15 research outputs found
Feasibility and robustness of dynamic 18F-FET PET based tracer kinetic models applied to patients with recurrent high-grade glioma prior to carbon ion irradiation
Characterization of the 9L gliosarcoma implanted in the Fischer rat: an orthotopic model for a grade IV brain tumor
Extracellular Superoxide Dismutase Regulates the Expression of Small GTPase Regulatory Proteins GEFs, GAPs, and GDI
Cocaine Induces Alterations in Mitochondrial Membrane Potential and Dual Cell Cycle Arrest in Rat C6 Astroglioma Cells
Structural mechanism of RPA loading on DNA during activation of a simple pre-replication complex
We report that during activation of the simian virus 40 (SV40) pre-replication complex, SV40 T antigen (Tag) helicase actively loads replication protein A (RPA) on emerging single-stranded DNA (ssDNA). This novel loading process requires physical interaction of Tag origin DNA-binding domain (OBD) with the RPA high-affinity ssDNA-binding domains (RPA70AB). Heteronuclear NMR chemical shift mapping revealed that Tag-OBD binds to RPA70AB at a site distal from the ssDNA-binding sites and that RPA70AB, Tag-OBD, and an 8-nucleotide ssDNA form a stable ternary complex. Intact RPA and Tag also interact stably in the presence of an 8-mer, but Tag dissociates from the complex when RPA binds to longer oligonucleotides. Together, our results imply that an allosteric change in RPA quaternary structure completes the loading reaction. A mechanistic model is proposed in which the ternary complex is a key intermediate that directly couples origin DNA unwinding to RPA loading on emerging ssDNA
Chronic arterial hypertension impedes glioma growth: a multiparametric MRI study in the rat.
CERVOXYInternational audienc
Cross-species transcriptional analysis reveals conserved and host-specific neoplastic processes in mammalian glioma
Chronic arterial hypertension impedes glioma growth: a multiparametric MRI study in the rat
Gene Therapy-Mediated Reprogramming Tumor Infiltrating T Cells Using IL-2 and Inhibiting NF-κB Signaling Improves the Efficacy of Immunotherapy in a Brain Cancer Model
Immune-mediated gene therapy using adenovirus expressing Flt3 ligand and thymidine kinase followed by ganciclovir administration (Flt3/TK) effectively elicits tumor regression in preclinical glioma models. Herein, we assessed new strategies to optimize Flt3L/TK therapeutic efficacy in a refractory RG2 orthotopic glioblastoma model. Specifically, we aimed to optimize the therapeutic efficacy of Flt3L/TK treatment in the RG2 model by overexpressing the following genes within the brain tumor microenvironment: 1) a TK mutant with enhanced cytotoxicity (SR39 mutant TK), 2) Flt3L-IgG fusion protein that has a longer half-life, 3) CD40L to stimulate DC maturation, 4) T helper cell type 1 polarizing dendritic cell cytokines interleukin-12 or C-X-C motif ligand 10 chemokine (CXCL)-10, 5) C-C motif ligand 2 chemokine (CCL2) or C-C motif ligand 3 chemokine (CCL3) to enhance dendritic cell recruitment into the tumor microenvironment, 6) T helper cell type 1 cytokines interferon-γ or interleukin-2 to enhance effector T-cell functions, and 7) IκBα or p65RHD (nuclear factor kappa-B [NF-κB] inhibitors) to suppress the function of Foxp3+ Tregs and enhanced effector T-cell functions. Anti-tumor immunity and tumor specific effector T-cell functions were assessed by cytotoxic T lymphocyte assay and intracellular IFN-γ staining. Our data showed that overexpression of interferon-γ or interleukin-2, or inhibition of the nuclear factor kappa-B within the tumor microenvironment, enhanced cytotoxic T lymphocyte-mediated immune responses and successfully extended the median survival of rats bearing intracranial RG2 when combined with Flt3L/TK. These findings indicate that enhancement of T-cell functions constitutes a critical therapeutic target to overcome immune evasion and enhance therapeutic efficacy for brain cancer. In addition, our study provides novel targets to be used in combination with immune-therapeutic strategies for glioblastoma, which are currently being tested in the clinic.Fil: Mineharu, Yohei. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of California at Los Angeles; Estados UnidosFil: Muhammad, AKM Ghulam. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of California at Los Angeles; Estados UnidosFil: Yagiz, Kader. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of California at Los Angeles; Estados UnidosFil: Candolfi, Marianela. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of California at Los Angeles; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Kroeger, Kurt M.. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of California at Los Angeles; Estados UnidosFil: Xiong, Weidong. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of California at Los Angeles; Estados UnidosFil: Puntel, Mariana. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of California at Los Angeles; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Liu, Chunyan. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of California at Los Angeles; Estados UnidosFil: Levy, Eva. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of California at Los Angeles; Estados UnidosFil: Lugo, Claudia. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of California at Los Angeles; Estados UnidosFil: Kocharian, Adrina. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of California at Los Angeles; Estados UnidosFil: Allison, James P.. Howard Hughes Medical Institute; Estados UnidosFil: Curran, Michael A.. Howard Hughes Medical Institute; Estados UnidosFil: Lowenstein, Pedro R.. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of California at Los Angeles; Estados Unidos. University of Michigan; Estados UnidosFil: Castro, Maria G.. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of California at Los Angeles; Estados Unidos. University of Michigan; Estados Unido