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Background: Immune checkpoint inhibitors (ICIs) have shown efficacy across multiple cancer types; however, ICIs are also associated with immune-mediated (im) adverse events (AEs) ...especially when used in combination. Methods: Published safety data from 35 melanoma and non-small cell lung cancer clinical trials was normalized for drug exposure using drug concentrations at 50% inhibition (IC
50
). Pharmacokinetic models from FDA, EMEA, and our own model were used to compare AEs across 4 ICIs: anti-PD-1 (nivolumab, pembrolizumab) and anti-CTLA-4 (ipilumumab, tremelimumab). Data was analyzed by ICI target and organ class (ie, GI, skin, liver, lung, and endocrine). To test dependence of AE rate (%) on drug dose dependence (DD) we calculated mean AE rates for low and high halves of the dose range, and used Pearson’s χ
2
-squared test for statistical significance (SS) ( p< 0.05). Results: We found AEs to be DD for anti-CTLA-4 monotherapies and anti-CTLA-4 + anti-PD-1 combinations, whereas DD was not SS for anti-PD-1 monotherapies (Table). For anti-CTLA-4 drugs DD was SS for GI, hepatic, skin, and endocrine AEs. In combination, there was DD upon anti-CTLA-4, but data were insufficient to confirm SS. For PD-1 drugs there was no significant DD found. Conclusions: For anti-PD-1 therapy, no DD for Grade 3/4 AEs was found across organ classes. However, for anti-CTLA-4 therapies, DD was SS for GI, skin, hepatic, and endocrine im AEs. Although not all data were sufficient to confirm SS, dose intensity of anti-CTLA-4 may be an important determinant of AEs, when co-administered with anti-PD-1. Table: see text
Adenosine receptor type 2 (A
R) inhibitor, AZD4635, has been shown to reduce immunosuppressive adenosine effects within the tumor microenvironment (TME) and to enhance the efficacy of checkpoint ...inhibitors across various syngeneic models. This study aims at investigating anti-tumor activity of AZD4635 alone and in combination with an anti-PD-L1-specific antibody (anti-PD-L1 mAb) across various TME conditions and at identifying,
mathematical quantitative modeling, a therapeutic combination strategy to further improve treatment efficacy.
The model is represented by a set of ordinary differential equations capturing: 1) antigen-dependent T cell migration into the tumor, with subsequent proliferation and differentiation into effector T cells (Teff), leading to tumor cell lysis; 2) downregulation of processes mediated by A
R or PD-L1, as well as other immunosuppressive mechanisms; 3) A
R and PD-L1 inhibition by, respectively, AZD4635 and anti-PD-L1 mAb. Tumor size dynamics data from CT26, MC38, and MCA205 syngeneic mice treated with vehicle, anti-PD-L1 mAb, AZD4635, or their combination were used to inform model parameters. Between-animal and between-study variabilities (BAV, BSV) in treatment efficacy were quantified using a non-linear mixed-effects methodology.
The model reproduced individual and cohort trends in tumor size dynamics for all considered treatment regimens and experiments. BSV and BAV were explained by variability in T cell-to-immunosuppressive cell (ISC) ratio; BSV was additionally driven by differences in intratumoral adenosine content across the syngeneic models. Model sensitivity analysis and model-based preclinical study simulations revealed therapeutic options enabling a potential increase in AZD4635-driven efficacy;
, adoptive cell transfer or treatments affecting adenosine-independent immunosuppressive pathways.
The proposed integrative modeling framework quantitatively characterized the mechanistic activity of AZD4635 and its potential added efficacy in therapy combinations, across various immune conditions prevailing in the TME. Such a model may enable further investigations,
simulations, of mechanisms of tumor resistance to treatment and of AZD4635 combination optimization strategies.
To investigate the mechanism of the combined effects of chlorogenic acid (CGA) and caffeine on lipid metabolism in high-fat diet-induced obese mice, eighty female ICR mice were randomly divided into ...eight groups and fed with a high-fat diet with/without CGA and/or caffeine for 14 weeks. The combination of CGA and caffeine effectively decreased body weight gain, intraperitoneal adipose tissue weight, serum LDL-c, FFA, TC, TG, leptin, IL-6 concentrations, and hepatic TG and TC levels and increased the serum adiponectin level. The CGA and caffeine combination also promoted the phosphorylation of AMPKα, inhibited the expressions of transcriptional regulators (SREBP-1c and LXRα), and decreased the expressions of FAS and HMGR. Besides, the expressions of ACO, ATGL and HSL were increased by the CGA and caffeine combinations. The results indicated that the combination of CGA and caffeine had anti-obesity effects and regulated lipid metabolism in high-fat diet-induced obese mice
via
the AMPKα-LXRα/SREBP-1c signaling pathway. Thus, chronic CGA and caffeine intakes may be potent for preventing obesity.
The combination of CGA and caffeine exhibits anti-obesity effects and regulates lipid metabolism
via
the AMPKα-LXRα/SREBP-1c signaling pathway in mice with high-fat diet-induced obesity.
This paper presents a novel model-free design method under polar coordinates space for the tracking problem of nonholonomic mobile robots. The proposed tracking controllers to track nonholonomic ...mobile robots without any prior knowledge of the robot model. It drives the tracking error to the predetermined neighborhood of zero with information which is not complete.
To investigate the preventive effect of Volvariella volvacea fruit body polypeptides (VVFP) on acute alcoholic liver injury in mice and its influence on the intestinal microbiota, VVFP (1–3 kDa ...molecular mass) which had been previously obtained by our laboratory was given by gavage to mice. The mice were randomly divided into six groups: blank control, model, positive control, low-dose VVFP, moderate-dose VVFP and high-dose VVFP. Serum indexes, liver indexes and histopathological sections were compared among these groups, and 16S rDNA gene high-throughput sequencing was used to analyze the diversity of the intestinal microflora and the relative abundance at the phyla and genus levels in each sample. Results showed that VVFP significantly reduced the levels of triglycerides (TG), total cholesterol (TC), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity in the serum and malondialdehyde (MDA) in the liver, and decreased the levels of the inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), and significantly increased the activities of alcohol dehydrogenase (ADH), total superoxide dismutase (T-SOD) and glutathione peroxidase (GSH-PX) in the liver. The 16S rRNA sequencing showed that VVFP significantly reduced the α-diversity indices Chao1 and observed species, increased the Shannon index, and regulated the abundance of Bacteroides, Firmicutes, Streptomyces, Lactobacillus and Vibrio, thereby reducing liver damage. In conclusion, VVFP can reduce alcoholic liver injury, which will provide a theoretical basis for the application of VVFP in the field of functional foods.
Optimizing cytokinin distribution patterns is a promising strategy for simultaneously enhancing grain yield, grain quality, and stress resistance in plants, as observed in ARGONAUTE2-overexpressing ...rice.
Abstract
Maintaining stable, high yields under fluctuating environmental conditions is a long-standing goal of crop improvement but is challenging due to internal trade-off mechanisms, which are poorly understood. Here, we identify ARGONAUTE2 (AGO2) as a candidate target for achieving this goal in rice (Oryza sativa). Overexpressing AGO2 led to a simultaneous increase in salt tolerance and grain length. These benefits were achieved via the activation of BIG GRAIN3 (BG3), encoding a purine permease potentially involved in cytokinin transport. AGO2 can become enriched on the BG3 locus and alter its histone methylation level, thus promoting BG3 expression. Cytokinin levels decreased in shoots but increased in roots of AGO2-overexpressing plants. While bg3 knockout mutants were hypersensitive to salt stress, plants overexpressing BG3 showed strong salt tolerance and large grains. The knockout of BG3 significantly reduced grain length and salt tolerance in AGO2-overexpressing plants. Both genes were transcriptionally suppressed by salt treatment. Salt treatment markedly increased cytokinin levels in roots but decreased them in shoots, resulting in a hormone distribution pattern similar to that in AGO2-overexpressing plants. These findings highlight the critical roles of the spatial distribution of cytokinins in both stress responses and grain development. Therefore, optimizing cytokinin distribution represents a promising strategy for improving both grain yield and stress tolerance in rice.
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