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1.
Cytogenet Genome Res ; : 1-11, 2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34649241

RESUMO

Atherosclerosis is the leading global cause of mortality. The occurrence of coronary artery disease (CAD) is regulated by a diversity of pathways, including circRNAs. However, the potential mechanisms of circRNAs in CAD remain unclear. Here, qRT-PCR was used to examine the expressions of miR-149 and circ_ROBO2. Their influences on cell proliferation, migration, and apoptosis were measured by CCK-8, trans-well, and flow cytometry assays, respectively. The protein levels of p-IκBα and NF-κB p65 were examined using western blot. The molecular interactions were validated using dual luciferase reporter and RNA pull-down assays. The expression patterns of circ_ROBO2 and miR-149 in CAD patients and PDGF-BB-treated human aortic smooth muscle cells (HASMCs) were upregulated and downregulated, respectively. Knockdown of circ_ROBO2 could markedly inhibit the capabilities of proliferation and migration, enhance the apoptotic rate, and suppress NF-κB signaling in PDGF-BB-treated HASMCs. Mechanistically, circ_ROBO2 acted as a sponge of miR-149 to activate TRAF6/NF-κB signaling. Rescue studies demonstrated that neither silencing miR-149 nor activation of NF-κB signaling obviously abolished the biological roles of circ_ROBO2 knockdown in PDGF-BB treated-HASMCs. This discovery elucidated a functional mechanism of circ_ROBO2 in CAD, suggesting that circRNAs serve a vital role in the progression of CAD.

2.
Front Cell Neurosci ; 15: 720271, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34658791

RESUMO

Background: Spinal cord injury (SCI) is a highly lethal and debilitating disease with a variety of etiologies. To date, there is no effective therapeutic modality for a complete cure. The pathological mechanisms of spinal cord injury at the molecular gene and protein expression levels remain unclear. Methods: This study used single-cell transcriptomic analysis and protein microarray analysis to analyzes changes in the gene expression profiles of cells and secretion of inflammatory factors respectively, around the lesion site in a rat SCI model. Results: Single-cell transcriptomic analysis found that three types of glial cells (microglia, astrocyte, and oligodendrocyte) becomes activated after acute injury, with GO exhibiting a variety of inflammatory-related terms after injury, such as metabolic processes, immune regulation, and antigen presentation. Protein microarray results showed that the levels of four inflammatory cytokines favoring SCI repair decreased while the levels of nine inflammatory cytokines hindering SCI repair increased after injury. Conclusion: These findings thus reveal the changes in cellular state from homeostatic to reactive cell type after SCI, which contribute to understand the pathology process of SCI, and the potential relationship between glial cells and inflammatory factors after SCI, and provides new theoretical foundation for further elucidating the molecular mechanisms of secondary SCI.

3.
Materials (Basel) ; 14(15)2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34361481

RESUMO

Newly developed Zn-Mn-Mg alloys can be invoked as biomedical materials because of their excellent mechanical properties. However, the corrosion behavior of Zn-Mn-Mg alloys was still lacking in research. It had grown to be a hot research topic to improve the corrosion behavior of Zn alloys by surface treatment to meet the application of degradable Zn alloys in biomedical applications. Micro arc oxidation (MAO) is a simple and effective method to improve the corrosion behavior of the alloy. MAO coatings were successfully prepared on the surface of Zn-Mn-Mg alloys by MAO in silicate-based solutions with different NaF concentrations. The microstructure and phase composition of MAO coatings prepared on Zn-Mn-Mg alloys with different NaF concentrations in the electrolyte was examined by a scanning electron microscope and X-ray diffraction. The results showed that the MAO coatings are porous and mainly composed of ZnO. With the increasing NaF concentration in the electrolyte, the average thickness increases. The distribution of the micro/nanopores was uniform, and the pore size ranged from the submicron scale to several micrometers after MAO treatment in the electrolyte containing different concentrations of NaF. Potential dynamic polarization curves and electrochemical impedance spectroscopy were employed to assess the corrosion behavior of MAO coatings in Hank's solution. The highest corrosion rate can be achieved after MAO treatment, with an electrolyte concentration of 1.5 g/L NaF in Hank's solution. These results indicated that MAO coating can accelerate the corrosion resistance of a Zn-Mn-Mg alloy.

4.
Aging (Albany NY) ; 13(16): 20793-20807, 2021 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-34459788

RESUMO

PURPOSE: Apatinib resistance is the main obstacle to the effective treatment of advanced head and neck squamous cell carcinoma (HNSCC). This study aimed to evaluate the function of Erb-B2 receptor tyrosine kinase 2 (ERBB2) and stimulator of interferon response cGAMP interactor (STING) in apatinib resistance in HNSCC. METHOD: The Cancer Genome Atlas database of HNSCC was used to analyze the relationship between vascular endothelial growth factor receptor 2 (VEGFR2) expression and prognosis. An apatinib resistant (AR) HNSCC cell line was constructed based on the CAL27 cell line. RNA sequencing was performed to explore the differentially expressed mRNAs. Quantitative real-time reverse transcription PCR (qRT-PCR) and western blotting were used to evaluate the expression and phosphorylation level VEGFR2, ERBB2, STING, and related proteins. Apatinib resistance was evaluated by colony formation and cell viability assays. A mouse subcutaneous tumor formation model was established to evaluate the efficiency of combination treatment and vascularization was evaluated by assessing CD31 immunofluorescence. RESULT: The expression of VEGFR2 was high in tumor of patients with HNSCC. Western blotting and qRT-PCR revealed that in AR cells, ERBB2 expression was high, whereas the expression of STING was low. Targeted treatment of ERBB2 using lapatinib could attenuate apatinib resistance. Further research confirmed that overexpressing STING could decrease ERBB2 expression. CONCLUSION: STING could sensitize AR cells to apatinib by decreasing ERBB2 expression. The combination of lapatinib or a STING agonist with apatinib ameliorated acquired apatinib resistance in a synergistic manner.

5.
Nat Commun ; 12(1): 4880, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34385444

RESUMO

Accurate and imperceptible monitoring of electrophysiological signals is of primary importance for wearable healthcare. Stiff and bulky pregelled electrodes are now commonly used in clinical diagnosis, causing severe discomfort to users for long-time using as well as artifact signals in motion. Here, we report a ~100 nm ultra-thin dry epidermal electrode that is able to conformably adhere to skin and accurately measure electrophysiological signals. It showed low sheet resistance (~24 Ω/sq, 4142 S/cm), high transparency, and mechano-electrical stability. The enhanced optoelectronic performance was due to the synergistic effect between graphene and poly (3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS), which induced a high degree of molecular ordering on PEDOT and charge transfer on graphene by strong π-π interaction. Together with ultra-thin nature, this dry epidermal electrode is able to accurately monitor electrophysiological signals such as facial skin and brain activity with low-motion artifact, enabling human-machine interfacing and long-time mental/physical health monitoring.


Assuntos
Eletrodos , Eletrofisiologia/métodos , Epiderme/fisiologia , Desenho de Equipamento/métodos , Monitorização Fisiológica/métodos , Dispositivos Eletrônicos Vestíveis , Artefatos , Compostos Bicíclicos Heterocíclicos com Pontes/química , Condutividade Elétrica , Eletrofisiologia/instrumentação , Eletrofisiologia/normas , Desenho de Equipamento/normas , Grafite/química , Humanos , Estrutura Molecular , Monitorização Fisiológica/instrumentação , Monitorização Fisiológica/normas , Movimento (Física) , Polímeros/química , Poliestirenos/química , Pele
6.
Gland Surg ; 10(6): 2002-2009, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34268084

RESUMO

Background: According to the global cancer burden data released in 2020, breast cancer (BC) has become the most common cancer in the world. Similar to those of other cancers, the present methods used in clinic for diagnosing early BC are invasive, inaccurate, and insensitive. Hence, new non-invasive methods capable of early diagnosis are needed. Methods: We applied next-generation sequencing and analyzed the messenger RNA (mRNA) profiles of plasma extracellular vesicles (EVs) derived from 14 BC patients and 6 patients with benign breast lesions. We used 3 regression models, namely support vector machine (SVM), linear discriminate analysis (LDA), and logistic regression (LR), to develop classifiers for use in making predictive BC diagnoses; and used 259 plasma samples, including those obtained from 144 patients with BC, 72 patients with benign breast lesions, and 43 healthy women, which were divided into training groups and validation groups to verify their performances as classifiers by quantitative reverse transcription polymerase chain reaction (RT-qPCR). The area under the curve (AUC) and accuracy, sensitivity, and specificity of the classifiers were cross-validated with the leave-1-out cross-validation (LOOCV) method. Results: Among all combinations assessed with the 3 different regression models, an 8-mRNA combination, named EXOBmRNA, exhibited high performance [accuracy =71.9% and AUC =0.718, 95% confidence interval (CI): 0.652 to 0.784] in the training cohort after LOOCV was performed, showing the largest AUC in the SVM model. The mRNAs in EXOBmRNA were HLA-DRB1, HAVCR1, ENPEP, TIMP1, CD36, MARCKS, DAB2, and CXCL14. In the validation cohort, the AUC of EXOBmRNA was 0.737 (95% CI: 0.636 to 0.837). In addition, gene function and pathway analyses revealed that different levels of gene expression were associated with cancer. Conclusions: We developed a high-performing predictive classifiers including 8 mRNAs from plasma extracellular vesicles for diagnosing breast cancer.

7.
Clin Chim Acta ; 520: 95-100, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34107314

RESUMO

BACKGROUND: Breast malignancy is the most frequently diagnosed malignancy in women worldwide, and the diagnosis relies on invasive examinations. However, most clinical breast changes in women are benign, and invasive diagnostic approaches cause unnecessary suffering for the patients. Thus, a novel noninvasive approach for discriminating malignant breast lesions from benign lesions is needed. METHODS: We performed cell-free DNA (cfDNA) sequencing on plasma samples from 173 malignant breast lesion patients, 158 benign breast lesion patients, and 102 healthy women. We then analyzed the cfDNA-based nucleosome profiles, which reflect the various tissues of origin and transcription factor activities. Moreover, by using machine learning classifiers along with the cfDNA sequencing data, we built classifiers for discriminating benign from malignant breast lesions. Receiver operating characteristic curve analyses were used to evaluate the performance of the classifiers. RESULTS: cfDNA-based nucleosome profiles reflected the various tissues of origin and transcription factor activities in benign and malignant breast lesions. The cfDNA-based transcription factor activities and breast malignancy-specific transcription factor-binding site accessibility profiles could accurately distinguish benign and malignant breast lesions, with area under the curve values of 0.777 and 0.824, respectively. CONCLUSIONS: Our proof-of-principle study established a methodology for noninvasively discriminating benign from malignant breast lesions.


Assuntos
Neoplasias da Mama , Ácidos Nucleicos Livres , Mama , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Ácidos Nucleicos Livres/genética , Diagnóstico Diferencial , Feminino , Humanos , Nucleossomos/genética , Curva ROC
8.
J Zhejiang Univ Sci B ; 22(4): 310-317, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33835765

RESUMO

Since December 2019, the novel coronavirus (severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)) has spread to many countries around the world, developing into a global pandemic with increasing numbers of deaths reported worldwide. To data, although some vaccines have been developed, there are no ideal drugs to treat novel coronavirus pneumonia (coronavirus disease 2019 (COVID-19)). By examining the structure of the coronavirus and briefly describing its possible pathogenesis based on recent autopsy reports conducted by various teams worldwide, this review analyzes the possible structural and functional changes of the human body upon infection with SARS-CoV-2. We observed that the most prominent pathological changes in COVID-19 patients are diffuse alveolar damage (DAD) of the lungs and microthrombus formation, resulting in an imbalance of the ventilation/perfusion ratio and respiratory failure. Although direct evidence of viral infection can also be found in other organs and tissues, the viral load is relatively small. The conclusion that the injuries of the extra-pulmonary organs are directly caused by the virus needs further investigation.


Assuntos
COVID-19/patologia , Pulmão/patologia , COVID-19/fisiopatologia , Corpo Humano , Humanos , Evasão da Resposta Imune , Pulmão/virologia , Carga Viral
9.
PLoS One ; 16(3): e0248597, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33725011

RESUMO

OBJECTIVE: Hemorrhagic fever with renal syndrome (HFRS), one of the main public health concerns in mainland China, is a group of clinically similar diseases caused by hantaviruses. Statistical approaches have always been leveraged to forecast the future incidence rates of certain infectious diseases to effectively control their prevalence and outbreak potential. Compared to the use of one base model, model stacking can often produce better forecasting results. In this study, we fitted the monthly reported cases of HFRS in mainland China with a model stacking approach and compared its forecasting performance with those of five base models. METHOD: We fitted the monthly reported cases of HFRS ranging from January 2004 to June 2019 in mainland China with an autoregressive integrated moving average (ARIMA) model; the Holt-Winter (HW) method, seasonal decomposition of the time series by LOESS (STL); a neural network autoregressive (NNAR) model; and an exponential smoothing state space model with a Box-Cox transformation; ARMA errors; and trend and seasonal components (TBATS), and we combined the forecasting results with the inverse rank approach. The forecasting performance was estimated based on several accuracy criteria for model prediction, including the mean absolute percentage error (MAPE), root-mean-squared error (RMSE) and mean absolute error (MAE). RESULT: There was a slight downward trend and obvious seasonal periodicity inherent in the time series data for HFRS in mainland China. The model stacking method was selected as the best approach with the best performance in terms of both fitting (RMSE 128.19, MAE 85.63, MAPE 8.18) and prediction (RMSE 151.86, MAE 118.28, MAPE 13.16). CONCLUSION: The results showed that model stacking by using the optimal mean forecasting weight of the five abovementioned models achieved the best performance in terms of predicting HFRS one year into the future. This study has corroborated the conclusion that model stacking is an easy way to enhance prediction accuracy when modeling HFRS.


Assuntos
Surtos de Doenças/estatística & dados numéricos , Monitoramento Epidemiológico , Febre Hemorrágica com Síndrome Renal/epidemiologia , Aprendizado de Máquina , Redes Neurais de Computação , China/epidemiologia , Conjuntos de Dados como Assunto , Previsões/métodos , Hantavirus/patogenicidade , Febre Hemorrágica com Síndrome Renal/virologia , Humanos , Incidência , Modelos Estatísticos , Estações do Ano
10.
Rev Sci Instrum ; 92(2): 025108, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33648077

RESUMO

To use acoustic-emission technology to detect leaks inside valves, the necessary first step is to model the valve-internal-leakage acoustic-emission signal (VILAES) mathematically. A multi-variable classification model that relates the VILAES characteristics and the leakage rate under varying pressure is built by combining time-frequency domain characteristics and the random-forest method. A Butterworth bandpass filter is used to preprocess the VILAES from a liquid medium, and the best frequency band for filtering is determined as being 140 kHz-180 kHz. Then, (i) the standard deviation, (ii) root mean square, (iii) wavelet packet entropy, (iv) peak standard-deviation probability density, and (v) spectrum area are calculated as the VILAES characteristics, and six parameters-the pressure and the five VILAES characteristics-are used as the inputs for the random-forest classification model. Analysis shows that the five VILAES characteristics increase with an increase in the leakage rate. The multi-variable classification model is established by random forest to determine whether the valve leakage is small, medium, or large. The random forest uses many decision trees to predict the final result. For the same experimental data, the accuracy and operating time of the multi-variable classification model are compared with those of a support-vector-machine classification method for the bandpass and wavelet packet filtering preprocessing methods. The results show that the modeling method based on the combination of time-frequency characteristics and random forest has shorter operating time and higher accuracy.

11.
NPJ Breast Cancer ; 7(1): 35, 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33772032

RESUMO

Gene expression signatures have been used to predict the outcome of chemotherapy for breast cancer. The nucleosome footprint of cell-free DNA (cfDNA) carries gene expression information of the original tissues and thus may be used to predict the response to chemotherapy. Here we carried out the nucleosome positioning on cfDNA from 85 breast cancer patients and 85 healthy individuals and two cancer cell lines T-47D and MDA-MB-231 using low-coverage whole-genome sequencing (LCWGS) method. The patients showed distinct nucleosome footprints at Transcription Start Sites (TSSs) compared with normal donors. In order to identify the footprints of cfDNA corresponding with the responses to neoadjuvant chemotherapy in patients, we mapped on nucleosome positions on cfDNA of patients with different responses: responders (pretreatment, n = 28; post-1 cycle, post-3/4 cycles, and post-8 cycles of treatment, n = 12) and nonresponders (pretreatment, n = 10; post-1 cycle, post-3/4 cycles, and post-8 cycles of treatment, n = 10). The coverage depth near TSSs in plasma cfDNA differed significantly between responders and nonresponders at pretreatment, and also after neoadjuvant chemotherapy treatment cycles. We identified 232 TSSs with differential footprints at pretreatment and 321 after treatment and found enrichment in Gene Ontology terms such as cell growth inhibition, tumor suppressor, necrotic cell death, acute inflammatory response, T cell receptor signaling pathway, and positive regulation of vascular endothelial growth factor production. These results suggest that cfDNA nucleosome footprints may be used to predict the efficacy of neoadjuvant chemotherapy for breast cancer patients and thus may provide help in decision making for individual patients.

12.
Cell Transplant ; 30: 963689720977144, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33525921

RESUMO

Here we presented a case of a 19-month-old boy who developed severe aplastic anemia postacute hepatitis. He was treated successfully with the umbilical cord-derived mesenchymal stromal cells (UC-MSCs) infusion and cyclosporine A (CsA). The boy achieved both hematopoietic recovery and normal lymphocyte proportion. So far, his condition still remains stable. To our knowledge, there is a rare previous report on the utility of MSCs infusion for the treatment of hepatitis-associated aplastic anemia (HAAA). Considering the efficacy, safety, and strong operability, particularly for pediatric patient, the infusion of UC-MSCs combined with CsA could be an effective alternative for the treatment of HAAA.

13.
Nat Prod Res ; 35(9): 1421-1427, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-31411058

RESUMO

Phytochemical investigation of Croton crassifolius led to the isolation of two new halimane diterpenoids (1 and 2), a new nor-clerodane diterpenoid (3), along with three known analogues (4-6). Their structures including absolute configurations were elucidated by spectroscopic analysis, single-crystal X-ray diffraction, and CD analysis. All isolates were evaluated for their inhibitory effects on the nitric oxide (NO) production induced by lipopolysaccharide (LPS) in RAW264.7 macrophage cells, and compound 1 exhibited moderate inhibition of NO production with an IC50 value of 25.8 ± 0.9 µM.


Assuntos
Croton/química , Diterpenos/isolamento & purificação , Animais , Cristalografia por Raios X , Diterpenos/química , Diterpenos/farmacologia , Diterpenos Clerodânicos/química , Diterpenos Clerodânicos/isolamento & purificação , Concentração Inibidora 50 , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Óxido Nítrico/biossíntese , Raízes de Plantas/química , Células RAW 264.7
14.
ACS Appl Mater Interfaces ; 12(50): 56361-56371, 2020 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-33270412

RESUMO

Epidermal electronics is regarded as the next-generation technology, and graphene is a promising electrode, which is a key building block of such devices. However, graphene has a tendency to crack at small strains with a rapidly increased resistance upon stretching. Here, to enable graphene applicable in epidermal electronics, we designed a novel graphene structure that is molybdenum chloride (MoCl5)-intercalated few-layer graphene (Mo-FLG) fabricated in a confined environment. In the case of bilayer graphene (BLG), MoCl5-intercalated bilayer graphene (Mo-BLG) exhibited a low sheet resistance of 40 Ω/square (sq) at a transmittance of 80%. Due to the self-barrier doping effect, the sheet resistance increased to only 60 Ω/sq after exposing to the atmosphere over 1 month. Transferred onto elastomer substrates, Mo-BLG can work as an electrode up to 80% strain and maintain a high conductivity that is durable over 2000 cycles at 30% strain. This mechano-electrostability is attributed to the special intercalated structure where the intercalated dopants act as lubricants to weaken the layer-layer interaction and allow a certain degree of sliding, as well as electrical crack-connectors to bridge the cracked domains at a high strain. Mo-BLG can be applied as epidermal electrodes to monitor electrophysiological signals such as electrocardiogram (ECG), electrooculogram (EOG), electroencephalography (EEG), and surface electromyogram (sEMG) with high signal-to-noise ratios (SNRs) comparable to commercial Ag/AgCl electrode. This is the first demonstration of epidermal electrodes based on intercalation-doped graphene applied in health monitoring, shedding light on the future development of graphene-based epidermal electronics.


Assuntos
Eletrocardiografia/instrumentação , Eletroencefalografia/instrumentação , Eletromiografia/instrumentação , Grafite/química , Cloretos/química , Elastômeros/química , Condutividade Elétrica , Eletrodos , Epiderme/fisiologia , Humanos , Molibdênio/química , Razão Sinal-Ruído
15.
BMJ Open ; 10(12): e039676, 2020 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-33293308

RESUMO

OBJECTIVES: Human brucellosis is a public health problem endangering health and property in China. Predicting the trend and the seasonality of human brucellosis is of great significance for its prevention. In this study, a comparison between the autoregressive integrated moving average (ARIMA) model and the eXtreme Gradient Boosting (XGBoost) model was conducted to determine which was more suitable for predicting the occurrence of brucellosis in mainland China. DESIGN: Time-series study. SETTING: Mainland China. METHODS: Data on human brucellosis in mainland China were provided by the National Health and Family Planning Commission of China. The data were divided into a training set and a test set. The training set was composed of the monthly incidence of human brucellosis in mainland China from January 2008 to June 2018, and the test set was composed of the monthly incidence from July 2018 to June 2019. The mean absolute error (MAE), root mean square error (RMSE) and mean absolute percentage error (MAPE) were used to evaluate the effects of model fitting and prediction. RESULTS: The number of human brucellosis patients in mainland China increased from 30 002 in 2008 to 40 328 in 2018. There was an increasing trend and obvious seasonal distribution in the original time series. For the training set, the MAE, RSME and MAPE of the ARIMA(0,1,1)×(0,1,1)12 model were 338.867, 450.223 and 10.323, respectively, and the MAE, RSME and MAPE of the XGBoost model were 189.332, 262.458 and 4.475, respectively. For the test set, the MAE, RSME and MAPE of the ARIMA(0,1,1)×(0,1,1)12 model were 529.406, 586.059 and 17.676, respectively, and the MAE, RSME and MAPE of the XGBoost model were 249.307, 280.645 and 7.643, respectively. CONCLUSIONS: The performance of the XGBoost model was better than that of the ARIMA model. The XGBoost model is more suitable for prediction cases of human brucellosis in mainland China.


Assuntos
Brucelose , Brucelose/epidemiologia , China/epidemiologia , Humanos , Incidência , Modelos Estatísticos , Estações do Ano
16.
Nanomedicine (Lond) ; 15(20): 1995-2017, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32812486

RESUMO

The global incidence of bone tissue injuries has been increasing rapidly in recent years, making it imperative to develop suitable bone grafts for facilitating bone tissue regeneration. It has been demonstrated that nanomaterials/nanocomposites scaffolds can more effectively promote new bone tissue formation compared with micromaterials. This may be attributed to their nanoscaled structural and topological features that better mimic the physiological characteristics of natural bone tissue. In this review, we examined the current applications of various nanomaterial/nanocomposite scaffolds and different topological structures for bone tissue engineering, as well as the underlying mechanisms of regeneration. The potential risks and toxicity of nanomaterials will also be critically discussed. Finally, some considerations for the clinical applications of nanomaterials/nanocomposites scaffolds for bone tissue engineering are mentioned.

17.
Theranostics ; 10(19): 8633-8647, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32754268

RESUMO

Rationale: The prognosis of gastric cancer (GC) patients is poor, and there is limited therapeutic efficacy due to genetic heterogeneity and difficulty in early-stage screening. Here, we developed and validated an individualized gene set-based prognostic signature for gastric cancer (GPSGC) and further explored survival-related regulatory mechanisms as well as therapeutic targets in GC. Methods: By implementing machine learning, a prognostic model was established based on gastric cancer gene expression datasets from 1699 patients from five independent cohorts with reported full clinical annotations. Analysis of the tumor microenvironment, including stromal and immune subcomponents, cell types, panimmune gene sets, and immunomodulatory genes, was carried out in 834 GC patients from three independent cohorts to explore regulatory survival mechanisms and therapeutic targets related to the GPSGC. To prove the stability and reliability of the GPSGC model and therapeutic targets, multiplex fluorescent immunohistochemistry was conducted with tissue microarrays representing 186 GC patients. Based on multivariate Cox analysis, a nomogram that integrated the GPSGC and other clinical risk factors was constructed with two training cohorts and was verified by two validation cohorts. Results: Through machine learning, we obtained an optimal risk assessment model, the GPSGC, which showed higher accuracy in predicting survival than individual prognostic factors. The impact of the GPSGC score on poor survival of GC patients was probably correlated with the remodeling of stromal components in the tumor microenvironment. Specifically, TGFß and angiogenesis-related gene sets were significantly associated with the GPSGC risk score and poor outcome. Immunomodulatory gene analysis combined with experimental verification further revealed that TGFß1 and VEGFB may be developed as potential therapeutic targets of GC patients with poor prognosis according to the GPSGC. Furthermore, we developed a nomogram based on the GPSGC and other clinical variables to predict the 3-year and 5-year overall survival for GC patients, which showed improved prognostic accuracy than clinical characteristics only. Conclusion: As a tumor microenvironment-relevant gene set-based prognostic signature, the GPSGC model provides an effective approach to evaluate GC patient survival outcomes and may prolong overall survival by enabling the selection of individualized targeted therapy.


Assuntos
Biomarcadores Tumorais/genética , Perfilação da Expressão Gênica/métodos , Neoplasias Gástricas/mortalidade , Fator de Crescimento Transformador beta1/genética , Fator B de Crescimento do Endotélio Vascular/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Nomogramas , Medicina de Precisão , Prognóstico , Modelos de Riscos Proporcionais , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Análise de Sobrevida , Análise Serial de Tecidos , Fator de Crescimento Transformador beta1/metabolismo , Microambiente Tumoral , Fator B de Crescimento do Endotélio Vascular/metabolismo , Adulto Jovem
18.
Hum Gene Ther ; 31(13-14): 743-755, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32414297

RESUMO

Recombinant adeno-associated viral (rAAV) vector-mediated gene therapy is being developed to treat X-linked retinitis pigmentosa (XLRP) in patients with mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene. In preparation for a clinical gene therapy trial, we conducted dose range finding (DRF) studies with an AAV2 capsid with three surface tyrosine residues changed to phenylalanine (AAV2tYF) vector administered by subretinal injection in a naturally occurring RPGR-mutant canine model (XLPRA2) to compare two different human RPGR (hRPGR) transgenes and to establish a reasonable starting dose for a clinical trial. Different dose levels of two candidate vectors (0.15 mL at 1.2 × 1010-3.0 × 1012 vg/mL of rAAV2tYF-GRK1-hRPGRco or 4 × 1010-3.0 × 1012 vg/mL of rAAV2tYF-GRK1-hRPGRstb), 6.0 × 1011 vg/mL rAAV5-GRK1-hRPGRco reference vector or Vehicle were subretinally administered, and the dogs were followed for 8 weeks postdose. Ophthalmic examinations, analyses of retinal structure by in vivo imaging using confocal scanning laser ophthalmoscopy (cSLO)/optical coherence tomography (OCT) in the Lower (4.0 × 1010 vg/mL) and Lowest (1.2 × 1010 vg/mL) Doses, immunological responses by cell based assays or enzyme-linked immunosorbent assay, RPGR transgene expression, and reversal of opsin mislocalization by immunohistochemistry were performed. No sustained signs of ocular discomfort or ophthalmic complications were noted in any of the injected eyes except some in the High Dose group (3.0 × 1012 vg/mL), which showed signs of retinal detachment and inflammation. A change in fundus reflectivity suggestive of a rescue effect was seen in the High, Mid (6.0 × 1011 vg/mL), and Low (1.2 × 1011 vg/mL) Dose groups. cSLO/OCT demonstrated qualitative and quantitative evidence of rescue effect in eyes treated with the Lower Dose. Anti-hRPGR antibodies were absent, but neutralizing antibody titers against AAV2 were detected in all animals dosed with rAAV2tYF in an apparent dose-related pattern. RPGR expression was stronger for rAAV2tYF-GRK1-hRPGRco compared to rAAV2tYF-GRK1-hRPGRstb at all dose levels. Subretinal administration of rAAV2tYF-GRK1-hRPGRco and rAAV2tYF-GRK1-hRPGRstb both corrected rod and cone opsin mislocalization, two early markers of disease in the XLPRA2 canine model of RPGR-XLRP. These results support the selection and use of rAAV2tYF-GRK1-hRPGRco (AGTC-501) and guided the initial doses in clinical studies in patients with XLRP caused by RPGR mutations.

19.
J Nanobiotechnology ; 18(1): 57, 2020 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-32245495

RESUMO

BACKGROUNDS: Intolerable toxicity and unsatisfactory therapeutic effects are still big problems retarding the use of chemotherapy against cancer. Nano-drug delivery system promised a lot in increasing the patients' compliance and therapeutic efficacy. As a unique nano-carrier, supermolecular aggregation nanovehicle has attracted increasing interests due to the following advantages: announcing drug loading efficacy, pronouncing in vivo performance and simplified production process. METHODS: In this study, the supermolecular aggregation nanovehicle of bortezomib (BTZ) was prepared to treat breast cancer. RESULTS: Although many supermolecular nanovehicles are inclined to disintegrate due to the weak intermolecular interactions among the components, the BTZ supermolecules are satisfying stable. To shed light on the reasons behind this, the forces driving the formation of the nanovehicles were detailed investigated. In other words, the interactions among BTZ and other two components were studied to characterize the nanovehicles and ensure its stability. CONCLUSIONS: Due to the promising tumor targeting ability of the BTZ nanovehicles, the supermolecule displayed promising tumor curing effects and negligible systemic toxicity.


Assuntos
Antineoplásicos/farmacologia , Bortezomib/química , Bortezomib/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Teste de Materiais , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas , Propriedades de Superfície
20.
Hum Gene Ther ; 31(3-4): 253-267, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31910043

RESUMO

Applied Genetic Technologies Corporation (AGTC) is developing a recombinant adeno-associated virus (rAAV) vector AGTC-501, also designated rAAV2tYF-GRK1-hRPGRco, to treat X-linked retinitis pigmentosa (XLRP) in patients with mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene. The vector contains a codon-optimized human RPGR cDNA (hRPGRco) driven by a photoreceptor-specific promoter (G protein-coupled receptor kinase 1 [GRK1]), and is packaged in an AAV2 capsid variant with three surface tyrosine residues changed to phenylalanine (AAV2tYF). We conducted a toxicity and efficacy study of this vector administered by subretinal injection in the naturally occurring RPGR mutant (X-linked progressive retinal atrophy 2 [XLPRA2]) dog model. Sixteen RPGR mutant dogs divided into four groups of three to five animals each received either a subretinal injection of 0.07 mL of AGTC-501 at low (1.2 × 1011 vector genome [vg]/mL), mid (6 × 1011 vg/mL), or high dose (3 × 1012 vg/mL), or of vehicle control in the right eye at early-stage disease. The left eye remained untreated. Subretinal injections were well tolerated and were not associated with systemic toxicity. Electroretinography, in vivo retinal imaging, and histological analysis showed rescue of photoreceptor function and structure in the absence of ocular toxicity in the low- and mid-dose treatment groups when compared with the vehicle-treated group. The high-dose group showed evidence of both photoreceptor rescue and posterior segment toxicity. These results support the use of AGTC-501 in clinical studies with patients affected with XLRP caused by RPGR mutations and define the no-observed-adverse-effect level at 6 × 1011 vg/mL.


Assuntos
Dependovirus/genética , Proteínas do Olho/genética , Genes Ligados ao Cromossomo X , Terapia Genética , Vetores Genéticos/genética , Retinite Pigmentosa/genética , Retinite Pigmentosa/terapia , Animais , Biomarcadores , Biópsia , Linhagem Celular , Códon , Cães , Eletrorretinografia , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Humanos , Imuno-Histoquímica , Mutação , Retinite Pigmentosa/diagnóstico , Tomografia de Coerência Óptica
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