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1.
Small ; : e2309435, 2024 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-38229146

RESUMO

Self-assembly of colloidal nanoparticles enables the easy building of assembly units into higher-order structures and the bottom-up preparation of functional materials. Nickel phosphides represent an important group of catalysts for hydrogen evolution reaction (HER) from water splitting. In this paper, the preparation of porous nickel phosphide superparticles and their HER efficiencies are reported. Ni and Ni2 P nanoparticles are self-assembled into binary superparticles via an oil-in-water emulsion method. After annealing and acid etching, the as-prepared Ni-Ni2 P binary superparticles change into porous nickel phosphide superparticles. The porosity and crystalline phase of the superparticles can be tuned by adjusting the ratio of Ni and Ni2 P nanoparticles. The resulting porous superparticles are effective in driving HER under acidic conditions, and the modulation of porosity and phase further optimize the electrochemical performance. The prepared Ni3 P porous superparticles not only possess a significantly enhanced specific surface area compared to solid Ni-Ni2 P superparticles but also exhibit an excellent HER efficiency. The calculations based on the density functional theories show that the (110) crystal facet exhibits a relatively lower Gibbs free energy of hydrogen adsorption. This work provides a self-assembly approach for the construction of porous metal phosphide nanomaterials with tunable crystalline phase and porosity.

2.
J Transl Med ; 21(1): 886, 2023 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-38057816

RESUMO

Ovarian cancer is the leading cause of death from gynecologic illnesses worldwide. High-grade serous ovarian cancer (HGSOC) is a gynecological tumor that accounts for roughly 70% of ovarian cancer deaths in women. Runt-related transcription factor 1(RUNX1) proteins were identified with overexpression in the HGSOC. However, the roles of RUNX1 in the development of HGSOC are poorly understood. In this study, combined with whole-transcriptome analysis and multiple research methods, RUNX1 was identified as vital in developing HGSOC. RUNX1 knockdown inhibits the physiological function of ovarian cancer cells and regulates apoptosis through the FOXO1-Bcl2 axis. Down-regulated RUNX1 impairs EMT function through the EGFR-AKT-STAT3 axis signaling. In addition, RUNX1 knockdown can significantly increase the sensitivity to clinical drug therapy for ovarian cancer. It is strongly suggested that RUNX1 work as a potential diagnostic and therapeutic target for HGSOC patients with better prognoses and treatment options. It is possible to generate novel potential targeted therapy strategies and translational applications for serous ovarian carcinoma patients with better clinical outcomes.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core , Neoplasias Ovarianas , Humanos , Feminino , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade alfa 2 de Fator de Ligação ao Core/uso terapêutico , Linhagem Celular Tumoral , Neoplasias Ovarianas/tratamento farmacológico , Prognóstico , Apoptose/genética
3.
Biomedicines ; 11(9)2023 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-37760803

RESUMO

Ovarian cancer is the leading cause of gynecological death worldwide, and its poor prognosis and high mortality seriously affect the life of ovarian cancer patients. Runt-related transcription factor 1 (RUNX1) has been widely studied in hematological diseases and plays an important role in the occurrence and development of hematological diseases. In recent years, studies have reported the roles of RUNX1 in solid tumors, including the significantly increased expression of RUNX1 in ovarian cancer. In ovarian cancer, the dysregulation of the RUNX1 signaling pathway has been implicated in tumor progression, metastasis, and response to therapy. At the same time, the decreased expression of RUNX1 in ovarian cancer can significantly improve the sensitivity of clinical chemotherapy and provide theoretical support for the subsequent diagnosis and treatment target of ovarian cancer, providing prognosis and treatment options to patients with ovarian cancer. However, the role of RUNX1 in ovarian cancer remains unclear. Therefore, this article reviews the relationship between RUNX1 and the occurrence and development of ovarian cancer, as well as the closely regulated signaling pathways, to provide some inspiration and theoretical support for future research on RUNX1 in ovarian cancer and other diseases.

4.
Ecotoxicol Environ Saf ; 264: 115413, 2023 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-37651794

RESUMO

The impact of maternal exposure to Bisphenol A on child cognitive development as well as its sex dimorphism remains uncertain. This study used data of 215 mothers and their children from a birth cohort in Shanghai. Urinary BPA were measured in spot urine samples of mothers at late pregnancy and children at age 2 years. Cognitive development was evaluated by Ages & Stages Questionnaires, Third Edition (ASQ-3) at age 2 years. Urinary BPA was detectable in 98.9% of mothers (geometric mean, GM: 2.6 µg/g. creatinine) and 99.8% children (GM: 3.4 µg/g. creatinine). Relative to the low and medium BPA tertiles, high tertile of maternal urinary BPA concentrations were associated with 4.8 points lower (95% CI: -8.3, -1.2) in gross motor and 3.7 points lower (95% CI: -7.4, -0.1) in problem-solving domain in girls only, with adjustment for maternal age, maternal education, pre-pregnancy BMI, passive smoking during pregnancy, parity, delivery mode, birth-weight for gestational age, child age at ASQ-3 test. This negative association remained with additional adjustment for child urinary BPA concentrations at age 2 years. No association was observed in boys. These results suggested the sex-dimorphism on the associations of maternal BPA exposure with gross motor and problem-solving domains in children at age 2 years. This study also indicated that optimal early child development should start with a healthy BPA-free "in utero" environment.


Assuntos
População do Leste Asiático , Exposição Materna , Fenóis , Pré-Escolar , Feminino , Humanos , Masculino , Gravidez , China , Creatinina , Estudos Prospectivos , Fenóis/urina
5.
Clin Transl Med ; 12(11): e973, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36377223

RESUMO

BACKGROUND: Colon cancer is the second leading cause of death worldwide. Exploring key regulators in colon cancer metastatic progression could lead to better outcomes for patients. METHODS: Initially, the transcriptional profiles of 681 colonrectal cancer (CRC) cases were used to discover signature genes that were significantly correlated with colon cancer metastasis. These signature genes were then validated using another independent 210 CRC cases' transcriptomics and proteomics profiles, and Kaplan-Meier regression analyses were used to screen the key regulators with patients' survival. Immunohistochemical staining was used to confirm the biomarkers, and transit knockdown was used to explore their implications on colon cancer cells migration and invasion abilities. The impact on the key signalling molecules in epithelial-mesenchymal transition (EMT) process that drive tumour metastasis was tested using Western blot. The response to clinical standard therapeutic drugs was compared to clinical prognosis of key regulators using an ROC plotter. RESULTS: Five genes (BGN, THBS2, SPARC, CDH11 and SPP1) were initially identified as potential biomarkers and therapeutic targets of colon cancer metastasis. The most significant signatures associated with colon cancer metastasis were determined to be BGN and THBS2. Furthermore, highly expression of BGN and THBS2 in tumours was linked to a worse survival rate. BGN and THBS2 knockdown significantly reduced colon cancer cells migration and invasion, as well as down-regulating three EMT-related proteins (Snail, Vimentin and N-cadherin), and increasing the proliferation inhibitory effect of 5-fluorouracil, irinotecan and oxaliplatin treatment. CONCLUSIONS: CRC metastatic progression, EMT phenotypic transition and poor survival time have been linked to BGN and THBS2. They could be utilized as potential diagnostic and therapeutic targets for colon cancer metastatic patients with a better prognosis.


Assuntos
Neoplasias do Colo , Humanos , Biglicano/metabolismo , Biglicano/farmacologia , Biomarcadores , Movimento Celular/genética , Neoplasias do Colo/diagnóstico , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Transição Epitelial-Mesenquimal/genética , Prognóstico
6.
Front Immunol ; 13: 996026, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36211388

RESUMO

The current immune checkpoint blockade therapy has been successful in treating some cancers but not others. New molecular targets and therapeutic approaches of cancer immunology need to be identified. Leukocyte associated immunoglobulin like receptor 1 (LAIR1) is an immune inhibitory receptor expressing on most immune cell types. However, it remains a question whether we can specifically and actively block LAIR1 signaling to activate immune responses for cancer treatment. Here we report the development of specific antagonistic anti-LAIR1 monoclonal antibodies and studied the effects of LAIR1 blockade on the anti-tumor immune functions. The anti-LAIR1 antagonistic antibody stimulated the activities of T cells, natural killer cells, macrophages, and dendritic cells in vitro. The single-cell RNA sequencing analysis of intratumoral immune cells in syngeneic human LAIR1 transgenic mice treated with control or anti-LAIR1 antagonist antibodies indicates that LAIR1 signaling blockade increased the numbers of CD4 memory T cells and inflammatory macrophages, but decreased those of pro-tumor macrophages, regulatory T cells, and plasmacytoid dendritic cells. Importantly, the LAIR1 blockade by the antagonistic antibody inhibited the activity of immunosuppressive myeloid cells and reactivated T cells from cancer patients in vitro and impeded tumor metastasis in a humanized mouse model. Blocking LAIR1 signaling in immune cells represents a promising strategy for development of anti-cancer immunotherapy.


Assuntos
Inibidores de Checkpoint Imunológico , Neoplasias , Animais , Anticorpos Monoclonais/uso terapêutico , Humanos , Imunoterapia , Camundongos , Linfócitos T Reguladores
7.
Am J Ophthalmol Case Rep ; 25: 101276, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35146182

RESUMO

PURPOSE: We report a rare case of recurrent Descemet's membrane detachment (DMD) post-trabeculectomy which was resolved spontaneously without surgical intervention. OBSERVATIONS: A 66-year-old patient with a history of acute angle closure glaucoma in his right eye presented to our hospital. The intraocular pressure (IOP) of his right was 40 mm Hg, and the visual acuity was10/20. After trabeculectomy of the affected eye, a severe Descemet's membrane detachment was found by AS-OCT. Part of Descemet's membrane was lying in front of the iris and lens. Surgical repair was performed, and viscoelastics and sterile air were injected into the anterior chamber to return the detached Descemet's membrane. AS-OCT showed that the DMD was successfully resolved. However, on the 7th day of follow-up, the DMD was detached again as seen on AS-OCT images. The patient refused reoperation to repair the DMD. Six months later, the patient visited our hospital again, and, interestingly, the DMD was completely resolved spontaneously without reoperation. CONCLUSIONS AND IMPORTANCE: Descemet's membrane is the basement membrane that lies between the stroma and the endothelial layer of the cornea. Minor DMD may be resolved spontaneously within a period of time without surgery, but large DMD is difficult to recover spontaneously. We believe that this is a rare case with spontaneous recovery of extensive DMD after trabeculectomy. But, despite all this, we still remain of the view that DMD should be treated immediately once it occurs.

8.
Oncogenesis ; 10(7): 49, 2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34253710

RESUMO

The C-terminal binding proteins (CtBPs), CtBP1 and CtBP2, are transcriptional co-repressor that interacts with multiple transcriptional factors to modulate the stability of chromatin. CtBP proteins were identified with overexpression in the high-grade serous ovarian carcinoma (HGSOC). However, little is known about CtBP proteins' regulatory roles in genomic stability and DNA repair in HGSOC. In this study, we combined whole-transcriptome analysis with multiple research methods to investigate the role of CtBP1/2 in genomic stability. Several key functional pathways were significantly enriched through whole transcription profile analysis of CtBP1/2 knockdown SKOV3 cells, including DNA damage repair, apoptosis, and cell cycle. CtBP1/2 knockdown induced cancer cell apoptosis, increased genetic instability, and enhanced the sensitivity to DNA damage agents, such as γ-irradiation and chemotherapy drug (Carboplatin and etoposide). The results of DNA fiber assay revealed that CtBP1/2 contribute differentially to the integrity of DNA replication track and stability of DNA replication recovery. CtBP1 protects the integrity of stalled forks under metabolic stress condition during prolonged periods of replication, whereas CtBP2 acts a dominant role in stability of DNA replication recovery. Furthermore, CtBP1/2 knockdown shifted the DSBs repair pathway from homologous recombination (HR) to non-homologous end joining (NHEJ) and activated DNA-PK in SKOV3 cells. Interesting, blast through TCGA tumor cases, patients with CtBP2 genetic alternation had a significantly longer overall survival time than unaltered patients. Together, these results revealed that CtBP1/2 play a different regulatory role in genomic stability and DSBs repair pathway bias in serous ovarian cancer cells. It is possible to generate novel potential targeted therapy strategy and translational application for serous ovarian carcinoma patients with a predictable better clinical outcome.

9.
J Fungi (Basel) ; 7(2)2021 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-33572180

RESUMO

Penicillium expansum is a major postharvest pathogen that mainly threatens the global pome fruit industry and causes great economic losses annually. In the present study, the antifungal effects and potential mechanism of cinnamon oil against P. expansum were investigated. Results indicated that 0.25 mg L-1 cinnamon oil could efficiently inhibit the spore germination, conidial production, mycelial accumulation, and expansion of P. expansum. In addition, it could effectively control blue mold rots induced by P. expansum in apples. Cinnamon oil could also reduce the expression of genes involved in patulin biosynthesis. Through a proteomic quantitative analysis, a total of 146 differentially expressed proteins (DEPs) involved in the carbohydrate metabolic process, most of which were down-regulated, were noticed for their large number and functional significance. Meanwhile, the expressions of 14 candidate genes corresponding to DEPs and the activities of six key regulatory enzymes (involving in cellulose hydrolyzation, Krebs circle, glycolysis, and pentose phosphate pathway) showed a similar trend in protein levels. In addition, extracellular carbohydrate consumption, intracellular carbohydrate accumulation, and ATP production of P. expansum under cinnamon oil stress were significantly decreased. Basing on the correlated and mutually authenticated results, we speculated that disturbing the fungal carbohydrate metabolic process would be partly responsible for the inhibitory effects of cinnamon oil on P. expansum growth. The findings would provide new insights into the antimicrobial mode of cinnamon oil.

10.
J Nat Prod ; 83(11): 3215-3222, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-33112136

RESUMO

Twenty-one aspidosperma-aspidosperma alkaloids, including the new tabernaesines A-J (1-9), were obtained from Tabernaemontana pachysiphon. The structures and absolute configurations were elucidated using HRMS and NMR experiments. Compounds 1-9 possessed a rare spiro heterocycle moiety between the monomeric units, while compounds 4 and 5 were characterized by an indole ring fused with an (N,N-diethyl)methyl amino group. Compounds 1, 5-7, 15, and 16 exhibited moderate cytotoxic potency against various human cancer cell lines at IC50 2.5-9.8 µM.


Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Alcaloides Indólicos/isolamento & purificação , Tabernaemontana/química , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacologia , Análise Espectral/métodos
11.
J Int Med Res ; 48(9): 300060520957447, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32961068

RESUMO

OBJECTIVE: To investigate the efficacy and safety of ab interno trabeculotomy using the VISCO360® Viscosurgical System (Sight Sciences, Inc., Menlo Park, CA, USA) combined with cataract extraction in the treatment of primary open-angle glaucoma (POAG). METHODS: Patients with POAG who underwent ab interno trabeculotomy combined with cataract extraction were retrospectively analyzed. Best-corrected visual acuity (BCVA), intraocular pressure (IOP), the number of antiglaucomatous medications, and complications were recorded preoperatively and 1 week, 1 month, 3 months, 6 months, 1 year, and 2 years postoperatively. RESULTS: Thirty-four patients (40 eyes) with POAG were included in this study, including 20 men (22 eyes) and 14 women (18 eyes). Compared with the preoperative IOP, the postoperative IOP was significantly lower at each time point. The greatest reduction in IOP was 60.7% at 1 month after surgery. The BCVA was also significantly improved at each postoperative time point. The number of antiglaucomatous medications used by the patients was significantly lower postoperatively than preoperatively. CONCLUSION: Ab interno trabeculotomy combined with cataract extraction is effective and safe for treatment of POAG.


Assuntos
Extração de Catarata , Catarata , Glaucoma de Ângulo Aberto , Trabeculectomia , Catarata/complicações , Feminino , Seguimentos , Glaucoma de Ângulo Aberto/cirurgia , Humanos , Pressão Intraocular , Masculino , Estudos Retrospectivos , Resultado do Tratamento
12.
J Immunother Cancer ; 8(2)2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32771992

RESUMO

BACKGROUND: Current immune checkpoint blockade strategies have been successful in treating certain types of solid cancer. However, checkpoint blockade monotherapies have not been successful against most hematological malignancies including multiple myeloma and leukemia. There is an urgent need to identify new targets for development of cancer immunotherapy. LILRB1, an immunoreceptor tyrosine-based inhibitory motif-containing receptor, is widely expressed on human immune cells, including B cells, monocytes and macrophages, dendritic cells and subsets of natural killer (NK) cells and T cells. The ligands of LILRB1, such as major histocompatibility complex (MHC) class I molecules, activate LILRB1 and transduce a suppressive signal, which inhibits the immune responses. However, it is not clear whether LILRB1 blockade can be effectively used for cancer treatment. METHODS: First, we measured the LILRB1 expression on NK cells from cancer patients to determine whether LILRB1 upregulated on NK cells from patients with cancer, compared with NK cells from healthy donors. Then, we developed specific antagonistic anti-LILRB1 monoclonal antibodies and studied the effects of LILRB1 blockade on the antitumor immune function of NK cells, especially in multiple myeloma models, in vitro and in vivo xenograft model using non-obese diabetic (NOD)-SCID interleukin-2Rγ-null mice. RESULTS: We demonstrate that percentage of LILRB1+ NK cells is significantly higher in patients with persistent multiple myeloma after treatment than that in healthy donors. Further, the percentage of LILRB1+ NK cells is also significantly higher in patients with late-stage prostate cancer than that in healthy donors. Significantly, we showed that LILRB1 blockade by our antagonistic LILRB1 antibody increased the tumoricidal activity of NK cells against several types of cancer cells, including multiple myeloma, leukemia, lymphoma and solid tumors, in vitro and in vivo. CONCLUSIONS: Our results indicate that blocking LILRB1 signaling on immune effector cells such as NK cells may represent a novel strategy for the development of anticancer immunotherapy.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Células Matadoras Naturais/imunologia , Receptor B1 de Leucócitos Semelhante a Imunoglobulina/antagonistas & inibidores , Animais , Anticorpos Monoclonais/farmacologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos NOD
13.
PLoS Pathog ; 15(7): e1007914, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31356650

RESUMO

Human cytomegalovirus (HCMV) is a ubiquitous pathogen that can cause disability in newborns and serious clinical diseases in immunocompromised patients. HCMV has a large genome with enormous coding potential; its viral particles are equipped with complicated glycoprotein complexes and can infect a wide range of human cells. Although multiple host cellular receptors interacting with viral glycoproteins have been reported, the mechanism of HCMV infection remains a mystery. Here we report identification of adipocyte plasma membrane-associated protein (APMAP) as a novel modulator active in the early stage of HCMV infection. APMAP is necessary for HCMV infection in both epithelial cells and fibroblasts; knockdown of APMAP expression significantly reduced HCMV infection of these cells. Interestingly, ectopic expression of human APMAP in cells refractory to HCMV infection, such as canine MDCK and murine NIH/3T3 cells, promoted HCMV infection. Furthermore, reduction in viral immediate early (IE) gene transcription at 6 h post infection and delayed nucleus translocation of tegument delivered pp65 at 4 h post infection were detected in APMAP-deficient cells but not in the wildtype cells. These results suggest that APMAP plays a role in the early stage of HCMV infection. Results from biochemical studies of APMAP and HCMV proteins suggest that APMAP could participate in HCMV infection through interaction with gH/gL containing glycoprotein complexes at low pH and mediate nucleus translocation of tegument pp65. Taken together, our results suggest that APMAP functions as a modulator promoting HCMV infection in multiple cell types and is an important player in the complex HCMV infection mechanism.


Assuntos
Infecções por Citomegalovirus/metabolismo , Infecções por Citomegalovirus/virologia , Citomegalovirus/patogenicidade , Glicoproteínas de Membrana/metabolismo , Adipócitos/metabolismo , Adipócitos/virologia , Animais , Membrana Celular/metabolismo , Membrana Celular/virologia , Citomegalovirus/genética , Citomegalovirus/metabolismo , Infecções por Citomegalovirus/etiologia , Cães , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Fibroblastos/metabolismo , Fibroblastos/virologia , Técnicas de Inativação de Genes , Interações entre Hospedeiro e Microrganismos , Humanos , Células Madin Darby de Rim Canino , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/genética , Camundongos , Células NIH 3T3 , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Estruturais Virais/metabolismo , Virulência , Internalização do Vírus
14.
Cancer Immunol Res ; 7(8): 1244-1257, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31213474

RESUMO

Therapeutic strategies are urgently needed for patients with acute myeloid leukemia (AML). Leukocyte immunoglobulin-like receptor B4 (LILRB4), which suppresses T-cell activation and supports tissue infiltration of AML cells, represents an attractive drug target for anti-AML therapeutics. Here, we report the identification and development of an LILRB4-specific humanized mAb that blocks LILRB4 activation. This mAb, h128-3, showed potent activity in blocking the development of monocytic AML in various models including patient-derived xenograft mice and syngeneic immunocompetent AML mice. MAb h128-3 enhanced the anti-AML efficacy of chemotherapy treatment by stimulating mobilization of leukemia cells. Mechanistic studies revealed four concordant modes of action for the anti-AML activity of h128-3: (i) reversal of T-cell suppression, (ii) inhibition of monocytic AML cell tissue infiltration, (iii) antibody-dependent cellular cytotoxicity, and (iv) antibody-dependent cellular phagocytosis. Therefore, targeting LILRB4 with antibody represents an effective therapeutic strategy for treating monocytic AML.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Apolipoproteínas E/metabolismo , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/metabolismo , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/metabolismo , Glicoproteínas de Membrana/metabolismo , Receptores Imunológicos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Anticorpos Bloqueadores , Anticorpos Monoclonais , Citotoxicidade Celular Dependente de Anticorpos , Antineoplásicos Imunológicos/uso terapêutico , Apolipoproteínas E/química , Apoptose , Linhagem Celular , Transformação Celular Neoplásica/efeitos dos fármacos , Técnicas de Cocultura , Modelos Animais de Doenças , Humanos , Leucemia Mieloide Aguda/patologia , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/química , Camundongos , Camundongos Knockout , Modelos Biológicos , Modelos Moleculares , Ligação Proteica/efeitos dos fármacos , Coelhos , Receptores Imunológicos/antagonistas & inibidores , Receptores Imunológicos/química , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Adv Mater ; 31(17): e1808294, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30848011

RESUMO

The ability to selectively kill cancerous cell populations while leaving healthy cells unaffected is a key goal in oncology. The use of nanovesicles (NVs) as chemotherapeutic delivery vehicles has been recently proven successful, yet monotherapy with monomodalities remains a significant limitation for solid tumor treatment. Here, as a proof of principle, a novel cell-membrane-derived NVs that can display full-length monoclonal antibodies (mAbs) is engineered. The high affinity and specificity of mAb for tumor-specific antigens allow these vesicular antibodies (VAs) to selectively deliver a cytotoxic agent to tumor cells and exert potent inhibition effects. These VAs can also regulate the tumor immune microenvironment. They can mediate antibody-dependent cellular cytotoxicity to eradicate tumor cells via recruitment and activation of natural killer cells in the tumor. Upon further encapsulation with chemotherapeutic agents, the VAs show unequaled cooperative effects in chemotherapy and immunotherapy in tumor-bearing mice. As far as it is known, this is the first report of a VA-based multifunctional combination therapy platform. This might lead to additional applications of vesicular antibodies in cancer theranostics.


Assuntos
Anticorpos Monoclonais/imunologia , Portadores de Fármacos/química , Nanopartículas/química , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Animais , Anticorpos Monoclonais/genética , Antígenos de Neoplasias/imunologia , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Transporte Biológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Terapia Combinada/métodos , Doxorrubicina/química , Doxorrubicina/uso terapêutico , Liberação Controlada de Fármacos , Tratamento Farmacológico/métodos , Humanos , Imunoterapia/métodos , Verde de Indocianina/química , Verde de Indocianina/uso terapêutico , Células Matadoras Naturais/efeitos dos fármacos , Camundongos , Camundongos Nus , Terapia de Alvo Molecular/métodos , Tamanho da Partícula , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/uso terapêutico , Propriedades de Superfície , Microambiente Tumoral/efeitos dos fármacos
16.
Nature ; 562(7728): 605-609, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30333625

RESUMO

Immune checkpoint blockade therapy has been successful in treating some types of cancer but has not shown clinical benefits for treating leukaemia1. This result suggests that leukaemia uses unique mechanisms to evade this therapy. Certain immune inhibitory receptors that are expressed by normal immune cells are also present on leukaemia cells. Whether these receptors can initiate immune-related primary signalling in tumour cells remains unknown. Here we use mouse models and human cells to show that LILRB4, an immunoreceptor tyrosine-based inhibition motif-containing receptor and a marker of monocytic leukaemia, supports tumour cell infiltration into tissues and suppresses T cell activity via a signalling pathway that involves APOE, LILRB4, SHP-2, uPAR and ARG1 in acute myeloid leukaemia (AML) cells. Deletion of LILRB4 or the use of antibodies to block LILRB4 signalling impeded AML development. Thus, LILRB4 orchestrates tumour invasion pathways in monocytic leukaemia cells by creating an immunosuppressive microenvironment. LILRB4 represents a compelling target for the treatment of monocytic AML.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/patologia , Receptores de Superfície Celular/metabolismo , Transdução de Sinais , Evasão Tumoral/imunologia , Animais , Apolipoproteínas E/metabolismo , Arginase/metabolismo , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD8-Positivos/citologia , Movimento Celular , Proliferação de Células , Feminino , Humanos , Tolerância Imunológica/imunologia , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Masculino , Glicoproteínas de Membrana , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Ligação Proteica , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Receptores de Superfície Celular/deficiência , Receptores de Superfície Celular/genética , Receptores Imunológicos , Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Evasão Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Sci Rep ; 6: 19042, 2016 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-26750243

RESUMO

The presence of neutralizing epitopes in human papillomavirus (HPV) L1 virus-like particles (VLPs) is the structural basis of prophylactic vaccines. An anti-HPV16 neutralizing monoclonal antibody (N-mAb) 26D1 was isolated from a memory B cell of a human vaccinee. The pre-binding of heparan sulfate to VLPs inhibited the binding of both N-mAbs to the antigen, indicating that the epitopes are critical for viral cell attachment/entry. Hybrid VLP binding with surface loop swapping between types indicated the essential roles of the DE and FG loops for both 26D1 (DEa in particular) and H16.V5 binding. Specifically, Tyr(135) and Val(141) on the DEa loop were shown to be critical residues for 26D1 binding via site-directed mutagenesis. Partially overlap between the epitopes between 26D1 and H16.V5 was shown using pairwise epitope mapping, and their binding difference is demonstrated to be predominantly in DE loop region. In addition, 26D1 epitope is immunodominant epitope recognized by both antibodies elicited by the authentic virus from infected individuals and polyclonal antibodies from vaccinees. Overall, a partially overlapping but distinct neutralizing epitope from that of H16.V5 was identified using a human N-mAb, shedding lights to the antibody arrays as part of human immune response to vaccination and infection.


Assuntos
Anticorpos Monoclonais/química , Anticorpos Neutralizantes/química , Proteínas do Capsídeo/imunologia , Papillomavirus Humano 16/imunologia , Vacinas contra Papillomavirus/química , Vacinas de Partículas Semelhantes a Vírus/química , Anticorpos Monoclonais/biossíntese , Anticorpos Neutralizantes/biossíntese , Afinidade de Anticorpos , Especificidade de Anticorpos , Linfócitos B/química , Linfócitos B/imunologia , Linfócitos B/virologia , Proteínas do Capsídeo/química , Mapeamento de Epitopos , Epitopos/química , Epitopos/imunologia , Feminino , Heparitina Sulfato/química , Heparitina Sulfato/farmacologia , Papillomavirus Humano 16/química , Humanos , Soros Imunes/química , Memória Imunológica , Simulação de Acoplamento Molecular , Mutação , Testes de Neutralização , Vacinas contra Papillomavirus/administração & dosagem , Vacinas contra Papillomavirus/imunologia , Ligação Proteica/efeitos dos fármacos , Domínios Proteicos , Vacinação , Vacinas de Partículas Semelhantes a Vírus/administração & dosagem , Vacinas de Partículas Semelhantes a Vírus/imunologia
18.
Nanoscale ; 5(6): 2394-402, 2013 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-23400550

RESUMO

A highly shape selective synthesis of Cu and Cu@Cu-Ni nanocubes and nanowires has been developed by modulating the coordination chemistry of transition metal ions with a trioctylphosphine (TOP)-Cl(-) ligand pair in oleylamine under mild organic solvent conditions. The as-prepared nanocubes have a face-centered cubic (fcc) phase and are covered by six {100} facets, whereas the as-prepared nanowires have a multi-twinned structure and grow along the [110] direction. Both the Ni(2+) and Cl(-) ions, along with TOP, play vital roles in determining the final morphology of the as-prepared nanocrystals (NCs). TOP can be used to selectively generate single-crystal seeds at the initial stage, which then grow into nanocubes in the presence of Cl(-) ions, while the absence of TOP leads to the formation of multi-twined crystal seeds that finally develop into nanowires. Moreover, Ni can be incorporated to form a Cu-Ni alloy shell over a Cu core at higher temperatures in a one-pot process, which makes diamagnetic Cu NCs magnetically responsive and has a significant influence on their optical properties.

19.
J Nanosci Nanotechnol ; 10(8): 5175-82, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21125867

RESUMO

We have synthesized anisotropic nickel phosphide nanocrystals, including triangular/hexagonal nanoplatelets, nanorods and nanowires, via a solution-phase synthetic method that uses nickel(II) acetylacetonate as a metal precursor and trioctylphosphine as a phosphorus source. Nickel phosphide nanoplatelets have been prepared from a one-pot reaction, and their dimensions in the length mostly vary from 20 to 50 nm, while their thicknesses are in a narrow range of 7-9 nm. Nickel phosphide nanorods with a width of approximately 6 nm and a typical length of 25-32 nm can be synthesized from either the one-pot reaction or the multi-injection approach, although the latter can generate nanorods with a much higher uniformity. A continuous injection approach has been used to synthesize nanowires that have a typical width of approximately 6 nm and a length ranging from tens of nanometers up to several hundred nanometers. Major factors that influence the growth of nickel phosphide nanocrystals have been investigated, and a multi-surfactant system is found to be essential for the formation of anisotropic nanostructure. Magnetic studies have revealed paramagnetic characteristics for all the synthesized samples.


Assuntos
Nanopartículas Metálicas/química , Nanoestruturas/química , Nanotecnologia/métodos , Níquel/química , Fosfinas/química , Anisotropia , Campos Eletromagnéticos , Nanopartículas Metálicas/ultraestrutura , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Nanoestruturas/ultraestrutura , Tamanho da Partícula
20.
Nanoscale Res Lett ; 5(4): 786-90, 2010 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-20672078

RESUMO

Previous preparation of iron phosphide nanowires usually employed toxic and unstable iron carbonyl compounds as precursor. In this study, we demonstrate that iron phosphide nanowires can be synthesized via a facile nonaqueous chemical route that utilizes a commonly available iron precursor, iron (III) acetylacetonate. In the synthesis, trioctylphosphine (TOP) and trioctylphosphine oxide (TOPO) have been used as surfactants, and oleylamine has been used as solvent. The crystalline structure and morphology of the as-synthesized products were characterized by powder X-ray diffraction (XRD) and transmission electron microscopy (TEM). The obtained iron phosphide nanowires have a typical width of ~16 nm and a length of several hundred nanometers. Structural and compositional characterization reveals a hexagonal Fe2P crystalline phase. The morphology of as-synthesized products is greatly influenced by the ratio of TOP/TOPO. The presence of TOPO has been found to be essential for the growth of high-quality iron phosphide nanowires. Magnetic measurements reveal ferromagnetic characteristics, and hysteresis behaviors below the blocking temperature have been observed.

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