106 results on '"Guo, Fukun"'
Search Results
102. Efficacy and advantage of immunotherapy for melanoma via intramuscular co-expression of plasmid-encoded PD-1 and CTLA-4 scFvs.
- Author
-
Yang Y, Huang Q, Cheng M, Deng L, Liu X, Zheng X, Wei J, Lei Y, Li X, Guo F, Deng Y, Zheng Y, Bi F, Wang G, and Liu M
- Abstract
Immunotherapy, in the shape of immune checkpoint inhibitors (ICIs), has completely changed the treatment of cancer. However, the increasing expense of treatment and the frequency of immune-related side effects, which are frequently associated with combination antibody therapies and Fc fragment of antibody, have limited the patient's ability to benefit from these treatments. Herein, we presented the therapeutic effects of the plasmid-encoded PD-1 and CTLA-4 scFvs (single-chain variable fragment) for melanoma via an optimized intramuscular gene delivery system. After a single injection, the plasmid-encoded ICI scFv in mouse sera continued to be above 150 ng/mL for 3 weeks and reached peak amounts of 600 ng/mL. Intramuscular delivery of plasmid encoding PD-1 and CTLA-4 scFvs significantly changed the tumor microenvironment, delayed tumor growth, and prolonged survival in melanoma-bearing mice. Furthermore, no significant toxicity was observed, suggesting that this approach could improve the biosafety of ICIs combination therapy. Overall, the expression of ICI scFvs in vivo using intramuscular plasmid delivery could potentially develop into a reliable, affordable, and safe immunotherapy technique, expanding the range of antibody-based gene therapy systems that are available., Competing Interests: None., (AJCR Copyright © 2024.)
- Published
- 2024
- Full Text
- View/download PDF
103. Kinase-independent role of mTOR and on-/off-target effects of an mTOR kinase inhibitor.
- Author
-
Fan C, Wunderlich M, Cai X, Yan Z, Zhang F, Davis AK, Xu L, Guo F, Lu QR, Azam M, Tian W, and Zheng Y
- Subjects
- Mice, Humans, Animals, Benzamides pharmacology, Pyrimidines pharmacology, Hematopoiesis, TOR Serine-Threonine Kinases metabolism, Morpholines pharmacology
- Abstract
mTOR, as a serine/threonine kinase, is a widely pursued anticancer target. Multiple clinical trials of mTOR kinase inhibitors are ongoing, but their specificity and safety features remain lacking. Here, we have employed an inducible kinase-inactive D2338A mTOR knock-in mouse model (mTOR
-/KI ) together with a mTOR conditional knockout model (mTOR-/- ) to assess the kinase-dependent/-independent function of mTOR in hematopoiesis and the on-/off-target effects of mTOR kinase inhibitor AZD2014. Despite exhibiting many similar phenotypes to mTOR-/- mice in hematopoiesis, the mTOR-/KI mice survived longer and showed differences in hematopoietic progenitor cells compared to mTOR-/- mice, suggesting a kinase-independent function of mTOR in hematopoiesis. Gene expression signatures in hematopoietic stem cells (HSCs) further revealed both kinase-dependent and independent effects of mTOR. AZD2014, a lead mTOR kinase inhibitor, appeared to work mostly on-target in suppressing mTOR kinase activity, mimicking that of mTOR-/KI HSCs in transcriptome analysis, but it also induced a small set of off-target responses in mTOR-/KI HSCs. In murine and human myeloid leukemia, besides kinase-inhibitory on-target effects, AZD2014 displayed similar off-target and growth-inhibitory cytostatic effects. These studies provide new insights into kinase-dependent/-independent effects of mTOR in hematopoiesis and present a genetic means for precisely assessing the specificity of mTOR kinase inhibitors., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2023
- Full Text
- View/download PDF
104. Gene targeting RhoA reveals its essential role in coordinating mitochondrial function and thymocyte development.
- Author
-
Zhang S, Konstantinidis DG, Yang JQ, Mizukawa B, Kalim K, Lang RA, Kalfa TA, Zheng Y, and Guo F
- Subjects
- Animals, Antigens, Surface, Apoptosis genetics, Apoptosis immunology, Cell Differentiation, Cell Lineage genetics, Cell Lineage immunology, Cell Survival genetics, Gene Expression Profiling, Immunophenotyping, Mice, Mice, Knockout, Phenotype, Receptors, Antigen, T-Cell, alpha-beta genetics, Receptors, Antigen, T-Cell, alpha-beta metabolism, T-Lymphocyte Subsets cytology, T-Lymphocyte Subsets metabolism, V(D)J Recombination, rhoA GTP-Binding Protein deficiency, Gene Targeting, Mitochondria genetics, Mitochondria metabolism, Thymocytes cytology, Thymocytes metabolism, rhoA GTP-Binding Protein genetics
- Abstract
Thymocyte development is regulated by complex signaling pathways. How these signaling cascades are coordinated remains elusive. RhoA of the Rho family small GTPases plays an important role in actin cytoskeleton organization, cell adhesion, migration, proliferation, and survival. Nonetheless, the physiological function of RhoA in thymocyte development is not clear. By characterizing a conditional gene targeting mouse model bearing T cell deletion of RhoA, we show that RhoA critically regulates thymocyte development by coordinating multiple developmental events. RhoA gene disruption caused a strong developmental block at the pre-TCR checkpoint and during positive selection. Ablation of RhoA led to reduced DNA synthesis in CD4(-)CD8(-), CD4(+)CD8(-), and CD4(-)CD8(+) thymocytes but not in CD4(+)CD8(+) thymocytes. Instead, RhoA-deficient CD4(+)CD8(+) thymocytes showed an impaired mitosis. Furthermore, we found that abrogation of RhoA led to an increased apoptosis in all thymocyte subpopulations. Importantly, we show that the increased apoptosis was resulted from reduced pre-TCR expression and increased production of reactive oxygen species (ROS), which may be because of an enhanced mitochondrial function, as manifested by increased oxidative phosphorylation, glycolysis, mitochondrial membrane potential, and mitochondrial biogenesis in RhoA-deficient thymocytes. Restoration of pre-TCR expression or treatment of RhoA-deficient mice with a ROS scavenger N-acetylcysteine partially restored thymocyte development. These results suggest that RhoA is required for thymocyte development and indicate, to our knowledge, for the first time that fine-tuning of ROS production by RhoA, through a delicate control of metabolic circuit, may contribute to thymopoiesis., (Copyright © 2014 by The American Association of Immunologists, Inc.)
- Published
- 2014
- Full Text
- View/download PDF
105. Mtor-Fanconi Anemia DNA Damage Repair Pathway in Cancer.
- Author
-
Guo F
- Abstract
mTOR is a serine/threonine kinase and plays a critical role in mammalian cell growth, survival, and metabolism. mTOR is present in two cellular complexes: mTORC1 and mTORC2. Dysregulation of the mTOR pathway has been related to tumorigenesis, poor prognosis and/or chemotherapy resistance in a variety of malignancies. Inhibition of mTORC1 by Rapamycin and its analogs has been explored to treat a number of tumors. However, the effectiveness of patient response is limited and not all patients respond. Second generation of mTOR inhibitors have recently been developed to target mTOR kinase activity and to suppress both mTORC1 and mTORC2. Dual mTORC1/mTORC2 inhibitors generally are more efficacious in preclinical studies and clinical trials. We and others have recently found that dual mTORC1/mTORC2 inhibitors sensitize T-cell acute lymphocytic leukemia and rhabdomyosarcoma cells to DNA damaging agents by suppression of expression of FANCD2 of the Fanconi anemia pathway, an important DNA repair mechanism that is associated with drug resistance of multiple types of cancer. This review will highlight mTOR and the Fanconi anemia pathway in cancer, with a particular attention to our newly discovered connection between mTOR and the Fanconi anemia pathway.
- Published
- 2014
- Full Text
- View/download PDF
106. Mouse gene targeting reveals an essential role of mTOR in hematopoietic stem cell engraftment and hematopoiesis.
- Author
-
Guo F, Zhang S, Grogg M, Cancelas JA, Varney ME, Starczynowski DT, Du W, Yang JQ, Liu W, Thomas G, Kozma S, Pang Q, and Zheng Y
- Subjects
- Animals, Cell Survival physiology, Cells, Cultured, Mice, Mice, Knockout, Mice, SCID, Gene Targeting methods, Hematopoiesis physiology, Hematopoietic Stem Cell Transplantation methods, TOR Serine-Threonine Kinases physiology
- Abstract
mTOR integrates signals from nutrients and growth factors to control protein synthesis, cell growth, and survival. Although mTOR has been established as a therapeutic target in hematologic malignancies, its physiological role in regulating hematopoiesis remains unclear. Here we show that conditional gene targeting of mTOR causes bone marrow failure and defects in multi-lineage hematopoiesis including myelopoiesis, erythropoiesis, thrombopoiesis, and lymphopoiesis. mTOR deficiency results in loss of quiescence of hematopoietic stem cells, leading to a transient increase but long-term exhaustion and defective engraftment of hematopoietic stem cells in lethally irradiated recipient mice. Furthermore, ablation of mTOR causes increased apoptosis in lineage-committed blood cells but not hematopoietic stem cells, indicating a differentiation stage-specific function. These results demonstrate that mTOR is essential for hematopoietic stem cell engraftment and multi-lineage hematopoiesis.
- Published
- 2013
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.