The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway functions as a central hub for transmitting signals from more than 50 cytokines, playing a pivotal role in ...maintaining hematopoiesis, immune balance, and tissue homeostasis. Dysregulation of this pathway has been implicated in various diseases, including immunodeficiency, autoimmune conditions, hematological disorders, and certain cancers. Proteins within this pathway have emerged as effective therapeutic targets for managing these conditions, with various approaches developed to modulate key nodes in the signaling process, spanning from receptor engagement to transcription factor activation. Following the success of JAK inhibitors such as tofacitinib for RA treatment and ruxolitinib for managing primary myelofibrosis, the pharmaceutical industry has obtained approvals for over 10 small molecule drugs targeting the JAK-STAT pathway and many more are at various stages of clinical trials. In this review, we consolidate key strategies employed in drug discovery efforts targeting this pathway, with the aim of contributing to the collective understanding of small molecule interventions in the context of JAK-STAT signaling. We aspire that our endeavors will contribute to advancing the development of innovative and efficacious treatments for a range of diseases linked to this pathway dysregulation.
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Background: The tumor microenvironment (TME) contains regulatory T (Treg) cells, which play a critical role in immunosuppression and are thus an attractive target for cancer therapy. The ideal ...approach would be to inhibit Tregs within tumors while sparing those in peripheral and normal tissues. Tumor-associated Tregs express the chemokine receptor CCR8, which is involved in the induction, expansion, migration, and immunosuppression of Tregs, making targeted inhibition of CCR8 signaling a potential therapeutic strategy against cancer. Methods: We have developed IPG0521, a monoclonal antibody antagonist of CCR8, and characterized its properties, including signaling blocking, chemotaxis, species cross-reactivity, anti-tumor efficacy, and synergistic antitumor effect with PD1 antibody. Single-cell RNA sequencing with CD45
+
cells isolated from tumors treated with or without IPG0521 was also employed for profiling the mechanism of the antitumor effect of IPG0521 in the murine H22 cancer model. Results: IPG0521 inhibits receptor-mediated signaling and chemotaxis in Treg cells with a single-digit nanomolar IC50. It is cross-reactive in five species: mouse, rat, dog, monkey, and human. IPG0521 has shown excellent anti-tumor efficacy in several murine syngeneic cancer models, and its anti-tumor effect is enhanced when combined with a PD-1 antibody. Its sustained anti-tumor efficacy has been demonstrated in the murine H22 cancer model via even withdrawing the antibody during the study. The results of deep single-cell RNA sequencing on tumor-infiltrating lymphocytes (TILs) showed that the transcriptional profiles of these Treg cells could be distinguished into three distinct subsets based on molecular, functional, and immunosuppressive properties. These subsets were defined as the Treg_Foxp3 high subset, which exhibited low immunosuppression, the Treg_Foxp3 mild subset, which demonstrated mild immunosuppression, and the Treg_Foxp3 low subset, which had high proliferation. IPG0521 treatment resulted in a significant increase in the Treg_
Foxp3 high subset and a significant decrease in the Treg _
Foxp3 mild subset while no change in the Treg_
Foxp3 low subset, indicating a reduction in Treg immunosuppression. This change in Treg cells also altered the composition of other immune cells, including a significant increase in neutrophils and natural killer (NK) cells, which ultimately inhibited tumor growth. Conclusions: IPG0521 has potent anti-tumor effects in multiple tumor types, including lung, liver, and breast cancers, in both syngeneic and immune-humanized mouse models. It inhibits Tregs immunosuppression and activates CD8+ T cells to achieve its anti-tumor effects. These results support the development of IPG0521, which is currently under IND filing, as a novel therapeutic agent for the treatment of cancers.
Abstract
Within the tumor microenvironment (TME), regulatory T (Treg) cells are one attractive cell type for targeting as they play a critical role in immunosuppression. Therapeutic strategies that ...specifically inhibit tumor-infiltrating Tregs while sparing peripheral and normal tissue Tregs are highly desirable. The tumor-associated Tregs express the chemokine receptor CCR8, which plays a role in the induction, expansion, chemotactic migration, and immunosuppression of tumor-associated Tregs. Thus, targeted inhibition of CCR8 is a potential therapeutic strategy against cancer. We have developed a monoclonal antibody antagonist of CCR8, IPG0521, which potently inhibited the receptor-mediated signaling and chemotaxis in Treg cells with single digital nanomolar IC50. RNA sequencing (RNA-seq)analysis indicated that CCL1-induced up-regulation of immunosuppressive genes, including PD-1, CTLA4, IL-10, TIGIT etc., were reversed by IPG0521 in tumor-derived Treg cells. IPG0521 potently inhibited the growth of multiple tumor types in both syngeinic and immune-humanized mouse models, including lung cancer, liver cancer, breast cancer, via inhibiting Treg and activating CD8+ T cells. These data pave the way for the development of IPG0521, which is under IND filing, as a novel therapeutic agent against cancer.
Citation Format: Guohuang Fan, Jianfei Wang, Na Wang, Yuanyuan Zhang, Yong Zhang, Binle Tian, Xuebing Jia. Development of a CCR8 monoclonal antibody which blocks CCR8 signaling and abolishes the immunosuppressive function of Treg for the treatment of cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2340.
Cutaneous melanoma is a highly malignant and metastatic skin cancer with high mortality. However, its underlying mechanisms remain largely unclear. Here, we found that retrotransposon-like 1 (RTL1) ...is highly enriched in melanoma tissue, especially in early and horizontal growth tissues. Knockdown of RTL1 in melanoma cells resulted in cell proliferation suppression; cell cycle arrest at G1 phase; and down-regulation of E2F1, CYCLIN D1, cyclin-dependent kinase 6 (CDK6) and c-MYC. Moreover, overexpression of RTL1 in melanoma cells accelerated cell proliferation, promoted passage of the cell cycle beyond G1 phase, and increased the expression of cell cycle related genes. Mechanistically, we found that knockdown of RTL1 inhibited the Wnt/β-Catenin pathway by regulating the expression of genes specifically involved in β-CATENIN stabilization. Furthermore, the overexpression and knockdown of β-CATENIN rescued the effects of RTL1 on melanoma cell proliferation and the cell cycle. These findings were also confirmed via tumour xenografts in nude mice. Together, our results demonstrated that RTL1 promotes melanoma cell proliferation by regulating the Wnt/β-Catenin signalling pathway.
Type 2 diabetes mellitus (T2DM) is a common metabolic disease influenced by both genetic and environmental factors. In this study, we performed an in-house genotyping and meta-analysis study using ...three independent GWAS datasets of T2DM and found that rs3743121, located 1 kb downstream of AQR, was a novel susceptibility SNP associated with T2DM. The risk allele C of rs3743121 was correlated with the increased expression of AQR in white blood cells, similar to that observed in T2DM models. The knockdown of AQR in HepG2 facilitated the glucose uptake, decreased the expression level of PCK2, increased the phosphorylation of GSK-3β, and restored the insulin sensitivity. Furthermore, the suppression of AQR inhibited the mTOR pathway and the protein ubiquitination process. Our study suggests that AQR is a novel type 2 diabetes-associated gene that regulates signaling pathways critical for glucose metabolism.
The CXC chemokine CXCL12 and its cognate receptor CXCR4 play an important role in inflammation, human immunodeficiency virus (HIV) infection and cancer metastasis. The signal transduction and ...intracellular trafficking of CXCR4 are involved in these functions, but the underlying mechanisms remain incompletely understood. In the present study, we demonstrated that the CXCR4 formed a complex with the cytolinker protein plectin in a ligand-dependent manner in HEK293 cells stably expressing CXCR4. The glutathione-
S-transferase (GST)–CXCR4 C-terminal fusion proteins co-precipitated with the full-length and the N-terminal fragments of plectin isoform 1 but not with the N-terminal deletion mutants of plectin isoform 1, thereby suggesting an interaction between the N-terminus of plectin and the C-terminus of CXCR4. This interaction was confirmed by confocal microscopic reconstructions showing co-distribution of these two proteins in the internal vesicles after ligand-induced internalization of CXCR4 in HEK293 cells stably expressing CXCR4. Knockdown of plectin with RNA interference (RNAi) significantly inhibited ligand-dependent CXCR4 internalization and attenuated CXCR4-mediated intracellular calcium mobilization and activation of extracellular signal regulated kinase 1/2 (ERK1/2). CXCL12-induced chemotaxis of HEK293 cells stably expressing CXCR4 and of Jurkat T cells was inhibited by the plectin RNAi. Moreover, CXCR4 tropic HIV-1 infection in MAGI (HeLa-CD4-LTR-Gal) cells was inhibited by the RNAi of plectin. Thus, plectin appears to interact with CXCR4 and plays an important role in CXCR4 signaling and trafficking and HIV-1 infection.
The feeding amount of bass farming is closely related to the number of bass. It is of great significance to master the number of bass to achieve accurate feeding and improve the economic benefits of ...the farm. In view of the interference caused by the problems of multiple targets and target occlusion in bass data for bass detection, this paper proposes a bass target detection model based on improved YOLOV5 in circulating water system. Firstly, acquiring by HD cameras, Mosaic-8, a data augmentation method, is utilized to expand datasets and improve the generalization ability of the model. And K-means clustering algorithm is applied to generate suitable coordinates of prior boxes to improve training efficiency. Secondly, Coordinate Attention mechanism (CA) is introduced into backbone feature extraction network and neck feature fusion network to enhance attention to targets of interest. Finally, Soft-NMS algorithm replaces Non-Maximum Suppression algorithm (NMS) to re-screen prediction boxes and keep targets with higher overlap, which effectively solves the problems of missed detection and false detection. The experiments show that the proposed model can reach 98.09% in detection accuracy and detection speed reaches 13.4ms. The proposed model can help bass farmers under the circulating water system to accurately grasp the number of bass, which has important application value to realize accurate feeding and water conservation.
Light traps have been widely used as effective tools to monitor multiple agricultural and forest insect pests simultaneously. However, the current detection methods of pests from light trapping ...images have several limitations, such as exhibiting extremely imbalanced class distribution, occlusion among multiple pest targets, and inter-species similarity. To address the problems, this study proposes an improved YOLOv3 model in combination with image enhancement to better detect crop pests in real agricultural environments. First, a dataset containing nine common maize pests is constructed after an image augmentation based on image cropping. Then, a linear transformation method is proposed to optimize the anchors generated by the k-means clustering algorithm, which can improve the matching accuracy between anchors and ground truths. In addition, two residual units are added to the second residual block of the original YOLOv3 network to obtain more information about the location of the underlying small targets, and one ResNet unit is used in the feature pyramid network structure to replace two DBL(Conv+BN+LeakyReLU) structures to enhance the reuse of pest features. Experiment results show that the mAP and mRecall of our proposed method are improved by 6.3% and 4.61%, respectively, compared with the original YOLOv3. The proposed method outperforms other state-of-the-art methods (SSD, Faster-rcnn, and YOLOv4), indicating that the proposed method achieves the best detection performance, which can provide an effective model for the realization of intelligent monitoring of maize pests.
•Proposing a pigeon behavior detection method base on YOLO v4 deep learning algorithm.•Using self-made data sets, comparison of multiple target detection models and comparison of multiple lightweight ...feature extraction networks.•Comparative study between parameter, weight size, computation, accuracy and FPS.•The proposed method contributes to the development of dovecote inspection robots.
The behavior of pigeons in the dovecote reflects their environmental comfort and health indicators. In order to solve the problems of time-consuming, labor-consuming, and subjectivity of traditional manual experience, an improved YOLO V4 light-weight target detection algorithm was proposed for row detection of breeding pigeons. Employ SPP, FPN, and PANet networks to strengthen the features retrieved from GhostNet as the backbone. To ensure accuracy, Ghostnet-yolo V4 reduced the model's number of parameters and raised its size to 43 MB. The light-weight feature extraction network GhostNet outperformed MobileNet V1~V3 under the modified model. Faster RCNN, SSD, YOLO V4 and YOLO V3 compression rates were increased by 43.4 percent, 35.8 percent, 70.1 percent, and 69.1 percent, respectively. The improved algorithm has an accuracy of 97.06 percent and a recognition speed of 0.028 s per frame. The improved model can provide a theoretical foundation and technological reference for detecting breeding pigeon behavior in real-time in a dovecote.
The flow within the control valve is rather complicated, which is induced by a variety of pneumatic sound sources, including turbulent mixing, turbulence and boundary layer interaction, shock wave, ...etc. Through presenting the aerodynamic noise generation mechanism, we introduce several classic prediction methods for control valve of steam turbine, and then give the suppression and elimination advises of the aerodynamic noise of the control valve. It mainly involves two approaches, the direct method - sound source approach method and the indirect method–the acoustic path approachment method, and it can provide important guidance to control the noise level for steam turbine control valve.
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