Abstract Mammalian target of rapamycin (mTOR) regulates cell proliferation, autophagy, and apoptosis by participating in multiple signaling pathways in the body. Studies have shown that the mTOR signaling pathway is also associated with cancer, arthritis, insulin resistance, osteoporosis, and other diseases. The mTOR signaling pathway, which is often activated in tumors, not only regulates gene transcription and protein synthesis to regulate cell proliferation and immune cell differentiation but also plays an important role in tumor metabolism. Therefore, the mTOR signaling pathway is a hot target in anti-tumor therapy research. In recent years, a variety of newly discovered mTOR inhibitors have entered clinical studies, and a variety of drugs have been proven to have high activity in combination with mTOR inhibitors. The purpose of this review is to introduce the role of mTOR signaling pathway on apoptosis, autophagy, growth, and metabolism of tumor cells, and to introduce the research progress of mTOR inhibitors in the tumor field.
Objective: A dimeric neolignan, bishonokiol A (BHNKA) isolated from Magnolia grandiflora, significantly inhibits the proliferation of human breast cancer cells. However, the exact mechanism of BHNKA induced breast cancer cell death is unknown. In this study, we investigated the pharmacological mechanism underlying BHNKA induced MCF-7 cell death. Methods: Cell viability measurement was performed by the MTT assay. Flow cytometry with PI staining, DAPI staining, and electron microscopy were used to analyze cellular death modes. In addition, western blotting, siRNA transfection, ATP assay, and fluorescence microscopy were used to determine the mechanism of BHNKA induced MCF-7 cell death. Results: BHNKA induced cell death by apoptosis, necroptosis and autophagy at the same concentration and time in MCF-7 cells, and electron microscopy confirmed these results. The mechanism of BHNKA triggered apoptosis and autophagy in MCF-7 cells was primarily due to an increase in the Bax/Bcl-2 ratio and simultaneous up-regulation of LC3-II protein expression, respectively. BHNKA induced necroptosis by activation of the RIP1-RIP3-MLKL necroptosis cascade, up-regulation of cyclophilin D (CypD) protein expression to stimulate ROS generation. We further demonstrated that siRNA-mediated down-regulation of CypD protected against BHNKA induced cell death. Conclusions: These results suggest that BHNKA may be a potential lead compound for development as an anti-breast cancer agent for induction of multiple cell death pathways.
To investigate the effect of hTERT promoter which regulated tumor targeting TRALL on the cervical cancer cell line HeLa.The mRNA expression of TRAIL on HeLa was examined by RT-PCR. The proliferation, apoptosis, motion of the transfected cervical cancer cell were detected by MTT, flow cytometry, and cell invasion assay respectively. The ultrastructure was observed by electron microscope.Compared with the control group, the expression of TRAILmRNA was significantly upregulated in hTERT-TRAIL (P<0.05). The apotosis rate and the inhibitory rate of cell growth of hTERT-TRAIL was significantly high (P<0.05). Electron microscope results indicated that hTERT promoter regulated tumor targeting TRALL facilitated the apoptosis of HeLa.The hTERT-TRAIL significantly inhibits the malignant proliferation and invasion ability of the cervical cancer cell line, and facilitates the apoptosisof HeLa, which lays a foundation for the treatment of patients with cervical cancer.
Abstract A 57-year-old woman with a metastatic bone malignant solitary fibrous tumor received 177 Lu-FAP-2286 therapy. After 1 treatment cycle, 68 Ga-FAP-2286 PET/CT revealed remission of the lesions. Moreover, the patient did not report any adverse effects.
Cyber Threat Intelligence (CTI) reports are factual records compiled by security analysts through their observations of threat events or their own practical experience with attacks. In order to utilize CTI reports for attack detection, existing methods have attempted to map the content of reports onto system-level attack provenance graphs to clearly depict attack procedures. However, existing studies on constructing graphs from CTI reports suffer from problems such as weak natural language processing (NLP) capabilities, discrete and fragmented graphs, and insufficient attack semantic representation. Therefore, we propose a system called CRUcialG for the automated reconstruction of attack scenario graphs (ASGs) by CTI reports. First, we use NLP models to extract systematic attack knowledge from CTI reports to form preliminary ASGs. Then, we propose a four-phase attack rationality verification framework from the tactical phase with attack procedure to evaluate the reasonability of ASGs. Finally, we implement the relation repair and phase supplement of ASGs by adopting a serialized graph generation model. We collect a total of 10,607 CTI reports and generate 5,761 complete ASGs. Experimental results on CTI reports from 30 security vendors and DARPA show that the similarity of ASG reconstruction by CRUcialG can reach 84.54%. Compared with SOTA (EXTRACTOR and AttackG), the recall of CRUcialG (extraction of real attack events) can reach 88.13% and 94.46% respectively, which is 40% higher than SOTA on average. The F1-score of attack phase verification is able to reach 90.04%.
Background and Purpose Indoleamine 2,3‐dioxygenase 1 (IDO1) is emerging as an important new therapeutic target for treatment of malignant tumours characterized by dysregulated tryptophan metabolism. However, the antitumour efficacy of existing small‐molecule inhibitors of IDO1 is still unsatisfactory and the underlying mechanism remains largely undefined. Hence, we discovered a novel potent small‐molecule inhibitor of IDO1, LW106, and studied its antitumour effects and the underlying mechanisms in two tumour models. Experimental Approach C57BL6 mice, athymic nude mice or Ido1 −/− mice were inoculated with IDO1‐expressing and ‐nonexpressing tumour cells and treated with vehicle, epacadostat or increasing doses of LW106. Xenografted tumours, plasma, spleens and other vital organs were harvested and subjected to kynurenine/tryptophan measurement and flow cytometric, histological and immunohistochemical analyses. Key Results LW106 dose‐dependently inhibited the outgrowth of xenografted tumours that were inoculated in C57BL6 mice but not nude mice or Ido1 −/− mice, showing a stronger antitumour efficacy than epacadostat, an existing IDO1 inhibitor. LW106 substantially elevated intratumoural infiltration of proliferative T eff cells, while reducing recruitment of proliferative T reg cells and non‐haematopoietic stromal cells such as endothelial cells and cancer‐associated fibroblasts. LW106 treatment resulted in a reduced subpopulation of cancer stem cells (CSCs) in xenografted tumours in which fewer proliferative/invasive tumour cells and more apoptotic tumour cells were observed. Conclusions and Implications LW106 inhibits tumour outgrowth by limiting stroma‐immune crosstalk and CSC enrichment in the tumour micro‐environment. LW106 has potential as a immunotherapeutic agent for use in combination with immune checkpoint inhibitors and (or) chemotherapeutic drugs for cancer treatment.
, a toxic Chinese medicine used for more than 2000 years, has the effect of "purging water to promote drinking" and "reducing swelling and dispersing modules". Diterpenes and triterpenes are the main bioactive components of
AIM: To study the mechanism responsible for alteration of T cell respons e in IDDM patients. METHODS: T cells from peripheral blood of I DDM patients were activated by anti-TCR antibodies. The level of TCR-mediated signaling pathway was analyzed. RESULTS: T cells from IDDM patients responded weakly to anti- TCR antibody-induced proliferation, as compared with T cells from normal subjec ts (P 0.05) . The defect could be partially remedied by the addition of rIL-2, while the anti-CD28 antibody stimulation did not restore the prolifera tive response of anti-TCR-induced cells from IDDM patients(P=0.03). CONCLUSION: Underresponsiveness of the T cells from IDDM patients to anti-TCR antibody may result from a defect in the signaling pathway, the CD28 c o-stimulation-signaling pathway is normal. Defect in the TCR signaling pathwa y increases the sensitivity of T cells from IDDM patients to apoptosis or anergy .
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