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2.
Nat Commun ; 11(1): 5066, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-33033255

RESUMO

The inducible co-stimulator (ICOS) is a member of the CD28/B7 superfamily, and delivers a positive co-stimulatory signal to activated T cells upon binding to its ligand (ICOS-L). Dysregulation of this pathway has been implicated in autoimmune diseases and cancer, and is currently under clinical investigation as an immune checkpoint blockade. Here, we describe the molecular interactions of the ICOS/ICOS-L immune complex at 3.3 Å resolution. A central FDPPPF motif and residues within the CC' loop of ICOS are responsible for the specificity of the interaction with ICOS-L, with a distinct receptor binding orientation in comparison to other family members. Furthermore, our structure and binding data reveal that the ICOS N110 N-linked glycan participates in ICOS-L binding. In addition, we report crystal structures of ICOS and ICOS-L in complex with monoclonal antibodies under clinical evaluation in immunotherapy. Strikingly, antibody paratopes closely mimic receptor-ligand binding core interactions, in addition to contacting peripheral residues to confer high binding affinities. Our results uncover key molecular interactions of an immune complex central to human adaptive immunity and have direct implications for the ongoing development of therapeutic interventions targeting immune checkpoint receptors.


Assuntos
Anticorpos/uso terapêutico , Complexo Antígeno-Anticorpo/química , Ligante Coestimulador de Linfócitos T Induzíveis/química , Proteína Coestimuladora de Linfócitos T Induzíveis/química , Mimetismo Molecular/imunologia , Sequência de Aminoácidos , Complexo Antígeno-Anticorpo/metabolismo , Antígenos CD28/metabolismo , Humanos , Interações Hidrofóbicas e Hidrofílicas , Ligante Coestimulador de Linfócitos T Induzíveis/metabolismo , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Cinética , Ligantes , Modelos Moleculares , Ligação Proteica , Multimerização Proteica
3.
Nat Commun ; 11(1): 4981, 2020 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-33020469

RESUMO

Antagonism or agonism of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) prevents weight gain and leads to dramatic weight loss in combination with glucagon-like peptide-1 receptor agonists in preclinical models. Based on the genetic evidence supporting GIPR antagonism, we previously developed a mouse anti-murine GIPR antibody (muGIPR-Ab) that protected diet-induced obese (DIO) mice against body weight gain and improved multiple metabolic parameters. This work reconciles the similar preclinical body weight effects of GIPR antagonists and agonists in vivo, and here we show that chronic GIPR agonism desensitizes GIPR activity in primary adipocytes, both differentiated in vitro and adipose tissue in vivo, and functions like a GIPR antagonist. Additionally, GIPR activity in adipocytes is partially responsible for muGIPR-Ab to prevent weight gain in DIO mice, demonstrating a role of adipocyte GIPR in the regulation of adiposity in vivo.


Assuntos
Adipócitos/efeitos dos fármacos , Fármacos Antiobesidade/farmacologia , Receptores dos Hormônios Gastrointestinais/agonistas , Receptores dos Hormônios Gastrointestinais/antagonistas & inibidores , Adipócitos/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Fármacos Antiobesidade/química , Fármacos Antiobesidade/uso terapêutico , Anticorpos/farmacologia , Anticorpos/uso terapêutico , Peso Corporal/efeitos dos fármacos , Membrana Celular/metabolismo , Células Cultivadas , AMP Cíclico/metabolismo , Dieta Hiperlipídica/efeitos adversos , Ácidos Graxos/metabolismo , Polipeptídeo Inibidor Gástrico/farmacologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Obesidade/patologia , Receptores dos Hormônios Gastrointestinais/deficiência , Receptores dos Hormônios Gastrointestinais/metabolismo
4.
Artigo em Russo | MEDLINE | ID: mdl-33081444

RESUMO

OBJECTIVE: To evaluate the efficacy and safety of tenoten for children in the treatment of specific developmental disorders of academic skills in children of 1-3 grades. MATERIAL AND METHODS: Two hundred and forty children, aged 7-9 years, (Total set, Safety population) with verified specific reading disorder (F81.0), specific spelling disorder (F81.1), specific disorder of arithmetical skills (F81.2), mixed disorder of scholastic skills (F81.3; F81.2+F81.0, or F81.2+F81.1, or F81.2+F81.0+F81.1), diagnosed with the use of logopedic or psychological testing (15-35 scores in Fotekova T.A. and Akhutina T.V. reading and writing tests; 5-15 scores in arithmetical subscale of the Wechsler Intelligence Scale for Children) were enrolled in the study. CT was conducted in 10 clinical centers in Russian Federation in 2015- 2019. Patients were randomized into two groups. The first one (n=122) received tenoten for children in a dose of 1 tablet 3 times a day, the second one (n=118) was administered placebo in the same dosage regimen. The clinical data on 237 children (121 of the tenoten group and 116 of the placebo group) were used for Intention-to-treat efficacy analysis. Data on 220 children (115 of the tenoten group and 105 of the placebo group) were included in Per-protocol analysis. The duration of study was 12 weeks. The mean total academic skills (reading, spelling, and counting) score in groups after 12 weeks of treatment was set as the primary efficacy endpoint. RESULTS: The mean total academic skills score increased by 18.55±15.87 points. The significant total difference between the median changes in the total score in the tenoten and placebo groups was 5 points. There was a trend towards positive changes in reading and spelling mean scores in tests that didn't reach statistical significance due to lack of normal distribution of points in samples. There were 73 adverse events (AEs) in 42 patients of the tenoten group and 95 AEs in 31 children of the placebo group. No serious or severe AEs were registered in the tenoten group. No AEs definitely related to the study treatment were registered. No negative drug interactions were observed in the tenoten group. CONCLUSIONS: Tenoten for children is an effective and safe treatment for specific developmental disorders of academic skills in primary school children. Tenoten for children is well tolerated. The treatment is characterized by a high level of adherence of children and their parents to therapy.


Assuntos
Anticorpos , Dislexia , Criança , Método Duplo-Cego , Dislexia/tratamento farmacológico , Humanos , Federação Russa
5.
Rinsho Ketsueki ; 61(8): 912-921, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32908055

RESUMO

Although multiple myeloma has been defined as incurable, and the treatment outcome has recently improved rapidly. Antibodies against multiple myeloma, elotuzumab, and daratumumab can safely enhance their effects even when added to the combination therapy of proteasome inhibitors and immunomodulators that have been used till date. Initially, triplet therapy combining antibody therapy with doublet therapy was approved in Japan for relapsed or refractory multiple myeloma. In 2019, daratumumab combination therapies were approved for newly diagnosed multiple myeloma patients, and these therapies are the new standard of care. Recently, the results of clinical trials that added daratumumab to the triplet therapies of proteasome inhibitors, immunomodulators, and dexamethasone have been reported. These trials report greater therapeutic effects, with a significant improvement in the MRD negative rate. We hope that quadruplet therapy including these antibodies will be available in clinical practice, leading to further improvements in the treatment outcomes.


Assuntos
Anticorpos/uso terapêutico , Mieloma Múltiplo , Humanos , Fatores Imunológicos , Japão , Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteassoma , Radioimunoterapia
6.
Rinsho Ketsueki ; 61(8): 922-928, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32908056

RESUMO

In 2018, two novel antibody therapies, inotuzumab ozogamicin (InO) and blinatumomab, against relapsed or refractory acute lymphoblastic leukemia were approved in Japan. In InO, the antitumor drug ozogamicin is conjugated to the anti-CD22 antibody. Blinatumomab is a bispecific T cell engager antibody comprising the variable regions of the anti-CD19 and the anti-CD3 antibodies. The remission rate of InO is about 75%; however, the frequency of sinusoidal obstruction syndrome is increased when allogeneic hematopoietic cell transplantation is performed after InO treatment. Blinatumomab has a remission rate of 45-70%. The management of cytokine release syndrome during blinatumomab treatment is required in certain cases. Although both the treatments have higher remission and negativity of minimal residual disease rates compared to those in conventional chemotherapy, it is difficult to maintain remission in the long term. Allogeneic hematopoietic stem cell transplantation should be performed as commonly as possible.


Assuntos
Anticorpos/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras , Antineoplásicos , Humanos , Inotuzumab Ozogamicina , Japão , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Indução de Remissão
7.
Rinsho Ketsueki ; 61(8): 929-936, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32908057

RESUMO

Treatment with eculizumab (Soliris®), a humanized anti-C5 monoclonal antibody improves the quality of life of patients with paroxysmal nocturnal hemoglobinuria (PNH), remarkably reduces hemolysis, improves symptoms associated with hemolysis, and prevents thrombosis. Because eculizumab therapy is not a curative treatment, it is necessary to continue infusion every two weeks, which has been an issue from the viewpoint of convenience. In recent years, an improved version of eculizumab, ravulizumab (Ultomiris®), which relies on the technology of recycling antibodies has been developed and can be administered every 8 weeks. Crovalimab (SKY59), which can be administered subcutaneously every four weeks, is also under development, and therefore, the convenience for patients with PNH is improving. However, many issues still persist, and several new anti-complement drugs are currently under development. Hopefully, a better drug will be developed by thorough examination of what drug is best for the patient by considering not only its efficacy and safety but also its convenience.


Assuntos
Anticorpos/uso terapêutico , Hemoglobinúria Paroxística , Proteínas do Sistema Complemento , Hemoglobinúria Paroxística/tratamento farmacológico , Hemólise , Humanos , Qualidade de Vida , Radioimunoterapia
9.
Nan Fang Yi Ke Da Xue Xue Bao ; 40(7): 1029-1035, 2020 Jul 30.
Artigo em Chinês | MEDLINE | ID: mdl-32895158

RESUMO

OBJECTIVE: To investigate the classification of idiopathic inflammatory myopathies (IIM) based on clinical manifestations and myositis- specific antibodies using cluster analysis. METHODS: We retrospectively analyzed the data of patients with IIM admitted in Nanfang Hospital in 2015-2019. The clinical data of the patients including serum creatine kinase (CK), interstitial lung disease (ILD), cancer, and myositis-specific antibodies were collected for two-step cluster analysis to identify the distinct clusters of patients, whose clinical characteristics were subsequently analysed. RESULTS: A total of 71 patients with IIM were included in this study, including 30 (42.3%) with polymyositis (PM), 20 (28.2%) with classic dermatomyositis (DM), 16 (22.5%) with amyopathic dermatomyositis (CADM), and 5 (7.0%) with immune-mediated necrotizing myopathy (IMNM). Two-step cluster analysis identified 3 distinctive subgroups: Cluster 1 of 15 (51.7%) patients characterized by rash, positive anti-MDA5 antibody and hypoproteinemia (P < 0.05) with normal or slightly elevated CK level, mainly corresponding to CADM; Cluster 2 of 4 (57.1%) patients with significantly elevated CK and positive anti-SRP antibody (P < 0.001) corresponding to IMNM; and Cluster 3 of 17 (48.6%) patients consisting primarily of patients with PM, characterized by positivity for anti- aminoacyl transfer RNA synthetases antibodies (P=0.022) corresponding to antisynthetase syndrome (ASS). CONCLUSIONS: Patients with IIM can be divided into 3 subgroups based on their clinical and serological characteristics (especially myositis-specific antibodies), and among them ASS may represent an independent IIM subgroup with unique clinical characteristics.


Assuntos
Miosite , Anticorpos , Autoanticorpos , Dermatomiosite , Humanos , Doenças Pulmonares Intersticiais , Estudos Retrospectivos
10.
Nan Fang Yi Ke Da Xue Xue Bao ; 40(6): 806-813, 2020 Jun 30.
Artigo em Chinês | MEDLINE | ID: mdl-32895213

RESUMO

OBJECTIVE: To prepare the recombinant peptide MVF-HER3 I composed of the 183-227aa peptide segment of human epidermal growth factor receptor 3 (HER3 I) and the measles virus protein 288-302 peptide segment (MVF), and prepare polyclonal antibodies (PcAb) against this recombinant peptide. METHODS: The MVF-HER3 I gene was synthesized chemically and subcloned into pET21b or pET32a plasmid containing Thioredoxin (Trx) tag gene. The recombinant plasmids were identified by endonuclease digestion. MVF-HER3 I was expressed in E.coli BL21(DE3) cells under an optimal bacterial expression condition. The fusion protein Trx-MVF-HER3 I was purified using nickel ion affinity chromatography, and the purified protein was digested by enterokinase to remove Trx tag. The digested mixture underwent further nickel ion affinity chromatography to obtain purified MVF-HER3 I. The purified MVF-HER3 I was used to immunize SD rats subcutaneously for preparing anti-MVF-HER3 I PcAb. The titer of PcAb was determined using ELISA. The bindings of anti-MVF-HER3 I PcAb to MVF-HER3 I, native HER3 and MCF7 cells were analyzed using immunoblotting, immunoprecipitation and laser confocal microscopy. The growth inhibition effect of the antibodies on MCF7 cells cultured in the absence or presence of NRG was assessed using sulforhodamine B. RESULTS: The recombinant peptide gene could not be expressed alone, but could be efficiently expressed after fusion with Trx gene under optimized conditions. The fusion peptide MVF-HER3 I was successfully prepared from Trx-MVF-HER3 I. The anti-MVF-HER3 I PcAb, with a titer reaching 1: 512 000, specifically bound to MVF-HER3 I, recognized native HER3 and bound to the membrane of MCF7 cells. The obtained PcAb could dose-dependently inhibit the growth of MCF7 cells irrespective of the presence or absence of NRG. CONCLUSIONS: We successfully obtained the recombinant peptide MVF-HER3 I and prepared its PcAb, which can facilitate further functional analysis of HER3 signaling pathway.


Assuntos
Receptor ErbB-3/imunologia , Animais , Anticorpos , Ensaio de Imunoadsorção Enzimática , Escherichia coli , Humanos , Plasmídeos , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes de Fusão
11.
BMJ Case Rep ; 13(9)2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32933909

RESUMO

Autoimmune encephalitis is a rare spectrum of disease that can be a complication of chronic immunosuppression. Diagnosis often requires the presence of antineuronal antibodies, but many causative antibodies have not yet been identified. Antibody-negative autoimmune encephalitis (AbNAE) is especially difficult to diagnose and must rely largely on exclusion of other causes. In chronically immune-suppressed transplant recipients, the differential is broad, likely resulting in underdiagnosis and worse outcomes. Here, we present a 58-year-old liver transplant recipient taking tacrolimus for prevention of chronic rejection who presented with 5 days of confusion, lethargy and lightheadedness. He was diagnosed with AbNAE after an extensive workup and recovered fully after high-dose corticosteroids. Our case highlights the importance of recognising the association between chronic immunosuppression and autoimmune encephalitis. Autoimmune encephalitis, even in the absence of characterised antibodies, should be considered when transplant recipients present with central neurologic symptoms.


Assuntos
Encefalite/induzido quimicamente , Doença de Hashimoto/induzido quimicamente , Imunossupressão/efeitos adversos , Imunossupressores/efeitos adversos , Transplante de Fígado , Complicações Pós-Operatórias/induzido quimicamente , Tacrolimo/efeitos adversos , Anticorpos/sangue , Encefalite/sangue , Doença de Hashimoto/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/sangue , Fatores de Tempo
12.
J Nanobiotechnology ; 18(1): 130, 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32912236

RESUMO

Fast point-of-care (POC) diagnostics represent an unmet medical need and include applications such as lateral flow assays (LFAs) for the diagnosis of sepsis and consequences of cytokine storms and for the treatment of COVID-19 and other systemic, inflammatory events not caused by infection. Because of the complex pathophysiology of sepsis, multiple biomarkers must be analyzed to compensate for the low sensitivity and specificity of single biomarker targets. Conventional LFAs, such as gold nanoparticle dyed assays, are limited to approximately five targets-the maximum number of test lines on an assay. To increase the information obtainable from each test line, we combined green and red emitting quantum dots (QDs) as labels for C-reactive protein (CRP) and interleukin-6 (IL-6) antibodies in an optical duplex immunoassay. CdSe-QDs with sharp and tunable emission bands were used to simultaneously quantify CRP and IL-6 in a single test line, by using a single UV-light source and two suitable emission filters for readout through a widely available BioImager device. For image and data processing, a customized software tool, the MultiFlow-Shiny app was used to accelerate and simplify the readout process. The app software provides advanced tools for image processing, including assisted extraction of line intensities, advanced background correction and an easy workflow for creation and handling of experimental data in quantitative LFAs. The results generated with our MultiFlow-Shiny app were superior to those generated with the popular software ImageJ and resulted in lower detection limits. Our assay is applicable for detecting clinically relevant ranges of both target proteins and therefore may serve as a powerful tool for POC diagnosis of inflammation and infectious events.


Assuntos
Biomarcadores/análise , Proteína C-Reativa/análise , Imunoensaio/métodos , Interleucina-6/análise , Pontos Quânticos/química , Sepse/diagnóstico , Anticorpos/imunologia , Betacoronavirus/isolamento & purificação , Proteína C-Reativa/imunologia , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Humanos , Interleucina-6/imunologia , Limite de Detecção , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , Sistemas Automatizados de Assistência Junto ao Leito , Sepse/metabolismo , Software , Raios Ultravioleta
15.
PLoS Biol ; 18(9): e3000821, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32886672

RESUMO

As a novel alternative to established surface display or combinatorial chemistry approaches for the discovery of therapeutic peptides, we present a method for the isolation of small, cysteine-rich domains from bovine antibody ultralong complementarity-determining regions (CDRs). We show for the first time that isolated bovine antibody knob domains can function as autonomous entities by binding antigen outside the confines of the antibody scaffold. This yields antibody fragments so small as to be considered peptides, each stabilised by an intricate, bespoke arrangement of disulphide bonds. For drug discovery, cow immunisations harness the immune system to generate knob domains with affinities in the picomolar to low nanomolar range, orders of magnitude higher than unoptimized peptides from naïve library screening. Using this approach, knob domain peptides that tightly bound Complement component C5 were obtained, at scale, using conventional antibody discovery and peptide purification techniques.


Assuntos
Anticorpos/química , Dissulfetos/isolamento & purificação , Domínios de Imunoglobulina , Fragmentos de Peptídeos/isolamento & purificação , Domínios e Motivos de Interação entre Proteínas , Animais , Anticorpos/imunologia , Anticorpos/metabolismo , Afinidade de Anticorpos , Formação de Anticorpos , Especificidade de Anticorpos , Antígenos/genética , Antígenos/imunologia , Linfócitos B/fisiologia , Bovinos , Complemento C5/química , Complemento C5/genética , Complemento C5/imunologia , Regiões Determinantes de Complementaridade/química , Regiões Determinantes de Complementaridade/genética , Regiões Determinantes de Complementaridade/imunologia , Dissulfetos/química , Dissulfetos/imunologia , Mapeamento de Epitopos/métodos , Humanos , Imunização , Domínios de Imunoglobulina/genética , Modelos Moleculares , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/imunologia , Domínios e Motivos de Interação entre Proteínas/genética
16.
Anesth Analg ; 131(4): 993-999, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32925314

RESUMO

BACKGROUND: The cellular immune system is of pivotal importance with regard to the response to severe infections. Monocytes/macrophages are considered key immune cells in infections and downregulation of the surface expression of monocytic human leukocyte antigen-DR (mHLA-DR) within the major histocompatibility complex class II reflects a state of immunosuppression, also referred to as injury-associated immunosuppression. As the role of immunosuppression in coronavirus disease 2019 (COVID-19) is currently unclear, we seek to explore the level of mHLA-DR expression in COVID-19 patients. METHODS: In a preliminary prospective monocentric observational study, 16 COVID-19-positive patients (75% male, median age: 68 [interquartile range 59-75]) requiring hospitalization were included. The median Acute Physiology and Chronic Health Evaluation-II (APACHE-II) score in 9 intensive care unit (ICU) patients with acute respiratory failure was 30 (interquartile range 25-32). Standardized quantitative assessment of HLA-DR on monocytes (cluster of differentiation 14+ cells) was performed using calibrated flow cytometry at baseline (ICU/hospital admission) and at days 3 and 5 after ICU admission. Baseline data were compared to hospitalized noncritically ill COVID-19 patients. RESULTS: While normal mHLA-DR expression was observed in all hospitalized noncritically ill patients (n = 7), 89% (8 of 9) critically ill patients with COVID-19-induced acute respiratory failure showed signs of downregulation of mHLA-DR at ICU admission. mHLA-DR expression at admission was significantly lower in critically ill patients (median, [quartiles]: 9280 antibodies/cell [6114, 16,567]) as compared to the noncritically ill patients (30,900 antibodies/cell [26,777, 52,251]), with a median difference of 21,508 antibodies/cell (95% confidence interval [CI], 14,118-42,971), P = .002. Reduced mHLA-DR expression was observed to persist until day 5 after ICU admission. CONCLUSIONS: When compared to noncritically ill hospitalized COVID-19 patients, ICU patients with severe COVID-19 disease showed reduced mHLA-DR expression on circulating CD14+ monocytes at ICU admission, indicating a dysfunctional immune response. This immunosuppressive (monocytic) phenotype remained unchanged over the ensuing days after ICU admission. Strategies aiming for immunomodulation in this population of critically ill patients should be guided by an immune-monitoring program in an effort to determine who might benefit best from a given immunological intervention.


Assuntos
Infecções por Coronavirus/imunologia , Estado Terminal , Antígenos HLA-DR/biossíntese , Antígenos HLA-DR/imunologia , Tolerância Imunológica/imunologia , Pneumonia Viral/imunologia , APACHE , Idoso , Anticorpos/análise , Anticorpos/imunologia , Infecções por Coronavirus/terapia , Cuidados Críticos , Regulação para Baixo/imunologia , Feminino , Humanos , Imunoterapia , Receptores de Lipopolissacarídeos/imunologia , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Pandemias , Pneumonia Viral/terapia , Estudos Prospectivos , Insuficiência Respiratória/imunologia , Insuficiência Respiratória/fisiopatologia
17.
Proc Natl Acad Sci U S A ; 117(33): 19694-19704, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32737164

RESUMO

Control can alter the eco-evolutionary dynamics of a target pathogen in two ways, by changing its population size and by directed evolution of new functions. Here, we develop a payoff model of eco-evolutionary control based on strategies of evolution, regulation, and computational forecasting. We apply this model to pathogen control by molecular antibody-antigen binding with a tunable dosage of antibodies. By analytical solution, we obtain optimal dosage protocols and establish a phase diagram with an error threshold delineating parameter regimes of successful and compromised control. The solution identifies few independently measurable fitness parameters that predict the outcome of control. Our analysis shows how optimal control strategies depend on mutation rate and population size of the pathogen, and how monitoring and computational forecasting affect protocols and efficiency of control. We argue that these results carry over to more general systems and are elements of an emerging eco-evolutionary control theory.


Assuntos
Evolução Biológica , Interações Hospedeiro-Patógeno , Anticorpos/imunologia , Humanos , Imunidade , Modelos Biológicos
18.
Nat Commun ; 11(1): 4115, 2020 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-32807795

RESUMO

The transcription factor STAT3 is frequently activated in human solid and hematological malignancies and remains a challenging therapeutic target with no approved drugs to date. Here, we develop synthetic antibody mimetics, termed monobodies, to interfere with STAT3 signaling. These monobodies are highly selective for STAT3 and bind with nanomolar affinity to the N-terminal and coiled-coil domains. Interactome analysis detects no significant binding to other STATs or additional off-target proteins, confirming their exquisite specificity. Intracellular expression of monobodies fused to VHL, an E3 ubiquitin ligase substrate receptor, results in degradation of endogenous STAT3. The crystal structure of STAT3 in complex with monobody MS3-6 reveals bending of the coiled-coil domain, resulting in diminished DNA binding and nuclear translocation. MS3-6 expression strongly inhibits STAT3-dependent transcriptional activation and disrupts STAT3 interaction with the IL-22 receptor. Therefore, our study establishes innovative tools to interfere with STAT3 signaling by different molecular mechanisms.


Assuntos
Anticorpos/metabolismo , Fator de Transcrição STAT3/metabolismo , Células A549 , Anticorpos/genética , Western Blotting , Calorimetria , Cristalografia por Raios X , Citometria de Fluxo , Polarização de Fluorescência , Imunofluorescência , Humanos , Espectrometria de Massas , Ligação Proteica , Domínios Proteicos/imunologia , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/imunologia , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Biologia Sintética
19.
Medicine (Baltimore) ; 99(34): e21887, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32846849

RESUMO

INTRODUCTION: The incidence of hepatocellular carcinoma (HCC) ranks sixth in the world, but its mortality is the third highest due to the lack of early diagnostic markers. Nowadays, the increase of autoantibody levels has been found in many cancers, and many studies have begun to pay attention to the detection of anti-p53 antibodies in HCC. The purpose of this study is to quantitatively and comprehensively analyze the potential diagnostic value of anti-p53 autoantibodies in HCC METHODS:: English articles up to November 2019 were collected. The overall sensitivity and specificity were calculated. Besides, the positive likelihood ratio, negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and summary receiver operating characteristic curves of the overall diagnostic accuracy of anti-p53 antibody were calculated by STATA software. Finally, according to the heterogeneity of the results, the subgroup analysis, and the publication bias were performed. RESULTS: A total of 16 eligible studies were incorporated into this meta-analysis, including 1323 patients with HCC and 1896 control. The pooled sensitivity was 0.28(0.17-0.41) and specificity was 0.98 (0.95-0.99). The pooled DOR was 10.44 (6.31-17.29) and the pooled NLR was 0.74 (0.63-0.86). The area under ROC curve of symmetrical ROC was 0.840. CONCLUSIONS: The anti-p53 antibody has a high specificity for HCC, but the low sensitivity is not perfect and would limit the clinical application. The anti-p53 antibody would help rule out HCC but not help rule in HCC for early diagnosis. Whether combined as a diagnostic panel with other biomarkers or laboratory tests may prove useful requires further study.


Assuntos
Anticorpos/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/diagnóstico , Neoplasias Hepáticas/patologia , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidade , Estudos de Casos e Controles , Estudos de Avaliação como Assunto , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Proteína Supressora de Tumor p53/antagonistas & inibidores
20.
Medicine (Baltimore) ; 99(34): e21893, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32846851

RESUMO

We examined the blood concentrations of neutrophil gelatinase-associated lipocalin (NGAL) and citrullinated alpha enolase peptide-1 (CEP-1) antibody in sepsis patients to evaluate their potential diagnostic, classified and prognostic utility together with C-reactive protein (CRP), procalcitonin (PCT), interleukin-6 (IL-6).Sixty-nine patients admitted at the emergency department with sepsis were studied, on admission, their demographic and clinical information were recorded. Blood levels of CRP, PCT, IL-6, NGAL, and CEP-1 antibody were measured. Relationships between sequential [sepsis-related] organ failure assessment score and blood biomarkers, between acute physiology and chronic health evaluation II score and blood biomarkers were investigated. Additionally, the mutual correlation among CRP, PCT, IL-6, NGAL, and CEP-1 antibody were investigated. Diagnostic and predictive values for clinical outcomes for biomarkers were assessed by receiver operator characteristic curve.Sixty-nine participants (38 sepsis, 31 septic shock) were compared with 40 healthy controls. The levels of CRP, PCT, IL-6, and NGAL were significantly higher in sepsis patients ([59.49 ± 48.88]; 0.71, [0.13-11.72]; 60.46, [33.26-201.20]; 265.61, [185.79-500.96], respectively) compared with healthy controls ([2.05 ± 1.85]; 0.02, [0.02-0.03]; 12.08, [7.22-16.84]; 19.73, [7.66-34.39], respectively) (P < .001). CRP, PCT, IL-6, and NGAL had better discriminatory performance with an area under the receiver operator characteristic curve (AUC) of (0.98; 0.98; 0.90; 0.97, respectively), 95% confidence interval (CI) = ([0.95; 1.00]; [0.96; 1.00]; [0.84; 0.96]; [0.94; 1.00], respectively) (P < .001), with a cut off value of (8.02 mg/L [Se = 88.40%, Sp = 100.00%]; 0.06 ng/mL [Se = 94.20%, Sp = 75.00%]; 30.63 pg/mL [Se = 78.30%, Sp = 95.00%]; 95.72 ng/mL [Se = 99.00%, Sp = 92.00%], respectively). Between the sepsis group and septic shock group, PCT and NGAL were significantly higher in septic shock group (2.44, [0.49-20.36]; 294.65 [203.34-1262.47], respectively) compared with sepsis group (0.41, [0.11-2.63]; 219.94, [146.38-385.24], respectively) (P < .05). Between survivors group and nonsurvivors group, PCT was obviously elevated in nonsurvivors group (2.47, [0.70-12.49]) compare with survivors group (0.41, [0.11-8.16]) (P < .05), with an AUC of 0.69, 95% CI = (0.57; 0.81) (P < .05), while CEP-1 antibody was decreased in nonsurvivors group (14.03, [4.94-17.17]) contrast to survivors group (18.78, [8.08-39.72]) (P < .05), with an AUC of 0.67, 95% CI = (0.54; 0.80) (P < .05). Additionally, CEP-1 antibody demonstrated a negative correlation with either sequential [sepsis-related] organ failure assessment score (r = -0.31, P < .05) or PCT (r = -0.27, P < .05).As CRP, PCT, and IL-6, NGAL was valuable in sepsis diagnosis. With a classificatory value, PCT and NGAL correlated with the degree severity of sepsis. PCT and CEP-1 antibody were meaningful in sepsis prognosis. CEP-1 antibody may be a protective factor for sepsis.


Assuntos
Anticorpos/sangue , Lipocalina-2/sangue , Sepse/sangue , Sepse/diagnóstico , Choque Séptico/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Anticorpos Anti-Proteína Citrulinada/sangue , Biomarcadores/sangue , Proteína C-Reativa/análise , Estudos de Casos e Controles , Diagnóstico Diferencial , Serviço Hospitalar de Emergência , Feminino , Humanos , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Escores de Disfunção Orgânica , Fosfopiruvato Hidratase/metabolismo , Valor Preditivo dos Testes , Pró-Calcitonina/sangue , Prognóstico , Estudos Prospectivos , Sepse/classificação , Sepse/mortalidade , Choque Séptico/sangue
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