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1.
Signal Transduct Target Ther ; 8(1): 42, 2023 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-36681668

RESUMO

The Omicron variants of SARS-CoV-2, primarily authenticated in November 2021 in South Africa, has initiated the 5th wave of global pandemics. Here, we systemically examined immunological and metabolic characteristics of Omicron variants infection. We found Omicron resisted to neutralizing antibody targeting receptor binding domain (RBD) of wildtype SARS-CoV-2. Omicron could hardly be neutralized by sera of Corona Virus Disease 2019 (COVID-19) convalescents infected with the Delta variant. Through mass spectrometry on MHC-bound peptidomes, we found that the spike protein of the Omicron variants could generate additional CD8 + T cell epitopes, compared with Delta. These epitopes could induce robust CD8 + T cell responses. Moreover, we found booster vaccination increased the cross-memory CD8 + T cell responses against Omicron. Metabolic regulome analysis of Omicron-specific T cell showed a metabolic profile that promoted the response of memory T cells. Consistently, a greater fraction of memory CD8 + T cells existed in Omicron stimulated peripheral blood mononuclear cells (PBMCs). In addition, CD147 was also a receptor for the Omicron variants, and CD147 antibody inhibited infection of Omicron. CD147-mediated Omicron infection in a human CD147 transgenic mouse model induced exudative alveolar pneumonia. Taken together, our data suggested that vaccination booster and receptor blocking antibody are two effective strategies against Omicron.


Assuntos
COVID-19 , Humanos , Animais , Camundongos , COVID-19/genética , Leucócitos Mononucleares , SARS-CoV-2 , Anticorpos Neutralizantes , Epitopos , Camundongos Transgênicos
3.
Chest ; 163(1): e31-e35, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36628682

RESUMO

CASE PRESENTATION: A 17-month-old male infant with history of an abnormal chest shadow in the left lung lower lobe was admitted to our hospital for the resection of the malformation. At 9 months of age, he was admitted to his local hospital because of a persistent cough. The chest CT scan in his local hospital indicated a cystic lesion in the left lung lower lobe associated with inflammation. However, no thoracic abnormalities were seen in antenatal ultrasonography, and no clinical symptoms were observed at birth. After anti-inflammatory treatments given to this infant, he achieved remission and was discharged from his local hospital.


Assuntos
Pulmão , Tomografia Computadorizada por Raios X , Recém-Nascido , Humanos , Masculino , Lactente , Feminino , Gravidez , Pulmão/diagnóstico por imagem , Tosse , Anti-Inflamatórios
4.
Cardiovasc Diabetol ; 21(1): 271, 2022 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-36471410

RESUMO

BACKGROUND: Diabetes was commonly seen in chronic total occlusion (CTO) patients but data regarding the impact of successful percutaneous coronary intervention (PCI) on clinical outcome of CTO patients with diabetes was controversial. And importantly, no studies have compared quality of life (QOL) after CTO-PCI in patients with and without diabetes. METHODS: Consecutive patients undergoing elective CTO-PCI were prospectively enrolled from Apr. 2018 to May 2021. Patients were subdivided into 2 groups: Diabetes and No Diabetes. Detailed baseline characteristics, assessment of symptoms and QOL, angiographic and procedural details, in-hospital complications, and 1 month and 1 year follow-up data were collected. These data were analyzed accordingly for risk predictors of clinical outcome in patients who have diabetes and received successful CTO-PCI. RESULTS: A total of 1076 patients underwent CTO-PCI attempts. Diabetes was present in 374 (34.76%) patients, who had more hypertension, previous PCI and stroke. Regarding the coronary lesions, diabetic patients suffered more LCX lesion, multivessel disease, number of lesions per patient, blunt stump, calcification and higher J-CTO score (p < 0.05). In-hospital major adverse cardiac event (MACE) (4.13% vs. 5.35%; p = 0.362) was similar in the two groups. At 1 month and 1 year follow-up after successful CTO-PCI, the incidence of MACE and all-cause mortality were also similar in the two groups (p > 0.05). Number of lesions per patient was an independent risk factor of MACE and all-cause mortality (p < 0.001) 1 year after successful CTO-PCI. Symptom and QOL were markedly improved regardless of diabetes both at 1 month and 1 year follow-up, and importantly, patients with diabetes showed similar degrees of improvement to those without diabetes (P > 0.05). CONCLUSIONS: Successful CTO-PCI could represent an effective strategy improving clinical outcome, symptoms and QOL in CTO patients with diabetes.


Assuntos
Oclusão Coronária , Diabetes Mellitus , Intervenção Coronária Percutânea , Humanos , Intervenção Coronária Percutânea/efeitos adversos , Oclusão Coronária/diagnóstico por imagem , Oclusão Coronária/cirurgia , Qualidade de Vida , Angiografia Coronária , Resultado do Tratamento , Fatores de Risco , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/etiologia , Doença Crônica , Sistema de Registros
5.
Biogerontology ; 2022 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-36418661

RESUMO

With the increasing number of aged population and growing burden of healthy aging demands, a rational standard for evaluation aging is in urgent need. The advancement of medical testing technology and the prospering of artificial intelligence make it possible to evaluate the biological status of aging from a more comprehensive view. In this review, we introduced common aging biomarkers and concluded several famous aging clocks. Aging biomarkers reflect changes in the organism at a molecular or cellular level over time while aging clocks tend to be more of a generalization of the overall state of the organism. We expect to construct a framework for aging evaluation measurement from both micro and macro perspectives. Especially, population-specific aging clocks and multi-omics aging clocks may better fit the demands to evaluate aging in a comprehensive and multidimensional manner and make a detailed classification to represent different aging rates at tissue/organ levels. This framework will promisingly provide a crucial basis for disease diagnosis and intervention assessment in geroscience.

6.
Signal Transduct Target Ther ; 7(1): 382, 2022 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-36424379

RESUMO

COVID-19 patients can develop clinical and histopathological features associated with fibrosis, but the pathogenesis of fibrosis remains poorly understood. CD147 has been identified as a universal receptor for SARS-CoV-2 and its variants, which could initiate COVID-19-related cytokine storm. Here, we systemically analyzed lung pathogenesis in SARS-CoV-2- and its delta variant-infected humanized CD147 transgenic mice. Histopathology and Transmission Electron Microscopy revealed inflammation, fibroblast expansion and pronounced fibrotic remodeling in SARS-CoV-2-infected lungs. Consistently, RNA-sequencing identified a set of fibrosis signature genes. Furthermore, we identified CD147 as a crucial regulator for fibroblast activation induced by SARS-CoV-2. We found conditional knockout of CD147 in fibroblast suppressed activation of fibroblasts, decreasing susceptibility to bleomycin-induced pulmonary fibrosis. Meplazumab, a CD147 antibody, was able to inhibit the accumulation of activated fibroblasts and the production of ECM proteins, thus alleviating the progression of pulmonary fibrosis caused by SARS-CoV-2. In conclusion, we demonstrated that CD147 contributed to SARS-CoV-2-triggered progressive pulmonary fibrosis and identified CD147 as a potential therapeutic target for treating patients with post-COVID-19 pulmonary fibrosis.


Assuntos
COVID-19 , Fibrose Pulmonar , Camundongos , Animais , Fibrose Pulmonar/genética , SARS-CoV-2 , COVID-19/genética
7.
Cell ; 185(17): 3138-3152.e20, 2022 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-35926506

RESUMO

Oakleaf butterflies in the genus Kallima have a polymorphic wing phenotype, enabling these insects to masquerade as dead leaves. This iconic example of protective resemblance provides an interesting evolutionary paradigm that can be employed to study biodiversity. We integrated multi-omic data analyses and functional validation to infer the evolutionary history of Kallima species and investigate the genetic basis of their variable leaf wing patterns. We find that Kallima butterflies diversified in the eastern Himalayas and dispersed to East and Southeast Asia. Moreover, we find that leaf wing polymorphism is controlled by the wing patterning gene cortex, which has been maintained in Kallima by long-term balancing selection. Our results provide macroevolutionary and microevolutionary insights into a model species originating from a mountain ecosystem.


Assuntos
Borboletas , Animais , Biodiversidade , Evolução Biológica , Borboletas/genética , Ecossistema , Fenótipo , Asas de Animais
8.
Drugs Aging ; 39(9): 695-703, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35995912

RESUMO

BACKGROUND: Taking ischemic and bleeding risks into consideration, insufficient data exist on dual antiplatelet therapy after percutaneous coronary intervention in elderly Chinese patients with coronary artery disease. OBJECTIVE: We aimed to investigate the effectiveness and safety of ticagrelor in comparison with clopidogrel on a background of aspirin for elderly Chinese patients with coronary artery disease 12 months after percutaneous coronary intervention. METHODS: A single-center retrospective cohort study was conducted. Selected from patients with coronary artery disease aged ≥ 75 years from January 2010 to July 2019, 908 eligible subjects receiving dual antiplatelet therapy after percutaneous coronary intervention for up to 12 months were consecutively enrolled in the study. The included patients received ticagrelor in combination with aspirin (n = 264) or clopidogrel in combination with aspirin (n = 644). Effectiveness endpoints were evaluated by the major adverse cardiovascular events, encompassing all-cause death, non-fatal myocardial infarction, and clinically driven revascularization. The safety endpoints were recorded as the incidence of Bleeding Academic Research Consortium bleeding. RESULTS: The patients who were treated with ticagrelor were slightly younger than those who were treated with clopidogrel (79.1 ± 3.7 vs 80.7 ± 4.5 years, p < 0.01). The ticagrelor cohort contained a higher percentage of patients undergoing a prior percutaneous coronary intervention (37.9% vs 24.5%, p < 0.01), and a lower percentage of smokers (19.3% vs 27.2%, p < 0.05), compared with the clopidogrel cohort. The levels of glucose, total cholesterol, and low-density lipoprotein-cholesterol in the ticagrelor group were higher while the level of triglycerides and high-density lipoprotein-cholesterol were lower (p < 0.05) than those in the clopidogrel group. Left main percutaneous coronary intervention was performed more frequently among the ticagrelor-treated patients (23.5% vs 9.3%, p < 0.01), while patients in the clopidogrel group underwent more left circumflex percutaneous coronary intervention (34.3% vs 23.1%, p < 0.01). We found that ticagrelor was associated with a lower incidence of major adverse cardiovascular events than clopidogrel using the inverse probability of treatment weighting model (odds ratio, 0.493; 95% confidence interval 0.356-0.684). There was no difference in terms of the risk of Bleeding Academic Research Consortium bleeding between the two groups (p > 0.05). CONCLUSIONS: Ticagrelor was associated with a lower incidence of major adverse cardiovascular events than clopidogrel at 12 months in elderly Chinese patients with coronary artery disease, without a significant increase of Bleeding Academic Research Consortium bleeding events.


Assuntos
Síndrome Coronariana Aguda , Doença da Artéria Coronariana , Intervenção Coronária Percutânea , Idoso , Aspirina/efeitos adversos , China , Colesterol , Clopidogrel/efeitos adversos , Estudos de Coortes , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/cirurgia , Hemorragia/induzido quimicamente , Humanos , Intervenção Coronária Percutânea/efeitos adversos , Inibidores da Agregação Plaquetária/efeitos adversos , Estudos Retrospectivos , Ticagrelor/efeitos adversos , Resultado do Tratamento
9.
Ital J Pediatr ; 48(1): 121, 2022 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-35870983

RESUMO

BACKGROUND: Prader-Willi syndrome (PWS) is a complex disorder caused by impaired paternally expressed genes on chromosome 15q11-q13. Variable findings have been reported about the phenotypic differences among PWS genetic subtypes. METHODS: A total of 110 PWS patients were diagnosed from 8,572 pediatric patients included from July 2013 to December 2021 by MLPA and MS-MLPA assays. Atypical deletions were defined by genomic CNV-sequencing. Maternal uniparental disomy (UPD) was subgrouped by microsatellite genotyping. Clinical data were collected for phenotype-genotype associations. Twenty-one patients received growth hormone (GH) treatment, and the anthropometric and laboratory parameters were evaluated and compared. RESULTS: Genetically, the 110 patients with PWS included 29 type I deletion, 56 type II deletion, 6 atypical deletion, 11 heterodisomy UPD, and 8 isodisomy UPD. The UPD group had significantly higher maternal age (31.4 ± 3.4 vs 27.8 ± 3.8 years), more anxiety (64.29% vs 26.09%) and autistic traits (57.14% vs 26.09%), and less hypopigmentation (42.11% vs 68.24%) and skin picking (42.86% vs 71.01%) than the deletion group. The type I deletion group was diagnosed at earlier age (3.7 ± 3.3 vs 6.2 ± 3.2 years) and more common in speech delay (95.45% vs 63.83%) than the type II. The isodisomy UPD group showed a higher tendency of anxiety (83.33% vs 50%) than the heterodisomy. GH treatment for 1 year significantly improved the SDS of height (- 0.43 ± 0.68 vs - 1.32 ± 1.19) and IGF-I (- 0.45 ± 0.48 vs - 1.97 ± 1.12). No significant changes were found in thyroid function or glucose/lipid metabolism. CONCLUSION: We explored the physical, psychological and behavioral phenotype-genotype associations as well as the GH treatment effect on PWS from a large cohort of Chinese pediatric patients. Our data might promote pediatricians' recognition and early diagnosis of PWS.


Assuntos
Síndrome de Prader-Willi , Estatura , Humanos , Idade Materna , Fenótipo , Síndrome de Prader-Willi/diagnóstico , Síndrome de Prader-Willi/tratamento farmacológico , Síndrome de Prader-Willi/genética , Dissomia Uniparental/genética
10.
Front Psychol ; 13: 839064, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35719497

RESUMO

The relationship of language style and online review has drawn increasing academic attention recently as it can provide customers with a guide to make the purchase. Extant research attaches importance to the language style that is presented in the use of function words, instead of product-related content words. This study aimed to examine the language style generated by customers' comments relating to the product based on content words, that is, product-centered language style (PCLS). We built a corpus of Chinese women clothes online reviews to explore the general picture and distinct features of PCLS and the distinct feature of PCLS. A content-word-centered Linguistic Inquiry and Word Count (LIWC) in terms of product performance is established. PCLS is calculated based on the language style matching (LSM) algorithm. Our results show that the PCLS in women clothes online review is featured by diverse and polarized language styles among three groups of women clothes buyers, and the prioritized arrangement of words of importance contributes to the PCLS. The findings benefit the women clothes industry in which it can help companies quickly find the distinctive and the transition of PCLS and offer an approach for companies to indiscriminately look into the significance of the product category from the linguistic perspective, which can help with product sale strategy and product design.

11.
Front Oncol ; 12: 868061, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35463345

RESUMO

Background: CA-125 is a clinical biomarker with predictive effect on the prognosis of different cancers. Numerous clinical trials have been conducted to investigate the possibility of using the pretreatment level of CA-125 to predict the prognosis of epithelial ovarian cancer (EOC). However, its value in predicting prognosis remains controversial. The purpose of this meta-analysis was to assess the predictive value of pretreatment CA-125 levels for prognosis in EOC patients. Methods: We searched the EMBASE, Cochrane library, PubMed and Web of Science databases for studies published up to 3 December 2021, according to specific inclusion and exclusion criteria. The clinical studies that were included investigated the relationship between pretreatment CA-125 levels and ovarian cancer prognosis. Combined hazard ratios (HR) of overall survival (OS) and progression-free survival (PFS) reported in the studies were compared and analyzed using fixed-effects/random-effects models. Sensitivity analysis was used to assess study stability, while Egger's and Begg's tests were used to assess publication bias. Results: This meta-analysis included 23 studies published in 2004 - 2021 with a total of 10,594 EOC patients. Comprehensive analysis demonstrated that the serum level of CA-125 before treatment was significantly correlated with overall survival (OS: HR=1.62, 95%CI=1.270-2.060, p<0.001) and progression-free survival (PFS: HR=1.59, PFS: HR=1.59, 95%CI=1.44~1.76, p<0.001). After comparing data from different FIGO stages and treatments, we discovered that a high pre-treatment serum CA-125 level was associated with a low survival rate. Conclusion: According to the results of this study, a higher pre-treatment serum CA-125 level is associated with poor survival outcomes, which can be utilized to predict the prognosis of EOC patients. Pre-treatment serum CA-125 level might provide reliable basis for predicting the risk of EOC disease progression. This study is registered with the International Prospective Register of Systematic Reviews (CRD42022300545). Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=300545, identifier [CRD42022300545].

12.
Waste Manag ; 144: 221-232, 2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-35397419

RESUMO

Due to rapid economic development and urbanisation, emerging megacities with dense populations have witnessed a significant increase in waste generation. Megacities face challenges in developing sustainable waste management systems. Considerable heterogeneity exists across megacities in management strategies. The two selected emerging megacities, Singapore (a city-state) and Shanghai, have similar developmental characteristics, but their waste management modes differ strikingly. This study assessed the two modes in terms of management strategies, environmental effects, economic costs, and social outcomes. Environmental footprint analysis and cost quantification were employed for the assessment based on public data. The research results would permit a deeper understanding of the long-term sustainability of each mode while considering the feasibility of implementation across different contexts. It was found that the waste management system in Singapore had a relatively lower environmental impact than Shanghai before Shanghai's new waste segregation and recycling policy in 2019. However, when the effect of fossil fuel substitution is taken into account, the environmental burden in Shanghai can be lowered more substantially than the one in Singapore. Although Shanghai had more economic burden for the waste segregation at source, it tended to implement the circular economy principles (e.g., reduce, reuse, and recycling) better and improve its sense of community significantly. Based on the practical experiences from the two representative megacities, suggestions for better waste management practices were provided for Singapore, Shanghai, and other emerging megacities with similar circumstances. In addition, challenges and opportunities related to household waste segregation and recycling were identified to guide future practices in emerging megacities.


Assuntos
Eliminação de Resíduos , Gerenciamento de Resíduos , China , Cidades , Reciclagem , Singapura , Resíduos Sólidos/análise
13.
Socioecon Plann Sci ; 82: 101279, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35281569

RESUMO

A regional healthcare coalition enables its member hospitals to conduct an integrated emergency supply management, which is seldom addressed in the existing literature. In this work, we propose a two-stage stochastic emergency supply planning model to facilitate cooperation and coordination in a regional healthcare coalition. Our model integrates pre-disaster emergency supplies pre-positioning and post-disaster emergency supplies transshipment and procurement and considers two planning goals, i.e., minimizing the expected total cost and the maximum supply shortage rate. With some comparison models and a case study on the West China Hospital coalition of Sichuan Province, China, under the background of the COVID-19 epidemic, we demonstrate the effectiveness and benefits of our model and obtain various managerial insights and policy suggestions for practice. We highlight the importance of conducting integrated management of emergency supplies pre-positioning, transshipment and procurement in the regional healthcare coalition for better preparation and responding to future potential disasters.

14.
Cell Prolif ; 54(8): e13092, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34189783

RESUMO

T cells participate in the repair process and immune response in the CNS post-traumatic injury and play both a beneficial and harmful role. Together with nerve cells and other immune cells, they form a microenvironment in the CNS post-traumatic injury. The repair of traumatic CNS injury is a long-term process. T cells contribute to the repair of the injury site to influence the recovery. Recently, with the advance of new techniques, such as mass spectrometry-based flow cytometry, modern live-cell imaging, etc, research focusing on T cells is becoming one of the valuable directions for the future therapy of traumatic CNS injury. In this review, we summarized the infiltration, contribution and regulation of T cells in post-traumatic injury, discussed the clinical significance and predicted the future research direction.


Assuntos
Sistema Nervoso Central/metabolismo , Transtornos de Estresse Pós-Traumáticos/patologia , Linfócitos T/imunologia , Barreira Hematoencefálica/imunologia , Barreira Hematoencefálica/metabolismo , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Sistema Nervoso Central/imunologia , Citocinas/metabolismo , Humanos , Transtornos de Estresse Pós-Traumáticos/imunologia , Transtornos de Estresse Pós-Traumáticos/metabolismo , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T/citologia , Linfócitos T/metabolismo
15.
BMC Cancer ; 21(1): 531, 2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-33971846

RESUMO

BACKGROUND: Cervical cancer continues to be one of the leading causes of cancer deaths among females in low and middle-income countries. In this study, we aimed to assess the independent prognostic value of clinical and potential prognostic factors in progression-free survival (PFS) in cervical cancer. METHODS: We conducted a retrospective study on 92 cervical cancer patients treated from 2017 to 2019 at the Zhuhai Hospital of Traditional Chinese and Western Medicine. Tumor characteristics, treatment options, progression-free survival and follow-up information were collected. Kaplan-Meier method was used to assess the PFS. RESULTS: Results showed that the number of retrieved lymph nodes had a statistically significant effect on PFS of cervical cancer patients (P = 0.002). Kaplan-Meier survival curve analysis showed that cervical cancer patients with initial symptoms age 25-39 had worse survival prognoses (P = 0.020). And the using of uterine manipulator in laparoscopic treatment showed a better prognosis (P < 0.001). A novel discovery of our study was to verify the prognostic values of retrieved lymph nodes count combining with FIGO staging system, which had never been investigated in cervical cancer before. According to the Kaplan-Meier survival curve analysis and receiver operating characteristic (ROC) curve analysis, significant improvements were found after the combination of retrieved lymph nodes count and FIGO stage in predicting PFS for cervical cancer patients (P < 0.001, AUC = 0.826, 95% CI: 0.689-0.962). CONCLUSION: Number of retrieved lymph nodes, initial symptoms age, uterine manipulator, and retrieved lymph nodes count combining with FIGO staging system could be potential prognostic factors for cervical cancer patients.


Assuntos
Neoplasias do Colo do Útero/mortalidade , Adulto , Idoso , Feminino , Humanos , Excisão de Linfonodo , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Neoplasias do Colo do Útero/patologia
16.
Front Immunol ; 12: 773168, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35003090

RESUMO

The fruitful results of tumor immunotherapy establish its indispensable status in the regulation of the tumorous immune context. It seems that the treatment of programmed cell death receptor 1 (PD-1) blockade is one of the most promising approaches for cancer control. The significant efficacy of PD-1 inhibitor therapy has been made in several cancer types, such as breast cancer, lung cancer, and multiple myeloma. Even so, the mechanisms of how anti-PD-1 therapy takes effect by impacting the immune microenvironment and how partial patients acquire the resistance to PD-1 blockade have yet to be studied. In this review, we discuss the cross talk between immune cells and how they promote PD-1 blockade efficacy. In addition, we also depict factors that may underlie tumor resistance to PD-1 blockade and feasible solutions in combination with it.


Assuntos
Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Microambiente Tumoral/efeitos dos fármacos , Animais , Resistencia a Medicamentos Antineoplásicos , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias/tratamento farmacológico , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/efeitos dos fármacos
17.
Signal Transduct Target Ther ; 6(1): 347, 2021 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-34564690

RESUMO

SARS-CoV-2 mutations contribute to increased viral transmissibility and immune escape, compromising the effectiveness of existing vaccines and neutralizing antibodies. An in-depth investigation on COVID-19 pathogenesis is urgently needed to develop a strategy against SARS-CoV-2 variants. Here, we identified CD147 as a universal receptor for SARS-CoV-2 and its variants. Meanwhile, Meplazeumab, a humanized anti-CD147 antibody, could block cellular entry of SARS-CoV-2 and its variants-alpha, beta, gamma, and delta, with inhibition rates of 68.7, 75.7, 52.1, 52.1, and 62.3% at 60 µg/ml, respectively. Furthermore, humanized CD147 transgenic mice were susceptible to SARS-CoV-2 and its two variants, alpha and beta. When infected, these mice developed exudative alveolar pneumonia, featured by immune responses involving alveoli-infiltrated macrophages, neutrophils, and lymphocytes and activation of IL-17 signaling pathway. Mechanistically, we proposed that severe COVID-19-related cytokine storm is induced by a "spike protein-CD147-CyPA signaling axis": Infection of SARS-CoV-2 through CD147 initiated the JAK-STAT pathway, which further induced expression of cyclophilin A (CyPA); CyPA reciprocally bound to CD147 and triggered MAPK pathway. Consequently, the MAPK pathway regulated the expression of cytokines and chemokines, which promoted the development of cytokine storm. Importantly, Meplazumab could effectively inhibit viral entry and inflammation caused by SARS-CoV-2 and its variants. Therefore, our findings provided a new perspective for severe COVID-19-related pathogenesis. Furthermore, the validated universal receptor for SARS-CoV-2 and its variants can be targeted for COVID-19 treatment.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , Anticorpos Monoclonais Humanizados/farmacologia , Basigina/antagonistas & inibidores , Basigina/metabolismo , COVID-19/metabolismo , Síndrome da Liberação de Citocina/tratamento farmacológico , SARS-CoV-2/metabolismo , Enzima de Conversão de Angiotensina 2/genética , Animais , Basigina/genética , COVID-19/genética , Chlorocebus aethiops , Síndrome da Liberação de Citocina/genética , Síndrome da Liberação de Citocina/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Camundongos Transgênicos , SARS-CoV-2/genética , Células Vero
18.
Signal Transduct Target Ther ; 5(1): 283, 2020 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-33277466

RESUMO

In face of the everlasting battle toward COVID-19 and the rapid evolution of SARS-CoV-2, no specific and effective drugs for treating this disease have been reported until today. Angiotensin-converting enzyme 2 (ACE2), a receptor of SARS-CoV-2, mediates the virus infection by binding to spike protein. Although ACE2 is expressed in the lung, kidney, and intestine, its expressing levels are rather low, especially in the lung. Considering the great infectivity of COVID-19, we speculate that SARS-CoV-2 may depend on other routes to facilitate its infection. Here, we first discover an interaction between host cell receptor CD147 and SARS-CoV-2 spike protein. The loss of CD147 or blocking CD147 in Vero E6 and BEAS-2B cell lines by anti-CD147 antibody, Meplazumab, inhibits SARS-CoV-2 amplification. Expression of human CD147 allows virus entry into non-susceptible BHK-21 cells, which can be neutralized by CD147 extracellular fragment. Viral loads are detectable in the lungs of human CD147 (hCD147) mice infected with SARS-CoV-2, but not in those of virus-infected wild type mice. Interestingly, virions are observed in lymphocytes of lung tissue from a COVID-19 patient. Human T cells with a property of ACE2 natural deficiency can be infected with SARS-CoV-2 pseudovirus in a dose-dependent manner, which is specifically inhibited by Meplazumab. Furthermore, CD147 mediates virus entering host cells by endocytosis. Together, our study reveals a novel virus entry route, CD147-spike protein, which provides an important target for developing specific and effective drug against COVID-19.


Assuntos
Basigina/genética , COVID-19/genética , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Animais , Basigina/imunologia , COVID-19/imunologia , COVID-19/patologia , COVID-19/virologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Camundongos , Pandemias , Ligação Proteica/imunologia , Domínios Proteicos/genética , Domínios Proteicos/imunologia , SARS-CoV-2/patogenicidade , Glicoproteína da Espícula de Coronavírus/genética , Internalização do Vírus
19.
Anal Chem ; 92(15): 10327-10335, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32614163

RESUMO

Liquid chromatography-mass spectrometry (LC-MS)-based proteomics approaches have been widely used to identify residual host-cell proteins (HCPs) in support of process and product characterization for protein therapeutics. Particularly, these methods can provide a general and unbiased approach for the detection of HCPs and may generate critical information on HCPs that are outside the coverage provided by a conventional immunoassay. A significant technical hurdle for HCP analysis is the overwhelmingly large background of biotherapeutic that obscures HCP detection and quantification. In this work, we developed a method that relies on hydrophilic interaction chromatography (HILIC) for HCP enrichment followed by in situ concentration and digestion prior to LC-MS analysis. This approach has enabled detection of HCPs in a drug substance that were not observed in other conventional flow rate LC-MS strategies. For example, 28% of HCPs identified in NISTmAb (20 out of 71) were not previously published or identified by established methods such as the native digestion technique. For an IgG1 protein spiked with 1000 ppm HCP standards, we detected 83 HCPs, 61 out of which were not identified by the native digestion method. Similar improvement in performance was demonstrated for an Fc-fusion protein therapeutic. Our method can be readily implemented in most protein mass spectrometry laboratories to support process development for protein therapeutics.


Assuntos
Cromatografia Líquida/métodos , Proteínas/química , Proteínas/uso terapêutico , Animais , Anticorpos Monoclonais , Anticorpos Monoclonais Humanizados , Células CHO , Cricetulus , Imunoglobulina G/química , Espectrometria de Massas em Tandem/métodos , Tripsina/metabolismo
20.
Sci Adv ; 6(3): eaay4508, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-32010770

RESUMO

Monolithic strong magnetic induction at the mtesla to tesla level provides essential functionalities to physical, chemical, and medical systems. Current design options are constrained by existing capabilities in three-dimensional (3D) structure construction, current handling, and magnetic material integration. We report here geometric transformation of large-area and relatively thick (~100 to 250 nm) 2D nanomembranes into multiturn 3D air-core microtubes by a vapor-phase self-rolled-up membrane (S-RuM) nanotechnology, combined with postrolling integration of ferrofluid magnetic materials by capillary force. Hundreds of S-RuM power inductors on sapphire are designed and tested, with maximum operating frequency exceeding 500 MHz. An inductance of 1.24 µH at 10 kHz has been achieved for a single microtube inductor, with corresponding areal and volumetric inductance densities of 3 µH/mm2 and 23 µH/mm3, respectively. The simulated intensity of the magnetic induction reaches tens of mtesla in fabricated devices at 10 MHz.

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