarkers and models of immune checkpoint inhibitors (ICIs) have been extensively studied in non-small cell lung cancer (NSCLC). However, evidence for many biomarkers remains inconclusive, and the opaqueness of machine learning models hinders practicality. We aimed to provide compelling evidence for biomarkers and develop a transparent decision tree model.METHODSWe consolidated data from 3,288 ICI-treated patients with NSCLC across real-world multicenter, public cohorts and the Choice-01 trial (ClinicalTrials.gov: NCT03856411). Over 50 features were examined for predicting durable clinical benefits (DCBs) from ICIs. Noteworthy biomarkers were identified to establish a decision tree model. Additionally, we explored the tumor microenvironment and peripheral CD8⁺ programmed death-1 (PD-1)+ T cell receptor (TCR) profiles.FINDINGSMultivariate logistic regression analysis identified tumor histology, PD-ligand 1 (PD-L1) expression, tumor mutational burden, line, and regimen of ICI treatment as significant factors. Mutation subtypes of EGFR, KRAS, KEAP1, STK11, and disruptive TP53 mutations were associated with DCB. The decision tree (DT10) model, using the ten clinicopathological and genomic markers, showed superior performance in predicting DCB in the training set (area under the curve [AUC] = 0.82) and consistently outperformed other models in test sets. DT10-predicted-DCB patients manifested longer survival, an enriched inflamed tumor immune phenotype (67%), and higher peripheral TCR diversity, whereas the DT10-predicted-NDB (non-durable benefit) group showed an enriched desert immune phenotype (86%) and higher peripheral TCR clonality.CONCLUSIONSThe model effectively predicted DCB after front-/subsequent-line ICI treatment, with or without chemotherapy, for squamous and non-squamous lung cancer, offering clinicians valuable insights into efficacy prediction using cost-effective variables.FUNDINGThis study was supported by the National Key R&D Program of China.

2023-05-26·Molecules (Basel, Switzerland)

Isolation, Identification and Molecular Mechanism Analysis of the Nematicidal Compound Spectinabilin from Newly Isolated Streptomyces sp. DT10.

Article

作者: Sun, Yuchen ; Tang, Lihua ; Chen, Yanlu ; Fang, Wenxia ; Odiba, Arome Solomon ; Xie, Jin ; Wu, Xiaogang ; Wang, Bin

Plant parasitic nematodes (PPNs) are highly destructive and difficult to control, while conventional chemical nematicides are highly toxic and cause serious environmental pollution. Additionally, resistance to existing pesticides is becoming increasingly common. Biological control is the most promising method for the controlling of PPNs. Therefore, the screening of nematicidal microbial resources and the identification of natural products are of great significance and urgency for the environmentally friendly control of PPNs. In this study, the DT10 strain was isolated from wild moss samples and identified as Streptomyces sp. by morphological and molecular analysis. Using Caenorhabditis elegans as a model, the extract of DT10 was screened for nematicidal activity, which elicited 100% lethality. The active compound was isolated from the extracts of strain DT10 using silica gel column chromatography and semipreparative high-performance liquid chromatography (HPLC). The compound was identified as spectinabilin (chemical formula C₂₈H₃₁O₆N) using liquid chromatography mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR). Spectinabilin exhibited a good nematicidal activity on C. elegans L1 worms, with a half-maximal inhibitory concentration (IC₅₀) of 2.948 μg/mL at 24 h. The locomotive ability of C. elegans L4 worms was significantly reduced when treated with 40 μg/mL spectinabilin. Further analysis of spectinabilin against known nematicidal drug target genes in C. elegans showed that it acts via target(s) different from those of some currently used nematicidal drugs such as avermectin and phosphine thiazole. This is the first report on the nematicidal activity of spectinabilin on C. elegans and the southern root-knot nematode Meloidogyne incognita. These findings may pave the way for further research and application of spectinabilin as a potential biological nematicide.

2023-02-10·Cardiovascular Therapeutics

DT-010 Exerts Cardioprotective Effects by Regulating the Crosstalk between the AMPK/PGC-1α Pathway and ERp57

Article

作者: Liu, Xiaoping ; Wu, Ximin ; Hu, Huihui ; Kang, Zhanfang ; Zhang, Xiaojing ; Deng, Xin

The AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) pathway performs a crucial role in energy metabolism and mitochondrial network. Our previous study found that DT-010, a novel danshensu (DSS) and tetramethylpyrazine (TMP) conjugate, had significant cardioprotective properties in vitro and in vivo. We also reported that ERp57 served as a major target of DSS using the chemical proteomics approach. In this article, we focus on exploring the interrelationship between the regulation of the AMPK/PGC-1α pathway and promoting ERp57 expression induced by DT-010 in tert-butylhydroperoxide- (t-BHP-) induced H9c2 cell injury. The results showed that DT-010 activated the AMPK/PGC-1α pathway and increased ERp57 protein expression. Importantly, the above phenomenon as well as the mitochondrial function can be partially reversed by siRNA-mediated ERp57 suppression. Meanwhile, silencing AMPK significantly inhibited the ERp57 expression induced by DT-010. In addition, molecular docking and kinase assay in vitro revealed that DT-010 had no direct regulation effects on AMPK activity. Taken together, DT-010 exerted cardioprotective effects by regulating the crosstalk of AMPK/PGC-1α pathway and ERp57, representing a potential therapeutic agent for ischemic heart disease.

100 项与 DT-010 相关的药物交易

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