RESUMO
Non-small cell lung cancer (NSCLC), a major life-threatening disease accounting for 85% of all lung cancer cases, has been treated with tyrosine kinase inhibitors (TKIs), but often resulted in drug resistance, and approximately 60% of TKI-resistant cases are due to acquired secondary (epithelial growth factor receptor) EGFR-T790M mutation. To identify alternative targets for TKI-resistant NSCLC with EGFR-T790M mutation, we found that the three globo-series glycosphingolipids are increasingly expressed on this type of NSCLC cell lines, and among them, the increase of stage-specific embryonic antigen-4 (SSEA-4) expression is the most significant. Compared to TKI-sensitive cell lines, SSEA-4 and the key enzyme ß3GalT5 responsible for the synthesis of SSEA3 are more expressed in TKI-resistant NSCLC cell lines with EGFR-T790M mutation, and the expression levels strongly correlate with poor survival in patients with EGFR mutation. In addition, we demonstrated that a SSEA-4 targeted monoclonal antibody, especially the homogeneous glycoform with well-defined Fc glycan designed to improve effective functions, is highly effective against this subpopulation of NSCLC in cell-based and animal studies. These findings provide a direction for the prediction of tumor recurrence and treatment of TKI-resistant NSCLC with EGFR-T790M mutation.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Antígenos Embrionários Estágio-Específicos , Animais , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Receptores ErbB/genética , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Recidiva Local de NeoplasiaRESUMO
Pancreatic cancer is usually asymptomatic in the early stages; the 5-y survival rate is around 9%; and there is a lack of effective treatment. Here we show that SSEA-4 is more expressed in all pancreatic cancer cell lines examined but not detectable in normal pancreatic cells; and high expression of SSEA-4 or the key enzymes B3GALT5 + ST3GAL2 associated with SSEA-4 biosynthesis significantly lowers the overall survival rate. To evaluate potential new treatments for pancreatic cancer, homogeneous antibodies with a well-defined Fc glycan for optimal effector functions and CAR-T cells with scFv construct designed to target SSEA-4 were shown highly effective against pancreatic cancer in vitro and in vivo. This was further supported by the finding that a subpopulation of natural killer (NK) cells isolated by the homogeneous antibody exhibited enhancement in cancer-cell killing activity compared to the unseparated NK cells. These results indicate that targeting SSEA-4 by homologous antibodies or CAR-T strategies can effectively inhibit cancer growth, suggesting SSEA-4 as a potential immunotherapy target for treating pancreatic disease.
Assuntos
Anticorpos/imunologia , Neoplasias Pancreáticas/tratamento farmacológico , Antígenos Embrionários Estágio-Específicos/imunologia , Animais , Linhagem Celular Tumoral , Terapia Baseada em Transplante de Células e Tecidos , Regulação da Expressão Gênica , Humanos , Imunoterapia , Imunoterapia Adotiva , Camundongos , Camundongos Nus , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The open radio access network (RAN) aims to bring openness and intelligence to the traditional closed and proprietary RAN technology and offer flexibility, performance improvement, and cost-efficiency in the RAN's deployment and operation. This paper provides a comprehensive survey of the Open RAN development. We briefly summarize the RAN evolution history and the state-of-the-art technologies applied to Open RAN. The Open RAN-related projects, activities, and standardization is then discussed. We then summarize the challenges and future research directions required to support the Open RAN. Finally, we discuss some solutions to tackle these issues from the open source perspective.
RESUMO
Incessant antigenic evolution enables the persistence and spread of influenza virus in the human population. As the principal target of the immune response, the hemagglutinin (HA) surface antigen on influenza viruses continuously acquires and replaces N-linked glycosylation sites to shield immunogenic protein epitopes using host-derived glycans. Anti-glycan antibodies, such as 2G12, target the HIV-1 envelope protein (Env), which is even more extensively glycosylated and contains under-processed oligomannose-type clusters on its dense glycan shield. Here, we illustrate that 2G12 can also neutralize human seasonal influenza A H3N2 viruses that have evolved to present similar oligomannose-type clusters on their HAs from around 20 years after the 1968 pandemic. Using structural biology and mass spectrometric approaches, we find that two N-glycosylation sites close to the receptor binding site (RBS) on influenza hemagglutinin represent the oligomannose cluster recognized by 2G12. One of these glycan sites is highly conserved in all human H3N2 strains and the other emerged during virus evolution. These two N-glycosylation sites have also become crucial for fitness of recent H3N2 strains. These findings shed light on the evolution of the glycan shield on influenza virus and suggest 2G12-like antibodies can potentially act as broad neutralizers to target human enveloped viruses.
Assuntos
Anticorpos Antivirais/imunologia , HIV-1/imunologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Vírus da Influenza A Subtipo H3N2/imunologia , Anticorpos Amplamente Neutralizantes , Reações Cruzadas , Infecções por HIV/imunologia , Humanos , Influenza Humana/imunologiaRESUMO
Herein we present a concept in cancer where an immune response is detrimental rather than helpful. In the cancer setting, the immune system is generally considered to be helpful in curtailing the initiation and progression of tumors. In this work we show that a patient's immune response to their tumor can, in fact, either enhance or inhibit tumor cell growth. Two closely related autoantibodies to the growth factor receptor TrkB were isolated from cancer patients' B cells. Although highly similar in sequence, one antibody was an agonist while the other was an antagonist. The agonist antibody was shown to increase breast cancer cell growth both in vitro and in vivo, whereas the antagonist antibody inhibited growth. From a mechanistic point of view, we showed that binding of the agonist antibody to the TrkB receptor was functional in that it initiated downstream signaling identical to its natural growth factor ligand, brain-derived neurotrophic factor (BDNF). Our study shows that individual autoantibodies may play a role in cancer patients.
Assuntos
Autoanticorpos/imunologia , Autoantígenos/imunologia , Neoplasias da Mama/patologia , Glicoproteínas de Membrana/imunologia , Metástase Neoplásica/imunologia , Receptor trkB/imunologia , Animais , Autoanticorpos/sangue , Autoanticorpos/isolamento & purificação , Autoanticorpos/metabolismo , Autoantígenos/sangue , Autoantígenos/metabolismo , Linfócitos B/imunologia , Linfócitos B/metabolismo , Fator Neurotrófico Derivado do Encéfalo/imunologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Neoplasias da Mama/sangue , Neoplasias da Mama/imunologia , Linhagem Celular Tumoral , Movimento Celular/imunologia , Proliferação de Células , Feminino , Humanos , Glicoproteínas de Membrana/agonistas , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/sangue , Camundongos , Receptor trkB/agonistas , Receptor trkB/antagonistas & inibidores , Receptor trkB/sangue , Transdução de Sinais/imunologiaRESUMO
The unique interaction between fluorine atoms has been exploited to alter protein structures and to develop synthetic and analytical applications. To expand such fluorous interaction for novel applications, polyproline peptides represent an excellent molecular nanoscaffold for controlling the presentation of perfluoroalkyl groups on their unique secondary structure. We develop approaches to synthesis fluorinated peptides to systematically investigate how the number, location and types of the fluorous groups on polyproline affect the conformation by monitoring the transition between the two major polyproline structures PPI and PPII. This work provides valuable information on how fluorous interaction affects the peptide structure and also benefits the design of functional fluorous molecules.
Assuntos
Desenho de Fármacos , Peptídeos/síntese química , Halogenação , Estrutura Molecular , Peptídeos/químicaRESUMO
measures such as progression-free survival (PFS) and overall survival (OS) are commonly reported in literature for oncology trials, while time to progression (TTP) and post progression survival (PPS) are not usually reported. A time-variant transition hazard model was developed using an ordinary differential equation (ODE) model to estimate TTP and PPS from summary level PFS and OS. The model was applied to published data from immune checkpoint inhibitor trials for non-small cell lung cancer (NSCLC) in a meta-analysis framework. This model-based method was able to robustly estimate TTP and PPS from summary level OS and PFS data, provided a quantitative approach for understanding the patterns of disease progression across different treatments through the time-variant disease progression rate function, and provided a summary of how different treatments affect TTP and PPS. The proposed method can be generalized to characterize and quantify multiple time-to-event endpoints jointly in oncology trials and improve our understanding of disease prognostics for different treatments.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Progressão da Doença , Intervalo Livre de Doença , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Intervalo Livre de ProgressãoRESUMO
Generating and improving antibodies and peptides that bind specifically to membrane protein targets such as ion channels and G protein-coupled receptors (GPCRs) can be challenging using established selection methods. Current strategies are often limited by difficulties in the presentation of the antigen or the efficiency of the selection process. Here, we report a method for obtaining antibodies specific for whole cell membrane-associated antigens which combines a cell-cell interaction format based on yeast display technology with fluorescence-activated cell sorting of dual fluorescent complexes. Using this method, we were able to direct the affinity maturation of an antagonist antibody specific for the proton-gated ion channel ASIC1a and showed that both the affinity and potency were improved. We were also able to use this method to do kinetic selections to generate clones with better dissociation profiles. In addition, this method was employed successfully to handle the difficult problem of selecting antibodies specific to a GPCR target, the mu-opioid receptor.
Assuntos
Anticorpos/imunologia , Descoberta de Drogas/métodos , Citometria de Fluxo/métodos , Canais Iônicos/imunologia , Receptores Acoplados a Proteínas G/imunologia , Animais , Afinidade de Anticorpos , Células CHO , Cricetinae , Cricetulus , Saccharomyces cerevisiaeRESUMO
Precipitation intensity estimation is a critical issue in the analysis of weather conditions. Most existing approaches focus on building complex models to extract rain streaks. However, an efficient approach to estimate the precipitation intensity from surveillance cameras is still challenging. This study proposes a convolutional neural network known as the signal filtering convolutional neural network (SF-CNN) to handle precipitation intensity using surveillance-based images. The SF-CNN has two main blocks, the signal filtering block (SF block) and the gradually decreasing dimension block (GDD block), to extract features for the precipitation intensity estimation. The SF block with the filtering operation is constructed in different parts of the SF-CNN to remove the noise from the features containing rain streak information. The GDD block continuously takes the pair of the convolutional operation with the activation function to reduce the dimension of features. Our main contributions are (1) an SF block considering the signal filtering process and effectively removing the useless signals and (2) a procedure of gradually decreasing the dimension of the feature able to learn and reserve the information of features. Experiments on the self-collected dataset, consisting of 9394 raining images with six precipitation intensity levels, demonstrate the proposed approach's effectiveness against the popular convolutional neural networks. To the best of our knowledge, the self-collected dataset is the largest dataset for monitoring infrared images of precipitation intensity.
Assuntos
Aprendizagem , Redes Neurais de ComputaçãoRESUMO
BACKGROUND: Glecaprevir and pibrentasvir are direct-acting antiviral agents with pangenotypic activity and a high barrier to resistance. We evaluated the efficacy and safety of 8-week and 12-week courses of treatment with 300 mg of glecaprevir plus 120 mg of pibrentasvir in patients without cirrhosis who had hepatitis C virus (HCV) genotype 1 or 3 infection. METHODS: We conducted two phase 3, randomized, open-label, multicenter trials. Patients with genotype 1 infection were randomly assigned in a 1:1 ratio to receive once-daily glecaprevir-pibrentasvir for either 8 or 12 weeks. Patients with genotype 3 infection were randomly assigned in a 2:1 ratio to receive 12 weeks of treatment with either glecaprevir-pibrentasvir or sofosbuvir-daclatasvir. Additional patients with genotype 3 infection were subsequently enrolled and nonrandomly assigned to receive 8 weeks of treatment with glecaprevir-pibrentasvir. The primary end point was the rate of sustained virologic response 12 weeks after the end of treatment. RESULTS: In total, 1208 patients were treated. The rate of sustained virologic response at 12 weeks among genotype 1-infected patients was 99.1% (95% confidence interval [CI], 98 to 100) in the 8-week group and 99.7% (95% CI, 99 to 100) in the 12-week group. Genotype 3-infected patients who were treated for 12 weeks had a rate of sustained virologic response at 12 weeks of 95% (95% CI, 93 to 98; 222 of 233 patients) with glecaprevir-pibrentasvir and 97% (95% CI, 93 to 99.9; 111 of 115) with sofosbuvir-daclatasvir; 8 weeks of treatment with glecaprevir-pibrentasvir yielded a rate of 95% (95% CI, 91 to 98; 149 of 157 patients). Adverse events led to discontinuation of treatment in no more than 1% of patients in any treatment group. CONCLUSIONS: Once-daily treatment with glecaprevir-pibrentasvir for either 8 weeks or 12 weeks achieved high rates of sustained virologic response among patients with HCV genotype 1 or 3 infection who did not have cirrhosis. (Funded by AbbVie; ENDURANCE-1 and ENDURANCE-3 ClinicalTrials.gov numbers, NCT02604017 and NCT02640157 .).
Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Quinoxalinas/uso terapêutico , Sulfonamidas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Ácidos Aminoisobutíricos , Antivirais/efeitos adversos , Benzimidazóis/efeitos adversos , Carbamatos , Ciclopropanos , Esquema de Medicação , Combinação de Medicamentos , Feminino , Genótipo , Hepatite C Crônica/virologia , Humanos , Imidazóis/efeitos adversos , Imidazóis/uso terapêutico , Lactamas Macrocíclicas , Leucina/análogos & derivados , Masculino , Pessoa de Meia-Idade , Prolina/análogos & derivados , Pirrolidinas , Quinoxalinas/efeitos adversos , RNA Viral/sangue , Sofosbuvir/efeitos adversos , Sofosbuvir/uso terapêutico , Sulfonamidas/efeitos adversos , Valina/análogos & derivados , Carga ViralRESUMO
The pangenotypic regimen of glecaprevir and pibrentasvir (G/P) is approved to treat adults with chronic hepatitis C virus (HCV) infection and has yielded high cure rates in adults in clinical trials. Approved treatment options for pediatrics may include ribavirin. A pangenotypic regimen for pediatric patients remains an unmet need. DORA is an ongoing phase 2/3, nonrandomized, open-label study evaluating the pharmacokinetics (PK), safety, and efficacy of G/P in pediatric patients with chronic HCV. This analysis includes Part 1 of the study, conducted in adolescent patients 12-17 years of age given the adult regimen of G/P (300 mg/120 mg) once daily for 8-16 weeks according to the indication durations used in adults. Patients were either treatment naïve or experienced with interferon-based regimens. The primary PK endpoint was steady-state exposures for glecaprevir and pibrentasvir; the primary efficacy endpoint was sustained virologic response 12 weeks after treatment (SVR12). The secondary efficacy endpoints were on-treatment virologic failure, relapse, and reinfection. Safety and tolerability were monitored. Part 1 enrolled 48 adolescent patients infected with genotypes 1, 2, 3, or 4, of whom 47 were administered G/P. All 47 patients (100%) achieved SVR12. No on-treatment virologic failures or relapses occurred. PK exposures of glecaprevir and pibrentasvir were comparable to exposures in adults. No adverse events (AEs) led to treatment discontinuation, and no serious AEs occurred. Conclusion: Adolescent patients with chronic HCV infection treated with G/P achieved a comparable exposure to adults, 100% SVR12 rate, and safety profile consistent with that in adults. This pangenotypic regimen demonstrated 100% efficacy within the adolescent population in as little as 8 weeks of treatment.
Assuntos
Benzimidazóis/farmacocinética , Benzimidazóis/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Pirrolidinas/farmacocinética , Pirrolidinas/uso terapêutico , Quinoxalinas/farmacocinética , Quinoxalinas/uso terapêutico , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapêutico , Adolescente , Benzimidazóis/efeitos adversos , Criança , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pirrolidinas/efeitos adversos , Quinoxalinas/efeitos adversos , Sulfonamidas/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: Glioma is a malignant brain tumor; its location is complex and is difficult to remove surgically. To diagnosis the brain tumor, doctors can precisely diagnose and localize the disease using medical images. However, the computer-assisted diagnosis for the brain tumor diagnosis is still the problem because the rough segmentation of the brain tumor makes the internal grade of the tumor incorrect. METHODS: In this paper, we proposed an Aggregation-and-Attention Network for brain tumor segmentation. The proposed network takes the U-Net as the backbone, aggregates multi-scale semantic information, and focuses on crucial information to perform brain tumor segmentation. To this end, we proposed an enhanced down-sampling module and Up-Sampling Layer to compensate for the information loss. The multi-scale connection module is to construct the multi-receptive semantic fusion between encoder and decoder. Furthermore, we designed a dual-attention fusion module that can extract and enhance the spatial relationship of magnetic resonance imaging and applied the strategy of deep supervision in different parts of the proposed network. RESULTS: Experimental results show that the performance of the proposed framework is the best on the BraTS2020 dataset, compared with the-state-of-art networks. The performance of the proposed framework surpasses all the comparison networks, and its average accuracies of the four indexes are 0.860, 0.885, 0.932, and 1.2325, respectively. CONCLUSIONS: The framework and modules of the proposed framework are scientific and practical, which can extract and aggregate useful semantic information and enhance the ability of glioma segmentation.
Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Glioma/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Redes Neurais de Computação , Algoritmos , Diagnóstico por Computador , Humanos , Aprendizado de Máquina SupervisionadoRESUMO
The diverse physiological roles of the neurotrophin family have long prompted exploration of their potential as therapeutic agents for nerve injury and neurodegenerative diseases. To date, clinical trials of one family member, brain-derived neurotrophic factor (BDNF), have disappointingly failed to meet desired endpoints. Contributing to these failures is the fact that BDNF is pharmaceutically a nonideal biologic drug candidate. It is a highly charged, yet is a net hydrophobic molecule with a low molecular weight that confers a short t1/2 in man. To circumvent these shortcomings of BDNF as a drug candidate, we have employed a function-based cellular screening assay to select activating antibodies of the BDNF receptor TrkB from a combinatorial human short-chain variable fragment antibody library. We report here the successful selection of several potent TrkB agonist antibodies and detailed biochemical and physiological characterization of one such antibody, ZEB85. By using a human TrkB reporter cell line and BDNF-responsive GABAergic neurons derived from human ES cells, we demonstrate that ZEB85 is a full agonist of TrkB, comparable in potency to BDNF toward human neurons in activation of TrkB phosphorylation, canonical signal transduction, and mRNA transcriptional regulation.
Assuntos
Comunicação Autócrina , Neurônios GABAérgicos/metabolismo , Biblioteca Gênica , Glicoproteínas de Membrana/agonistas , Receptor trkB/agonistas , Transdução de Sinais/efeitos dos fármacos , Anticorpos de Cadeia Única , Transcrição Gênica/efeitos dos fármacos , Linhagem Celular , Humanos , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Fosforilação/efeitos dos fármacos , Receptor trkB/genética , Receptor trkB/metabolismo , Anticorpos de Cadeia Única/genética , Anticorpos de Cadeia Única/farmacologiaRESUMO
Most antibodies currently in use have been selected based on their binding affinity. However, nowadays, antibodies that can not only bind but can also alter the function of cell surface signaling components are increasingly sought after as therapeutic drugs. Therefore, the identification of such functional antibodies from a large antibody library is the subject of intensive research. New methods applied to combinatorial antibody libraries now allow the isolation of functional antibodies in the cellular environment. These selected agonist antibodies have provided new insights into important issues of signal transduction. Notably, when certain antibodies bind to a given receptor, the cell fate induced by them may be the same or different from that induced by natural agonists. In addition, combined with phenotypic screening, this platform allows us to discover unexpected experimental results and explore various phenomena in cell biology, such as those associated with stem cells and cancer cells.
Assuntos
Anticorpos/imunologia , Descoberta de Drogas/métodos , Biblioteca de Peptídeos , Receptores Acoplados a Proteínas G/imunologia , Animais , Anticorpos/genética , Pleiotropia Genética , Humanos , Receptores Acoplados a Proteínas G/genéticaRESUMO
BACKGROUND & AIMS: Eight-week glecaprevir/pibrentasvir leads to high rates of sustained virological response at post-treatment week 12 (SVR12) across HCV genotypes (GT) 1-6 in treatment-naïve patients without cirrhosis. We evaluated glecaprevir/pibrentasvir once daily for 8â¯weeks in treatment-naïve patients with compensated cirrhosis. METHODS: EXPEDITION-8 was a single-arm, multicenter, phase IIIb trial. The primary and key secondary efficacy analyses were to compare the lower bound of the 95% CI of the SVR12 rate in i) patients with GT1,2,4-6 in the per protocol (PP) population, ii) patients with GT1,2,4-6 in the intention-to-treat (ITT) population, iii) patients with GT1-6 in the PP population, and iv) patients with GT1-6 in the ITT population, to pre-defined efficacy thresholds based on historical SVR12 rates for 12â¯weeks of glecaprevir/pibrentasvir in the same populations. Safety was also assessed. RESULTS: A total of 343 patients were enrolled. Most patients were male (63%), white (83%), and had GT1 (67%). The SVR12 rate in patients with GT1-6 was 99.7% (n/Nâ¯=â¯334/335; 95%CI 98.3-99.9) in the PP population and 97.7% (n/Nâ¯=â¯335/343; 95% CI 96.1-99.3) in the ITT population. All primary and key secondary efficacy analyses were achieved. One patient (GT3a) experienced relapse (0.3%) at post-treatment week 4. Common adverse events (≥5%) were fatigue (9%), pruritus (8%), headache (8%), and nausea (6%). Serious adverse events (none related) occurred in 2% of patients. No adverse event led to study drug discontinuation. Clinically significant laboratory abnormalities were infrequent. CONCLUSIONS: Eight-week glecaprevir/pibrentasvir was well tolerated and led to a similarly high SVR12 rate as the 12-week regimen in treatment-naïve patients with chronic HCV GT1-6 infection and compensated cirrhosis. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03089944. LAY SUMMARY: This study was the first to evaluate an 8-week direct-acting antiviral (DAA) regimen active against all major types of hepatitis C virus (HCV) in untreated patients with compensated cirrhosis. High virological cure rates were achieved with glecaprevir/pibrentasvir across HCV genotypes 1-6, and these high cure rates did not depend on any patient or viral characteristics present before treatment. This may simplify care and allow non-specialist healthcare professionals to treat these patients, contributing to global efforts to eliminate HCV.
Assuntos
Ácidos Aminoisobutíricos/administração & dosagem , Antivirais/administração & dosagem , Benzimidazóis/administração & dosagem , Ciclopropanos/administração & dosagem , Genótipo , Hepacivirus/genética , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Lactamas Macrocíclicas/administração & dosagem , Leucina/análogos & derivados , Cirrose Hepática/complicações , Cirrose Hepática/tratamento farmacológico , Prolina/análogos & derivados , Pirrolidinas/administração & dosagem , Quinoxalinas/administração & dosagem , Sulfonamidas/administração & dosagem , Idoso , Ácidos Aminoisobutíricos/efeitos adversos , Antivirais/efeitos adversos , Benzimidazóis/efeitos adversos , Ciclopropanos/efeitos adversos , Combinação de Medicamentos , Feminino , Hepacivirus/enzimologia , Hepatite C Crônica/sangue , Hepatite C Crônica/virologia , Humanos , Lactamas Macrocíclicas/efeitos adversos , Leucina/administração & dosagem , Leucina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Prolina/administração & dosagem , Prolina/efeitos adversos , Pirrolidinas/efeitos adversos , Quinoxalinas/efeitos adversos , RNA Viral/sangue , RNA Viral/genética , Sulfonamidas/efeitos adversos , Resposta Viral Sustentada , Proteínas não Estruturais Virais/genéticaRESUMO
We have shown that glycosylation of influenza A virus (IAV) hemagglutinin (HA), especially at position N-27, is crucial for HA folding and virus survival. However, it is not known whether the glycosylation of HA and the other two major IAV surface glycoproteins, neuraminidase (NA) and M2 ion channel, is essential for the replication of IAV. Here, we show that glycosylation of HA at N-142 modulates virus infectivity and host immune response. Glycosylation of NA in the stalk region affects its structure, activity, and specificity, thereby modulating virus release and virulence, and glycosylation at the catalytic domain affects its thermostability; however, glycosylation of M2 had no effect on its function. In addition, using IAV without the stalk and catalytic domains of NA as a live attenuated vaccine was shown to confer a strong IAV-specific CD8+ T-cell response and a strong cross-strain as well as cross-subtype protection against various virus strains.
Assuntos
Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Vírus da Influenza A/imunologia , Vacinas contra Influenza/imunologia , Células A549 , Animais , Anticorpos Antivirais/imunologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular , Linhagem Celular Tumoral , Proteção Cruzada/imunologia , Cães , Feminino , Células HEK293 , Humanos , Influenza Humana/imunologia , Influenza Humana/prevenção & controle , Células Madin Darby de Rim Canino , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/prevenção & controle , Virulência/imunologiaRESUMO
BACKGROUND/PURPOSE: This study assessed the quality of life (QoL) and pregnancy outcomes among infertile women undergoing in vitro fertilization (IVF) treatment to investigate the association between QoL and IVF pregnancy outcomes. METHODS: This study included 686 women with 1205 embryo transfers (ETs). QoL was measured using the fertility quality of life (FertiQoL) tool before ET. FertiQoL comprises two modules: a Core module (including mind/body, emotional, relational, and social domains) and a Treatment module (covering treatment environment and tolerability domains). The FertiQol total and subscale scores were computed and scored in the range of 0-100 (higher scores indicate better QoL). Multivariate generalized estimating equation analyses were carried out to assess the association between QoL and IVF pregnancy outcomes, with adjustment for time-varying factors across multiple ETs for a given person. RESULTS: The lowest score in the core module was for the emotional domain (62.0), and that in the Treatment module was for the tolerability domain (59.4). QoL scores were significantly and positively associated with pregnancy outcomes (i.e., ongoing pregnancy, live birth); with a one unit increase in the emotional domain score, the probabilities of ongoing pregnancy and live birth significantly increased by 2.4% and 2.6%, respectively (p < 0.05). CONCLUSION: This study evaluated the prospective association between QoL and IVF pregnancy outcomes among infertile women. The results highlight the importance of developing clinical strategies to improve QoL among infertile women undergoing IVF treatment, which may further improve the pregnancy rates of this population.
Assuntos
Transferência Embrionária/estatística & dados numéricos , Infertilidade Feminina/psicologia , Resultado da Gravidez , Qualidade de Vida/psicologia , Adulto , Estudos Transversais , Feminino , Fertilização in vitro , Humanos , Estudos Longitudinais , Gravidez , Inquéritos e Questionários , TaiwanRESUMO
BACKGROUND: Untreated, chronic hepatitis C virus (HCV) infection may lead to progressive liver damage, which can be mitigated by successful treatment. This integrated analysis reports the safety, efficacy, and pharmacokinetics (PK) of the ribavirin-free, direct-acting, antiviral, fixed-dose combination of glecaprevir/pibrentasvir (G/P) in patients with chronic HCV genotype 1-6 infections and compensated liver disease, including patients with chronic kidney disease stages 4 or 5 (CKD 4/5). METHODS: Data from 9 Phase II and III clinical trials, assessing the efficacy and safety of G/P treatment for 8-16 weeks, were included. The presence of cirrhosis was determined at screening using a liver biopsy, transient elastography, or serum biomarkers. The objectives were to evaluate safety, the rate of sustained virologic response at post-treatment week 12 (SVR12), and steady-state PK by cirrhosis status. RESULTS: Among 2369 patients, 308 (13%) were Child-Pugh Class A, including 20 with CKD 4/5. Overall, <1% of patients experienced an adverse event (AE) that led to G/P discontinuation or G/P-related serious AEs (SAEs). The most common AEs were headache and fatigue, occurring at similar frequencies with and without cirrhosis. SAEs were more common in patients with CKD 4/5, but all were unrelated to G/P. There were no cases of drug-induced liver injury or clinically relevant hepatic decompensation. SVR12 rates were 96.4% (297/308) with compensated cirrhosis and 97.5% (2010/2061) without cirrhosis. PK analysis demonstrated a 2.2-fold increase in glecaprevir exposure, but not pibrentasvir exposure, in patients with compensated cirrhosis. CONCLUSIONS: G/P was safe and efficacious in patients with compensated liver disease, including those with CKD 4/5. CLINICAL TRIALS REGISTRATION: NCT02243280, NCT02243293, NCT02604017, NCT02640482, NCT02640157, NCT02636595, NCT02642432, NCT02651194, and NCT02446717.
Assuntos
Antivirais/farmacocinética , Benzimidazóis/farmacocinética , Hepatite C Crônica/tratamento farmacológico , Hepatopatias/tratamento farmacológico , Quinoxalinas/farmacocinética , Sulfonamidas/farmacocinética , Idoso , Ácidos Aminoisobutíricos , Antivirais/efeitos adversos , Benzimidazóis/efeitos adversos , Ciclopropanos , Interpretação Estatística de Dados , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Hepatite C Crônica/virologia , Humanos , Lactamas Macrocíclicas , Leucina/análogos & derivados , Cirrose Hepática/tratamento farmacológico , Hepatopatias/virologia , Masculino , Prolina/análogos & derivados , Pirrolidinas , Quinoxalinas/efeitos adversos , Sulfonamidas/efeitos adversos , Resposta Viral SustentadaRESUMO
BACKGROUND & AIMS: Proton pump inhibitors (PPIs) are commonly prescribed to treat acid-related disorders. Some direct-acting antiviral regimens for chronic hepatitis C virus (HCV) infection have reduced efficacy in patients taking concomitant acid-reducing agents, including PPIs, due to interactions between drugs. We analyzed data from 9 multicenter, phase 2 and 3 trials to determine the efficacy and pharmacokinetics of an HCV therapeutic regimen comprising glecaprevir and pibrentasvir (glecaprevir/pibrentasvir) in patients taking concomitant acid-reducing agents. METHODS: We analyzed data from 2369 patients infected with HCV genotypes 1-6 and compensated liver disease treated with an all-oral regimen of glecaprevir/pibrentasvir for 8-16 weeks. We compared efficacy and pharmacokinetics among patients receiving at least 1 dose of an acid-reducing agent (a PPI, an H2 blocker, or antacid). High-dose PPI was defined as daily dose greater than 20 mg omeprazole dose equivalent. The objectives were to evaluate rate of sustained virologic response 12 weeks post-treatment (SVR12) and to assess steady-state glecaprevir and pibrentasvir exposures in patients on acid-reducing agents. RESULTS: Of the 401 patients (17%) who reported use of acid-reducing agents, 263 took PPIs (11%; 109 patients took a high-dose PPI and 154 patients took a low-dose PPI). Rates of SVR12 were 97.0% among patients who used acid-reducing agents and 97.5% among those not using acid-reducing agents (P = .6). An SVR12 was achieved in 96.3% taking a high-dose PPI and 97.4% taking a low-dose PPI, with no virologic failures in those receiving a high-dose PPI (P = .7). Glecaprevir, but not pibrentasvir, bioavailability was affected; its exposure decreased by 41% in patients taking a high-dose PPI. CONCLUSIONS: In an analysis of data from 9 clinical trials, we observed a high rate of SVR12 (approximately 97%) among patients treated with glecaprevir/pibrentasvir for HCV infection-even among patients taking concomitant ARA or high-dose PPI. This was despite decreased glecaprevir exposures in patients when on high-dose PPIs. ClinicalTrials.gov numbers, NCT02243280 (SURVEYOR-I), NCT02243293 (SURVEYOR-II), NCT02604017 (ENDURANCE-1), NCT02640482 (ENDURANCE-2), NCT02640157 (ENDURANCE-3), NCT02636595 (ENDURANCE-4), NCT02642432 (EXPEDITION-1), NCT02651194 (EXPEDITION-4), NCT02446717 (MAGELLAN-I).
Assuntos
Antivirais/administração & dosagem , Antivirais/farmacocinética , Benzimidazóis/administração & dosagem , Benzimidazóis/farmacocinética , Hepatite C Crônica/tratamento farmacológico , Inibidores da Bomba de Prótons/administração & dosagem , Pirrolidinas/administração & dosagem , Pirrolidinas/farmacocinética , Quinoxalinas/administração & dosagem , Quinoxalinas/farmacocinética , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacocinética , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Combinação de Medicamentos , Interações Medicamentosas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resposta Viral Sustentada , Resultado do Tratamento , Adulto JovemRESUMO
Patients with hepatitis C virus (HCV) who have virological failure (VF) after treatment containing a nonstructural protein 5A (NS5A) inhibitor have limited retreatment options. MAGELLAN-1 Part 2 was a randomized, open-label, phase 3 study to evaluate the efficacy and safety of ribavirin (RBV)-free glecaprevir and pibrentasvir (G/P; 300 mg/120 mg) in patients with chronic HCV and past VF on at least one NS3/4A protease and/or NS5A inhibitor-containing therapy. Patients with compensated liver disease, with or without cirrhosis, and HCV genotype (GT) 1, 4, 5, or 6 were randomized 1:1 to receive 12 or 16 weeks of G/P. The primary endpoint was sustained virological response (SVR) at 12 weeks posttreatment (SVR12). Among 91 patients treated, 87 had GT1 and 4 had GT4 infection. SVR12 was achieved by 89% (39 of 44) and 91% (43 of 47) of patients who received 12 and 16 weeks of G/P, respectively. Virological relapse occurred in 9% (4 of 44) of patients treated with 12 weeks of G/P; there were no relapses with 16 weeks of treatment. Past treatment history with one class of inhibitor (protease or NS5A) had no impact on SVR12, whereas past treatment with both classes of inhibitors was associated with lower SVR12 rate. The most common adverse event (AE) was headache (≥10% of patients), and there were no serious AEs assessed as related to study drugs or AEs leading to discontinuation. CONCLUSION: Sixteen weeks of G/P treatment achieved a high SVR12 rate in patients with HCV GT1 infection and past failure to regimens containing either NS5A inhibitors or NS3 protease inhibitors. (Hepatology 2018;67:1253-1260).