IntroductionThe small membrane-bound GTPase Ras acts as a guanyl nucleotidedependent switch, cycling between guanosine diphosphate (GDP)-and guanosine triphosphate (GTP)-bound forms. Ras guanyl nucleotide exchange factors (Ras GEFs) catalyze release of GDP, allowing Ras to bind the relatively prevalent cellular GTP. Conversely, Ras GTPase activating proteins (Ras GAPs), such as P120GAP and neurofibromin, enhance the hydrolysis of GTP by Ras, returning the GTPase to its inactive state. 1 Between phases of activation and inactivation, Ras-GTP can bind downstream effectors. For example, recruitment of Raf to the plasma membrane by Ras-GTP activates the Raf-Mek-extracellular signal-regulated kinase (Erk) kinase cascade. This and other effector pathways bring about alterations in gene transcription and other biochemical changes that underlie the Ras-regulated cellular processes. Ras signaling plays an essential role in immune-receptor signaling. Antigen interactions with both B-cell receptor (BCR) and T-cell receptor (TCR) initiate complex intracellular signaling events, including Ras activation, and these play important roles in both the development and activation of lymphocytes. [2][3][4][5] In principle, Ras can be regulated by controlling either the rate of GTP hydrolysis or the rate of nucleotide exchange. The seminal Ras regulation experiments involved the analysis of metabolically labeled guanyl nucleotides associated with immune-precipitated Ras from human peripheral blood lymphocytes and the Jurkat T-cell line. 6 These studies showed that Ras-GTP levels rise rapidly after stimulation of T cells with anti-TCR antibodies. Furthermore, strong and prompt Ras activation was observed after treatment with the diacylglycerol (DAG) analog phorbol 12-myristate 13-acetate (PMA). This latter result is in line with the idea that TCR stimulation is linked to phosphatidylinositol hydrolysis and DAG second messenger generation. Using a permeable cell assay, Ras guanyl nucleotide exchange rates were constitutively high; the major effect of prior cell stimulation was to decrease the GTPase rate. In line with this hypothesis, cellular extracts prepared from PMA-treated cells had lower cellular Ras GAP activity. It was surmised that PKC down-regulated a Ras GAP, although the mechanistic details were never uncovered. A second report from the same group indicated that, indeed, a sizable fraction of the Ras activation in lymphocytes was eliminated by PKC inhibitors, although evidence for a PKC-independent component was also apparent. 7 Subsequent work in many labs, including important work by some of the authors cited above, 6 provided a rather different view of Ras regulation in nonlymphoid cells. In most cells, there does not appear to be a link between DAG or PKC and Ras activation. Furthermore, in most cells Ras is regulated by the recruitment of the Ras GEF Sos (son of sevenless) to the plasma membrane by means of adaptor proteins and tyrosine-phosphorylated docking sites. 1 The discovery of RasGRP1 and the demonstration that...

This phase III trial demonstrated that adding a single dose of fosaprepitant to a 5-HT 3 receptor antagonist and corticosteroid in a nonanthracycline and cyclophosphamide-based moderately emetogenic chemotherapy population significantly improved the prevention of chemotherapy-induced nausea and vomiting. The use of this regimen may eliminate the need for multiday antiemetic therapy in such patients.

No abstract

BackgroundFerroptosis is a newly defined form of programmed cell death that plays an important role in many cancers. However, ferroptosis-related lncRNAs (FRLs) involved in the regulation of colon cancer are not thoroughly understood. This study aimed to identify a prognostic FRL signature in colon cancer and explore its potential molecular function.MethodsRNA-seq data and relevant clinical information were obtained from The Cancer Genome Atlas (TCGA) database, and a list of ferroptosis-related genes was extracted from the FerrDb website. Analysis of differentially expressed FRLs was performed using the ‘limma’ package in R software. By implementing coexpression analysis and univariate Cox analysis, we then identified prognostic FRLs. Using Cox regression analysis with the least absolute shrinkage and selection operator (LASSO) algorithm, we constructed a prognostic model based on 4 FRLs. We evaluated the prognostic power of this model using Kaplan–Meier (K-M) survival curve analysis and receiver operating characteristic (ROC) curve analysis. Moreover, the relationships between the signature and immune landscape, somatic mutation and drug sensitivity were explored. Finally, in vitro experiments were conducted to validate the functions of AP003555.1 and AC000584.1.ResultsA 4-FRL signature was constructed. Two risk groups were classified based on the risk score calculated by this signature. The signature-based risk score exhibited a more powerful capacity for survival prediction than traditional clinicopathological features in colon patients. Additionally, we observed a significant difference in immune cells, such as CD4+ and CD8+ T cells and macrophages, between the two groups. Moreover, the high-risk group exhibited lower IC50 values for certain chemotherapy drugs, such as cisplatin, docetaxel, bleomycin or axitinib. Finally, the in vitro experiments showed that ferroptosis processes were suppressed after AP003555.1 and AC000584.1 knockdown.ConclusionThe proposed 4-FRL signature is a promising biomarker to predict clinical outcomes and therapeutic responses in colon cancer patients.

In advanced atherosclerosis (AS), defective function-induced cell death leads to the formation of the characteristic necrotic core and vulnerable plaque. The forms and mechanisms of cell death in AS have recently been elucidated. Among them, ferroptosis, an iron-dependent form of necrosis that is characterized by oxidative damage to phospholipids, promotes AS by accelerating endothelial dysfunction in lipid peroxidation. Moreover, disordered intracellular iron causes damage to macrophages, vascular smooth muscle cells (VSMCs), vascular endothelial cells (VECs), and affects many risk factors or pathologic processes of AS such as disturbances in lipid peroxidation, oxidative stress, inflammation, and dyslipidemia. However, the mechanisms through which ferroptosis initiates the development and progression of AS have not been established. This review explains the possible correlations between AS and ferroptosis, and provides a reliable theoretical basis for future studies on its mechanism.