SummaryExosomes (EXO) derived from dendritic cells (DC), which express major histocompatibility complex (MHC) and costimulatory molecules, have been used for antitumour vaccines. However, they are still less effective by showing only prophylatic immunity in animal models or very limited immune responses in clinical trials. In this study, we showed that ovalbumin (OVA) protein-pulsed DC (DC OVA )-derived EXO (EXO OVA ) displayed MHC class I-OVA I peptide (pMHC I) complexes, CD11c, CD40, CD80, CCR7, DEC205, Toll-like receptor 4 (TLR4), TLR9, MyD88 and DC-SIGN molecules, but at a lower level than DC OVA . EXO OVA can be taken up by DC through LFA-1/CD54 and C-type lectin/mannose (glucosamine)-rich C-type lectin receptor (CLR) interactions. Mature DC pulsed with EXO OVA , which were referred to as mDC EXO , expressed a higher level of pMHC I, MHC II, and costimulatory CD40, CD54 and CD80 than DC OVA . The mDC EXO could more strongly stimulate OVAspecific CD8 + T-cell proliferation in vitro and in vivo, and more efficiently induce OVA-specific cytotoxic T-lymphocyte responses, antitumour immunity and CD8 + T-cell memory in vivo than EXO OVA and DC OVA .In addition, mDC EXO could also more efficiently eradicate established tumours. Therefore, mature DC pulsed with EXO may represent a new, highly effective DC-based vaccine for the induction of antitumour immunity.
The efficacy and safety of chidamide, a new subtype-selective histone deacetylase (HDAC) inhibitor, have been demonstrated in a pivotal phase II clinical trial, and chidamide has been approved by the China Food and Drug Administration (CFDA) as a treatment for relapsed or refractory peripheral T cell lymphoma (PTCL). This study sought to further evaluate the real-world utilization of chidamide in 383 relapsed or refractory PTCL patients from April 2015 to February 2016 in mainland China. For patients receiving chidamide monotherapy (n = 256), the overall response rate (ORR) and disease control rate (DCR) were 39.06 and 64.45%, respectively. The ORR and DCR were 51.18 and 74.02%, respectively, for patients receiving chidamide combined with chemotherapy (n = 127). For patients receiving chidamide monotherapy and chidamide combined with chemotherapy, the median progression-free survival (PFS) was 129 (95% CI 82 to 194) days for the monotherapy group and 152 (95% CI 93 to 201) days for the combined therapy group (P = 0.3266). Most adverse events (AEs) were of grade 1 to 2. AEs of grade 3 or higher that occurred in ≥5% of patients receiving chidamide monotherapy included thrombocytopenia (10.2%) and neutropenia (6.2%). For patients receiving chidamide combined with chemotherapy, grade 3 to 4 AEs that occurred in ≥5% of patients included thrombocytopenia (18.1%), neutropenia (12.6%), anemia (7.1%), and fatigue (5.5%). This large real-world study demonstrates that chidamide has a favorable efficacy and an acceptable safety profile for refractory and relapsed PTCL patients. Chidamide combined with chemotherapy may be a new treatment choice for refractory and relapsed PTCL patients but requires further investigation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-017-0439-6) contains supplementary material, which is available to authorized users.
Typical and atypical antipsychotic drugs, though both effective, act on different neurotransmitter receptors and are dissimilar in some clinical effects and side effects. The typical antipsychotic drug haloperidol has been shown to cause a decrease in the expression of brain-derived neurotrophic factor (BDNF), which plays an important role in neuronal cell survival, differentiation, and neuronal connectivity. However, it is still unknown whether atypical antipsychotic drugs similarly regulate BDNF expression. We examined the effects of chronic (28 days) administration of typical and atypical antipsychotic drugs on BDNF mRNA expression in the rat hippocampus using in situ hybridization. Quantitative analysis revealed that the typical antipsychotic drug haloperidol (1 mg/kg) down-regulated BDNF mRNA expression in both CA1 (P < 0.05) and dentate gyrus (P < 0.01) regions compared with vehicle control. In contrast, the atypical antipsychotic agents clozapine (10 mg/kg) and olanzapine (2.7 mg/kg) up-regulated BDNF mRNA expression in CA1, CA3, and dentate gyrus regions of the rat hippocampus compared with their respective controls (P < 0.01). These findings demonstrate that the typical and atypical antipsychotic drugs differentially regulate BDNF mRNA expression in rat hippocampus.
Exosomes (EXO) derived from tumour cells have been used to stimulate antitumour immune responses, but only resulting in prophylatic immunity. Tumour-derived heat shock protein 70 (HSP70) molecules are molecular chaperones with a broad repertoire of tumour antigen peptides capable of stimulating dendritic cell (DC) maturation and T-cell immune responses. To enhance EXO-based antitumour immunity, we generated an engineered myeloma cell line J558HSP expressing endogenous P1A tumour antigen and transgenic form of membrane-bound HSP70 and heat-shocked J558HS expressing cytoplasmic HSP70, and purified EXOHSP and EXOHS from J558HSP and J558HS tumour cell culture supernatants by ultracentrifugation. We found that EXOHSP were able to more efficiently stimulate maturation of DCs with up-regulation of Iab, CD40, CD80 and inflammatory cytokines than EXOHS after overnight incubation of immature bone-marrow-derived DCs (5 × 106 cells) with EXO (100 μg), respectively. We also i.v. immunized BALB/c mice with EXO (30 μg/mouse) and assessed P1A-specific T-cell responses after immunization. We demonstrate that EXOHSP are able to stimulate type 1 CD4+ helper T (Th1) cell responses, and more efficient P1A-specific CD8+ cytotoxic T lymphocyte (CTL) responses and antitumour immunity than EXOHS. In addition, we further elucidate that EXOHSP-stimulated antitumour immunity is mediated by both P1A-specific CD8+ CTL and non-P1A-specific natural killer (NK) responses. Therefore, membrane-bound HSP70-expressing tumour cell-released EXO may represent a more effective EXO-based vaccine in induction of antitumour immunity.
Neuroanatomical studies suggest that neuronal atrophy and destruction occur over the course of many years in neurodegenerative conditions such as schizophrenia and Alzheimer's disease. In schizophrenia, early intervention with atypical neuroleptics such as olanzapine has been shown to prevent development of some of the more serious and debilitating symptoms in many patients. The mechanisms whereby olanzapine slows or prevents symptom progression in schizophrenia remain unclear. A previous study found that olanzapine increased mRNA for the copper/zinc isoform of the superoxide dismutase enzyme (SOD-1). We investigated the effects of olanzapine in PC12 cells exposed to hydrogen peroxide. We measured cell viability, observed evidence of necrosis and apoptosis, checked the SOD-1 mRNA by Northern blot analyses, and determined SOD-1 enzyme activity. We found that: (1) the decrease in cell viability induced by hydrogen peroxide was attenuated in PC12 cells pretreated with olanzapine; (2) olanzapine increased SOD enzyme activity in PC12 cells; (3) inhibiting SOD activity with diethyldithiocarbamic acid prevented the cytoprotective actions of olanzapine; and (4) the decrease in SOD-1 mRNA level induced by hydrogen peroxide was blocked by pretreatment with olanzapine. These data indicate that the neuroprotective action of olanzapine includes the upregulation of SOD.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.