Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 37
Filtrar
1.
Int J Chron Obstruct Pulmon Dis ; 19: 2023-2034, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39291240

RESUMO

Background: There has been a growing body of research focusing on patients with Congestive Heart Failure (CHF) and chronic obstructive pulmonary disease (COPD) admitted to the intensive care unit (ICU). However, the optimal blood pressure (BP) level for such patients remains insufficiently explored. This study aimed to investigate the associations between systolic blood pressure (SBP) and in-hospital mortality among ICU patients with both CHF and COPD. Methods: This retrospective cohort study enrolled 6309 patients from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. SBP was examined as both a continuous and categorical variable, with the primary outcome being in-hospital mortality. The investigation involved multivariable logistic regression, restricted cubic spline regression, and subgroup analysis to determine the relationship between SBP and mortality. Results: The cohort consisted of 6309 patients with concurrent CHF and COPD (3246 females and 3063 males), with an average age of 73.0 ± 12.5 years. The multivariate analysis revealed an inverse association between SBP and in-hospital mortality, both as a continuous variable (odds ratio = 0.99 [95% CI, 0.99~1]) and as a categorical variable (divided into quintiles). Restricted cubic spline analysis demonstrated an L-shaped relationship between SBP and mortality risk (P nonlinearity < 0.001), with an inflection point at 99.479 mmHg. Stratified analyses further supported the robustness of this correlation. Conclusion: The relationship between SBP and in-hospital mortality in patients with both CHF and COPD follows an L-shaped pattern, with an inflection point at approximately 99.479 mmHg.


Assuntos
Pressão Sanguínea , Insuficiência Cardíaca , Mortalidade Hospitalar , Unidades de Terapia Intensiva , Doença Pulmonar Obstrutiva Crônica , Humanos , Masculino , Feminino , Estudos Retrospectivos , Doença Pulmonar Obstrutiva Crônica/mortalidade , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Idoso , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/diagnóstico , Pessoa de Meia-Idade , Unidades de Terapia Intensiva/estatística & dados numéricos , Fatores de Risco , Idoso de 80 Anos ou mais , Bases de Dados Factuais , Prognóstico , Análise Multivariada , Fatores de Tempo , Razão de Chances , Modelos Logísticos , Distribuição de Qui-Quadrado , Medição de Risco
2.
Mol Pharm ; 21(4): 1719-1728, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38411904

RESUMO

Therapeutic proteins with a high concentration and low viscosity are highly desirable for subcutaneous and certain local injections. The shape of a protein is known to influence solution viscosity; however, the precise quantification of protein shape and its relative impact compared to other factors like charge-charge interactions remains unclear. In this study, we utilized seven model proteins of varying shapes and experimentally determined their shape factors (v) based on Einstein's viscosity theory, which correlate strongly with the ratios of the proteins' surface area to the 2/3 power of their respective volumes, based on protein crystal structures resolved experimentally or predicted by AlphaFold. This finding confirms the feasibility of computationally estimating protein shape factors from amino acid sequences alone. Furthermore, our results demonstrated that, in high-concentration electrolyte solutions, a more spherical protein shape increases the protein's critical concentration (C*), the transition concentration beyond which protein viscosity increases exponentially relative to concentration increases. In summary, our work elucidates protein shape as a key determinant of solution viscosity through quantitative analysis and comparison with other contributing factors. This provides insights into molecular engineering strategies to optimize the molecular design of therapeutic proteins, thus optimizing their viscosity.


Assuntos
Anticorpos Monoclonais , Eletrólitos , Anticorpos Monoclonais/química , Viscosidade , Soluções/química
3.
Int J Hyperthermia ; 41(1): 2306818, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38403276

RESUMO

PURPOSE: To evaluate the safety and efficacy of indocyanine green fluorescence imaging for real-time guidance of laparoscopic thermal ablation in patients with liver cancer. MATERIALS AND METHODS: A total of 27 patients with 40 liver lesions underwent fluorescence-assisted laparoscopic ablation between January 2020 to March 2023. The sensitivity of indocyanine green (ICG)-fluorescence imaging, technique effectiveness rate and complications of fluorescence-assisted laparoscopic thermal ablation were evaluated. RESULTS: In total, 33 out of the 40 lesions were identified by ICG-fluorescence imaging technique, with the sensitivity of 82.5%. The sensitivity of ICG-fluorescence imaging of tumor detection in liver surface of parenchyma was significantly higher than that in the deeply located hepatic parenchyma (96.8% vs 33.3%, p = 0.002). ICG-fluorescence imaging procedures detected 4 lesions that cannot be seen on intraoperative ultrasound. It provides clear demarcation lines on the hepatic surface. Technical success is achieved if the necrotic zone had at least a 5 mm ablative margin around the outer edge of the ICG-fluorescence image. Technical success of fluorescence laparoscopic radiofrequency ablation (FLRFA) and fluorescence laparoscopic microwave ablation (FLMWA) was 100% (27/27). Technical effectiveness is defined by the complete necrotic lesions of the local tumor tissue during follow-up. According to the CT/MRI one month after FLRFA or FLMWA, the technical efficacy rate was 92.5% (37/40) and local tumor progression occurred in 7.5% (3/40) of the enrolled lesions. During the follow-up period, no major complications were observed. CONCLUSION: ICG-fluorescence imaging guided laparoscopic thermal ablation was feasible, safe and effective.


Assuntos
Laparoscopia , Neoplasias Hepáticas , Humanos , Verde de Indocianina , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/patologia , Laparoscopia/métodos , Imagem Óptica/métodos
4.
Adv Mater ; 36(5): e2308286, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37971203

RESUMO

Cancer represents a serious disease with significant implications for public health, imposing substantial economic burden and negative societal consequences. Compared to conventional cancer treatments, such as surgery and chemotherapy, energy-based therapies (ET) based on athermal and thermal ablation provide distinct advantages, including minimally invasive procedures and rapid postoperative recovery. Nevertheless, due to the complex pathophysiology of many solid tumors, the therapeutic effectiveness of ET is often limited. Nanotechnology offers unique opportunities by enabling facile material designs, tunable physicochemical properties, and excellent biocompatibility, thereby further augmenting the outcomes of ET. Numerous nanomaterials have demonstrated the ability to overcome intrinsic therapeutic resistance associated with ET, leading to improved antitumor responses. This comprehensive review systematically summarizes the underlying mechanisms of ET-associated resistance (ETR) and highlights representative applications of nanoplatforms used to mitigate ETR. Overall, this review emphasizes the recent advances in the field and presents a detailed account of novel nanomaterial designs in combating ETR, along with efforts aimed at facilitating their clinical translation.


Assuntos
Hipertermia Induzida , Nanoestruturas , Neoplasias , Humanos , Nanomedicina/métodos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Nanotecnologia/métodos , Nanoestruturas/uso terapêutico
5.
ACS Nano ; 17(19): 19441-19458, 2023 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-37733578

RESUMO

Radiofrequency ablation (RFA) is one of the most common minimally invasive techniques for treating hepatocellular carcinoma (HCC), which could destroy tumors through hyperthermia and generate massive tumor-associated antigens (TAAs). However, residual malignant tissues or small satellite lesions are hard to eliminate, generally resulting in metastases and recurrence. Herein, an advanced in situ nanovaccine formed by layered double hydroxides carrying cGAMP (STING agonist) (LDHs-cGAMP) and adsorbed TAAs was designed to potentiate the RFA-induced antitumor immune response. As-prepared LDHs-cGAMP could effectively enter cancerous or immune cells, inducing a stronger type I interferon (IFN-I) response. After further adsorption of TAAs, nanovaccine generated sustained immune stimulation and efficiently promoted activation of dendritic cells (DCs). Notably, infiltrations of cytotoxic lymphocytes (CTLs) and activated DCs in tumor and lymph nodes were significantly enhanced after nanovaccine treatment, which distinctly inhibited primary, distant, and metastasis of liver cancer. Furthermore, such a nanovaccine strategy greatly changed the tumor immune microenvironment and promoted the response efficiency of anti-programmed death ligand 1 (αPD-L1) immunotherapy, significantly arresting the poorly immunogenic hepa1-6 liver cancer progression. These findings demonstrate the potential of nanovaccine as a booster for RFA in liver cancer therapy and provide a promising in situ cancer vaccination strategy.

6.
Soft comput ; : 1-9, 2023 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-37362271

RESUMO

In recent years, the research on the domestic and international sports industry has made considerable achievements, but there are still some loopholes in the content, that is, there is still a vacancy in the comprehensive quantitative evaluation of the economic development of the sports industry, especially in the statistics of the output value of the sports industry, which lacks a comprehensive understanding of the economic development of the industry. In the state of dual demand research and application, it is still necessary to reveal the publicity and education of industrial scale, industrial structure, industrial function and industrial safety between people and industries, which is also a necessary way to develop the talent guarantee industry. In this work, we should establish an economic model related to the sports industry. It mainly applies the deep learning algorithm and data information mining technology. After allowing the extraction of information from the sports industry database, it is converted into an economic model of the sports industry. It uses scientific and efficient processing methods to analyze a large number of diverse data, in order to find the hidden laws and knowledge behind it. Therefore, this paper uses data mining technology to process and analyze the economic development data of sports industry in detail and conducts corresponding quantitative analysis according to the requirements of data development. Finally, this paper points out that the neural network in the deep learning algorithm has further training and learning on the economic data of the sports industry, which is convenient for the subsequent prediction of the economic development of the sports industry to make a greater breakthrough.

7.
Front Oncol ; 12: 891724, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35719978

RESUMO

Background: Radiofrequency ablation (RFA) destroys tumors through hyperthermic injury, which induces the release of immunogenic intracellular substrates and damages associated molecular patterns (DAMPs) to evoke a systemic immune response, but its therapeutic effect is limited. This study aimed to combine RFA with an immunomodulator, resiquimod (R848), to enhance the RFA-induced antitumor immunity. Methods: We performed RFA on subcutaneous tumors in immunocompetent mice and intraperitoneally injected R848 to observe the efficacy of the combination therapy. Our research investigated changes in the composition of tumor-infiltrating immune cells in primary and distant tumors by flow cytometry. Natural killer (NK) cell depletion experiment was applied to confirm the role of NK cell in the combination therapy. The expression levels of cytokines and chemokines were detected by real-time quantitative PCR. Immunohistochemical test was conducted to reveal tumor angiogenesis, tumor proliferation, and apoptosis after the different treatments. Results and Conclusion: Compared with RFA or R848 monotherapy, the combination therapy significantly slowed the tumor growth, prolonged the survival time, and shrank the tumor-draining lymph nodes of tumor-bearing mice. The flow cytometry results showed that tumor-infiltrating immune cells, total T cells, the ratio of CD8+ T and NK cells to CD45+ cells, and functional NK cells were obviously increased after the combined treatment. Distal tumor growth was also suppressed, and the profile of tumor-infiltrating immune cells was remodeled, too. In addition, the additive effect of the combination therapy disappeared after NK cell depletion. Furthermore, immunohistochemical results verified that R848 inhibited tumor angiogenesis in murine liver cancer, and the combination therapy promoted tumor cell apoptosis. In conclusion, our data suggest that RFA combined with R848 stimulated a stronger antitumor immune response and effectively inhibited liver cancer progression in a NK cell-dependent manner. Meanwhile, we confirmed that R848 inhibited tumor angiogenesis and promoted apoptosis in murine liver cancer. Overall, this is a promising therapeutic strategy to improve the efficacy of RFA in the treatment of liver cancer and provides a novel option for combined thermal ablation and immunotherapy.

8.
ACS Omega ; 7(18): 15507-15517, 2022 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-35571839

RESUMO

With energy savings and emission reduction becoming national policies in recent years, the environmental impacts of industrial production are more and more critical. Most of the studies have concentrated on the environmental effects of the industrial production process. Little attention has been paid to the energy consumption and pollution emission in extracting, processing, and transporting the feedstock and other secondary materials. An integrated multiobjective optimization framework is proposed for the steam cracking process on the basis of a life cycle assessment and data-driven modeling methods. A multiobjective economic-environmental optimization model is developed on the basis of industrial and simulated data. A multiobjective optimization model combined with energy cost is also developed for comparative study. The nondominated sorting genetic algorithm-II is utilized to solve the problems, and the Pareto front is obtained. An industrial case study is carried out to indicate the effectiveness of the proposed method. The results show that the LCA-based method can better represent the environmental impacts in comparison with the standard energy cost model. Therefore, the proposed method can achieve a better tradeoff between economic benefits and environmental impacts for guiding ethylene production.

9.
Chem Commun (Camb) ; 58(35): 5363-5366, 2022 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-35411363

RESUMO

A catalytic asymmetric construction of the bispiro[pyrazolone-dihydropyrrole-oxindole] skeleton catalyzed by chiral DMAP-derived catalyst was successfully achieved by employing recently explored pyrazolone-derived MBH carbonate in high yields with excellent stereoselectivities. The proposed transition state indicated that the intermolecular hydrogen bonds and π-π interactive forces played an essential role in stereoselective chemical transformation.


Assuntos
Pirazolonas , Carbonatos , Catálise , Reação de Cicloadição , Estrutura Molecular , Oxindóis , Pirróis , Esqueleto , Estereoisomerismo
10.
Clin Microbiol Infect ; 27(4): 576-582, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32553881

RESUMO

OBJECTIVE: The aim was to evaluate the efficacy, safety and completion rate of 3-month, once-weekly rifapentine and isoniazid for tuberculosis (TB) prevention among Chinese silicosis patients. METHODS: Male silicosis patients without human immunodeficiency virus infection, aged 18 years to 65 years, with or without latent TB infection, were randomized 1:1 to receive rifapentine/isoniazid under direct observation (3RPT/INH group) or were untreated (observation group). Active TB incidence was compared between the two groups with 37 months of follow-up. Safety profile and complete rates were evaluated. RESULTS: A total of 1227 adults with silicosis were screened; 513 eligible participants were enrolled and assigned to 3RPT/INH (n = 254) vs. observation (n = 259). Twenty-eight participants were diagnosed with active TB, and 9 and 19 in the 3RPT/INH group and observation groups, respectively. In the intention-to-treat analysis, the cumulative active TB rate was 3.5% (9/254) in the 3RPT/INH group and 7.3% (19/259) in the observation group (log rank p 0.055). On per protocol analysis, the cumulative active TB rates were 0.7% (1/139) and 7.3% (19/259), respectively (log rank p 0.01). Owing to an unexpected high frequency of adverse events (70.4%) and Grade 3 or 4 AEs (7.9%), the completion rate of the 3RPT/INH regimen was 54.7% (139/254). Twenty-six (10.8%) participants had flu-like systemic drug reactions; five (2.1%) experienced hepatotoxicity. DISCUSSION: Weekly rifapentine/isoniazid prophylaxis prevented active TB among Chinese people with silicosis when taken, irrespective of LTBI screening; efficacy was reduced by lack of compliance. The regimen must be used with caution because of the high rates of adverse effects. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov number: NCT02430259.


Assuntos
Antituberculosos/farmacologia , Isoniazida/farmacologia , Rifampina/análogos & derivados , Silicose/complicações , Tuberculose Pulmonar/prevenção & controle , Antituberculosos/administração & dosagem , Área Sob a Curva , China , Esquema de Medicação , Meia-Vida , Humanos , Isoniazida/administração & dosagem , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Rifampina/administração & dosagem , Rifampina/farmacocinética , Rifampina/farmacologia , Tuberculose Pulmonar/complicações
11.
Curr Med Imaging ; 17(3): 374-383, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32652919

RESUMO

PURPOSE: Both CT and PET radiomics is considered as a potential prognostic biomarker in head and neck cancer. This study investigates the value of fused pre-treatment functional imaging (18F-FDG PET/CT) radiomics for modeling of local recurrence of head and neck cancers. MATERIALS AND METHODS: Firstly, 298 patients have been divided into a training set (n = 192) and verification set (n = 106). Secondly, PETs and CTs are fused based on wavelet transform. Thirdly, radiomics features are extracted from the 3D tumor area from PETCT fusion. The training set is used to select the features reduction and predict local recurrence, and the random forest prediction models combining radiomics and clinical variables are constructed. Finally, the ROC curve and KM analysis are used to evaluate the prediction efficiency of the model on the validation set. RESULTS: Two PET/CT fusion radiomics features and three clinic parameters are extracted to construct the radiomics model. AUC value in the verification set 0.70 is better than no fused sets 0.69. The accuracy of 0.66 is not the highest value (0.67). Either consistency index CI 0.70 (from 0.67 to 0.70) or the p-value 0.025 (from 0.03 to 0.025) get the best result in all four models. CONCLUSION: The radiomics model based on the fusion of PETCT is better than the model based on PET or CT alone in predicting local recurrence, the inclusion of clinical parameters may result in more accurate predictions, which has certain guiding significance for the development of personalized, precise treatment scheme.


Assuntos
Neoplasias de Cabeça e Pescoço , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Fluordesoxiglucose F18 , Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Humanos , Recidiva Local de Neoplasia/diagnóstico por imagem , Tomografia por Emissão de Pósitrons
12.
Mol Pharm ; 18(1): 267-274, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33307701

RESUMO

Adenosine triphosphate (ATP) is amphiphilic in nature and has the characteristics of a hydrotrope because of the charged triphosphate moiety and the large aromatic ring located on each end of its structure. Previous studies revealed that ATP can effectively maintain the solubility and prevent liquid-liquid phase separation (LLPS) of some biological proteins. In this study, we assessed the impact of ATP on the stability of a model therapeutic IgG1 antibody (MA1) to evaluate its potential application in protein formulation design. In our system, ATP promotes rapid LLPS of MA1 and we demonstrate that the ATP-MA1 static interaction drives phase separation of MA1. The attractive protein-protein interaction increased exclusively in the presence of ATP but not in the presence of other ATP analogues, such as adenosine diphosphate, adenosine monophosphate, and adenine. Through an intrinsic fluorescence quenching study, we revealed that ATP bound to MA1 electrostatically and formed static interactions; furthermore, such static ATP-MA1 interactions significantly altered the surface property of the protein and the protein-protein interactions and subsequently induced LLPS of MA1. This ATP-induced LLPS could be effectively eliminated by Mg2+, which chelated with ATP and thus negated ATP-MA1 static interaction. Our results revealed the unique molecular mechanism of ATP-induced rapid LLPS of MA1.


Assuntos
Trifosfato de Adenosina/química , Anticorpos Monoclonais/química , Imunoglobulina G/química , Adenina/química , Difosfato de Adenosina/química , Monofosfato de Adenosina/química , Concentração de Íons de Hidrogênio , Extração Líquido-Líquido/métodos , Mapas de Interação de Proteínas/efeitos dos fármacos , Eletricidade Estática
13.
J Phys Chem B ; 124(44): 9773-9784, 2020 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-33089692

RESUMO

Stabilizing G-quadruplex (G4) structures formed in the c-MYC oncogene promoter represents a fundamental strategy for cancer therapy. However, most G4 stabilizers lack selectivity over various G4s in the genomes. By investigating the binding characteristics of a conjugated imidazole/carbazole (IZCZ-3) molecule with the G4s of c-MYC, c-KIT, and telomere through molecular docking and molecular dynamics simulations, the present study demonstrates that though the binding affinities between IZCZ-3 and the monomeric G4s are inconsistent with the experimental data, the dimeric c-MYC and c-KIT G4s can be targeted by IZCZ-3 through forming concomitant π-π stacking interactions with the intermolecular assembly producing significant contributions to the binding affinity. In the intermolecular dimeric G4-IZCZ-3 binding complexes, IZCZ-3 prefers the c-MYC G4 that has two exposed G-tetrads per monomer over the single G-tetrad-exposed c-KIT G4 by creating more aggregation effects. Taking the aggregation effects into account, the binding affinity order of IZCZ-3 follows c-MYC G4 > c-KIT G4 > telomeric G4, agreeing well with the experimental observation. Thus, the selectivity of IZCZ-3 for c-MYC G4 probably comes from its role in stabilizing the sandwichlike intermolecular aggregates, providing a framework for the development of selective stabilizers targeting c-MYC G4.


Assuntos
Quadruplex G , Simulação de Dinâmica Molecular , Ligantes , Simulação de Acoplamento Molecular , Telômero/genética
14.
Can J Infect Dis Med Microbiol ; 2020: 4783062, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33062082

RESUMO

OBJECTIVE: To explore the clinical characteristics of patients with different severity in the early outbreak of COVID-19, hoping to provide reference for clinical diagnosis and treatment. METHODS: We retrospectively analyzed the clinical data of 95 COVID-19 patients in Wuhan Red Cross Hospital of China from January 17 to February 13, 2020. All patients were investigated with epidemiological questionnaires. Outcomes were followed up until April 1, 2020. RESULTS: There were 53 males and 42 females, aged 22-84 years (mean 57.3 years). Clinical classification included 54 cases of common type, 27 cases of severe type, and 14 cases of critical type. Six patients had been exposed to the local Huanan seafood market. There were 38 clusters of COVID-19, including 27 family clusters and 11 work unit clusters. Common symptoms included fever (86 (90.5%) of 95), cough (73 (76.8%)), and fatigue (50 (52.6%)). Laboratory findings showed that the most common abnormalities were lymphopenia (75 (78.9%)), elevated D-dimer (60 (63.2%)), and elevated C-reactive protein (56 (58.9%)) on admission. All patients had abnormal chest computed tomography, showing patchy shadows or ground-glass opacities. Severe and critical cases were older, more likely to have shortness of breath, more likely to have underlying comorbidities, and more likely to have abnormal laboratory findings than common cases. The prognosis of patients with different degrees of severity was significantly different. All common and severe patients (100%) were cured and discharged from the hospital, while 10 (71.4%) of 14 critical patients died. CONCLUSIONS: COVID-19 has fast transmission speed and high pathogenicity. We must assess the severity of the disease and take corresponding treatment measures as early as possible.

15.
Int J Pharm ; 588: 119681, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32721563

RESUMO

Although protein aggregation is commonly encountered during the manufacturing and storage of bio-therapeutics, the actual aggregation mechanism remains unclear, and little has been reported about the protein aggregation kinetics from time zero under particular solution conditions. In this study, we used real-time dynamic light scattering (DLS) to continuously monitor the time-dependent evolution of the Z-average hydrodynamic radius of a model IgG1 (JM2) immediately after the JM2 solution was subjected to various low temperatures (0-4 °C). We observed that JM2 aggregated to form nuclei first, and then it subsequently grew to small liquid droplets via a two-step, first-order, reversible process without causing irreversible structural changes: a slow first step defined as the "nucleation" step, wherein nuclei formed slowly until reaching a transitional time point (tonset), and a much faster second step initiated after tonset and the nucleus size of the protein increased rapidly, which eventually caused liquid droplet formation and liquid-liquid phase separation (LLPS). The "nucleation" rate constant (Knucleation) and particle growth rate constant (Kgrowth), as well as tonset, were found to be temperature, pH and concentration dependent. The aggregation of JM2 could be universally described by these two-step first-order kinetics: under conditions where JM2 aggregated very slowly, the second step was not observed within the experimental time scale, while under conditions where JM2 aggregated very rapidly, the first step could not be recorded. We believe that these three parameters, Knucleation, Kgrowth, and tonset, can be used to quantify and compare the aggregation kinetics of JM2 under different solution and temperature conditions and, furthermore, serve as a theoretical base to account for the key characteristics of the aggregation kinetics of JM2 and other protein therapeutics under conditions of interest.


Assuntos
Anticorpos Monoclonais/química , Imunoglobulina G/química , Difusão Dinâmica da Luz , Concentração de Íons de Hidrogênio , Cinética , Modelos Teóricos , Agregados Proteicos , Estabilidade Proteica , Temperatura
16.
RSC Adv ; 9(53): 31070-31077, 2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-35529355

RESUMO

Au/CeO2 was demonstrated to be a high efficiency catalyst for the conversion of 2-phenoxyacetophenol (PP-ol) employing O2 as an oxidant and methyl alcohol as the solvent without using an erosive strong base or acid. Mechanistic investigations, including emission quenching experiments, electron spin-resonance (ESR) and intermediate verification experiments, were carried out. The results verified that the superoxide anion activated by Au/CeO2 from molecular oxygen plays a vital role in the oxidation of lignin model compounds, and the cleavage of both the ß-O-4 and Cα-Cß linkages was involved. Au/CeO2 also performed well in the oxidative conversion of organosolv lignin under mild conditions (453 K), producing vanillin (10.5 wt%), methyl vanillate (6.8 wt%), methylene syringate (3.4 wt%) and a ring-opened product. Based on the detailed characterization data and mechanistic results, Au/CeO2 was confirmed to be a promising catalytic system.

18.
Eur J Pharm Biopharm ; 120: 1-8, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28754261

RESUMO

Liquid-liquid phase separation (LLPS) has long been observed during the physical stability investigation of therapeutic protein formulations. The buffer conditions and the presence of various excipients are thought to play important roles in the formulation development of monoclonal antibodies (mAbs). In this study, the effects of several small-molecule excipients (histidine, alanine, glycine, sodium phosphate, sodium chloride, sorbitol and sucrose) with diverse physical-chemical properties on LLPS of a model IgG1 (JM2) solutions were investigated by multiple techniques, including UV-vis spectroscopy, circular dichroism, differential scanning calorimetry/fluorimetry, size exclusion chromatography and dynamic light scattering. The LLPS of JM2 was confirmed to be a thermodynamic equilibrium process with no structural changes or irreversible aggregation of proteins. Phase diagrams of various JM2 formulations were constructed, suggesting that the phase behavior of JM2 was dependent on the solution pH, ionic strength and the presence of other excipients such as glycine, alanine, sorbitol and sucrose. Furthermore, we demonstrated that for this mAb, the interaction parameter (kD) determined at low protein concentration appeared to be a good predictor for the occurrence of LLPS at high concentration.


Assuntos
Anticorpos Monoclonais/química , Excipientes/química , Soluções Farmacêuticas/química , Mapas de Interação de Proteínas/fisiologia , Proteínas/química , Varredura Diferencial de Calorimetria/métodos , Química Farmacêutica/métodos , Dicroísmo Circular/métodos , Concentração de Íons de Hidrogênio , Extração Líquido-Líquido/métodos , Concentração Osmolar , Bibliotecas de Moléculas Pequenas/química , Termodinâmica , Raios Ultravioleta
19.
Int J Pharm ; 530(1-2): 173-186, 2017 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-28755991

RESUMO

Recently, increasing research efforts have been devoted into developing high-concentration protein drugs for subcutaneous injection, especially for those with short half-lives and high-dose requirement. Proteins at high concentrations normally present increased colloidal and structural instability, such as aggregation, fibrillation and gelation, which significantly challenges the high-concentration formulation development of protein drugs. Here we used endostatin, a 20kD recombinant protein, as a model drug for high-concentration formulation optimization. The colloidal and conformational stability of endostatin at high concentration of 30mg/mL were investigated in formulations containing various excipients, including saccharides (mannitol, sorbitol and sucrose), salts (ArgHCl and NaCl), and surfactants (tween 20 and 80). Protein fibrillation was characterized and semi-quantified by optical polarized light microscopy and transmission electron microscopy, and the amount of fiber formation at elevated temperature of 40°C was determined. The soluble protein aggregates were characterized by dynamic and static light scattering before and after dilution. The conformational stability were characterized by polyacrylamide gel electrophoresis, fluorescence, circular dichroism, and differential scanning calorimetry. We observed that the soluble aggregation, fibrillation and gelation, induced by conformational and colloidal instabilities of the protein solution, could be substantially optimized by using suitable stabilizers such as combinations of saccharides and surfactants; while formation of gel and soluble aggregates at high protein concentration (e.g., 30mg/mL) and elevated temperature (40°C) could be prevented by avoiding the usage of salts. It's worth emphasizing that some stabilizers, such as salts and surfactants, could show opposite contributions in conformational and colloidal stabilities of endostatin. Therefore, cautions are needed when one attempts to correlate the colloidal stability of high-concentration proteins with their conformational stability, and the colloidal and conformational protein stabilities must be harmonized by a balanced selection of various types of excipients.


Assuntos
Composição de Medicamentos , Endostatinas/química , Excipientes/química , Química Farmacêutica , Estabilidade Proteica
20.
J Environ Sci (China) ; 57: 196-210, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28647240

RESUMO

Minimizing soil ammonia (NH3) and nitrous oxide (N2O) emission factors (EFs) has significant implications in regional air quality and greenhouse gas (GHG) emissions besides nitrogen (N) nutrient loss. The aim of this study was to investigate the impacts of different N fertilizer treatments of conventional urea, polymer-coated urea, ammonia sulfate, urease inhibitor (NBPT, N-(n-butyl) thiophosphoric triamide)-treated urea, and nitrification inhibitor (DCD, dicyandiamide)-treated urea on emissions of NH3 and GHGs from subtropical wheat cultivation. A field study was established in a Cancienne silt loam soil. During growth season, NH3 emission following N fertilization was characterized using active chamber method whereas GHG emissions of N2O, carbon dioxide (CO2), and methane (CH4) were by passive chamber method. The results showed that coated urea exhibited the largest reduction (49%) in the EF of NH3-N followed by NBPT-treated urea (39%) and DCD-treated urea (24%) over conventional urea, whereas DCD-treated urea had the greatest suppression on N2O-N (87%) followed by coated urea (76%) and NBPT-treated urea (69%). Split fertilization of ammonium sulfate-urea significantly lowered both NH3-N and N2O-N EF values but split urea treatment had no impact over one-time application of urea. Both NBPT and DCD-treated urea treatments lowered CO2-C flux but had no effect on CH4-C flux. Overall, application of coated urea or urea with NPBT or DCD could be used as a mitigation strategy for reducing NH3 and N2O emissions in subtropical wheat production in Southern USA.


Assuntos
Agricultura/métodos , Poluentes Atmosféricos/análise , Fertilizantes , Triticum/crescimento & desenvolvimento , Amônia/análise , Dióxido de Carbono/análise , Efeito Estufa , Metano/análise , Nitrogênio/análise , Óxido Nitroso/análise , Solo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA