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1.
Nat Nanotechnol ; 2021 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-34697490

RESUMO

Trivalent arsenic (AsIII) is an effective agent for treating patients with acute promyelocytic leukaemia, but its ionic nature leads to several major limitations like low effective concentrations in leukaemia cells and substantial off-target cytotoxicity, which limits its general application to other types of leukaemia. Here, building from our clinical discovery that cancerous cells from patients with different leukaemia forms featured stable and strong expression of CD71, we designed a ferritin-based As nanomedicine, As@Fn, that bound to leukaemia cells with very high affinity, and efficiently delivered cytotoxic AsIII into a large diversity of leukaemia cell lines and patient cells. Moreover, As@Fn exerted strong anti-leukaemia effects in diverse cell-line-derived xenograft models, as well as in a patient-derived xenograft model, in which it consistently outperformed the gold standard, showing its potential as a precision treatment for a variety of leukaemias.

2.
Langmuir ; 37(35): 10461-10468, 2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34431681

RESUMO

A colloidal nanocrystal cluster (CNC) is a hierarchical nanostructure formed by clustering several nanocrystals into one nano-ensemble, which may exhibit unique optical or catalytic properties different from individual nanocrystals owing to the mutual interactions among neighboring component nanocrystals. However, there is still no universal synthetic route that could be applicable to diverse material compositions with precisely controlled hierarchical structures (i.e., nanocrystal number density, component nanocrystal size, and overall diameter of the CNC) up to now. Herein, a general and novel synthetic strategy was reported for crafting a wide range of inorganic CNCs (i.e., noble metal, semiconductor, and metal oxide) via utilizing amphiphilic star-like poly(4-vinylpyridine)-block-polystyrene diblock copolymers as nanoreactors prepared by sequential atom transfer radical polymerization. The hierarchical structure of rationally designed CNCs could be readily tailored by varying the P4VP molecular weight of star-like nanoreactors and the parameter optimization during the CNC preparation process, which was inaccessible by conventional synthetic methods.

3.
Gland Surg ; 10(6): 1951-1961, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34268079

RESUMO

Background: To assess the role of atrial fibrillation on perioperative outcomes in patients with pancreatic cancer undergoing open pancreaticoduodenectomy (OPD). Methods: We investigated patients with pancreatic cancer undergoing OPD during 2012-2014 within National Inpatient Sample database. The study population was divided into two groups based on the presence of atrial fibrillation. In-hospital mortality, length of stay, cost of hospitalization, and in-hospital complications were compared between the two groups. Logistic regression models and linear regression were used to adjust for potential confounders. Propensity score matching was also utilized. Results: Of the 12,785 patients aged ≥18 years undergoing OPD during years 2012-2014, 11,469 (90%) had no atrial fibrillation and 1,316 (10%) had atrial fibrillation. Patients with atrial fibrillation were found to have significantly higher cost, but similar mortality and LOS compared to those without atrial fibrillation. The risk of gastrointestinal anastomotic leakage, cardiac complications, respiratory complications, pulmonary embolism, and perioperative shock were found to be significantly higher in atrial fibrillation group than non-atrial fibrillation group in both multivariate regression model and propensity score matching model. In older patients (>65 years), atrial fibrillation was found to be associated with a significantly higher cost, longer hospital stays, higher incidence of cardiac complications, respiratory complications, and postoperative shock, yet similar mortality. Conclusions: Atrial fibrillation was found to be associated with higher cost in pancreatic cancer patients undergoing OPD, as well as increased occurrence of cardiac complications, respiratory complications, pulmonary embolism, and perioperative shock. Surgeons should pay special attention to patients with atrial fibrillation, and consider working together with cardiologists and anesthesiologists to jointly develop a management plan.

4.
Proc Natl Acad Sci U S A ; 118(25)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34161256

RESUMO

Perovskite oxides (ABO3) have been widely recognized as a class of promising noble-metal-free electrocatalysts due to their unique compositional flexibility and structural stability. Surprisingly, investigation into their size-dependent electrocatalytic properties, in particular barium titanate (BaTiO3), has been comparatively few and limited in scope. Herein, we report the scrutiny of size- and dopant-dependent oxygen reduction reaction (ORR) activities of an array of judiciously designed pristine BaTiO3 and doped BaTiO3 (i.e., La- and Co-doped) nanoparticles (NPs). Specifically, a robust nanoreactor strategy, based on amphiphilic star-like diblock copolymers, is employed to synthesize a set of hydrophobic polymer-ligated uniform BaTiO3 NPs of different sizes (≤20 nm) and controlled compositions. Quite intriguingly, the ORR activities are found to progressively decrease with the increasing size of BaTiO3 NPs. Notably, La- and Co-doped BaTiO3 NPs display markedly improved ORR performance over the pristine counterpart. This can be attributed to the reduced limiting barrier imposed by the formation of -OOH species during ORR due to enhanced adsorption energy of intermediates and the possibly increased conductivity as a result of change in the electronic states as revealed by our density functional theory-based first-principles calculations. Going beyond BaTiO3 NPs, a variety of other ABO3 NPs with tunable sizes and compositions may be readily accessible by exploiting our amphiphilic star-like diblock copolymer nanoreactor strategy. They could in turn provide a unique platform for both fundamental and practical studies on a suite of physical properties (dielectric, piezoelectric, electrostrictive, catalytic, etc.) contingent upon their dimensions and compositions.

5.
Adv Mater ; : e2005888, 2021 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-34096108

RESUMO

Metal halide perovskite nanocrystals (PNCs) have recently garnered tremendous research interest due to their unique optoelectronic properties and promising applications in photovoltaics and optoelectronics. Metal halide PNCs can be combined with polymers to create nanocomposites that carry an array of advantageous characteristics. The polymer matrix can bestow stability, stretchability, and solution-processability while the PNCs maintain their size-, shape- and composition-dependent optoelectronic properties. As such, these nanocomposites possess great promise for next-generation displays, lighting, sensing, biomedical technologies, and energy conversion. The recent advances in metal halide PNC/polymer nanocomposites are summarized here. First, a variety of synthetic strategies for crafting PNC/polymer nanocomposites are discussed. Second, their array of intriguing properties is examined. Third, the broad range of applications of PNC/polymer nanocomposites is highlighted, including light-emitting diodes (LEDs), lasers, and scintillators. Finally, an outlook on future research directions and challenges in this rapidly evolving field are presented.

6.
J Colloid Interface Sci ; 600: 421-429, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34023703

RESUMO

Multi-stimuli responsive fluorescence probe could pave the way for monitoring more complex environmental changes. Here we prepared multifunctional nanoparticle Fe3O4@SiO2@P(DMAEMA-co-TPEE), which displayed yolk-shell morphology with well-defined polymer brush. With superparamagnetic Fe3O4 component and pH/temperature dual sensitive PDMAEMA polymer brush, the as prepared nanoparticles (YS-NPs) exhibited as multi-stimuli responsive fluorescence probe for real-time visual monitoring of environmental changes such as magnetic field, temperature and pH. Such YS-NPs could also be applied as a sensitive detector for CO2 in aqueous solution. Notably, the solution of YS-NPs showed high colloidal stability during the environmental changes, and surface aggregation-induced emission (S-AIE) was proposed for the aggregation of TPE residue on the surface of YS-NPs.


Assuntos
Nanocompostos , Nanopartículas , Polímeros , Temperatura
7.
J Phys Chem Lett ; 12(13): 3456-3463, 2021 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-33792312

RESUMO

The past few years witnessed the rapid development of bottom-up synthesis strategies for preparing various nanostructures (i.e., nanoparticles, nanorods, nanowires, etc.) with distinct morphology-dependent properties. In this study, we reported a facile and efficient synthesis method for preparing anatase titanium dioxide (TiO2) nanorings based on multiarm, starlike amphiphilic polystyrene-b-poly(acrylic acid) (PS-b-PAA) diblock copolymers as nanoreactors which were prepared via a sequential atom-transfer radical polymerization (ATRP) technique followed by the conversion of polystyrene-b-poly(tert-butyl acrylate) (PS-b-PtBA) to PS-b-PAA. The outer PAA block of nanoreactors possessed carboxylic acid groups which could coordinate with a titanium precursor followed by high-temperature calcination to form crystalline TiO2 nanorings. The living nature of ATRP enabled the precise preparation of starlike diblock copolymer nanoreactors with a controlled length of each block (i.e., PtBA and PS), thereby tailoring the inner diameter and wall thickness of the resulting TiO2 nanorings, which were inaccessible to conventional routes.

9.
Angew Chem Int Ed Engl ; 60(13): 7259-7266, 2021 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-33393190

RESUMO

Approaches to achieve stable perovskite nanocrystals (PNCs) of interest, in particular those with large structural anisotropy, through protective coating of the inorganic shell at a single-nanocrystal (NC) level are comparatively few and limited in scope. Reported here is a robust amphiphilic-diblock-copolymer-enabled strategy for crafting highly-stable anisotropic CsPbBr3 nanosheets (NSs) by in situ formation of a uniform inorganic shell (1st shielding) that is intimately ligated with hydrophobic polymers (2nd shielding). The dual-protected NSs display an array of remarkable stabilities (i.e., thermal, photostability, moisture, polar solvent, aliphatic amine, etc.) and find application in white-light-emitting diodes. In principle, by anchoring other multidentate amphiphilic polymer ligands on the surface of PNCs, followed by templated-growth of shell materials of interest, a rich variety of dual-shelled, multifunctional PNCs with markedly improved stabilities can be created for use in optics, optoelectronics, and sensory devices.

10.
Cancer Sci ; 112(4): 1357-1368, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33416209

RESUMO

In recent years, the excellent curative effect of CD19-specific chimeric antigen receptor (CAR) T-cell therapy has brought hope to patients with relapsing or refractory B-cell hematological malignancies, however relapse after CAR T-cell infusion has hindered the widespread clinical application of this immunotherapy and targeted antigen-negative relapse has caused widespread concern. Consequently, strategies for increasing targeted antigens have been created. In addition to the most widely applied target, namely CD19, researchers have further explored the possibility of other targets, such as CD20, CD22, CD33, and CD123, and have tested a series of combination antigen CAR T-cell therapies. Here, we summarize the current preclinical and clinical studies of dual-target CAR T cells.


Assuntos
Antígenos de Neoplasias/imunologia , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/terapia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/imunologia , Animais , Humanos , Imunoterapia/métodos , Linfócitos T/imunologia
11.
Nat Biomed Eng ; 5(5): 414-428, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33046865

RESUMO

Therapeutic leukaemia vaccines have shown modest potency. Here, we show that the co-encapsulation of a leukaemia-associated epitope peptide highly expressed in leukaemia patients and of the immune checkpoint inhibitor anti-programmed-cell-death-protein-1 (anti-PD-1) in degradable poly(lactic acid) microcapsules resulted in the sustained release of the peptide and of the antibody, which led to the recruitment of activated antigen-presenting cells to the injection site, their uptake of the peptide and the transportation of the anti-PD-1 antibody to lymph nodes, enhancing the expansion of epitope-specific T cells and the activation of cytotoxic T cells. After single subcutaneous injections of vaccine formulations with different epitope peptides, mice bearing leukaemia xenografts derived from humanized cell lines or from primary cells from patients showed better therapeutic outcomes than mice receiving repeated injections of free antigen, antibody and a commercial adjuvant. The sustained release of a tumour-associated peptide and of anti-PD-1 may represent a generalizable strategy for boosting antitumour immune responses to leukaemia.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Antineoplásicos Imunológicos/química , Vacinas Anticâncer/administração & dosagem , Epitopos/química , Leucemia/terapia , Animais , Antineoplásicos Imunológicos/imunologia , Vacinas Anticâncer/farmacologia , Cápsulas , Linhagem Celular Tumoral , Preparações de Ação Retardada , Epitopos/imunologia , Feminino , Humanos , Injeções Subcutâneas , Células K562 , Leucemia/imunologia , Camundongos , Poliésteres/química , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linfócitos T Citotóxicos/imunologia , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Front Immunol ; 11: 564099, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33329526

RESUMO

Background: The administration of second- or third-generation anti-CD19 chimeric antigen receptor (CAR) T cells has remarkably improved the survival of patients with relapsed or refractory B cell malignancies. However, there are limited clinical results from fourth-generation CAR-T cell therapy, and the factors affecting response rate and survival have not been fully determined. Methods: Lymphoma patients with progression or relapse after intensive treatments, including hematopoietic stem cell transplantation, and life expectancy >2 months were enrolled in the study. Peripheral lymphocytes were collected through apheresis, and magnetically selected T cells were lentivirally transduced with a 4th-generation CAR featuring an anti-CD19 CAR and the iCasp9 suicide switch (4SCAR19). The patients received 4SCAR19 T cell infusion after approximately seven days of expansion and a conditioning regimen comprising cyclophosphamide/fludarabine. The efficacy, safety, and risk factors were evaluated. Results: A total of 21 patients with relapsed/refractory B cell non-Hodgkin lymphoma were enrolled and received 4SCAR19 T cell infusions at a median dose of 8.9×105 CAR-T cells/kg. The overall response rate was 67% [95% confidence interval (CI), 43 to 85], with 43% of patients achieving a complete response and 24% having a partial response. The overall and complete response rates were 58 and 33% in the diffuse large B-cell lymphoma (DLBCL) group and 78 and 56% in the non-DLBCL group, respectively. The median overall survival was 23.8 months (95% CI, not reached), with a median follow-up of 13.7 months. Factors affecting overall survival were International Prognostic Index (IPI), disease type, and remission status after CAR-T cell treatment. The most common adverse events of grade 3 or 4 during treatment were neutropenia (76%), leukopenia (71%), and thrombocytopenia (29%). The incidence of cytokine release syndrome (CRS) was 14%, and all cases were grade 1. One patient developed grade 3 neurotoxicity. No deaths were attributed to infusion of 4SCAR19 T cells, CRS, or neurotoxicity. Conclusions: In this study, patients with relapsed or refractory B cell non-Hodgkin's lymphoma who received 4SCAR19 T cell therapy had durable responses and few of adverse events. The IPI model is suitable for evaluating the prognosis of patients receiving CAR-T cell therapy. Trial registration: Chinese Clinical Trial Registry (http://www.chictr.org.cn): ChiCTR-OOC-16007779.


Assuntos
Antígenos CD19/imunologia , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/terapia , Recidiva Local de Neoplasia/terapia , Receptores de Antígenos Quiméricos/imunologia , Adulto , Idoso , Síndrome da Liberação de Citocina/etiologia , Feminino , Seguimentos , Humanos , Leucopenia/etiologia , Masculino , Pessoa de Meia-Idade , Neutropenia/etiologia , Prognóstico , Intervalo Livre de Progressão , Fatores de Risco , Taxa de Sobrevida , Trombocitopenia/etiologia
13.
Cell Death Dis ; 11(8): 712, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32873786

RESUMO

Utilizing oxidative stress has recently been regarded as a potential strategy for tumor therapy. The NUAK family SNF1-like kinase 1 (NUAK1) is a critical component of the antioxidant defense system and is necessary for the survival of tumors. Therefore, NUAK1 is considered an attractive therapeutic target in cancer. However, antioxidant therapy induced elevated ROS levels to activate the Unc-51-like kinase 1 (ULK1) pathway to promote protective autophagy and ULK1-dependent mitophagy. Thus, the combined inhibition of NUAK1 and ULK1 showed a strong synergistic effect in different tumor types. Herein, the potential antitumor activities of a dual NUAK1/ULK1 inhibitor MRT68921 were evaluated in both tumor cell lines and animal models. MRT68921 significantly kills tumor cells by breaking the balance of oxidative stress signals. These results highlight the potential of MRT68921 as an effective agent for tumor therapy.


Assuntos
Proteína Homóloga à Proteína-1 Relacionada à Autofagia/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Repressoras/antagonistas & inibidores , Animais , Autofagia/efeitos dos fármacos , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Linhagem Celular Tumoral , China , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Mitofagia , Neoplasias/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas Repressoras/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Exp Cell Res ; 388(1): 111801, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31877304

RESUMO

Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by autoimmune-mediated platelet destruction and impaired platelet production, which can lead to an increased risk of bleeding. The clinical management of ITP currently remains a challenge for hematologists. We explored the role of interleukin-9 (IL-9) in the treatment of CD41-induced ITP, and investigated its underlying mechanisms in a CD41-induced ITP mouse model. IL-9 treatment increased the numbers of mature megakaryocytes (CD41+CD42d+) and CD41+Sca-1+ cells in the bone marrow in these model mice, while IL-9 receptor (IL-9R) small interfering RNA (siRNA) inhibited the process. Moreover, phosphorylated signal transducer and activator of transcription 5 (STAT5), as a downstream molecule of IL-9R, was increased after IL-9 treatment. We next investigated the source of IL-9 in bone marrow, osteoblasts produced the highest level of IL-9. These results confirmed that IL-9 could prevent CD41-induced ITP in BALB/c mice by regulating osteoblasts and activating IL-9R/STAT5 signaling in megakaryocytes, thus providing further evidence for IL-9 as a promising therapeutic agent for the treatment of ITP.


Assuntos
Interleucina-9/uso terapêutico , Janus Quinases/metabolismo , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais , Animais , Células Cultivadas , Interleucina-9/farmacologia , Masculino , Megacariócitos/efeitos dos fármacos , Megacariócitos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Púrpura Trombocitopênica Idiopática/prevenção & controle , Receptores de Interleucina-9/metabolismo
15.
Front Oncol ; 10: 584367, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33614478

RESUMO

Tumor vaccines aim to expand tumor-specific T cells and reactivate existing tumor-specific T cells that are in a dormant or unresponsive state. As such, there is growing interest in improving the durable anti-tumor activity of tumor vaccines. Failure of vaccine-activated T cells to protect against tumors is thought to be the result of the immune escape mechanisms of tumor cells and the intricate immunosuppressive tumor microenvironment. In this review, we discuss how tumor cells and the tumor microenvironment influence the effects of tumor infiltrating lymphocytes and summarize how to improve the efficacy of tumor vaccines by improving the design of current tumor vaccines and combining tumor vaccines with other therapies, such as metabolic therapy, immune checkpoint blockade immunotherapy and epigenetic therapy.

16.
Sci Adv ; 5(11): eaax4424, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31819900

RESUMO

The past few years have witnessed rapid advances in the synthesis of high-quality perovskite nanocrystals (PNCs). However, despite the impressive developments, the stability of PNCs remains a substantial challenge. The ability to reliably improve stability of PNCs while retaining their individual nanometer size represents a critical step that underpins future advances in optoelectronic applications. Here, we report an unconventional strategy for crafting dual-shelled PNCs (i.e., polymer-ligated perovskite/SiO2 core/shell NCs) with exquisite control over dimensions, surface chemistry, and stabilities. In stark contrast to conventional methods, our strategy relies on capitalizing on judiciously designed star-like copolymers as nanoreactors to render the growth of core/shell NCs with controlled yet tunable perovskite core diameter, SiO2 shell thickness, and surface chemistry. Consequently, the resulting polymer-tethered perovskite/SiO2 core/shell NCs display concurrently a stellar set of substantially improved stabilities (i.e., colloidal stability, chemical composition stability, photostability, water stability), while having appealing solution processability, which are unattainable by conventional methods.

17.
Database (Oxford) ; 20192019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31819989

RESUMO

Therapeutic vaccines represent a promising immunotherapeutic modality against cancer. Discovery and validation of antigens is the key to develop effective anti-cancer vaccines. Neoantigens, arising from somatic mutations in individual cancers, are considered as ideal cancer vaccine targets because of their immunogenicity and lack of expression in normal tissues. However, only few databases support convenient access to these neoantigens for use in vaccines. To address this gap, we developed a web-accessible database, called NeoPeptide, which contains most of the important characteristics of neoantigens (such as mutation site, subunit sequence, major histocompatibility complex restriction) derived from published literature and other immunological resources. NeoPeptide also provides links to resources for further characterization of the novel features of these neoantigens. NeoPeptide will be regularly updated with newly identified and published neoantigens. Our work will help researchers in identifying neoantigens in different cancers and hasten the search for appropriate cancer vaccine candidates.


Assuntos
Biologia Computacional , Bases de Dados de Proteínas , Peptídeos/imunologia , Linfócitos T/imunologia , Sequência de Aminoácidos , Lógica Fuzzy , Peptídeos/química , Estatística como Assunto
18.
Front Oncol ; 9: 1350, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31867275

RESUMO

Background: The therapeutic efficacy of chimeric antigen receptor (CAR) T-cells targeting CD19 has been illustrated in the treatment of diffuse large B-cell lymphoma (DLBCL). However, there is a 21-35% relapse rate after anti-CD19 CAR T-cell induced remission. In addition, CAR T-cell therapy has severe adverse reactions, such as cytokine release syndrome (CRS) and CART-related encephalopathy syndrome (CRES). Because of the potential mortality associated with severe CRES, patients with primary central nervous system lymphoma (PCNSL) are usually excluded from clinical trials involving CAR T-cell therapy. Here, we report a case of refractory and relapsed primary central nervous system diffuse large B-cell lymphoma (PCNS-DLBCL). Case Presentation: The patient is a 67-year-old male who was diagnosed with PCNSL in 2011. He achieved complete remission (CR) after receiving 6 cycles of temozolomide and high-dose methotrexate. In December 2016, he experienced his first relapse and was treated with surgery and multicourse chemotherapy. He achieved CR again after the treatment. However, he experienced a second relapse in August 2017. MRI revealed a residual mass of 26 mm*35 mm*30 mm on the right side of the post-operative cavity and stale hemorrhage in the left basal ganglia. After confirming the expression of CD19 and CD70 in his tumor samples, the patient was given lymphodepletion chemotherapy followed by infusion of 4th generation CD19-CAR T-cells (4SCART19) and 4th generation CD70-CAR T-cells (4SCART70). One month later, the patient had symptomatic improvement, and brain MRI showed CR. Both CART19 and CART70 cells were detected in the 10th month after CAR T-cell infusion. Notably, neither CRS nor CRES occurred during treatment and follow-up. To date, the patient has maintained disease-free survival with more than 17 months of follow-up. Conclusions: The results of this study indicate that combination of CD19- and CD70-specific CAR T-cells may effectively target PCNSL and maintain disease-free survival without inducing CRS or CRES. Therefore, central nervous system lymphoma is not an absolute contraindication for dual-target CAR T-cell therapy.

20.
Am J Cancer Res ; 9(8): 1622-1634, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31497346

RESUMO

Epidermal growth factor receptor pathway substrate 8 (EPS8), which acts as an oncoprotein in various carcinomas, is associated with tumor progression. However, its impact on multiple myeloma (MM) has not been determined. Here, we investigate the role of EPS8 in MM and consider the potential of EPS8 as an anti-MM target. We confirmed overexpression of EPS8 in MM cells compared with plasma cells derived from healthy volunteers. Knockdown of EPS8 significantly abrogated MM cell survival, migration and invasion. Moreover, depletion of EPS8 overcomes drug resistance. TNFα or bone marrow stromal cell culture supernatants induce EPS8, which is blocked by the IKKß inhibitor MLN120B, suggesting that EPS8 is regulated by NF-κB signaling in MM cells. Mithramycin (MTM), a selective EPS8 inhibitor, suppressed MM cell proliferation and exerted potent anti-MM activity in xenograft tumor models. A synergistic effect of MTM and bortezomib (BTZ) was also observed in vitro and in vivo. Mechanistically, treatment of MM cells with MTM reduced the expression of EPS8 and related pathways. Additionally, the EPS8-knockdown phenotype can be rescued by shRNA-resistant EPS8. Taken together, we describe overexpression of EPS8 in MM by highlighting its role as a potential target and reveal therapeutic targeting of EPS8 by MTM as a novel therapy for MM.

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