BackgroundsImmunotherapy is less effective in patients with epidermal growth factor receptor (EGFR) mutant non-small-cell lung cancer (NSCLC). Lower programmed cell death-ligand 1 (PD-L1) expression ...and tumor mutation burden (TMB) are reported to be the underlying mechanism. Being another important factor to affect the efficacy of immunotherapy, tumor microenvironment (TME) characteristics of this subgroup of NSCLC are not comprehensively understood up to date. Hence, we initiated this study to describe the specific TME of EGFR-mutant lung adenocarcinoma (LUAD) from cellular compositional and functional perspectives to better understand the immune landscape of this most common subtype of NSCLC.MethodsWe used single-cell transcriptome sequencing and multiplex immunohistochemistry to investigate the immune microenvironment of EGFR-mutant and EGFR wild-type LUADs and determined the efficacy of immunotherapy. We analyzed single cells from nine treatment-naïve samples and compared them to three post-immunotherapy samples previously reported from single cell perspective using bioinformatics methods.ResultsWe found that EGFR-mutant malignant epithelial cells had similar characteristics to the epithelial cells in non-responders. EGFR-mutant LUAD lacked CD8+ tissue-resident memory (TRM) cells, which could promote tertiary lymphoid structure generation by secreting CXCL13. In addition, other cell types, including tumor-associated macrophages and cancer-associated fibroblasts, which are capable of recruiting, retaining, and expanding CD8+ TRM cells in the TME, were also deficient in EGFR-mutant LUAD. Furthermore, EGFR-mutant LUAD had significantly less crosstalk between T cells and other cell types via programmed cell death-1 (PD-1) and PD-L1 or other immune checkpoints compared with EGFR wild-type LUAD.ConclusionsOur findings provide a comprehensive understanding of the immune landscape of EGFR-mutant LUAD at the single-cell level. Based on the results, many cellular components might have negative impact on the specific TME of EGFR-mutant LUAD through influencing CD8+ TRM. Lack of CD8+ TRM might be a key factor responsible for the suppressive TME of EGFR-mutant LUAD.
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) have been first-line therapy in the treatment of non-small cell lung cancer (NSCLC) harboring
sensitive mutations. Progression ...inevitably happens after 10-14 months of first- or second-generation EGFR TKIs treatment for acquired resistance. Owing to the successful identification of
T790M, third-generation EGFR TKIs such as osimertinib were developed to target such resistance mutation. Nowadays, osimertinib has shown its efficacy both in first-line and second-line after resistance to previous generations of TKI treatment of
-mutant NSCLC. However, drug resistance also emerges on third-generation EGFR TKIs. Multiple mechanisms of acquired resistance have been identified, and some novel strategies were reported to overcome third-generation TKI resistance. Immune checkpoint inhibitors (ICIs) have dramatically changed the prognosis of selected patients. For patients with
-addicted metastatic NSCLC, ICIs have also revealed a potential role. In this review, we will take stock of mechanisms of acquired resistance to third-generation TKIs and discuss current challenges and future perspectives in clinical practice.
Klotho, an antiaging protein, has been shown to play a protective role in renal tubular epithelial-mesenchymal transition (EMT) during the development of diabetic kidney disease (DKD). Long noncoding ...RNAs (lncRNAs) participate in the progression of EMT in many diseases. However, the effect of Klotho on lncRNAs during the development of DKD is still unknown. In this study, we found that Klotho overexpression in high-fat diet (HFD)- and streptozotocin (STZ)-induced DKD mice significantly inhibited the expression of lncRNA nuclear-enriched abundant transcript 1 (Neat1). We demonstrated that NEAT1 was significantly upregulated in both bovine serum albumin (BSA)-stimulated HK2 cells and mice with HFD- and STZ-induced diabetes. In addition, we observed that Klotho displays colocalization with NEAT1. Furthermore, overexpression of Klotho can inhibit the high expression of NEAT1 in BSA-stimulated HK2 cells, while silencing Klotho can further upregulate the expression of NEAT1. Silencing NEAT1 in HK2 cells resulted in inhibition of the EMT-related markers alpha smooth muscle actin (α-SMA) and vimentin (VIM) and the renal fibrosis-related markers transforming growth factor-β1 (TGF-β1) and connective tissue growth factor (CTGF). The effect of NEAT1 on DKD was partly mediated by regulation of the ERK1/2 signaling pathway. Finally, we found that silencing NEAT1 can reverse the activation of EMT and fibrosis caused by Klotho silencing in a manner dependent on the ERK1/2 signaling pathway. These findings reveal a new regulatory pathway by which Klotho regulates ERK1/2 signaling via NEAT1 to protect against EMT and renal fibrosis, suggesting that NEAT1 is a potential therapeutic target for DKD.
Drones and drone swarms, characterized by their low price and ease of deployment, are being utilized to launch assaults, and presenting a great threat to the public and homeland security in recent ...years. Countering drones or drone swarms is thus of great significance. Some effective counter approaches for a small group of drones have been studied. However, these approaches may be insufficient to counter a large-scale drone swarm due to the lack of efficient time-saving detecting technologies. Towards this end, this paper proposes a fast counter approach to deprive the drone swarm of its coordination and clustering capabilities in a short time by splitting the drone swarm into several unconnected components. To achieve efficient splitting, two efficient algorithms for searching critical nodes are proposed, namely, the genetic algorithm and the particle swarm optimization algorithm. Extensive simulation results are presented to validate the superior performances of the proposed two algorithms for splitting the drone swarms in different formations. The results show that the drone swarms lose their coordination ability as they are forced to split into multiple components with a constraint of group size. The high accuracy and efficiency of the proposed algorithms are also verified by a series of comparative experiments.
It is known that thyroid hormones play pivotal roles in a wide variety of pathological and physiological events. Thyroid diseases, mainly including hyperthyroidism, hypothyroidism, and thyroid ...cancer, are highly prevalent worldwide health problems and frequently associated with severe clinical manifestations. However, etiology of hyperthyroidism, hypothyroidism, and thyroid cancer is not fully understood. Purinergic signaling accounts for a complex network of receptors and extracellular enzymes responsible for the recognition and degradation of extracellular nucleotides and adenosine. It has been established that purinergic signaling modulates pathways in a wide range of physiopathological conditions including hypertension, diabetes, hepatic diseases, psychiatric and neurodegeneration, rheumatic immune diseases, and cancer. More recently, the purinergic system is found to exist in thyroid gland and play an important role in the pathophysiology of thyroid diseases. Therefore, throughout this review, we focus on elaborating the changes in purinergic receptors, extracellular enzymes, and extracellular nucleotides and adenosine in hyperthyroidism, hypothyroidism, and thyroid cancer. Profound understanding of the relationship between the purinergic signaling with thyroid diseases provides a promising research area for insights into the molecular basis of thyroid diseases and also develops new and exciting insights into the treatment of thyroid diseases, especially thyroid cancer.
Elaiophylins belong to a special family of 16-membered macrodiolides with C
-symmetry. They have exhibited remarkable biological activities, such as antimicrobial, anthelmintic, anticancer, ...immunosuppressive, anti-inflammatory, antiviral, and α-glucosidase inhibitory activities. A member of elaiophylins, efomycin M, is as a specific small molecule inhibitor of selectin in preclinical trial for the treatment of psoriasis, ischemia-reperfusion, and allergy. The biosynthetic investigation of elaiophylins has uncovered a unique thioesterase, which is responsible for the formation of C
-symmetric diolide. We herein summarize the natural occurrence, bioactivity, and biosynthesis of elaiophylins covering the literatures from 1959 to 2019. Hopefully, this review will inspire further research interests of these compounds and encourage the discovery of new analogues by metabolic engineering or genome mining.
Abstract
The remarkable advances in next-generation sequencing technology have enabled the wide usage of sequencing as a clinical tool. To promote the advance of precision oncology for breast cancer ...in China, here we report a large-scale prospective clinical sequencing program using the Fudan-BC panel, and comprehensively analyze the clinical and genomic characteristics of Chinese breast cancer. The mutational landscape of 1,134 breast cancers reveals that the most significant differences between Chinese and Western patients occurred in the hormone receptor positive, human epidermal growth factor receptor 2 negative breast cancer subtype. Mutations in p53 and Hippo signaling pathways are more prevalent, and 2 mutually exclusive and 9 co-occurring patterns exist among 9 oncogenic pathways in our cohort. Further preclinical investigation partially suggests that
NF2
loss-of-function mutations can be sensitive to a Hippo-targeted strategy. We establish a public database (Fudan Portal) and a precision medicine knowledge base for data exchange and interpretation. Collectively, our study presents a leading approach to Chinese precision oncology treatment and reveals potentially actionable mutations in breast cancer.
Two new glycerolipids, syngaculipids A and B (1 and 2), one first naturally occurring metabolite (8), together with five known compounds (3–7) were isolated from the AcOEt fraction of Syngnathus acus ...L. (Hai‐Long). Their structures were elucidated by comprehensive spectral analyses involving UV, IR, MS, 1D and 2D NMR spectra and ECD calculations. All the isolated compounds were evaluated for their cytotoxicity against A549 and HCT‐116 cell lines. Compound 8 exhibited moderate cytotoxicity with IC50 values of 34.5 and 38.9 μM on the A549 and HCT‐116 cell lines, respectively.
This paper describes the experimental and numerical study on the axial compressive behaviour of circular-in-circular concrete-filled double-skin steel tube (CFDST) stub columns with large void ratio. ...Nine specimens with various void ratio (Rv), diameter-to-thickness ratio of outer tube (Do/to) and compressive strength of concrete (fcu) were tested under axial compression. The failure patterns, load versus displacement (strain) relationship, ultimate capacity and elastic composite stiffness of the specimens were investigated. The experimental results show that all specimens have good structural performance. The typical failure patterns of this new type of columns include local buckling of outer or inner tubes and crushing of concrete infill at the primary buckling locations of both tubes. It is observed from the tests that, there are three key stages in the load versus displacement (strain) relationship, namely: approximative elastic, elastoplastic and nonlinear post-peak, and with the augment of Rv and Do/to and the reduce of fcu, the ultimate capacity and elastic composite stiffness of the specimens decrease. Apart from tests, a finite element (FE) model was developed to further study the axial compressive behaviour of circular-in-circular CFDST stub columns with large void ratio, and the model was validated against the experimental results. Finally, a simplified analytical model to predict the ultimate capacity of circular-in-circular CFDST stub columns with large void ratio was developed, and the accuracy of the model was verified by the available experimental results. It can be used by the practising engineers in the future design of this type of columns.
In this paper, we experimentally and numerically investigate the axial compressive behaviour of circular-in-circular CFDST stub columns with large void ratio (i.e. from 0.8 to 0.9). Finally, we suggest a simplified analytical model to predict the ultimate capacity of circular-in-circular CFDST stub columns with large void ratio on the basis of systematic parametric study using the finite element (FE) model, and the accuracy of the model is verified by comparison with numerical and the available experimental results. Display omitted
•New axial compressive tests on circular CFDST stub columns with void ratio of 0.8–0.9.•FE model for axially compressed circular CFDST stub columns with large void ratio.•Simplified analytical model for the ultimate capacity of circular CFDST stub columns with large void ratio.
PDF
