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1.
Emerg Microbes Infect ; 12(1): 2202269, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37038652

RESUMO

Breakthrough infections by SARS-CoV-2 variants pose a global challenge to COVID-19 pandemic control, and the development of more effective vaccines of broad-spectrum protection is needed. In this study, we constructed pVAX1-based plasmids encoding receptor-binding domain (RBD) chimera of SARS-CoV-1 and SARS-CoV-2 variants, including pAD1002 (encoding RBDSARS/BA1), pAD1003 (encoding RBDSARS/Beta) and pAD131 (encoding RBDBA1/Beta). Plasmids pAD1002 and pAD131 were far more immunogenic than pAD1003 in terms of eliciting RBD-specific IgG when intramuscularly administered without electroporation. Furthermore, dissolvable microneedle array patches (MAP) greatly enhanced the immunogenicity of these DNA constructs in mice and rabbits. MAP laden with pAD1002 (MAP-1002) significantly outperformed inactivated SARS-CoV-2 virus vaccine in inducing RBD-specific IFN-γ+ effector and memory T cells, and generated T lymphocytes of different homing patterns compared to that induced by electroporated DNA in mice. In consistence with the high titer neutralization results of MAP-1002 antisera against SARS-CoV-2 pseudoviruses, MAP-1002 protected human ACE2-transgenic mice from Omicron BA.1 challenge. Collectively, MAP-based DNA constructs encoding chimeric RBDs of SARS-CoV-1 and SARS-CoV-2 variants, as represented by MAP-1002, are potential COVID-19 vaccine candidates worthy further translational study.


Assuntos
COVID-19 , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave , Vacinas de DNA , Animais , Humanos , Camundongos , Coelhos , Vacinas contra COVID-19 , SARS-CoV-2 , Pandemias , DNA , Camundongos Transgênicos , Anticorpos Antivirais , Anticorpos Neutralizantes , Glicoproteína da Espícula de Coronavírus
2.
Cereb Cortex ; 33(13): 8273-8285, 2023 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-37005067

RESUMO

Brain network dynamics not only endow the brain with flexible coordination for various cognitive processes but also with a huge potential of neuroplasticity for development, skill learning, and after cerebral injury. Diffusive and progressive glioma infiltration triggers the neuroplasticity for functional compensation, which is an outstanding pathophysiological model for the investigation of network reorganization underlying neuroplasticity. In this study, we employed dynamic conditional correlation to construct framewise language networks and investigated dynamic reorganizations in 83 patients with left hemispheric gliomas involving language networks (40 patients without aphasia and 43 patients with aphasia). We found that, in healthy controls (HCs) and patients, the language network dynamics in resting state clustered into 4 temporal-reoccurring states. Language deficits-severity-dependent topological abnormalities of dFCs were observed. Compared with HCs, suboptimal language network dynamics were observed for those patients without aphasia, while more severe network disruptions were observed for those patients with aphasia. Machine learning-based dFC-linguistics prediction analyses showed that dFCs of the 4 states significantly predicted individual patients' language scores. These findings shed light on our understanding of metaplasticity in glioma. Glioma-induced language network reorganizations were investigated under a dynamic "meta-networking" (network of networks) framework. In healthy controls and patients with glioma, the framewise language network dynamics in resting-state robustly clustered into 4 temporal-reoccurring states. The spatial but not temporal language deficits-severity-dependent abnormalities of dFCs were observed in patients with left hemispheric gliomas involving language network. Language network dynamics significantly predicted individual patients' language scores.


Assuntos
Afasia , Glioma , Humanos , Mapeamento Encefálico , Imageamento por Ressonância Magnética , Encéfalo , Idioma , Glioma/complicações , Afasia/etiologia , Afasia/psicologia , Plasticidade Neuronal/fisiologia
3.
Materials (Basel) ; 15(24)2022 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-36556515

RESUMO

Innovative sustainable techniques for transportation infrastructure enhancement have been proposed in recent decades [...].

4.
J Immunol Res ; 2022: 4626813, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36249426

RESUMO

Calreticulin (CRT) is a major calcium-binding luminal resident protein on the endoplasmic reticulum that can also be released extracellular as well as anchored on surface of cells. Previously, we demonstrated that soluble recombinant CRT fragment 39-272 (CRT/39-272) exhibited potent immunostimulatory effects as well as immunoregulation effects on immune cells. Here, we constructed stable B16 melanoma cell lines expressing recombinant CRT/39-272 on the membrane (B16-tmCRT/39-272) to investigate the roles of cell surface CRT on tumor progression. We found that B16-tmCRT/39-272 cells subcutaneously inoculated into C57BL/6 mice exhibited stronger tumorigenicity than the B16-EGFP control cells. The tumor associated macrophages infiltrated in tumors were mainly M2 phenotype. Regulatory T cells (Tregs) were also expanded more in bearing mice. Consistent with the in vivo results, B16-tmCRT/39-272 promoted macrophage polarization toward F4/80+CD206+ M2 macrophages and promoted transforming growth factor beta (TGF-ß) secretion in vitro, which could promote naïve CD4+ T cell differentiation into Tregs. These results imply that the tmCRT/39-272 could accelerate tumor development by enhancing M2 macrophage polarization to induce TGF-ß secretion, and then promoted Treg differentiation in the tumor microenvironment. Our data may provide useful clues for better understanding of the potentiating roles of CRT in tumorigenesis.


Assuntos
Calreticulina , Melanoma Experimental , Animais , Cálcio/metabolismo , Calreticulina/genética , Calreticulina/metabolismo , Linhagem Celular Tumoral , Camundongos , Camundongos Endogâmicos C57BL , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Microambiente Tumoral
5.
Front Oncol ; 12: 986387, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36226056

RESUMO

Objective: Cingulate cortex and cingulum both play crucial roles in limbic system. The aim of study is to observe and analyze surgical outcomes of cingulate gyrus glioma through extents of resection (EORs), overall survival (OS), and postsurgical neurological outcome. Method: The authors retrospectively studied 95 consecutive adult cases of primary cingulate gliomas that all underwent craniotomies and tumor resection. The patients were classified into unitary sub-region based on the four-division model. The information of clinical symptoms, pathology, EOR, postoperative neurological outcome and survival were analyzed through group comparison. Result: Low-grade gliomas (LGGs) were more prevalent (69.47%) for cingulate gyrus. Diffuse astrocytoma (40.00%) was most common histopathological diagnosis in total. Regarding sub-regions tumor involved in, midcingulate cortex (MCC) glioma was most prevalent (54.74%) followed by anterior cingulate cortex (ACC) glioma. Among all patients, 83 patients (87.37%) received EOR ≥ 90%. In LGG group, 58 patients (87.88%) received EOR ≥ 90%. The achievement of EOR significantly correlated with survival (P = 0.006). MCC cases were significantly associated with short-term morbidity in either language or motor function (P = 0.02). Majority of ACC cases (80.65%) escaped from any short-term deficits and nearly 90% free for permanent morbidity. Tumors in the dominant hemisphere were significantly associated with language dysfunction or cognition dysfunction, either short-term (P=0.0006) or long-term morbidity (P=0.0111). Age was the only postoperative susceptible predictor for all types of transient (P=0.021) and permanent (P=0.02) neurological deficit. Conclusion: Regarding cingulate gyrus glioma, the management of surgical plans could be carried out into four sub-region level. In spite of short-term neurological dysfunction caused by surgical procedure, majority of transient dysfunction could be relieved or recovered in long-term. The necessary effort to prolong overall survival is still to achieve advisable EOR.

6.
Int Immunopharmacol ; 112: 109228, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36095947

RESUMO

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease. RA development is mediated by the abnormal activation of multiple signaling pathways. Recent studies have revealed that type-I interferon (IFN-I) signaling plays an essential role in the occurrence and development of RA. However, how to target IFN-I signaling to develop anti-rheumatoid arthritis drugs remains largely unexplored. Here, our study showed that IFN-I signaling was over-activated in articular synovial cells from collagen II-induced arthritis (CIA) mice. Interestingly, we found that a small molecule compound, menthone, strongly inhibited the activation of the IFN-I signaling pathway. Further studies revealed that menthone promoted K48-linked polyubiquitination of Tyk2, thus lowering the protein level and stability of Tyk2. Importantly, menthone administration in the local articulus of CIA mice significantly attenuated the local inflammation in CIA mice. This study could promote our understanding of rheumatoid arthritis, and also suggests a potential strategy to develop anti-RA drugs.


Assuntos
Artrite Experimental , Artrite Reumatoide , Camundongos , Animais , Inflamação/tratamento farmacológico , Transdução de Sinais , Colágeno/metabolismo , Ubiquitinação , Interferons/metabolismo
7.
J Immunol Res ; 2022: 8802004, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35983078

RESUMO

An endoplasmic reticulum resident protein, calreticulin (CRT), participates in many cellular processes. CRT is a tumor-associated antigen with an important role in antitumor immunity. Previously, we reported that the recombinant CRT fragment 39-272 (CRT/39-272) exhibited superior immunobiological activity, activating macrophages to release cytokines and promoting dendritic cell (DC) maturation. However, the effect of CRT/39-272 in vivo, especially its adjuvant effect on in vivo antitumor immune responses, was not fully investigated. In this study, we constructed a fusion protein linking CRT/39-272 to an ovalbumin (OVA) peptide (residues 182-297, OVAp) and used the fusion protein (OVAp-CRT) to examine the adjuvant effect of CRT. We investigated whether CRT/39-272 could induce bone marrow-derived DC maturation and strongly promote the proliferation of OVA-specific T cells in vitro. Compared with OVAp, OVAp-CRT induced stronger antigen-specific T lymphocyte responses, including antigen-specific T cell proliferation, interferon-γ secretion, and cytotoxic T lymphocyte responses. OVAp-CRT-immunized mice generated significantly increased OVAp-specific antibody and CD4+/CD8+ memory T cells, which mediated long-term protective effects. OVAp-CRT upregulated CD40, CD80, and CD86 expressions in splenic conventional DCs. Furthermore, OVAp-CRT protected immunized mice against OVA-expressing B16 melanoma cells in vivo. Moreover, mice that were adoptively transferred with OVAp-CRT-pulsed DCs showed inhibited tumor growth and prolonged mouse survival. Our results demonstrate that CRT/39-272 can be used as a potential new adjuvant for tumor vaccines, and this finding may be useful in tumor vaccine development.


Assuntos
Vacinas Anticâncer , Melanoma , Adjuvantes Imunológicos/metabolismo , Animais , Calreticulina/genética , Calreticulina/metabolismo , Células Dendríticas , Melanoma/metabolismo , Melanoma/terapia , Camundongos , Camundongos Endogâmicos C57BL , Ovalbumina , Linfócitos T Citotóxicos
8.
Stem Cell Reports ; 17(7): 1561-1575, 2022 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-35777356

RESUMO

Clinical data reveal that patients with allogeneic hematopoietic stem cell transplantation (HSCT) are vulnerable to infection and prone to developing severe sepsis, which greatly compromises the success of transplantation, indicating a dysregulation of inflammatory immune response in this clinical setting. Here, by using a mouse model of haploidentical bone marrow transplantation (haplo-BMT), we found that uncontrolled macrophage inflammation underlies the pathogenesis of both LPS- and E.coli-induced sepsis in recipient animals with graft-versus-host disease (GVHD). Deficient neutrophil maturation in GVHD mice post-haplo-BMT diminished modulation of macrophage-induced inflammation, which was mechanistically dependent on MMP9-mediated activation of TGF-ß1. Accordingly, adoptive transfer of mature neutrophils purified from wild-type donor mice inhibited both sterile and infectious sepsis in GVHD mice post-haplo-BMT. Together, our findings identify a novel mature neutrophil-dependent regulation of macrophage inflammatory response in a haplo-BMT setting and provide useful clues for developing clinical strategies for patients suffering from post-HSCT sepsis.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Sepse , Animais , Transplante de Medula Óssea , Doença Enxerto-Hospedeiro/etiologia , Inflamação , Macrófagos , Camundongos , Neutrófilos , Sepse/etiologia
9.
Brain Commun ; 4(2): fcac046, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35415604

RESUMO

For patients with glioma located in or adjacent to the linguistic eloquent cortex, awake surgery with an emphasis on the preservation of language function is preferred. However, the brain network basis of postoperative linguistic functional outcomes remains largely unknown. In this work, 34 patients with left cerebral gliomas who underwent awake surgery were assessed for language function and resting-state network properties before and after surgery. We found that there were 28 patients whose language function returned to at least 80% of the baseline scores within 3 months after surgery or to 85% within 6 months after surgery. For these patients, the spontaneous recovery of language function synchronized with changes within the language and cognitive control networks, but not with other networks. Specifically, compared with baseline values, language functions and global network properties were the worst within 1 month after surgery and gradually recovered within 6 months after surgery. The recovery of connections was tumour location dependent and was attributed to both ipsihemispheric and interhemispheric connections. In contrast, for six patients whose language function did not recover well, severe network disruptions were observed before surgery and persisted into the chronic phase. This study suggests the synchronization of functional network normalization and spontaneous language recovery in postoperative patients with glioma.

10.
J Nat Prod ; 85(4): 1109-1117, 2022 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-35302365

RESUMO

Rheumatoid arthritis (RA) is an autoimmune disease with nearly 1.6 billion patients worldwide and an incidence of 0.5-1%. In recent years, basic and clinical studies have revealed that immune cell responses and corresponding secretion of inflammatory factors are important in the control of RA development. Our study found that a natural plant ingredient, menthone, could be used as a potential antirheumatism compound. In vivo observations demonstrated that menthone alleviates collagen II-induced arthritis (CIA) in mice. Furthermore, we found that menthone regulates the number of Th1 and Th17 cells in CIA mice. Importantly, menthone significantly inhibits the release of pro-inflammatory cytokines, including TNF-α, IL-1ß, and IL-6, in CIA mice. Our study suggests a potential component for the development of drugs to treat rheumatoid arthritis.


Assuntos
Artrite Experimental , Artrite Reumatoide , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Citocinas , Humanos , Mentol , Camundongos , Camundongos Endogâmicos DBA , Células Th17
11.
Cells ; 11(4)2022 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-35203346

RESUMO

Given the importance of B lymphocytes in inflammation and immune defense against pathogens, mice transgenic for Cre under the control of Cd19 promoter (Cd19Cre/+ mice) have been widely used to specifically investigate the role of loxP-flanked genes in B cell development/function. However, impacts of expression/insertion of the Cre transgene on the phenotype and function of B cells have not been carefully studied. Here, we show that the number of marginal zone B and B1a cells was selectively reduced in Cd19Cre/+ mice, while B cell development in the bone marrow and total numbers of peripheral B cells were comparable between Cd19Cre/+ and wild type C57BL/6 mice. Notably, humoral responses to both T cell-dependent and independent antigens were significantly increased in Cd19Cre/+ mice. We speculate that these differences are mainly attributable to reduced surface CD19 levels caused by integration of the Cre-expressing cassette that inactivates one Cd19 allele. Moreover, our literature survey showed that expression of Cd19Cre/+ alone may affect the development/progression of inflammatory and anti-infectious responses. Thus, our results have important implications for the design and interpretation of results on gene functions specifically targeted in B cells in the Cd19Cre/+ mouse strain, for instance, in the context of (auto) inflammatory/infectious diseases.


Assuntos
Antígenos CD19 , Linfócitos B , Animais , Anticorpos/metabolismo , Antígenos CD19/metabolismo , Integrases , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo
12.
Front Immunol ; 12: 719727, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34621268

RESUMO

Infectious pneumonia is one of the most common complications after bone marrow transplantation (BMT), which is considered to be associated with poor reconstitution and functional maturation of alveolar macrophages (AMs) post-transplantation. Here, we present evidence showing that lack of IL-13-secreting group 2 innate lymphoid cells (ILC2s) in the lungs may underlay poor AM reconstitution in a mouse model of haploidentical BMT (haplo-BMT). Recombinant murine IL-13 was able to potentiate monocyte-derived AM differentiation in vitro. When intranasally administered, a cocktail of granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-13, and CCL2 not only promoted donor monocyte-derived AM reconstitution in haplo-BMT-recipient mice but also enhanced the innate immunity of the recipient animals against pulmonary bacterial infection. These results provide a useful clue for a clinical strategy to prevent pulmonary bacterial infection at the early stage of recipients post-BMT.


Assuntos
Transplante de Medula Óssea , Diferenciação Celular , Citocinas/metabolismo , Reconstituição Imune , Macrófagos Alveolares/fisiologia , Mielopoese , Animais , Transplante de Medula Óssea/métodos , Diferenciação Celular/efeitos dos fármacos , Citocinas/farmacologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Interleucina-13/metabolismo , Interleucina-13/farmacologia , Linfócitos/citologia , Linfócitos/imunologia , Linfócitos/metabolismo , Macrófagos Alveolares/citologia , Macrófagos Alveolares/efeitos dos fármacos , Camundongos , Modelos Animais , Mielopoese/efeitos dos fármacos , Transplante Haploidêntico
14.
J Bone Miner Res ; 36(6): 1174-1188, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33651383

RESUMO

Potentiation of receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis by IgG immunocomplexes (ICs) is generally considered an important pathway leading to cartilage and bone destruction in rheumatoid arthritis (RA). However, whether IgG ICs possess pro-osteoclastogenic potential independent of RANKL and inflammatory cytokines is unclear. Here we demonstrate that by fully cross-linking human FcγRIIa (hFcγRIIa) or co-ligating hFcγRIIa and TLR4, IgG ICs alone could drive the differentiation of human blood monocytes into nuclear factor of activated T cells cytoplasmic 1 (NFATc1-negative nonclassical osteoclasts (NOCs). Surprisingly, IgG ICs could also overrule RANKL-induced classical osteoclast (COC) differentiation in vitro. In mouse model of collagen-induced arthritis, hFcγRIIa-transgenic, but not nontransgenic control, mice suffered from cartilage/bone destruction accompanied by the presence of NFATc1- NOCs lining the eroded cartilage surface in affected joints. Our results not only identify a novel subset of IC-induced NOCs but also provide a possible explanation for the uncoupling of FcγR-mediated cartilage destruction from RANKL-related bone erosion in autoinflammatory arthritis. © 2021 American Society for Bone and Mineral Research (ASBMR)..


Assuntos
Reabsorção Óssea , Osteoclastos , Animais , Diferenciação Celular , Citocinas , Humanos , Imunoglobulina G , Ligantes , Camundongos , Ligante RANK
15.
Materials (Basel) ; 13(22)2020 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-33233383

RESUMO

Due to its ability to degrade nitrogen oxides under ultraviolet, titanium dioxide has been applied in asphalt concrete to degrade automobile exhaust in recent years. To highlight the protection of road traffic environmental quality and mitigate automobile exhaust on human health, this study proposes combining titanium dioxide and active carbon into Sand-fog seal to form a pavement coating material with a photocatalytic function. It uses active carbon to reinforce the material's function, and the coupling agent for modification makes it well dispersed in the Sand-fog seal. The indoor experiments were carried out at 30 °C and relative humidity of 30%. It tested the composite material's degradation efficiency on nitrogen dioxide in relation to component proportions, coupling agents, and dosages. The study concluded that the optimal photocatalytic efficiency could be achieved when the ratio of active carbon to titanium dioxide is 0.6. After being modified by the titanate coupling agent and through Scanning Electron Microscope tests, it can be seen that materials can be well dispersed into the Sand-fog seal. When the composite material accounts for 10% of the fog seal, it can achieve the optimal photocatalytic efficiency of about 23.9%. The British pendulum tests show it has good skid resistance performance. Half a kilometer of concrete roadway was sprayed with the material coating in Tianjin, China. The photocatalytic experimental road degrades nitrogen oxides better than the original road. The method is feasible for practical implementation.

16.
Mediators Inflamm ; 2020: 2109325, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33082707

RESUMO

Much evidence suggests that trained immunity is inappropriately activated in the synovial tissue in rheumatoid arthritis (RA), but the underlying mechanism remains unclear. Here, we describe how RA-specific autoantibody deposits can train human monocytes to exert the hyperactive inflammatory response, particularly via the exacerbated release of tumor necrosis factor α (TNFα). Comparative transcriptomic analysis by plate-bound human IgG (cIgG) or ß-glucan indicated that metabolic shift towards glycolysis is a crucial mechanism for trained immunity. Moreover, the cIgG-trained gene signatures were enriched in synovial tissues from patients with ACPA- (anticitrullinated protein antibody-) positive arthralgia and undifferentiated arthritis, and early RA and established RA bore a great resemblance to the myeloid pathotype, suggesting a historical priming event in vivo. Additionally, the expression of the cIgG-trained signatures is higher in the female, older, and ACPA-positive populations, with a predictive role in the clinical response to infliximab. We conclude that RA-specific autoantibodies can train monocytes in the inflamed lesion as early as the asymptomatic stage, which may not merely improve understanding of disease progression but may also suggest therapeutic and/or preventive strategies for autoimmune diseases.


Assuntos
Artrite Reumatoide/metabolismo , Autoanticorpos/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Humanos , Imunoglobulina G/metabolismo , Monócitos/metabolismo , Análise de Sequência de RNA , Membrana Sinovial/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
17.
J Immunother Cancer ; 8(1)2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32217759

RESUMO

BACKGROUND: Tumor-associated macrophages (TAMs) resemble M2-polarized cells with potent immunosuppressive activity and play a pivotal role in tumor growth and progression. Converting TAMs to proinflammatory M1-like phenotype is thus an attractive strategy for antitumor immunotherapy. METHODS: A mouse IgG1 (kappa) monoclonal Ab, M-860, specific to human lactoferrin (LTF) was generated by using the traditional hybridoma cell fusion technology. TAMs were generated by culturing human and mouse CD14+ monocytes in tumor-conditioned media containing a cytokine cocktail containing recombinant interleukin-4 (IL-4), interleukin-10 (IL-10) and macrophage colony stimulating factor (M-CSF). TAMs after treatment with immunocomplex (IC) between human LTF and M860 (LTF-IC) were phenotypically and functionally characterized by flow cytometry (FACS), ELISA, Q-PCR and killing assays. The antitumor effects of LTF-IC were further analyzed using in vivo experiments employing tumor-bearing human FcγRIIa-transgenic mouse models. RESULTS: Through coligation of membrane-bound CD14 and FcγRIIa, LTF-IC rendered TAMs not only M2 to M1 conversion, evidenced by increased tumor necrosis factor α production, down-regulated M2-specific markers (CD206, arginase-1 and vascular endothelial growth factor) and upregulated M1-specific markers (CD86 and HLA-DR) expression, but also potent tumoricidal activity in vitro. LTF-IC administration conferred antitumor protective efficacy and prolonged animal survival in FcγRIIa-transgenic mice, accompanied by accumulation of M1-like macrophages as well as significantly reduced infiltration of immunosuppressive myeloid-derived suppressor cells and regulatory T cells in solid tumor tissues. CONCLUSIONS: LTF-IC is a promising cancer therapeutic agent capable of converting TAMs into tumoricidal M1-like cells.


Assuntos
Anticorpos Monoclonais/farmacologia , Citocinas/imunologia , Lactoferrina/imunologia , Macrófagos/imunologia , Melanoma Experimental/imunologia , Linfócitos T Reguladores/imunologia , Animais , Anticorpos Monoclonais/imunologia , Complexo Antígeno-Anticorpo/imunologia , Linhagem Celular Tumoral , Técnicas de Cocultura , Meios de Cultivo Condicionados , Modelos Animais de Doenças , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fenótipo
18.
Oper Neurosurg (Hagerstown) ; 19(1): E54, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31674637

RESUMO

Temporoinsular gliomas are frequently large-sized tumors that require meticulous planning to ensure maximum surgical resection and minimal neurologic deficits in patients. Here, we demonstrate our technique encompassing multi-modal imaging guidance and awake brain mapping which enables maximum safe resection of such tumors. The patient, a 39-yr-old man, presented with depression and memory loss for 18 mo. Preoperative magnetic resonance imaging (MRI; MAGNETOM Verio, Siemens) revealed a nonenhancing lesion in the left dominant temporoinsular lobe. Three-dimensional magnetic resonance spectroscopy was used to analyze the choline/N-acetyl-aspartate index which suggested a low-grade glioma diagnosis. Informed patient consent was obtained. After craniotomy, the mouth motor, speech arrest, and word generation areas were mapped via direct cortical stimulation under awake mapping. A strip electrode was placed across the precentral gyrus for continuous motor evoked potential monitoring. Cortical incisions were made in nonfunctional cortical areas and tumor was resected in the temporal lobe. Following this, tumor at the inferior insular zone was carefully debunked with Cavitron Ultrasonic Surgical Aspirator (Integra Lifescience) also through the temporal window. The hippocampus was preserved since it was not invaded by tumor. Subcortical mapping combined with Diffuse Tensor Imaging tractography-based navigation (Medtronic lnc.) was performed to localize the motor and language pathways. Intraoperative MRI evaluation showed tumor resection extent of 95%. Pathological and molecular analysis revealed a diagnosis of Grade II IDH-mutant oligodendroglioma. After surgery the patient was administered chemotherapy (Temozolomide). He recovered without language or motor deficits.


Assuntos
Neoplasias Encefálicas , Glioma , Adulto , Mapeamento Encefálico , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/cirurgia , Glioma/diagnóstico por imagem , Glioma/cirurgia , Humanos , Imageamento por Ressonância Magnética , Masculino , Vigília
19.
J Neurosurg ; 133(6): 1662-1670, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31731269

RESUMO

OBJECTIVE: H3 K27M-mutant gliomas present heterogeneously in terms of pathology, imaging, and prognosis. This study aimed to summarize the imaging characteristics of adult H3 K27M-mutant gliomas. METHODS: The authors retrospectively identified all cases of glioma diagnosed using histopathological studies (n = 3300) that tested positive for histone H3 K27M mutations (n = 75) between January 2016 and December 2018 in a single hospital. Preoperative and follow-up MR images of 66 adult patients (age ≥ 18 years) were reviewed for anatomical location, degree of contrast enhancement, enhancement patterns, hemorrhage, edema, diffusion restriction, tumor dissemination, and tumor spread. RESULTS: The study included 66 cases (40 in men, 26 in women) of H3 K27M-mutant glioma in adult patients. Tumors were found in the following sites: thalamus (n = 38), brainstem (n = 6), brainstem with cerebellar or thalamic involvement (n = 4), whole brain (n = 8), corpus callosum (n = 3), hypothalamus (n = 1), hemispheres (n = 2), and spinal cord (n = 4). All pure brainstem lesions were located posteriorly, and all corpus callosal lesions were in the genu. Most spinal tumors were long-segment lesions. Hemispheric lesions mimicked gliomatosis cerebri in presentation, with the addition of traditional midline structure involvement. Most tumors were solid with relatively uniform signals on plain MRI. Of the 61 cases with contrast-enhanced MR images, 36 (59%) showed partial to no enhancement, whereas 25 (41%) showed diffuse or irregular peripheral enhancement. Hemorrhage and edema were rare. Most lesions were solid and showed mild diffusion restriction on diffusion-weighted imaging. Tumor dissemination to the leptomeninges (n = 8) and subependymal layer (n = 3) was observed. CONCLUSIONS: The authors described the MRI features of diffuse midline glioma with H3 K27M mutation in the largest study done to date in adult patients. Tumors were found in both midline and nonmidline structures, with the thalamus being the most common site. Although adult H3 K27M-mutant gliomas demonstrated highly variable presentations in this cohort of patients, the authors were able to observe shared characteristics within each location.

20.
Molecules ; 24(20)2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31600968

RESUMO

Lactoferrin (LF) is a soluble glycoprotein of the transferring family found in most biological fluids, functioning as a major first line defense molecule against infection in mammals. It also shows certain anti-tumor activity, but its clinical application in tumor therapy is limited because high dosage is required. In this study, we demonstrate that M860, a monoclonal antibody against human LF (hLF), could significantly increase the anti-tumor potential of low dosage hLF by forming LF-containing immune complex (IC). Human monocytes primed with LF-IC, but not hLF or M860 alone, or control ICs, showed strong tumoricidal activity on leukemia cell lines Jurkat and Raji through induction of secreted Granzyme B (GzB). LF-IC is able to colligate membrane-bound CD14 (a TLR4 co-receptor) and FcγRIIa (a low affinity activating Fcγ receptor) on the surface of human monocytes, thereby triggering the Syk-PI3K-AKT-mTOR pathway leading to GzB production. Our work identifies a novel pathway for LF-mediated tumoricidal activity and may extend the clinical application of LF in tumor therapy.


Assuntos
Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Granzimas/biossíntese , Lactoferrina/antagonistas & inibidores , Biomarcadores , Sinergismo Farmacológico , Expressão Gênica , Granzimas/genética , Humanos , Lactoferrina/administração & dosagem , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quinase Syk/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
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