ABSTRACT
Chidamide (CS055/HBI-8000, tucidinostat) has shown promising effects in the clinical treatment of various hematologic tumors. Diffuse large B-cell lymphoma (DLBCL) has shown highly heterogeneous biological characteristics. There are complex mechanisms of the role of chidamide in DLBCL for in-depth study. It is essential to probe further into the mechanism of drug-tumor interactions as a guide to clinical application and to understand the occurrence and progression of DLBCL. In vitro and in vivo models were utilized to determine the effects of chidamide on signaling pathways involved in the DLBCL tumor microenvironment. The experimental results show that chidamide inhibited the proliferation of DLBCL cell lines in a dose- and time-dependent manner, and down-regulated the expression of NOTCH1 and NFATC1 in DLBCL cells as well as decreased the concentration of IL-10 in the supernatant. In addition, chidamide significantly lowered the expression of PD1 or TIM3 on CD4+T cells and CD8+T cells and elevated the levels of IL-2, IFN-γ, and TNF-α in the serum of animal models, which augmented the function of circulating T cells and tumor-infiltrating T cells and ultimately significantly repressed the growth of tumors. These findings prove that chidamide can effectively inhibit the cell activity of DLBCL cell lines by inhibiting the activation of NOTCH1 and NFATC1 signaling pathways. It can also improve the abnormal DLBCL microenvironment in which immune escape occurs, and inhibit immune escape. This study provides a new therapeutic idea for the exploration of individualized precision therapy for patients with malignant lymphoma.
Subject(s)
Aminopyridines , Benzamides , Cell Proliferation , Lymphoma, Large B-Cell, Diffuse , NFATC Transcription Factors , Receptor, Notch1 , Signal Transduction , Tumor Microenvironment , Xenograft Model Antitumor Assays , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/immunology , Lymphoma, Large B-Cell, Diffuse/pathology , Lymphoma, Large B-Cell, Diffuse/metabolism , Humans , NFATC Transcription Factors/metabolism , Receptor, Notch1/metabolism , Receptor, Notch1/genetics , Aminopyridines/pharmacology , Aminopyridines/therapeutic use , Signal Transduction/drug effects , Benzamides/pharmacology , Benzamides/therapeutic use , Animals , Mice , Tumor Microenvironment/drug effects , Tumor Microenvironment/immunology , Cell Line, Tumor , Cell Proliferation/drug effects , T-Lymphocytes/immunology , T-Lymphocytes/drug effects , T-Lymphocytes/metabolism , Disease Models, AnimalABSTRACT
Land-atmosphere coupling (LAC) plays a significant role in weather and climate and is related to droughts and heatwaves. We propose a simple and efficient LAC diagnosis method based on the analysis of water isotopes in atmospheric water vapour and precipitation. Using the method, we identify the primary LAC hotspot regions of the globe and reveal the seasonality of LAC strength. We find that LAC strength exhibits a relationship with latitude. Low latitudes present stronger LAC strength and contribute more significantly to the overall LAC area compared to boreal middle and high latitudes. It's important to note that LAC primarily manifests in the troposphere and is detected in the lower stratosphere of low latitudes, with limited influence observed in the stratosphere. However, the impact of LAC is noticeable in the upper stratosphere in boreal middle and high latitudes. Moreover, the seasonality of LAC strength is pronounced. On a global scale, the season with the strongest LAC is boreal autumn in the Northern Hemisphere but boreal summer in the Southern Hemisphere. Notably, this pattern does not exhibit a seesaw effect between the two hemispheres. Our isotope-based LAC diagnosis method captures the major LAC hotspots found in previous work and validates the seasonality of LAC within these hotspots. This substantiates the reliability and effectiveness of our isotope-based approach.
