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1.
J Neurooncol ; 151(2): 313-324, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33394265

RESUMO

PURPOSE: Acromegaly is a rare neuroendocrine condition that can lead to significant morbidity. Despite China's vast population size, studies on acromegaly remain sparse. This study aimed to investigate the clinical characteristics and predictors of biochemical remission after surgery for acromegaly using the China Acromegaly Patient Association (CAPA) database. METHODS: A retrospective nationwide study was conducted using patient-reported data from CAPA database between 1998 and 2018. The principal component analysis (PCA) and logistic regression analysis were employed to determine independent predictors of biochemical remission at 3 months in patients after surgery. RESULTS: Of the 546 surgical cases (mean age: 36.8 years; 59.5% females), macroadenomas and invasive tumors (Knosp score 3-4) were 83.9% and 64.1%, respectively. Ninety-five percent of patients were treated with endonasal surgery and 36.8% exhibited biochemical remission at 3-months postoperatively. The following independent predictors of biochemical remission were identified: preoperative growth hormone (GH) levels between 12 and 28 µg/L [odds ratio (OR) = 0.58; 95% confidence interval (CI), 0.37-0.92; p = 0.021], preoperative GH levels > 28 µg/L (OR = 0.55; 95% CI, 0.34-0.88; p = 0.013), macroadenoma (OR = 0.56; 95% CI, 0.32-0.96; p = 0.034), giant adenomas (OR = 0.14; 95% CI, 0.05-0.38; p < 0.001), Knosp score 3-4 (OR = 0.37; 95% CI, 0.24-0.57; p < 0.001), and preoperative medication usage (OR = 2.32; 95% CI, 1.46-3.70; p < 0.001). CONCLUSIONS: In this nationwide study spanning over two decades, we highlight that higher preoperative GH levels, large tumor size, and greater extent of tumor invasiveness are associated with a lower likelihood of biochemical remission at 3-months after surgery, while preoperative medical therapy increases the chance of remission.

2.
Ther Apher Dial ; 2020 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-33012089

RESUMO

HD care may experience great stress with the coronavirus disease 2019 (COVID-19) pandemic. A modified HD modality named bed-sided short-duration renal replacement therapy (BSRRT) was used in noncritical maintenance HD (MHD) patients diagnosed with COVID-19 in Wuhan due to extreme situation. To determine the safety and efficacy as a substitution for intermittent HD (IHD), we conducted this study. We used the data of 88 noncritical COVID-19 MHD patients collected from 65 medical units at the hospitals in Wuhan, China, from January 1 to March 10, 2020. t-test, Wilcoxon rank sum test, and Fisher exact probability method were used to compare the baseline characteristics, treatment, and death. Log-rank test and Cox regression multivariate analysis was used to compare the survival of noncritical patients who were transferred to BSRRT modality versus those who were continued on the IHD. Univariate analysis showed the level of reported fatigue symptom at present, bilateral lung computed tomography infiltration and steroid treatment differed between the two groups. The outcome of death of the two groups did not show significant differences in univariate analysis (P = .0563). Multivariate Cox regression analysis dialysis showed modality of treatment after COVID-19 diagnosis was not a significant predictor of death (P = .1000). These data suggest that for noncritical COVID-19 MHD patients, the transfer from IHD to BSRRT does not have significant difference in the risk of death compared with IHD group. This finding suggests this modified modality could be an option for the substitution for IHD during the COVID-19 pandemic period.

4.
Eur J Pharmacol ; 889: 173493, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-32860808

RESUMO

Gastric cancer (GC) is one of the most common malignant neoplasms of the digestive system, with China leading in terms of morbidity and mortality rates. Betulinic acid (BA) is a widely-occurring pentacyclic triterpenoid that has been reported to exhibit potent anti-inflammatory, antioxidant, and antitumor activities. BA can combat tumors by inducing apoptosis, regulating cell cycle, and inhibiting autophagy, but its mechanism of action in the context of GC is unclear. A preliminary study found that higher expression of vasodilator-stimulated phosphoprotein (VASP) was correlated with migration in the GC cell line. In this study, BGC-823 cells and MNK45 cells were treated with BA for investigating its effect on the proliferation and migration of cells. Moreover, the expression of VASP and upstream signal molecules were also investigated in this background. The results showed BA could inhibit the proliferation and migration the GC cells. Furthermore, NF-κB acted as a transcription factor to upregulate VASP expression. Moreover, BA could downregulate the expression of VASP at the protein and mRNA level by inhibiting NF-κB activity. In conclusion, these results suggest that BA could inhibit the expression of VASP by negatively regulating NF-κB, thereby inhibiting the proliferation and migration of the GC cells. Our study provides a theoretical basis for exploring the molecular mechanism underlying BA-induced inhibition of proliferation and migration in GC cells.

5.
J Med Chem ; 63(12): 6407-6422, 2020 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-32352779

RESUMO

After two decades teetering at the intersection of laboratory tool and therapeutic reality, with two siRNA drugs now clinically approved, this modality has finally come into fruition. Consistent with other emerging modalities, initial proof-of-concept efforts concentrated on coupling pharmacologic efficacy with desirable safety profiles. Consequently, thorough investigations of siRNA absorption, distribution, metabolism, and excretion (ADME) properties are lacking. Advancing ADME knowledge will aid establishment of in vitro-in vivo correlations and pharmacokinetic-pharmacodynamic relationships to optimize candidate selection through discovery and translation. Here, we outline the emerging siRNA design principles and discuss the consequences for siRNA disposition and biotransformation. We propose a conceptual framework for siRNA ADME evaluation, contextualizing the site of biotransformation product formation with PK-PD modulation, and end with a discussion around safety and regulatory considerations and future directions for this modality.


Assuntos
Biotransformação , Desenho de Fármacos , Desenvolvimento de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Preparações Farmacêuticas/química , RNA Interferente Pequeno/química , Animais , Humanos , Preparações Farmacêuticas/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacocinética , Distribuição Tecidual
6.
J Am Soc Nephrol ; 31(7): 1387-1397, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32385130

RESUMO

BACKGROUND: Reports indicate that those most vulnerable to developing severe coronavirus disease 2019 (COVID-19) are older adults and those with underlying illnesses, such as diabetes mellitus, hypertension, or cardiovascular disease, which are common comorbidities among patients undergoing maintenance hemodialysis. However, there is limited information about the clinical characteristics of hemodialysis patients with COVID-19 or about interventions to control COVID-19 in hemodialysis centers. METHODS: We collected data retrospectively through an online registration system that includes all patients receiving maintenance hemodialysis at 65 centers in Wuhan, China. We reviewed epidemiologic and clinical data of patients with laboratory-confirmed COVID-19 between January 1, 2020 and March 10, 2020. RESULTS: Of 7154 patients undergoing hemodialysis, 154 had laboratory-confirmed COVID-19. The mean age of the 131 patients in our analysis was 63.2 years; 57.3% were men. Many had underlying comorbidities, with cardiovascular disease (including hypertension) being the most common (68.7%). Only 51.9% of patients manifested fever; 21.4% of infected patients were asymptomatic. The most common finding on chest computed tomography (CT) was ground-grass or patchy opacity (82.1%). After initiating comprehensive interventions-including entrance screening of body temperature and symptoms, universal chest CT and blood tests, and other measures-new patients presenting with COVID-19 peaked at 10 per day on January 30, decreasing to 4 per day on February 11. No new cases occurred between February 26 and March 10, 2020. CONCLUSIONS: We found that patients receiving maintenance hemodialysis were susceptible to COVID-19 and that hemodialysis centers were high-risk settings during the epidemic. Increasing prevention efforts, instituting universal screening, and isolating patients with COVID-19 and directing them to designated hemodialysis centers were effective in preventing the spread of COVID-19 in hemodialysis centers.


Assuntos
Infecções por Coronavirus/epidemiologia , Suscetibilidade a Doenças/epidemiologia , Falência Renal Crônica/epidemiologia , Pneumonia Viral/epidemiologia , Sistema de Registros , Diálise Renal/métodos , Fatores Etários , Idoso , Distribuição de Qui-Quadrado , China/epidemiologia , Comorbidade , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/terapia , Feminino , Humanos , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/terapia , Prevalência , Radiografia Torácica/métodos , Diálise Renal/estatística & dados numéricos , Estudos Retrospectivos , Medição de Risco , Fatores Sexuais , Estatísticas não Paramétricas , Análise de Sobrevida , Tomografia Computadorizada por Raios X/métodos
7.
Medicine (Baltimore) ; 99(12): e19038, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32195929

RESUMO

Conventional levator aponeurosis plication is a widely accepted technique for correction of mild to moderate ptosis. However, this method is associated with a high recurrence rate. The objective of this study was to investigate the clinical efficacy of levator aponeurosis posterior layer plication technique for correction of mild to moderate ptosis.A convenience sampling approach was used to recruit 450 patients with mild to moderate blepharoptosis at the Guangzhou Eye-Nose-Face Aesthetic Plastic Surgery Hospital between August, 2015 and December, 2017. All participants were treated with levator aponeurosis posterior layer plication technique. The primary outcome was the postoperative change in marginal reflex distance 1 (MRD1). The paired t test was used to determine the clinical efficacy. Outcomes were assessed at 1 week, 1 month, 3 months, and 6 months after surgery.The mean preoperative MRD1 was 1.7 ±â€Š0.5 mm, and the mean postoperative MRD1 at 6-month follow-up was 3.7 ±â€Š0.4 mm (P < .0001). According to the postoperative survey, 427 (94.9%) patients were satisfied with surgical outcomes.This modified levator aponeurosis plication technique is a simple and effective procedure for correction of mild to moderate blepharoptosis. It results in good MRD1 and high patient satisfaction.


Assuntos
Blefaroptose/cirurgia , Procedimentos Cirúrgicos Oftalmológicos/métodos , Adolescente , Adulto , Aponeurose/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Adulto Jovem
8.
Biomed Res Int ; 2020: 1874387, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32104680

RESUMO

Objective: To explore the ability of asiatic acid to interfere with the invasion and proliferation of breast cancer cells by inhibiting WAVE3 expression and activation through the PI3K/AKT signaling pathway. Methods: The MDA-MB-231 cells with strong invasiveness were screened by transwell assay, and plasmids with high expression of WAVE3 were constructed for transfection. The transfection effect and protein expression level of plasmids were verified by PCR and WB. The effects of asiatic acid on cell proliferation and invasion were investigated by flow cytometry. The xenografted tumor models in nude mice were established to study the antitumor activity of asiatic acid. Results: Asiatic acid significantly inhibited the activity of MDA-MB-231 cells, and the expression level of WAVE3 increased significantly in the tissue of ductal carcinoma in situ and was lower than that in the metastasis group. After plasmid transfection, the mRNA and protein expression of WAVE3 increased significantly in the cells. Asiatic acid at different concentrations had an impact on cell apoptosis and invasion and could significantly inhibit the expression of WAVE3, P53, p-PI3K, p-AKT, and other proteins. The T/C(%) of asiatic acid (50 mg/kg) for MDA-MB-231(F10) xenografted tumor in nude mice was 46.33%, with a tumor inhibition rate of 59.55%. Asiatic acid could significantly inhibit the growth of MDA-MB-231 (F10) xenografted tumors in nude mice (p < 0.05). Conclusions: Asiatic acid interferes with the ability of breast cancer cells to invade and proliferate by inhibiting WAVE3 expression and activation and the mechanism of action may be related to the PI3K/AKT signaling pathway.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Triterpenos Pentacíclicos/farmacologia , Família de Proteínas da Síndrome de Wiskott-Aldrich/genética , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Proteína Oncogênica v-akt/genética , Fosfatidilinositol 3-Quinases/genética , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Glycobiology ; 30(6): 374-381, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-31965157

RESUMO

An in vitro gut-immune co-culture model with apical and basal accessibility, designed to more closely resemble a human intestinal microenvironment, was employed to study the role of the N-linked protein glycosylation pathway in Campylobacter jejuni pathogenicity. The gut-immune co-culture (GIC) was developed to model important aspects of the human small intestine by the inclusion of mucin-producing goblet cells, human enterocytes and dendritic cells, bringing together a mucus-containing epithelial monolayer with elements of the innate immune system. The utility of the system was demonstrated by characterizing host-pathogen interactions facilitated by N-linked glycosylation, such as host epithelial barrier functions, bacterial invasion and immunogenicity. Changes in human intestinal barrier functions in the presence of 11168 C. jejuni (wildtype) strains were quantified using GICs. The glycosylation-impaired strain 11168 ΔpglE was 100-fold less capable of adhering to and invading this intestinal model in cell infectivity assays. Quantification of inflammatory signaling revealed that 11168ΔpglE differentially modulated inflammatory responses in different intestinal microenvironments, suppressive in some but activating in others. Virulence-associated outer membrane vesicles produced by wildtype and 11168ΔpglE C. jejuni were shown to have differential composition and function, with both leading to immune system activation when provided to the gut-immune co-culture model. This analysis of aspects of C. jejuni infectivity in the presence and absence of its N-linked glycome is enabled by application of the gut-immune model, and we anticipate that this system will be applicable to further studies of C. jejuni and other enteropathogens of interest.

10.
Lab Chip ; 20(3): 446-467, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-31932816

RESUMO

Over the last decade, progress has been made on the development of microphysiological systems (MPS) for absorption, distribution, metabolism, and excretion (ADME) applications. Central to this progress has been proof of concept data generated by academic and industrial institutions followed by broader characterization studies, which provide evidence for scalability and applicability to drug discovery and development. In this review, we describe some of the advances made for specific tissue MPS and outline the desired functionality for such systems, which are likely to make them applicable for practical use in the pharmaceutical industry. Single organ MPS platforms will be valuable for modelling tissue-specific functions. However, dynamic organ crosstalk, especially in the context of disease or toxicity, can only be obtained with the use of inter-linked MPS models which will enable scientists to address questions at the intersection of pharmacokinetics (PK) and efficacy, or PK and toxicity. In the future, successful application of MPS platforms that closely mimic human physiology may ultimately reduce the need for animal models to predict ADME outcomes and decrease the overall risk and cost associated with drug development.

11.
Plant Signal Behav ; 14(7): 1607465, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31055999

RESUMO

Glucose is an important building component in organisms and a central molecule of energy metabolism. It is also a key signaling molecule involved in regulation of many physiologic processes, including organism morphogenesis, anabolism and catabolism, pest and disease stress, environmental stress response. The signal transduction pathway mediated by heterotrimeric G proteins is one of the most important pathways for Arabidopsis to recognize, perceive and transduce external stimuli. AtRGS1 (Arabidopsis thaliana regulator of G-protein signaling) metabolism is currently thought to be through endosome.This paper introduces relationship between autophagy and RGS1.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/citologia , Arabidopsis/metabolismo , Autofagia , Glucose/metabolismo , Proteínas RGS/metabolismo , Transdução de Sinais
12.
Mol Biol Evol ; 36(5): 875-889, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30861529

RESUMO

The occurrence of parallel speciation strongly implies the action of natural selection. However, it is unclear how general a phenomena parallel speciation is since it was only shown in a small number of animal species. In particular, the adaptive process and mechanisms underlying the process of parallel speciation remain elusive. Here, we used an integrative approach incorporating population genomics, common garden, and crossing experiments to investigate parallel speciation of the wild rice species Oryza nivara from O. rufipogon. We demonstrated that O. nivara originated multiple times from different O. rufipogon populations and revealed that different O. nivara populations have evolved similar phenotypes under divergent selection, a reflection of recurrent local adaptation of ancient O. rufipogon populations to dry habitats. Almost completed premating isolation was detected between O. nivara and O. rufipogon in the absence of any postmating barriers between and within these species. These results suggest that flowering time is a "magic" trait that contributes to both local adaptation and reproductive isolation in the origin of wild rice species. Our study thus demonstrates a convincing case of parallel ecological speciation as a consequence of adaptation to new environments.


Assuntos
Especiação Genética , Oryza/genética , Adaptação Biológica , Ásia Sudeste , Ásia Ocidental , Ecossistema , Fenótipo , Filogeografia , Polimorfismo de Nucleotídeo Único , Isolamento Reprodutivo , Seleção Genética , Sequenciamento Completo do Genoma
13.
FASEB J ; 33(6): 7037-7048, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30870006

RESUMO

The effective therapeutic approach of cerebral infarction is limited because of its underlying complexity. Recently, multiple long noncoding RNAs (lncRNAs) have been identified in the pathogenesis of cerebral infarction. Here, the current study aims to explore the interaction among lncRNA cyclin-dependent kinase inhibitor-2B-antisense RNA 1 (CDKN2B-AS1), transcription factor B-cell lymphoma/leukemia 11A (BCL11A), and MAPKK kinase kinase 1 (MAP4K1) and further investigate whether they affect cerebral infarction progression. The expression of CDKN2B-AS1, BCL11A, and MAP4K1 was altered in lymphocytes extracted from patients with cerebral infarction. In order to identify their roles in regulatory T (Treg) cells, the proliferation and apoptosis of the CD4+CD25+ Treg cells were examined, and levels of IL-4, IL-10, and TGF-ß were determined. Also, the RNA crosstalk among CDKN2B-AS1, BCL11A, and MAP4K1 was validated. Finally, we established a rat model of middle cerebral arterial occlusion to evaluate the neurologic impairment and cerebral infarction volume. The results revealed that lymphocytes in patients with cerebral infarction presented with the up-regulated expression of CDKN2B-AS1. Moreover, BCL11A could specifically bind to CDKN2B-AS1 and MAP4K1 promoter so as to inhibit MAP4K1. Moreover, it was observed that down-regulated CDKN2B-AS1 inhibited CD4+CD25+ Treg-cell proliferation, reduced levels of IL-4, IL-10, and TGF-ß and cerebral infarction volume, and elevated MAP4K1 expression. Collectively, our study provides evidence that CDKN2B-AS1 silencing could increase MAP4K1 expression to inhibit the CD4+CD25+ Treg-cell proliferation by reducing enrichment of transcription factor BCL11A, thereby protecting against cerebral infarction progression, highlighting a promising therapeutic strategy for treating cerebral infarction.-Lei, J.-J., Li, H.-Q., Mo, Z.-H., Liu, K.-J., Zhu, L.-J., Li, C.-Y., Chen, W.-L., Zhang, L. Long noncoding RNA CDKN2B-AS1 interacts with transcription factor BCL11A to regulate progression of cerebral infarction through mediating MAP4K1 transcription.


Assuntos
Proteínas Serina-Treonina Quinases/metabolismo , RNA Longo não Codificante/metabolismo , Proteínas Repressoras/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Estudos de Casos e Controles , Infarto Cerebral , Feminino , Inativação Gênica , Humanos , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Ligação Proteica , Proteínas Serina-Treonina Quinases/genética , RNA Longo não Codificante/genética , Ratos , Proteínas Repressoras/genética , Linfócitos T Reguladores/metabolismo , Regulação para Cima
14.
Neural Regen Res ; 14(6): 1004-1012, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30762012

RESUMO

When watching someone performs an action, mirror neurons are activated in a way that is very similar to the activation that occurs when actually performing that action. Previous single-sample case studies indicate that hand-action observation training may lead to activation and remodeling of mirror neuron systems, which include important language centers, and may improve language function in aphasia patients. In this randomized-block-design experiment, we recruited 24 aphasia patients from, Zhongda Hospital, Southeast University, China. The patients were divided into three groups where they underwent hand-action observation and repetition, dynamic-object observation and repetition, or conventional speech therapy. Training took place 5 days per week, 35 minutes per day, for 2 weeks. We assessed language function via picture naming tests for objects and actions and the Western Aphasia Battery. Among the participants, one patient, his wife and four healthy student volunteers underwent functional magnetic resonance imaging to analyze changes in brain activation during hand-action observation and dynamic-object observation. Results demonstrated that, compared with dynamic-object observation, hand-action observation led to greater performance with respect to the aphasia quotient and affiliated naming sub-tests and a greater Western Aphasia Battery test score. The overall effect was similar to that of conventional aphasia training, yet hand-action observation had advantages compared with conventional training in terms of vocabulary extraction and spontaneous speech. Thus, hand-action observation appears to more strongly activate the mirror neuron system compared with dynamic-object observation. The activated areas included Broca's area, Wernicke's area, and the supramarginal gyrus. These results suggest that hand-action observation combined with repetition might better improve language function in aphasia patients compared with dynamic-object observation combined with repetition. The therapeutic mechanism of this intervention may be associated with activation of additional mirror neuron systems, and may have implications for the possible repair and remodeling of damaged nerve networks. The study protocol was approved by the Ethical Committee of Nanjing Medical University, China (approval number: 2011-SRFA-086) on March 11, 2011. This trial has been registered in the ISRCTN Registry (ISRCTN84827527).

15.
J Comput Assist Tomogr ; 43(1): 128-135, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30211800

RESUMO

OBJECTIVE: To study the potential application of magnetic resonance imaging (MRI) for classification of retained placental tissue (RPT) in the uterus postnatally. METHODS: Twenty-two patients with clinically or pathologically proven RPT were studied. RESULTS: The thickness ratio (D1/D2) of invaded (D1) to normal (D2) myometrium could be categorized into 3 groups (>0.6, 0.1-0.6, and <0.1) correlating with the 3 types of RPT: accreta vera (RPA), increta (RPI), and percreta (RPP) (r = -0.861, P < 0.01). After uterine arterial embolization, the RPT showed lower signal intensity than the myometrium without flow voids on T2-weighted images. Two cases of RPP showed gradual enhancement, except 1 case of infection and 2 cases that did not involve enhancement examinations, whereas 17 cases of RPA and RPI showed early enhancement. CONCLUSIONS: Magnetic resonance imaging can facilitate diagnosis of RPT severity. Dynamic contrast enhancement can indicate RPT activity and blood supply, thereby ensuring appropriate clinical decision making.


Assuntos
Imagem por Ressonância Magnética/métodos , Placenta Retida/diagnóstico por imagem , Período Pós-Parto , Adulto , Feminino , Humanos , Gravidez , Útero/diagnóstico por imagem , Adulto Jovem
16.
Sci Rep ; 8(1): 4530, 2018 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-29540740

RESUMO

Microphysiological systems (MPSs) are in vitro models that capture facets of in vivo organ function through use of specialized culture microenvironments, including 3D matrices and microperfusion. Here, we report an approach to co-culture multiple different MPSs linked together physiologically on re-useable, open-system microfluidic platforms that are compatible with the quantitative study of a range of compounds, including lipophilic drugs. We describe three different platform designs - "4-way", "7-way", and "10-way" - each accommodating a mixing chamber and up to 4, 7, or 10 MPSs. Platforms accommodate multiple different MPS flow configurations, each with internal re-circulation to enhance molecular exchange, and feature on-board pneumatically-driven pumps with independently programmable flow rates to provide precise control over both intra- and inter-MPS flow partitioning and drug distribution. We first developed a 4-MPS system, showing accurate prediction of secreted liver protein distribution and 2-week maintenance of phenotypic markers. We then developed 7-MPS and 10-MPS platforms, demonstrating reliable, robust operation and maintenance of MPS phenotypic function for 3 weeks (7-way) and 4 weeks (10-way) of continuous interaction, as well as PK analysis of diclofenac metabolism. This study illustrates several generalizable design and operational principles for implementing multi-MPS "physiome-on-a-chip" approaches in drug discovery.


Assuntos
Técnicas de Cocultura/métodos , Diclofenaco/farmacocinética , Dispositivos Lab-On-A-Chip , Fígado/metabolismo , Animais , Avaliação Pré-Clínica de Medicamentos , Humanos , Procedimentos Analíticos em Microchip , Modelos Biológicos , Fenótipo , Ratos
18.
AAPS J ; 19(5): 1499-1512, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28752430

RESUMO

Investigation of the pharmacokinetics (PK) of a compound is of significant importance during the early stages of drug development, and therefore several in vitro systems are routinely employed for this purpose. However, the need for more physiologically realistic in vitro models has recently fueled the emerging field of tissue-engineered 3D cultures, also referred to as organs-on-chips, or microphysiological systems (MPSs). We have developed a novel fluidic platform that interconnects multiple MPSs, allowing PK studies in multi-organ in vitro systems along with the collection of high-content quantitative data. This platform was employed here to integrate a gut and a liver MPS together in continuous communication, and investigate simultaneously different PK processes taking place after oral drug administration in humans (e.g., intestinal permeability, hepatic metabolism). Measurement of tissue-specific phenotypic metrics indicated that gut and liver MPSs can be fluidically coupled with circulating common medium without compromising their functionality. The PK of diclofenac and hydrocortisone was investigated under different experimental perturbations, and results illustrate the robustness of this integrated system for quantitative PK studies. Mechanistic model-based analysis of the obtained data allowed the derivation of the intrinsic parameters (e.g., permeability, metabolic clearance) associated with the PK processes taking place in each MPS. Although these processes were not substantially affected by the gut-liver interaction, our results indicate that inter-MPS communication can have a modulating effect (hepatic metabolism upregulation). We envision that our integrative approach, which combines multi-cellular tissue models, multi-MPS platforms, and quantitative mechanistic modeling, will have broad applicability in pre-clinical drug development.


Assuntos
Diclofenaco/farmacocinética , Hidrocortisona/farmacocinética , Mucosa Intestinal/metabolismo , Fígado/metabolismo , Humanos , Técnicas In Vitro
19.
BMC Musculoskelet Disord ; 18(1): 241, 2017 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-28577531

RESUMO

BACKGROUND: The application of laminar screws is an alternative fixation for the first thoracic vertebra (T1). This paper is to determine the anatomical characteristics for adequate laminar screw fixation, and present a modified method of sagittal reconstruction of T1 to provide more accurate measurements. METHODS: Computed tomography (CT) images of 62 patients (32 males, 30 females) were used for the analysis. The following parameters of the T-1 lamina were measured using Mimics software: lamina length, axis angle, minimal outer cortical width, cancellous width, minimal outer cortical height, cancellous height, and spinous process height. Right or left modified sagittal reconstructions (parallel to right or left screws) were innovatively used for measurement. RESULTS: There were no significant differences between the left and right sides for each measurement performed (P > 0.05), but significant differences were detected between males and females (P < 0.05). The mean length of the T1 lamina was 32.8 mm of the T1 minimal outer cortical width was 7.4 mm, and 3.8% of males had a minimal outer cortical width < 5 mm, while 8.6% of females had a minimal outer cortical width < 5 mm. The mean minimal outer cortical height was 10.8 mm, and 1.9% of males had a minimal outer cortical height < 9 mm, while 7.7% of females had a minimal outer cortical height < 9 mm. CONCLUSION: This study suggests there are no anatomical limitations for T1 laminar screw placement in most people. The modified sagittal reconstruction method described allows for easy and precise measurement to aid in the insertion of laminar screws in T1, and gives good visualization of laminar screw insertion direction.


Assuntos
Parafusos Ósseos/normas , Vértebras Torácicas/diagnóstico por imagem , Vértebras Torácicas/cirurgia , Tomografia Computadorizada por Raios X/métodos , Tomografia Computadorizada por Raios X/normas , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
20.
Sci Rep ; 7: 46733, 2017 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-28429756

RESUMO

Numerous crystal structures of HIV gp120 have been reported, alone or with receptor CD4 and cognate antibodies; however, no sole gp120/CD4 complex without stabilization by an antibody is available. Here, we report a crystal structure of the gp120/CD4 complex without the aid of an antibody from HIV-1 CRF07_BC, a strain circulating in China. Interestingly, in addition to the canonical binding surface, a second interacting interface was identified. A mutagenesis study on critical residues revealed that the stability of this interface is important for the efficiency of Env-mediated membrane fusion. Furthermore, we found that a broad neutralizing antibody, ibalizumab, which targets CD4 in the absence of gp120, occupies the same binding surface as the second interface identified here on gp120. Therefore, we identified the possibility of the involvement of a second gp120-CD4 interaction interface during viral entry, and also provided a reasonable explanation for the broad activity of neutralizing antibody ibalizumab.


Assuntos
Antígenos CD4/química , Proteína gp120 do Envelope de HIV/química , HIV-1/metabolismo , Domínios Proteicos , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Neutralizantes/farmacologia , Antígenos CD4/metabolismo , Células COS , Linhagem Celular , Linhagem Celular Tumoral , Chlorocebus aethiops , Cristalografia por Raios X , Células HEK293 , Proteína gp120 do Envelope de HIV/genética , Proteína gp120 do Envelope de HIV/metabolismo , HIV-1/genética , Células HeLa , Humanos , Simulação de Dinâmica Molecular , Ligação Proteica/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos
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