Discovery of Trisubstituted N-Phenylpyrazole Containing Diamides with Improved Insecticidal Activity.

To increase the structural diversity of insecticides and meet the needs of effective integrated insect management, the structure of chlorantraniliprole was modified based on a previously established three-dimensional quantitative structure-activity relationship (3D-QSAR) model. The pyridinyl moiety in the structure of chlorantraniliprole was replaced with a 4-fluorophenyl group. Further modifications of this 4-fluorophenyl group by introducing a halogen atom at position 2 and an electron-withdrawing group (e.g., iodine, cyano, and trifluoromethyl) at position 5 led to 34 compounds with good insecticidal efficacy against Mythimna separata, Plutella xylostella, and Spodoptera frugiperda. Among them, compound IV f against M. separata showed potency comparable to that of chlorantraniliprole. IV p against P. xylostella displayed a 4.5 times higher potency than chlorantraniliprole. In addition, IV d and chlorantraniliprole exhibited comparable potencies against S. frugiperda. Transcriptome analysis showed that the molecular target of compound IV f is the ryanodine receptor. Molecular docking was further performed to verify the mode of action and insecticidal activity against resistant P. xylostella.

YTHDF1's Regulatory Involvement in Breast Cancer Prognosis, Immunity, and the ceRNA Network.

YTH N6-methyladenosine RNA binding protein 1 (YTHDF1), an m6A reader, has a role in the development and progression of breast cancer as well as the immunological microenvironment. The networks of competing endogenous RNA in cancer have received much attention in research. In tumor gene therapy, the regulatory networks of m6A and competing endogenous RNA are increasingly emerging as a new route. We evaluated the relationship between the YTHDF1 expression, overall survival, and clinicopathology of breast cancer using TCGA, PrognoScan, and other datasets. We used Western blot to demonstrate that YTHDF1 is substantially expressed in breast cancer tissues. Furthermore, we explored YTHDF1's functions in the tumor mutational burden, microsatellite instability, and tumor microenvironment. Our findings indicate that YTHDF1 is a critical component of the m6A regulatory proteins in breast cancer and may have a particular function in the immunological microenvironment. Crucially, we investigated the relationship between YTHDF1 and the associated competitive endogenous RNA regulatory networks, innovatively creating three such networks (Dehydrogenase/Reductase 4-Antisense RNA 1-miR-378g-YTHDF1, HLA Complex Group 9-miR-378g-YTHDF1, Taurine Up-regulated 1-miR-378g-YTHDF1). Furthermore, we showed that miR-378g could inhibit the expression of YTHDF1, and that miR-378g/YTHDF1 could impact MDA-MB-231 proliferation. We speculate that YTHDF1 may serve as a biomarker for poor prognosis and differential diagnosis, impact the growth of breast cancer cells via the ceRNA network axis, and be a target for immunotherapy against breast cancer.

Exosomal miRNAs assist in the crosstalk between tumor cells and immune cells and its potential therapeutics.

Exosomes are small extracellular vesicles that carry active substances (including proteins, lipids, and nucleic acids) and are essential for homeostasis and signal transmission. Recent studies have focused on the function of exosomal miRNAs in tumor progression. Researchers have expanded the use of exosomes and miRNAs as potential therapeutic tools and biomarkers to detect tumor progression. Immune cells, as an important part of the tumor microenvironment (TME), secrete a majority of exosome-derived miRNAs involved in the biological processes of malignancies. However, the underlying mechanisms remain unclear. Currently, there is no literature that systematically summarizes the communication of exosome-derived miRNAs between tumor cells and immune cells. Based on the cell specificity of exosome-derived miRNAs, this review provides the first comprehensive summary of the significant miRNAs from the standpoint of exosome sources, which are tumor cells and immune cells. Furthermore, we elaborated on the potential clinical applications of these miRNAs, attempting to propose existing difficulties and future possibilities in tumor diagnostics and therapy.

Pre-metastatic niche: from revealing the molecular and cellular mechanisms to the clinical applications in breast cancer metastasis.

Breast cancer (BC) is one of the most commonly diagnosed cancers and the leading cause of cancer-related deaths in women worldwide. Metastasis is a major contributor to high cancer mortality and is usually the endpoint of a series of sequential and dynamic events. One of the critical events is forming a pre-metastatic niche (PMN) that occurs before macroscopic tumor cell invasion and provides a suitable environment for tumor cells to colonize and progress into metastases. Due to the unique characteristics of PMN in cancer metastasis, developing therapies to target PMN may bring new advantages in preventing cancer metastasis at an early stage. Various biological molecules, cells, and signaling pathways are altered in BC, regulating the functions of distinctive immune cells and stromal remodeling, inducing angiogenesis, and effect metabolic reprogramming and organotropism to promote PMN formation. In this review, we elucidate the multifaceted mechanisms contributing to the development of PMN in BC, discuss the characteristics of PMN, and highlight the significance of PMN in providing potential diagnostic and therapeutic strategies for BC metastasis, which may bring promising insights and foundations for future studies.

An improved Yolov5s based on transformer backbone network for detection and classification of bronchoalveolar lavage cells.

Biological tissue information of the lung, such as cells and proteins, can be obtained from bronchoalveolar lavage fluid (BALF), through which it can be used as a complement to lung biopsy pathology. BALF cells can be confused with each other due to the similarity of their characteristics and differences in the way sections are handled or viewed. This poses a great challenge for cell detection. In this paper, An Improved Yolov5s Based on Transformer Backbone Network for Detection and Classification of BALF Cells is proposed, focusing on the detection of four types of cells in BALF: macrophages, lymphocytes, neutrophils and eosinophils. The network is mainly based on the Yolov5s network and uses Swin Transformer V2 technology in the backbone network to improve cell detection accuracy by obtaining global information; the C3Ghost module (a variant of the Convolutional Neural Network architecture) is used in the neck network to reduce the number of parameters during feature channel fusion and to improve feature expression performance. In addition, embedding intersection over union Loss (EIoU_Loss) was used as a bounding box regression loss function to speed up the bounding box regression rate, resulting in higher accuracy of the algorithm. The experiments showed that our model could achieve mAP of 81.29% and Recall of 80.47%. Compared to the original Yolov5s, the mAP has improved by 3.3% and Recall by 3.67%. We also compared it with Yolov7 and the newly launched Yolov8s. mAP improved by 0.02% and 2.36% over Yolov7 and Yolov8s respectively, while the FPS of our model was higher than both of them, achieving a balance of efficiency and accuracy, further demonstrating the superiority of our model.

Role of neutrophils on cancer cells and other immune cells in the tumor microenvironment.

The notion that neutrophils only perform a specific set of single functions in the body has changed with the advancement of research methods. As the most abundant myeloid cells in human blood, neutrophils are currently emerging as important regulators of cancer. Given the duality of neutrophils, neutrophil-based tumor therapy has been clinically carried out in recent years and has made some progress. But due to the complexity of the tumor microenvironment, the therapeutic effect is still not satisfactory. Therefore, in this review, we discuss the direct interaction of neutrophils with the five most common cancer cells and other immune cells in the tumor microenvironment. Also, this review covered current limitations, potential future possibilities, and therapeutic approaches targeting neutrophil function in cancer therapy.

Tumor-derived Cav-1 promotes pre-metastatic niche formation and lung metastasis in breast cancer.

Rationale: Breast cancer (BC), as one of the most frequently diagnosed cancer, has a poor prognosis due to the development of distant metastasis. Among the BC metastatic sites, lung is one of the most common sites. Caveolin-1 (Cav-1) is a functional membrane protein that plays a vital role in tumor metastasis. Although studies have revealed that Cav-1 levels were elevated in patients with advanced cancer, whether Cav-1 affects BC lung metastasis by influencing the formation of pre-metastatic niche (PMN) through exosomes has not been explored. Methods: Differential ultracentrifugation, transmission electron microscopy and nanoparticle tracking analysis were used to verify the presence of exosomes. Transwell assays were used to examine the biological effects of exosomes containing Cav-1. Both in vitro cell cultures and mammary tumor cell-induced mouse models were used to assess the lung metastasis. The regulatory mechanisms of PMN formation were revealed using western blot, flow cytometry, RT-qPCR, immunofluorescence assays, gene overexpression assays and RNA interference assays. Results: Exosomes have critical functions in transporting Cav-1 between primary BC and metastatic organ microenvironments. Cav-1 in BC-derived exosomes can act as a signaling molecule to mediate intercellular communication and regulate the PMN before lung metastasis by regulating the expression of PMN marker genes and inflammatory chemokines in lung epithelial cells, promoting the secretion of tenascin-C (TnC) in lung fibroblasts to cause extracellular matrix (ECM) deposition, and inhibiting the PTEN/CCL2/VEGF-A signaling pathway in lung macrophages to facilitate their M2-type polarization and angiogenesis. Conclusion: Our study investigated the mechanisms of lung PMN formation induced by Cav-1 in BC-derived exosomes. Our data may provide new directions for exploring the mechanisms and developing treatment strategies of BC lung metastasis.

3D-QSAR-Based Molecular Design to Discover Ultrahigh Active N-Phenylpyrazoles as Insecticide Candidates.

Three-dimensional quantitative structure-activity relationship (3D-QSAR) is one of the most important and effective tools to direct molecular design in new pesticide development. Chlorantraniliprole is an anthranilic diamide ryanodine receptor (RyR) agonist with ultrahigh activity, high selectivity, and mammalian safety. To continue our studies on new insecticide development, here, we designed new insecticidal N-phenylpyrazoles by using 3D-QSAR of chlorantraniliprole analogues as a guide. Most of the target compounds synthesized exhibited medium to excellent activity against Mythimna separata, Plutella xylostella, and Spodoptera frugiperda. Compounds III b and III y showed similar activity against M. separata as chlorantraniliprole (LC50 values: 0.21, 0.25, and 0.16 µg mL-1 respectively). Compounds III b exhibited a 3-fold higher potency against P. xylostella than chlorantraniliprole. For S. frugiperda, the potency of III a and III b was 2.9 and 2.0 times higher than that of the positive control, respectively. The mode of action of the title compounds was validated by calcium imaging experiments and molecular docking using their target RyRs. III b can dock well with mutated P. xylostella RyRs, implying a potentially lower cross-resistance risk as compared with commercial RyR agonists. Density functional theory calculations suggested the feasibility of higher potency with the structural modifications. Compound III b was found to be an ultrahigh active insecticidal candidate with a broad spectrum for integrated pest management.

Facile synthesis, crystal structure, quantum calculation, and biological evaluations of novel selenenyl sulfide compounds as potential agrochemicals.

BACKGROUND: In order to design compounds with fresh molecular skeleton to break through the limitation of available agrochemicals, a series of 36 novel selenenyl sulfide compounds were chemically synthesized, and their biological activities were fully evaluated against tobacco mosaic virus (TMV), 14 plant pathogenic fungi, three insect species and plant acetohydroxyacid synthase (AHAS). RESULTS: All the target compounds were characterized by proton nuclear magnetic resonance (1 H-NMR), carbon-13 (13 C)-NMR, selenium-77 (77 Se)-NMR, and high-resolution mass spectrometry (HRMS). The crystal structure of 10j indicated that the Se-S bond was successfully constructed. Compounds 10d, 10h, 10s, 10u, 10aa, 10ac, 10ae, 10ag, and 10ai exhibited 40%, 43%, 39%, 41%, 47%, 46%, 47%, 42%, and 39% anti-TMV activities at 500 mg L-1 , better than that of ribavirin. The median effective concentration (EC50 ) against Sclerotinia sclerotiorum of 10ac was 6.69 mg L-1 and EC50 values against Physalospora piricola and Pyricularia grisea of 10z were 12.25 mg L-1 and 15.27 mg L-1 , respectively, superior to the corresponding values of chlorothalonil. Compounds 10c and 10v demonstrated 100% larvicidal activity against Culex pipiens pallens at 5 mg L-1 , while 10a displayed 100% insecticidal activity against Mythimna separata at 200 mg L-1 . Compounds 10c, 10j, and 10o showed > 60% inhibitions against plant AHAS at 10 µmol L-1 . From the quantum calculation, highest occupied molecular orbital (HOMO) was considered as a factor that affects the anti-TMV activity. CONCLUSION: The preliminary results suggested that more efforts should be devoted to exploring the selenenyl sulfides for the discovery of new leads of antiviral agent, fungicide, insecticide or AHAS inhibitors as potential agrochemicals for crop protection. © 2023 Society of Chemical Industry.

3D-QSAR Directed Discovery of Novel Halogenated Phenyl 3-Trifluoroethoxypyrazole Containing Ultrahigh Active Insecticidal Anthranilic Diamides.

Pests are one of the major factors causing crop damage and food security problems worldwide. Based on our previous studies on the discovery of insecticidal leads targeting the ryanodine receptors (RyRs), a three-dimensional quantitative structure-activity relationship (3D-QSAR) model was established to design and synthesize a series of anthranilic diamides containing a halogenated phenyl 3-trifluoroethoxypyrazole moiety. The preliminary bioassays disclosed that IIb, IIIb, and IIIf against Mythimna separata showed comparable activity to chloranthraniliprole (LC50: 0.16, 0.16, 0.14, and 0.13 mg·L-1, respectively). More than half of the target compounds displayed good activity against Plutella xylostella, where IIIf was the most active compound, 25 times more active than chloranthraniliprole (LC50: 6.0 × 10-6 versus 1.5 × 10-4 mg·L-1). For Spodoptera frugiperda, IIIf displayed slightly inferior potency to chlorantraniliprole (LC50: 0.47 versus 0.31 mg·L-1). For RyR mutants of S. frugiperda (G4891E, I4734M), compound IIIf could show higher affinity than chlorantraniliprole according to the binding mode and energy in molecular docking experiments. Calcium imaging technique, molecular docking, density functional theory calculations, and electrostatic potential studies validated that the RyR was the target of the most active candidate IIIf, which deserves further development.

HOTAIR/miR-203/CAV1 Crosstalk Influences Proliferation, Migration, and Invasion in the Breast Cancer Cell.

In recent years, malignant breast cancer metastasis has caused a great increase in mortality. Research on the genetic and molecular mechanisms of malignant breast cancer has continued to deepen, and targeted therapy has become the general trend. Among them, competing endogenous RNA (ceRNA)-related molecules have received much attention. Homeobox transcript antisense RNA (HOTAIR) has been reported to function extensively as a ceRNA in breast cancer. Notably, miR-203 and Caveolin 1 (CAV1) have also been found to play a role in breast cancer. However, the relationship between the three remains unclear. In this study, we present a new mechanic through bioinformatics tool and basic experiments: the HOTAIR/miR-203/CAV1 axis, which complemented the role network of HOTAIR as a ceRNA, thus, it will provide a novel potential idea for breast cancer research and therapy.

Novel Fluorinated Aniline Anthranilic Diamides Improved Insecticidal Activity Targeting the Ryanodine Receptor.

The diamide insecticides show exceptional activity against Lepidoptera insects via activation of ryanodine receptors (RyRs). In the present study, a series of anthranilic diamides containing a fluoroaniline moiety were designed, synthesized, and evaluated for insecticidal potency. Most titled compounds exerted moderate to remarkably high activity against Mythimna separata, Plutella xylostella, and Spodoptera frugiperda. The insecticidal activity of compound II l and II ac against M. separata was 26.7 and 26.7% at 0.1 mg L-1, respectively, equivalent to that of chlorantraniliprole (0.1 mg L-1, 30.0%). Compounds II l, II y, and II z exhibited 8.0-, 1.8-, and 4.7-fold higher potency than chlorantraniliprole against P. xylostella, respectively, as compared with their LC50s. Compounds II k and II aa showed good insecticidal activity against S. frugiperda with LC50 of 0.56 and 0.46 mg L-1, respectively, comparable to that of the commercial insecticide chlorantraniliprole with LC50 of 0.31 mg L-1. Calcium imaging experiments indicated RyRs as the action target. Molecular docking suggested a higher binding energy of 8.647 kcal/mol between II l and the M. separata RyR than the 7.820 kcal/mol between chlorantraniliprole and the M. separata RyR. Meanwhile, the docking results of II l with mutated P. xylostella RyR at site G4946E showed that II l could have a good inhibition effect on the resistant P. xylostella. The density functional theory calculations suggested the importance of the fluoroaniline moiety in potency. Those novel anthranilic diamides containing a fluorinated aniline moiety are good insecticidal candidates.

Improving Insecticidal Activity of Chlorantraniliprole by Replacing the Chloropyridinyl Moiety with a Substituted Cyanophenyl Group.

Insect ryanodine receptors (RyRs) are molecular targets of the anthranilic diamide insecticides. In the present study, a new series of anthranilic diamides containing a cyanophenyl pyrazole moiety were rationally designed by active-fragment assembly and computer-aided design using the 3D structure of Plutella xylostella RyRs as a receptor and chlorantraniliprole as a ligand. Most of the titled compounds showed good toxicity against Mythimna separate, P. xylostella, and Spodoptera frugiperda. Compounds CN06, CN11, and CN16 with corresponding LC50 values of 0.15, 0.29, and 0.52 mg·L-1, respectively, against M. separate showed comparable activity to that of chlorantraniliprole (0.13 mg·L-1). Surprisingly, CN06, CN11, and CN16 with corresponding LC50 values of 1.6 × 10-5, 3.0 × 10-5, and 2.8 × 10-5 mg·L-1, respectively, against P. xylostella were at least 5-fold more active than chlorantraniliprole (1.5 × 10-4 mg·L-1). In the case of S. frugiperda, CN06, CN11, and CN16 had good potency but lower than chlorantraniliprole in terms of LC50 values (0.58, 0.54, and 0.56 mg·L-1 versus 0.31 mg·L-1). Molecular docking of CN06 and chlorantraniliprole to P. xylostella RyRs validated the molecular design, and the calcium imaging technique further proved the potential target of CN06 as RyRs. Compounds CN06, CN11, and CN16 could be more effective than chlorantraniliprole in targeting the resistant RyR mutants of S. frugiperda (G4891E, I4734M) through the binding mode and energy obtained by molecular docking. Density functional theory calculations (DFT) and electrostatic potential (ESP) studies gave the structure-activity relationship. Compounds CN06, CN11, and CN16 could be used as potent insecticide leads for further optimization.

Mesenchymal Stem Cell-Derived Extracellular Vesicles: Pleiotropic Impacts on Breast Cancer Occurrence, Development, and Therapy.

Breast cancer (BC) is one of the most devastating cancers, with high morbidity and mortality, among the female population worldwide. In BC, mesenchymal stem cells (MSCs), as pluripotent stromal stem cells, play a significant role in TME formation and tumor progression. Recently, an increasing number of studies have demonstrated that extracellular vesicles (EVs) are essential for the crosstalk between MSCs and BC cells. MSC-derived EVs (MSC-EVs) can deliver a diversity of molecules, including lipids, proteins, and nucleic acids, etc., to target cells, and produce corresponding effects. Studies have demonstrated that MSC-EVs exert both inhibitory and promotive effects in different situations and different stages of BC. Meanwhile, MSC-EVs provide novel therapeutic options for BC, such as EVs as carriers for drug delivery. Therefore, in this review, we summarize the role of MSC-EVs in BC progression and application in clinical treatment, in the hope of providing a basis for further research.

Design, synthesis and biological activity of diamide compounds based on 3-substituent of the pyrazole ring†.

BACKGROUND: Diamide insecticides have attracted significant attention due to their high efficacy and low toxicity to non-target organisms since they were introduced to the market. In order to tackle the problems of insecticide resistance and ecological safety, 16 novel nitrobenzene substituted anthranilic diamides with ester, hydroxyl or sulfonyl at the 3-position of the pyrazole ring were designed and synthesized. RESULTS: All of these compounds possessed good activity against the ryanodine receptor (RyR) from Spodoptera frugiperda and relatively lower activity against mammalian RyR1, showing a better insect-selectivity compared to chlorantraniliprole in a cell-based assay. The molecular docking analysis predicted the binding conformations of these compounds, which showed a good correlation between the insecticidal activity and the binding scores. In vitro studies using a calcium imaging method demonstrated that the novel compounds could not only activate the RyR but may also target the dihydropyridine receptor on the plasma membrane of insect neurons, implicating a similar but not same mode of action. CONCLUSION: Substituted anthranilic diamides with an ester at the 3-position of the pyrazole ring exhibited a promising insecticidal activity and better insect-selectivity, which provided insight into the rational design of a new generation of effective diamide insecticides.

Synthesis and evaluation of novel xanthine-acrylamides and xanthine-acrylates as insecticidal agents.

BACKGROUND: The design and discovery of novel pesticidal agents according to bioactive natural products is an important aspect of agrochemical innovation. New xanthine derivatives derived from natural xanthine or methylxanthines are rich resources that possess great potential to afford new active pesticidal molecules. Herein novel xanthine derivatives were designed through a strategy of combining the methylxanthine caffeine skeleton with the acrylamide or acrylate motif of cinnamic acid derivatives. RESULTS: A series of novel (E)-3-(1,3,7-trimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)acrylic acid derivatives, caffeine-(E)-acrylamides and caffeine-(E)-acrylates, were synthesized and confirmed via melting points, 1 H NMR, 13 C NMR and high-resolution mass spectrometry. A single crystal of compound I12 was obtained to illustrate the trans-configuration of the vinyl double bond. Preliminary insecticidal evaluations showed that some of the compounds had favorable insecticidal potentials against Mythimna separata Walker at 200 mg L-1 . Some of the compounds exhibited excellent insecticidal activity against Plutella xylostella L. at low test concentrations, e.g. I18 and I24 with LC50 values of 0.0435 and 0.0133 mg L-1 , respectively, were found to be more potent than the insecticide control triflumuron. The structure-activity relationship (SAR) analysis is also given in detail. CONCLUSION: Compounds I12, I18, I24 and I26 generated from the integration of natural methylxanthine (caffeine) and acrylate moieties could be novel insecticidal leading compounds for further structural optimization. The SAR analysis may bring a new inspiration to the extensive and deep investigations on new xanthine derivatives in the agrochemical area.

Synthesis and evaluation of novel 1-(((6-substitutedbenzo[d]thiazol-2-yl)amino)(heteroaryl)methyl)naphthalen-2-ol as pesticidal agents.

To discover new agrochemicals with prominent pesticidal properties, a series of novel ß-naphthol derivatives containing benzothiazolylamino and various heteroaryl groups (8a-q) were efficiently synthesised via Betti reaction. The bioassay results showed that most of the synthesised compounds exhibited favourable insecticidal potentials, particularly towards oriental armyworm (50-100% at 200 mg·L-1) and diamondback moth (50-95% at 10 mg·L-1). Compounds 8 b, 8f, 8 g, 8j, 8k, 8n, and 8o possessed LC50 values of 0.0988-5.8864 mg·L-1 against diamondback moth. Compounds 8i, 8 l, and 8 m also displayed lethality rates of 30-90% against spider mite at the concentration of 100 mg·L-1. Overall, some compounds could be considered as new insecticidal/acaricidal leading structures for further investigation. The calcium imaging experiments revealed that 8 h, 8i, and viii could activate the release of calcium ions in insect (M. separata) central neurons at a higher concentration (50 mg·L-1). The SAR analysis provided valuable information for further structural modifications.

Caveolin-1-deficient fibroblasts promote migration, invasion, and stemness via activating the TGF-ß/Smad signaling pathway in breast cancer cells.

Cancer-associated fibroblasts (CAFs) represent one of the main components in the tumor stroma and play a key role in breast cancer progression. Transforming growth factor-ß (TGF-ß) has been established to mediate breast cancer metastasis by regulating the epithelial-mesenchymal transition (EMT) and stemness of cancer cells. Caveolin-1 (CAV-1) is a scaffold protein of caveolae that is related to the proliferation and metabolism of cancer cells. It is now well demonstrated that CAV-1 deficiency in the tumor stroma is positively correlated with distant metastasis, but the mechanism remains unclear. Here, we explore whether CAV-1-deficient fibroblasts play an essential role in the EMT and stemness of breast cancer cells (BCCs) through TGF-ß signaling. We establish a specific small interfering RNA (siRNA) to inhibit CAV-1 expression in fibroblasts and coculture them with BCCs to investigate the effect of CAV­1-deficient fibroblasts and the tumor microenvironment on breast cancer progression. This study refreshingly points out that CAV-1 deficiency in fibroblasts enhances TGF-ß1 secretion and then activates the TGF-ß1/Smad signaling pathway of BCCs, thus promoting the metastasis and stemness of BCCs. Collectively, our findings indicate an unexpected role of CAV-1 deficiency in fibroblasts and the tumor microenvironment as a permissive factor, which is regulated by the TGF-ß1 signaling pathway in BCCs.

Small Extracellular Vesicles: Functions and Potential Clinical Applications as Cancer Biomarkers.

Cancer, as the second leading cause of death worldwide, is a major public health concern that imposes a heavy social and economic burden. Effective approaches for either diagnosis or therapy of most cancers are still lacking. Dynamic monitoring and personalized therapy are the main directions for cancer research. Cancer-derived extracellular vesicles (EVs) are potential disease biomarkers. Cancer EVs, including small EVs (sEVs), contain unique biomolecules (protein, nucleic acid, and lipids) at various stages of carcinogenesis. In this review, we discuss the biogenesis of sEVs, and their functions in cancer, revealing the potential applications of sEVs as cancer biomarkers.

Design, Synthesis and Biological Evaluation of Novel Thienylpyridyl- and Thioether-Containing Acetamides and Their Derivatives as Pesticidal Agents.

Referring to the structural information of the "hit" compound A from the reported pharmacophore-based virtual screening, a series of novel thienylpyridyl- and thioether/sulfoxide/sulfone-containing acetamide derivatives have been designed and synthesized. The structures of new compounds were confirmed by 1H NMR, 13C NMR and HRMS. The single-crystal structure of A was firstly reported. All the new synthesized compounds were evaluated for insecticidal activities on Mythimna separata Walker and Plutella xylostella L. Through a step-by-step structural optimization, the high insecticidal agents, especially towards Plutella xylostella L., have been found, and thienylpyridyl- and sulfone/thioether-containing acetamides Iq, Io, Ib and A, which are comparable with the control insecticides cartap, triflumuron and chlorantraniliprole in the present study, can be used as novel lead structures for new insecticides innovation research. In addition, some of the compounds, e.g., A, Ih, Id, Io and Iq, also exhibited favourable fungicidal activities against Physalospora piricola, Rhizoctonia cerealis and Sclerotinia sclerotiorum and would provide useful guidance for the design and development of new fungicides.