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1.
Structure ; 2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34506732

RESUMO

The tripartite AcrAB-TolC assembly, which spans both the inner and outer membranes in Gram-negative bacteria, is an efflux pump that contributes to multidrug resistance. Here, we present the in situ structure of full-length Escherichia coli AcrAB-TolC determined at 7 Å resolution by electron cryo-tomography. The TolC channel penetrates the outer membrane bilayer through to the outer leaflet and exhibits two different configurations that differ by a 60° rotation relative to the AcrB position in the pump assembly. AcrA protomers interact directly with the inner membrane and with AcrB via an interface located in proximity to the AcrB ligand-binding pocket. Our structural analysis suggests that these AcrA-bridged interactions underlie an allosteric mechanism for transmitting drug-evoked signals from AcrB to the TolC channel within the pump. Our study demonstrates the power of in situ electron cryo-tomography, which permits critical insights into the function of bacterial efflux pumps.

3.
Commun Biol ; 4(1): 625, 2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34035440

RESUMO

Type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) is the predominant Ca2+-release channel in neurons. IP3R1 mediates Ca2+ release from the endoplasmic reticulum into the cytosol and thereby is involved in many physiological processes. Here, we present the cryo-EM structures of full-length rat IP3R1 reconstituted in lipid nanodisc and detergent solubilized in the presence of phosphatidylcholine determined in ligand-free, closed states by single-particle electron cryo-microscopy. Notably, both structures exhibit the well-established IP3R1 protein fold and reveal a nearly complete representation of lipids with similar locations of ordered lipids bound to the transmembrane domains. The lipid-bound structures show improved features that enabled us to unambiguously build atomic models of IP3R1 including two membrane associated helices that were not previously resolved in the TM region. Our findings suggest conserved locations of protein-bound lipids among homotetrameric ion channels that are critical for their structural and functional integrity despite the diversity of structural mechanisms for their gating.


Assuntos
Receptores de Inositol 1,4,5-Trifosfato/ultraestrutura , Bicamadas Lipídicas/química , Animais , Canais de Cálcio/metabolismo , Canais de Cálcio/ultraestrutura , Microscopia Crioeletrônica/métodos , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Bicamadas Lipídicas/metabolismo , Fosfatidilcolinas/química , Conformação Proteica , Domínios Proteicos , Estrutura Secundária de Proteína , Ratos
5.
Cell Calcium ; 97: 102412, 2021 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-33905995

RESUMO

New electron cryomicroscopy structures of RYR1 show that mutations associated with Malignant Hyperthermia drive conformational changes in the cytoplasmic domains of the closed channel to more closely resemble those of the open channel.

6.
Nat Methods ; 18(2): 156-164, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33542514

RESUMO

This paper describes outcomes of the 2019 Cryo-EM Model Challenge. The goals were to (1) assess the quality of models that can be produced from cryogenic electron microscopy (cryo-EM) maps using current modeling software, (2) evaluate reproducibility of modeling results from different software developers and users and (3) compare performance of current metrics used for model evaluation, particularly Fit-to-Map metrics, with focus on near-atomic resolution. Our findings demonstrate the relatively high accuracy and reproducibility of cryo-EM models derived by 13 participating teams from four benchmark maps, including three forming a resolution series (1.8 to 3.1 Å). The results permit specific recommendations to be made about validating near-atomic cryo-EM structures both in the context of individual experiments and structure data archives such as the Protein Data Bank. We recommend the adoption of multiple scoring parameters to provide full and objective annotation and assessment of the model, reflective of the observed cryo-EM map density.


Assuntos
Microscopia Crioeletrônica/métodos , Modelos Moleculares , Cristalografia por Raios X , Conformação Proteica , Proteínas/química
7.
Leukemia ; 35(1): 75-89, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32205861

RESUMO

Chimeric antigen receptor (CAR) T-cells targeting CD19 demonstrate remarkable efficacy in treating B-lineage acute lymphoblastic leukemia (BL-ALL), yet up to 39% of treated patients relapse with CD19(-) disease. We report that CD19(-) escape is associated with downregulation, but preservation, of targetable expression of CD20 and CD22. Accordingly, we reasoned that broadening the spectrum of CD19CAR T-cells to include both CD20 and CD22 would enable them to target CD19(-) escape BL-ALL while preserving their upfront efficacy. We created a CD19/20/22-targeting CAR T-cell by coexpressing individual CAR molecules on a single T-cell using one tricistronic transgene. CD19/20/22CAR T-cells killed CD19(-) blasts from patients who relapsed after CD19CAR T-cell therapy and CRISPR/Cas9 CD19 knockout primary BL-ALL both in vitro and in an animal model, while CD19CAR T-cells were ineffective. At the subcellular level, CD19/20/22CAR T-cells formed dense immune synapses with target cells that mediated effective cytolytic complex formation, were efficient serial killers in single-cell tracking studies, and were as efficacious as CD19CAR T-cells against primary CD19(+) disease. In conclusion, independent of CD19 expression, CD19/20/22CAR T-cells could be used as salvage or front-line CAR therapy for patients with recalcitrant disease.


Assuntos
Antígenos CD19/imunologia , Imunoterapia Adotiva , Leucemia de Células B/imunologia , Leucemia de Células B/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Antígenos CD19/química , Antígenos de Neoplasias , Biomarcadores , Linhagem Celular Tumoral , Citocinas/metabolismo , Citotoxicidade Imunológica , Modelos Animais de Doenças , Expressão Gênica , Humanos , Imunoterapia Adotiva/métodos , Leucemia de Células B/genética , Leucemia de Células B/terapia , Camundongos Transgênicos , Ligação Proteica , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/metabolismo , Relação Estrutura-Atividade , Transdução Genética , Transgenes , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Nat Commun ; 11(1): 5099, 2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-33037202

RESUMO

Mutations in the skeletal muscle Ca2+ release channel, the type 1 ryanodine receptor (RYR1), cause malignant hyperthermia susceptibility (MHS) and a life-threatening sensitivity to heat, which is most severe in children. Mice with an MHS-associated mutation in Ryr1 (Y524S, YS) display lethal muscle contractures in response to heat. Here we show that the heat response in the YS mice is exacerbated by brown fat adaptive thermogenesis. In addition, the YS mice have more brown adipose tissue thermogenic capacity than their littermate controls. Blood lactate levels are elevated in both heat-sensitive MHS patients with RYR1 mutations and YS mice due to Ca2+ driven increases in muscle metabolism. Lactate increases brown adipogenesis in both mouse and human brown preadipocytes. This study suggests that simple lifestyle modifications such as avoiding extreme temperatures and maintaining thermoneutrality could decrease the risk of life-threatening responses to heat and exercise in individuals with RYR1 pathogenic variants.


Assuntos
Hipertermia Maligna/genética , Mutação , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Termogênese/fisiologia , Tecido Adiposo Marrom/metabolismo , Adolescente , Adulto , Animais , Criança , Pré-Escolar , Feminino , Resposta ao Choque Térmico/genética , Resposta ao Choque Térmico/fisiologia , Humanos , Lactente , Lactatos/sangue , Masculino , Hipertermia Maligna/etiologia , Hipertermia Maligna/mortalidade , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Estudos Retrospectivos , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Termogênese/genética , Proteína Desacopladora 1/genética , Adulto Jovem
9.
Nat Med ; 26(5): 720-731, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32341580

RESUMO

Recurrent medulloblastoma and ependymoma are universally lethal, with no approved targeted therapies and few candidates presently under clinical evaluation. Nearly all recurrent medulloblastomas and posterior fossa group A (PFA) ependymomas are located adjacent to and bathed by the cerebrospinal fluid, presenting an opportunity for locoregional therapy, bypassing the blood-brain barrier. We identify three cell-surface targets, EPHA2, HER2 and interleukin 13 receptor α2, expressed on medulloblastomas and ependymomas, but not expressed in the normal developing brain. We validate intrathecal delivery of EPHA2, HER2 and interleukin 13 receptor α2 chimeric antigen receptor T cells as an effective treatment for primary, metastatic and recurrent group 3 medulloblastoma and PFA ependymoma xenografts in mouse models. Finally, we demonstrate that administration of these chimeric antigen receptor T cells into the cerebrospinal fluid, alone or in combination with azacytidine, is a highly effective therapy for multiple metastatic mouse models of group 3 medulloblastoma and PFA ependymoma, thereby providing a rationale for clinical trials of these approaches in humans.


Assuntos
Neoplasias Encefálicas/terapia , Vacinas Anticâncer/administração & dosagem , Líquido Cefalorraquidiano/efeitos dos fármacos , Ependimoma/terapia , Imunoterapia Adotiva/métodos , Meduloblastoma/terapia , Animais , Neoplasias Encefálicas/líquido cefalorraquidiano , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Neoplasias Cerebelares/líquido cefalorraquidiano , Neoplasias Cerebelares/imunologia , Neoplasias Cerebelares/patologia , Neoplasias Cerebelares/terapia , Líquido Cefalorraquidiano/imunologia , Criança , Pré-Escolar , Sistemas de Liberação de Medicamentos/métodos , Ependimoma/líquido cefalorraquidiano , Ependimoma/imunologia , Ependimoma/patologia , Feminino , Células HEK293 , Humanos , Lactente , Injeções Intraventriculares , Masculino , Meduloblastoma/líquido cefalorraquidiano , Meduloblastoma/imunologia , Meduloblastoma/patologia , Camundongos , Metástase Neoplásica , Receptores de Antígenos Quiméricos/administração & dosagem , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/transplante , Resultado do Tratamento , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Acta Crystallogr D Struct Biol ; 75(Pt 10): 861-877, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31588918

RESUMO

Diffraction (X-ray, neutron and electron) and electron cryo-microscopy are powerful methods to determine three-dimensional macromolecular structures, which are required to understand biological processes and to develop new therapeutics against diseases. The overall structure-solution workflow is similar for these techniques, but nuances exist because the properties of the reduced experimental data are different. Software tools for structure determination should therefore be tailored for each method. Phenix is a comprehensive software package for macromolecular structure determination that handles data from any of these techniques. Tasks performed with Phenix include data-quality assessment, map improvement, model building, the validation/rebuilding/refinement cycle and deposition. Each tool caters to the type of experimental data. The design of Phenix emphasizes the automation of procedures, where possible, to minimize repetitive and time-consuming manual tasks, while default parameters are chosen to encourage best practice. A graphical user interface provides access to many command-line features of Phenix and streamlines the transition between programs, project tracking and re-running of previous tasks.


Assuntos
Automação/métodos , Substâncias Macromoleculares/química , Design de Software , Validação de Programas de Computador , Microscopia Crioeletrônica/métodos , Cristalografia por Raios X/métodos , Modelos Moleculares , Conformação Molecular
13.
Cell Res ; 28(12): 1158-1170, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30470765

RESUMO

Inositol-1,4,5-trisphosphate receptors (InsP3Rs) are cation channels that mobilize Ca2+ from intracellular stores in response to a wide range of cellular stimuli. The paradigm of InsP3R activation is the coupled interplay between binding of InsP3 and Ca2+ that switches the ion conduction pathway between closed and open states to enable the passage of Ca2+ through the channel. However, the molecular mechanism of how the receptor senses and decodes ligand-binding signals into gating motion remains unknown. Here, we present the electron cryo-microscopy structure of InsP3R1 from rat cerebellum determined to 4.1 Å resolution in the presence of activating concentrations of Ca2+ and adenophostin A (AdA), a structural mimetic of InsP3 and the most potent known agonist of the channel. Comparison with the 3.9 Å-resolution structure of InsP3R1 in the Apo-state, also reported herein, reveals the binding arrangement of AdA in the tetrameric channel assembly and striking ligand-induced conformational rearrangements within cytoplasmic domains coupled to the dilation of a hydrophobic constriction at the gate. Together, our results provide critical insights into the mechanistic principles by which ligand-binding allosterically gates InsP3R channel.


Assuntos
Sinalização do Cálcio , Cálcio/metabolismo , Cerebelo/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/química , Ativação do Canal Iônico , Conformação Proteica , Adenosina/análogos & derivados , Adenosina/química , Regulação Alostérica , Animais , Microscopia Crioeletrônica/métodos , Receptores de Inositol 1,4,5-Trifosfato/agonistas , Ligantes , Modelos Moleculares , Ratos
14.
Nature ; 561(7723): 331-337, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30185905

RESUMO

Successful T cell immunotherapy for brain cancer requires that the T cells can access tumour tissues, but this has been difficult to achieve. Here we show that, in contrast to inflammatory brain diseases such as multiple sclerosis, where endothelial cells upregulate ICAM1 and VCAM1 to guide the extravasation of pro-inflammatory cells, cancer endothelium downregulates these molecules to evade immune recognition. By contrast, we found that cancer endothelium upregulates activated leukocyte cell adhesion molecule (ALCAM), which allowed us to overcome this immune-evasion mechanism by creating an ALCAM-restricted homing system (HS). We re-engineered the natural ligand of ALCAM, CD6, in a manner that triggers initial anchorage of T cells to ALCAM and conditionally mediates a secondary wave of adhesion by sensitizing T cells to low-level ICAM1 on the cancer endothelium, thereby creating the adhesion forces necessary to capture T cells from the bloodstream. Cytotoxic HS T cells robustly infiltrated brain cancers after intravenous injection and exhibited potent antitumour activity. We have therefore developed a molecule that targets the delivery of T cells to brain cancer.

15.
J Struct Biol ; 204(3): 555-563, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30237066

RESUMO

With the rapidly growing number of macromolecular structures solved to near-atomic resolution using electron cryomicroscopy (cryoEM), map interpretation and model building directly from the density without the use of structural templates has become increasingly important. As part of the 2015/2016 Map and Model Challenge, we attempted to assess our latest de novo modeling tool, Pathwalking, in terms of performance and usability, as well as identify areas for future improvements. In total, we applied Pathwalking to six density maps between 3 and 4.5 Šresolution selected from the challenge data sets. In five of the six cases, Pathwalking was able to accurately determine the protein fold and in three of these cases, the final all atom model had less than 1.6 ŠRMSD when compared to the known structure. Model building and refinement was nearly completely automated, used default parameters and took less than 30 min to complete a refined all atom model. A direct outgrowth of this work was a more streamlined automated command line Pathwalking utility, as well as a novel sequence assignment and optimization routine, which attempts to register sidechain density with expected side chain volume. In total, Pathwalking offers a nearly complete, robust and efficient method for constructing atomistic protein structures directly from a density map without the aid of a template.


Assuntos
Algoritmos , Automação , Microscopia Crioeletrônica/métodos , Conformação Proteica , Proteínas/química , Cristalografia por Raios X , Modelos Moleculares , Software
16.
Cancer Res ; 78(2): 489-500, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29183891

RESUMO

Triple-negative breast cancer (TNBC) is an aggressive disease lacking targeted therapy. In this study, we developed a CAR T cell-based immunotherapeutic strategy to target TEM8, a marker initially defined on endothelial cells in colon tumors that was discovered recently to be upregulated in TNBC. CAR T cells were developed that upon specific recognition of TEM8 secreted immunostimulatory cytokines and killed tumor endothelial cells as well as TEM8-positive TNBC cells. Notably, the TEM8 CAR T cells targeted breast cancer stem-like cells, offsetting the formation of mammospheres relative to nontransduced T cells. Adoptive transfer of TEM8 CAR T cells induced regression of established, localized patient-derived xenograft tumors, as well as lung metastatic TNBC cell line-derived xenograft tumors, by both killing TEM8+ TNBC tumor cells and targeting the tumor endothelium to block tumor neovascularization. Our findings offer a preclinical proof of concept for immunotherapeutic targeting of TEM8 as a strategy to treat TNBC.Significance: These findings offer a preclinical proof of concept for immunotherapeutic targeting of an endothelial antigen that is overexpressed in triple-negative breast cancer and the associated tumor vasculature. Cancer Res; 78(2); 489-500. ©2017 AACR.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos , Imunoterapia , Neoplasias Pulmonares/terapia , Proteínas de Neoplasias/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Superfície Celular/metabolismo , Linfócitos T/transplante , Neoplasias de Mama Triplo Negativas/terapia , Animais , Apoptose , Biomarcadores Tumorais , Estudos de Casos e Controles , Proliferação de Células , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/secundário , Camundongos , Proteínas dos Microfilamentos , Prognóstico , Taxa de Sobrevida , Linfócitos T/imunologia , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Sports Med ; 47(12): 2621-2639, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28884352

RESUMO

BACKGROUND: Golf is commonly considered a low-impact sport that carries little risk of injury to the knee and is generally allowed following total knee arthroplasty (TKA). Kinematic and kinetic studies of the golf swing have reported results relevant to the knee, but consensus as to the loads experienced during a swing and how the biomechanics of an individual's technique may expose the knee to risk of injury is lacking. OBJECTIVES: Our objective was to establish (1) the prevalence of knee injury resulting from participation in golf and (2) the risk factors for knee injury from a biomechanical perspective, based on an improved understanding of the internal loading conditions and kinematics that occur in the knee from the time of addressing the ball to the end of the follow-through. METHODS: A systematic literature search was conducted to determine the injury rate, kinematic patterns, loading, and muscle activity of the knee during golf. RESULTS: A knee injury prevalence of 3-18% was established among both professional and amateur players, with no clear dependence on skill level or sex; however, older players appear at greater risk of injury. Studies reporting kinematics indicate that the lead knee is exposed to a complex series of motions involving rapid extension and large magnitudes of tibial internal rotation, conditions that may pose risks to the structures of a natural knee or TKA. To date, the loads experienced by the lead knee during a golf swing have been reported inconsistently in the literature. Compressive loads ranging from 100 to 440% bodyweight have been calculated and measured using methods including inverse dynamics analysis and instrumented knee implants. Additionally, the magnitude of loading appears to be independent of the club used. CONCLUSIONS: This review is the first to highlight the lack of consensus regarding knee loading during the golf swing and the associated risks of injury. Results from the literature suggest the lead knee is subject to a higher magnitude of stress and more demanding motions than the trail knee. Therefore, recommendations regarding return to golf following knee injury or surgical intervention should carefully consider the laterality of the injury.


Assuntos
Golfe/lesões , Traumatismos do Joelho/etiologia , Articulação do Joelho/fisiopatologia , Fenômenos Biomecânicos , Humanos , Cinética , Traumatismos do Joelho/prevenção & controle , Articulação do Joelho/anatomia & histologia , Fatores de Risco , Rotação , Torque
18.
Biophys J ; 112(12): 2479-2493, 2017 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-28636906

RESUMO

Although electron cryo-microscopy (cryo-EM) has recently achieved resolutions of better than 3 Å, at which point molecular modeling can be done directly from the density map, analysis and annotation of a cryo-EM density map still primarily rely on fitting atomic or homology models to the density map. In this article, we present, to our knowledge, a new method for flexible fitting of known or modeled protein structures into cryo-EM density maps. Unlike existing methods that are guided by local density gradients, our method is guided by correspondences between the α-helices in the density map and model, and does not require an initial rigid-body fitting step. Compared with current methods on both simulated and experimental density maps, our method not only achieves greater accuracy for proteins with large deformations but also runs as fast or faster than many of the other flexible fitting routines.


Assuntos
Microscopia Crioeletrônica/métodos , Modelos Moleculares , Simulação por Computador , Conformação Proteica em alfa-Hélice , Proteínas/química , Proteínas/metabolismo , Fatores de Tempo
19.
J Struct Biol ; 196(3): 289-298, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27436409

RESUMO

As electron cryo-microscopy (cryo-EM) can now frequently achieve near atomic resolution, accurate interpretation of these density maps in terms of atomistic detail has become paramount in deciphering macromolecular structure and function. However, there are few software tools for modeling protein structure from cryo-EM density maps in this resolution range. Here, we present an extension of our original Pathwalking protocol, which can automatically trace a protein backbone directly from a near-atomic resolution (3-6Å) density map. The original Pathwalking approach utilized a Traveling Salesman Problem solver for backbone tracing, but manual adjustment was still required during modeling. In the new version, human intervention is minimized and we provide a more robust approach for backbone modeling. This includes iterative secondary structure identification, termini detection and the ability to model multiple subunits without prior segmentation. Overall, the new Pathwalking procedure provides a more complete and robust tool for annotating protein structure function in near-atomic resolution density maps.


Assuntos
Microscopia Crioeletrônica/métodos , Proteínas/ultraestrutura , Software , Algoritmos , Modelos Moleculares , Conformação Proteica , Estrutura Secundária de Proteína
20.
J Clin Invest ; 126(8): 3036-52, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-27427982

RESUMO

In preclinical models of glioblastoma, antigen escape variants can lead to tumor recurrence after treatment with CAR T cells that are redirected to single tumor antigens. Given the heterogeneous expression of antigens on glioblastomas, we hypothesized that a bispecific CAR molecule would mitigate antigen escape and improve the antitumor activity of T cells. Here, we created a CAR that joins a HER2-binding scFv and an IL13Rα2-binding IL-13 mutein to make a tandem CAR exodomain (TanCAR) and a CD28.ζ endodomain. We determined that patient TanCAR T cells showed distinct binding to HER2 or IL13Rα2 and had the capability to lyse autologous glioblastoma. TanCAR T cells exhibited activation dynamics that were comparable to those of single CAR T cells upon encounter of HER2 or IL13Rα2. We observed that TanCARs engaged HER2 and IL13Rα2 simultaneously by inducing HER2-IL13Rα2 heterodimers, which promoted superadditive T cell activation when both antigens were encountered concurrently. TanCAR T cell activity was more sustained but not more exhaustible than that of T cells that coexpressed a HER2 CAR and an IL13Rα2 CAR, T cells with a unispecific CAR, or a pooled product. In a murine glioblastoma model, TanCAR T cells mitigated antigen escape, displayed enhanced antitumor efficacy, and improved animal survival. Thus, TanCAR T cells show therapeutic potential to improve glioblastoma control by coengaging HER2 and IL13Rα2 in an augmented, bivalent immune synapse that enhances T cell functionality and reduces antigen escape.


Assuntos
Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Subunidade alfa2 de Receptor de Interleucina-13/metabolismo , Receptor ErbB-2/metabolismo , Linfócitos T/metabolismo , Evasão Tumoral , Animais , Antígenos de Neoplasias/metabolismo , Antineoplásicos/química , Linhagem Celular Tumoral , Humanos , Imunoterapia Adotiva , Interleucina-13/metabolismo , Ativação Linfocitária , Camundongos , Camundongos SCID , Recidiva Local de Neoplasia , Transplante de Neoplasias , Ligação Proteica , Multimerização Proteica , Receptores de Antígenos de Linfócitos T/metabolismo , Transgenes
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