Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 409
Filtrar
1.
AAPS J ; 23(3): 64, 2021 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-33942188

RESUMO

In the absence of regulatory guidelines for the bioanalysis of new drug modalities, many of which contain multiple functional domains, bioanalytical strategies have been carefully designed to characterize the intact drug and each functional domain in terms of quantity, functionality, biotransformation, and immunogenicity. The present review focuses on the bioanalytical challenges and considerations for RNA-based drugs, bispecific antibodies and multi-domain protein therapeutics, prodrugs, gene and cell therapies, and fusion proteins. Methods ranging from the conventional ligand binding assays and liquid chromatography-mass spectrometry assays to quantitative polymerase chain reaction or flow cytometry often used for oligonucleotides and cell and gene therapies are discussed. Best practices for method selection and validation are proposed as well as a future perspective to address the bioanalytical needs of complex modalities.

2.
BMC Med Inform Decis Mak ; 21(Suppl 1): 143, 2021 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-33941163

RESUMO

BACKGROUND: Protein-protein interactions (PPIs) are the core of protein function, which provide an effective means to understand the function at cell level. Identification of PPIs is the crucial foundation of predicting drug-target interactions. Although traditional biological experiments of identifying PPIs are becoming available, these experiments remain to be extremely time-consuming and expensive. Therefore, various computational models have been introduced to identify PPIs. In protein-protein interaction network (PPIN), Hub protein, as a highly connected node, can coordinate PPIs and play biological functions. Detecting hot regions on Hub protein interaction interfaces is an issue worthy of discussing. METHODS: Two clustering methods, LCSD and RCNOIK are used to detect the hot regions on Hub protein interaction interfaces in this paper. In order to improve the efficiency of K-means clustering algorithm, the best k value is selected by calculating the distance square sum and the average silhouette coefficients. Then, the optimization of residue coordination number strategy is used to calculate the average coordination number. In addition, the pair potentials and relative ASA (PPRA) strategy is also used to optimize the predicted results. RESULTS: DataHub dataset and PartyHub dataset were used to train two clustering models respectively. Experiments show that LCSD and RCNOIK have the same coverage with Hub protein datasets, and RCNOIK is slightly higher than LCSD in Precision. The predicted hot regions are closer to the standard hot regions. CONCLUSIONS: This paper optimizes two clustering methods based on PPRA strategy. Compared our methods for hot regions prediction against the well-known approaches, our improved methods have the higher reliability and are effective for predicting hot regions on Hub protein interaction interfaces.

3.
J Mol Neurosci ; 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33791913

RESUMO

Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO) is a rare mitochondrial disorder associated with mutations in the POLG gene, which encodes the DNA polymerase gamma catalytic subunit. A few POLG-related SANDO cases have been reported, but the genotype-phenotype correlation remains unclear. Here, we report a patient with SANDO carrying two novel missense variants (c.2543G>C, p.G848A and c.452 T>C, p.L151P) in POLG. We also reviewed previously reported cases to systematically evaluate the clinical and genetic features of POLG-related SANDO. A total of 35 distinct variants in the coding region of POLG were identified in 63 patients with SANDO. The most frequent variant was the p.A467T variant, followed by the p.W748S variant. The clinical spectrum of SANDO is heterogeneous. No clear correlation has been observed between the mutation types and clinical phenotypes. Our findings expand the mutational spectrum of POLG and contribute to clinical management and genetic counseling for POLG-related SANDO.

4.
J Phys Chem A ; 125(15): 3088-3094, 2021 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-33830768

RESUMO

Charge separation and intersystem crossing play critical roles in various applications of organic long persistent luminescence materials, including light-emitting diodes, chemical sensors, theranostics, and many biomedical and information applications. Using first-principles calculations, we demonstrate that an azobenzene acting as a photoswitch can be used for altering the configuration of a donor-switch-acceptor (D-S-A) molecular system to ensure charge separation and promote intersystem crossing upon photoexcitation. The trans to cis photoisomerization of an azobenzene switch creates an electron trap that stabilizes the charge-separated state. The cis conformation further facilitates the singlet to triplet intersystem crossing in the excited state. Our theoretical study of the D-S-A system may help the design of long persistent luminescent organic devices.

5.
J Forensic Sci ; 2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33904593

RESUMO

In December 2019, a buffer tank burst accident occurred in the maintenance of liquefied natural gas (LNG) bus in China. Failure analysis revealed the bus-mounted buffer tank had been subjected to an excessive internal pressurization, although the tank material met the specifications for engineering practice. The physical evidence related to the failed tank showed that a chemical explosion was impossible. As water was used to pouring the frozen pipeline prior to the accident, according to the consequences observed, the rapid phase transition (RPT) explosion of the residual LNG due to external heat from water was regarded as the main causation of incident. The explosion energy was inversely estimated by the TNT equivalent method, and the rapid expansion of natural gas produced excessive pressure, thus causing the buffer tank to explode.

6.
Chem Commun (Camb) ; 2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33908488

RESUMO

Herein, a novel co-catalytic ferrocene/hemin/G-quadruplexes/Fe3O4 nanoparticles (Fc/HGQs/Fe3O4) nanocomposite was synthesized to significantly magnify the electrochemical signal of ferrocene (Fc) using the synergistic catalysis of hemin/G-quadruplexes (HGQs) and Fe3O4 nanoparticles as hydrogen peroxide enzyme mimics for the construction of ultrasensitive electrochemical biosensors. The fabricated electrochemical biosensor can achieve ultrasensitive detection of miRNA-155 ranging from 0.1 fM to 1 nM, as well as a limit of detection of 74.8 aM. This strategy provides a new route to exploring efficient signal labels for signal amplification and provides an impetus to find novel methods for the construction of biosensors for biological detection and the early clinic diagnosis of diseases.

7.
Med Sci Monit ; 27: e929438, 2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33850093

RESUMO

BACKGROUND Hepatic stellate cells (HSCs) play a vital role in hepatic fibrogenesis. Our recent clinical study indicated that the Zi Qi decoction, a Traditional Chinese Medicine formula, exhibited good efficacy in alleviating liver fibrosis, but the underlying mechanism remains elusive. MATERIAL AND METHODS Rats repeatedly injected with CCl4 and cells stimulated with lipopolysaccharide were used as in vivo and in vitro models for liver fibrosis, respectively. The viability of LX-2 cells was evaluated with MTT assay. Relative messenger RNA (mRNA) expression of representative extracellular matrix (ECM) components was detected with real-time quantitative polymerase chain reaction (RT-qPCR). Moreover, total and phosphorylation levels of ECM proteins and pathway-related proteins were detected with western blotting. Immunofluorescent staining was used to show the nuclear translocation of nuclear factor kappa b (NF-kappaB) p65. Hematoxylin & eosin (H&E) and Masson trichrome staining and immunohistochemistry were performed to evaluate the extent of liver fibrosis. The levels of alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyl transpeptidase (GGT), Hyp, tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) were tested with an enzyme-linked immunosorbent assay. In addition, 7.0T micro-magnetic resonance imaging (micro-MRI) was used to evaluate the severity of hepatic damage. RESULTS The Zi Qi decoction inhibited lipopolysaccharide-mediated upregulation of mRNA and protein levels of representative ECM proteins both in vivo and in vitro. The Zi Qi decoction also suppressed activation of the Toll-like receptor 4 (TLR4)-related NF-kappaB signaling pathway and subsequently inhibited the nuclear translocation of activated NF-kappaB. Moreover, another TLR4 downstream pathway, mitogen-activated protein kinase (MAPK), was simultaneously restrained. The results of liver pathology and MRI in rat models also suggested the efficacy of the Zi Qi decoction in attenuating liver damage. CONCLUSIONS The Zi Qi decoction inhibited liver fibrosis by inhibiting the TLR4-related NF-kB and MAPK signaling pathways and preventing activation of HSCs.

8.
Molecules ; 26(8)2021 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-33920637

RESUMO

Colloidal lithography is an efficient and low-cost method to prepare an ordered nanostructure array with new shapes and properties. In this study, square-shaped and cone-shaped Au nanostructures were obtained by 70° angle deposition onto polystyrene bead array with the diameter of 500 nm when a space of 120 nm is created between the neighbor beads by plasma etching. The gaps between the units decrease when the Au deposition time increases, which leads to the polarized enhanced local field, in agreement with the surface-enhanced Raman scattering spectra (SERS) observations and finite-difference time-domain (FDTD) simulations. When the Au deposition time increased to 5 min, 5 nm gaps form between the neighbor units, which gave an enhancement factor of 5 × 109. The SERS chip was decorated for the detection of the liver cancer cell marker Alpha-fetoprotein (AFP) with the detection limit down to 5 pg/mL.

9.
J Am Chem Soc ; 2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33913717

RESUMO

Copper is currently the material with the most promise as catalyst to drive carbon dioxide (CO2) electroreduction to produce value-added multicarbon (C2+) compounds. However, a copper catalyst on a carbon-based gas diffusion layer electrode often has poor stability-especially when performing at high current densities-owing to electrolyte flooding caused by the hydrophobicity decrease of the gas diffusion layer during operation. Here, we report a bioinspired copper catalyst on a gas diffusion layer that mimics the unique hierarchical structuring of Setaria's hydrophobic leaves. This hierarchical copper structure endows the CO2 reduction electrode with sufficient hydrophobicity to build a robust gas-liquid-solid triple-phase boundary, which can not only trap more CO2 close to the active copper surface but also effectively resist electrolyte flooding even under high-rate operation. We consequently achieved a high C2+ production rate of 255 ± 5.7 mA cm-2 with a 64 ± 1.4% faradaic efficiency, as well as outstanding operational stability at 300 mA cm-2 over 45 h in a flow reactor, largely outperforming its wettable copper counterparts.

10.
Rev. bras. med. esporte ; 27(spe): 69-72, Mar. 2021. tab, graf
Artigo em Inglês | LILACS-Express | LILACS | ID: biblio-1156150

RESUMO

ABSTRACT With the deepening of urban public sports service construction in China, the construction of public sports service system has become an important guarantee for mass sports rights in China. In view of this, this study takes City XX as an example, and analyzes the difference of public sports service construction in this city using the Theil index method, and determines the measurement index. It analyzes the equality degree of service resource allocation among and within the four regions of City XX, including A, B, C, D, and so on. The influencing factors of sports service efficiency are analyzed. The results show that there are significant differences in the allocation of public sports service resources among districts and counties of City XX. From the overall difference, the total Theil index of national fitness and sports clubs showed an upward trend, while others showed a downward trend. From the perspective of regional differences, there were 6 indicators with the highest equalization level in area C and 5 indicators in area A. The lowest level was found. Population density, per capita GDP, aging rate and urbanization rate of city XX have obvious positive correlations with public sports service efficiency. The aging rate is the most positive factor, while per capita GDP and population density have little influence. This study can provide some reference value for other cities in China in the construction of public sports services.


RESUMO Com o aprofundamento da construção de serviços públicos desportivos urbanos na China, a construção de um sistema público de serviço desportivo tornou-se uma importante garantia para o exercício dos direitos desportivos em massa na China. Em vista disso, este estudo toma a Cidade XX como exemplo, e analisa a diferença de construção de serviços públicos desportivo nessa Cidade pelo método índice de Theil, e determina o índice de medição. Analisa o grau de igualdade de alocação de recursos entre e dentro das quatro regiões da Cidade XX, incluindo as regiões A, B, C, D, e assim por diante. Os fatores que influenciam a eficiência do serviço esportivo são analisados. Os resultados mostram que há diferenças significativas na alocação de recursos públicos de serviços esportivos entre os distritos e condados da Cidade XX. A partir da diferença global, o índice total serviços de atividades físicas em âmbito nacional e clubes desportivos mostrou uma tendência ascendente, enquanto outros mostraram uma tendência descendente. Sob a perspectiva das diferenças regionais, havia seis indicadores com o mais alto nível de equalização na área C e 5 indicadores na área A. O nível mais baixo foi encontrado. A densidade populacional, o PIB per capita, a taxa de envelhecimento e taxa de urbanização da Cidade XX têm uma correlação positiva óbvia com a eficiência do serviço desportivo público. A taxa de envelhecimento é o fator mais positivo, enquanto o PIB per capita e a densidade populacional têm pouca influência. Este estudo pode fornecer algum valor de referência para outras cidades da China na construção de serviços desportivos públicos.


RESUMEN La profundización de la construcción de servicios deportivos públicos urbanos en China se ha convertido en una garantía importante para los derechos deportivos de masas en China. Ante esto, este estudio toma como ejemplo la Ciudad XX y analiza la diferencia de construcción de servicios públicos deportivos en esta ciudad utilizando el método del índice de Theil y determina el índice de medición. Verifica el grado de igualdad en la asignación de recursos de servicios entre y dentro de las cuatro regiones de la Ciudad XX incluyendo A, B, C, D, etc. También analiza los factores que influyen en la eficiencia del servicio deportivo. Los resultados muestran que existen diferencias significativas en la asignación de los recursos de los servicios deportivos públicos entre los distritos y condados de la Ciudad XX. A partir de la diferencia general, el índice de Theil total de los clubes deportivos y de educación física nacionales mostró una tendencia al alza, mientras que otros mostraron una tendencia a la baja. Desde la perspectiva de las diferencias regionales, se encontraron 6 indicadores con el nivel más alto de igualación en el área C y 5 indicadores en el área A. Se encontró también el nivel más bajo. La densidad de población, el PIB per cápita, la tasa de envejecimiento y la tasa de urbanización de la ciudad XX tienen evidentes correlaciones positivas con la eficiencia de los servicios deportivos públicos. La tasa de envejecimiento es el factor más positivo, mientras que el PIB per cápita y la densidad de población tienen poca influencia. Este estudio puede aportar algún valor de referencia para otras ciudades de China en la construcción de servicios deportivos públicos.

11.
Nat Commun ; 12(1): 1401, 2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33658516

RESUMO

Effective treatments for patients suffering from heat hypersensitivity are lacking, mostly due to our limited understanding of the pathogenic mechanisms underlying this disorder. In the nervous system, activating transcription factor 4 (ATF4) is involved in the regulation of synaptic plasticity and memory formation. Here, we show that ATF4 plays an important role in heat nociception. Indeed, loss of ATF4 in mouse dorsal root ganglion (DRG) neurons selectively impairs heat sensitivity. Mechanistically, we show that ATF4 interacts with transient receptor potential cation channel subfamily M member-3 (TRPM3) and mediates the membrane trafficking of TRPM3 in DRG neurons in response to heat. Loss of ATF4 also significantly decreases the current and KIF17-mediated trafficking of TRPM3, suggesting that the KIF17/ATF4/TRPM3 complex is required for the neuronal response to heat stimuli. Our findings unveil the non-transcriptional role of ATF4 in the response to heat stimuli in DRG neurons.


Assuntos
Fator 4 Ativador da Transcrição/metabolismo , Nociceptividade/fisiologia , Células Receptoras Sensoriais/fisiologia , Canais de Cátion TRPM/metabolismo , Fator 4 Ativador da Transcrição/genética , Animais , Membrana Celular/metabolismo , Quimiocina CXCL12/metabolismo , Gânglios Espinais/citologia , Gânglios Espinais/fisiologia , Células HEK293 , Temperatura Alta , Humanos , Injeções Espinhais , Cinesina/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Técnicas de Patch-Clamp , Transporte Proteico , Receptores CXCR4/metabolismo , Canais de Cátion TRPM/genética
12.
PLoS One ; 16(3): e0248102, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33735257

RESUMO

Rattus tanezumi is a common domestic rat and host of the bubonic plague pathogen in China and Southeast Asia (SEA). The origin, genetic differentiation and dispersal of R. tanezumi have received increasing attention from researchers. The population genetics of R. tanezumi based on its mitochondrial cytochrome b gene have been studied to explain the origin, relationships and dispersal of populations. In this study, we captured a total of 229 rats; morphological and molecular biological identification cytochrome oxidase subunit I (COI) confirmed 131 R. tanezumi individuals collected from 6 provincial areas, and their Cytb gene sequences were analyzed. The results showed that the population in Mohan (MH), Yunnan, had the highest genetic diversity, while that in Ningde (ND), Fujian, had the lowest. Tajima's D statistic for all populations was negative and nonsignificant, indicating the possible expansion of R. tanezumi populations. Low gene flow occurred between the Zhangmu (ZM) R. tanezumi population and other populations, and the genetic differentiation among them was high. Furthermore, our analyses revealed the ZM lineage was the oldest lineage among the groups and diverged ~1.06 Mya, followed by the Luoyang (LY) lineages (~0.51 Mya) and Yunnan lineage (~0.33 Mya). In southeastern Yunnan, the Jinshuihe (JSH) and MH populations were more closely related to the populations in southeastern China (Fuzhou (FZ), ND, Quanzhou (QZ), Nanchang (NC)) and inland areas (Chongqing (CQ), LY) than to those in other areas of Yunnan (Jiegao (JG) and Qingshuihe (QSH)), indicating that R. tanezumi may have spread from southeastern Yunnan to the interior of China. In summary, R. tanezumi may have originated in ZM and adjacent areas, spread to Yunnan, and then spread from the southeast of Yunnan inland or directly eastward from ZM to inland China.

13.
Medicine (Baltimore) ; 100(12): e24884, 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33761646

RESUMO

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent chronic liver disease characterized by excess accumulation of fat in hepatocytes. Because no drug has been approved for NAFLD treatment, this work analyzed the effects of agents resulting from 2 research hotspots, metabolic target agents, and natural plant drugs, on NAFLD with network meta-analysis. METHODS: Public databases were searched through August 14, 2020. Randomized controlled trials that compared obeticholic acid, elafibranor, cenicriviroc, selonsertib, curcumin, silymarin, and resveratrol to placebo were included. Liver pathology improvement, hepatic biochemical indicators, and lipid metabolism indicators were analyzed. RESULTS: Thirty-five studies were included in the meta-analysis. Obeticholic acid was found to significantly increase the frequency of liver biopsy improvement compared to placebo (OR: 2.10; 95% CI: 1.60, 2.77). The ranking results among the hepatic biochemical indicators showed that obeticholic acid (94.9%) and elafibranor (86.3%) have a relative advantage in reducing alanine aminotransferase (ALT) levels, and obeticholic acid also had an advantage (95.4%) in reducing aspartate aminotransferase (AST) levels. Considering lipid metabolic indicators, elafibranor (expSMD: 0.01; 95% CI: 0.00, 0.05; SUCRA: 100%), and obeticholic acid (expSMD: 0.48; 95% CI: 0.28,0.84; SUCRA: 75.6%) significantly reduced triglyceride (TG) levels compared with placebo; moreover, obeticholic acid, but not elafibranor, caused a serious increase in total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels and a decrease in high-density lipoprotein cholesterol (HDL-C) levels. CONCLUSIONS: Novel metabolic targeted agents generally have better effects than natural plant drugs, especially obeticholic acid, and elafibranor. However, obeticholic acid showed serious adverse effects such as increasing LDL-C levels and decreasing HDL-C levels. Curcumin showed potential advantages for NAFLD but lacked statistical significance.


Assuntos
Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Preparações de Plantas/uso terapêutico , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Chalconas/uso terapêutico , Ácido Quenodesoxicólico/efeitos adversos , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/uso terapêutico , HDL-Colesterol/sangue , HDL-Colesterol/efeitos dos fármacos , LDL-Colesterol/sangue , LDL-Colesterol/efeitos dos fármacos , Curcumina/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Humanos , Metanálise em Rede , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/enzimologia , Propionatos/uso terapêutico , Triglicerídeos/sangue
14.
Science ; 371(6536): 1338-1345, 2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33766881

RESUMO

Dearomative cycloaddition reactions represent an ideal means of converting flat arenes into three-dimensional architectures of increasing interest in medicinal chemistry. Quinolines, isoquinolines, and quinazolines, despite containing latent diene and alkene subunits, are scarcely applied in cycloaddition reactions because of the inherent low reactivity of aromatic systems and selectivity challenges. Here, we disclose an energy transfer-mediated, highly regio- and diastereoselective intermolecular [4 + 2] dearomative cycloaddition reaction of these bicyclic azaarenes with a plethora of electronically diverse alkenes. This approach bypasses the general reactivity and selectivity issues, thereby providing various bridged polycycles that previously have been inaccessible or required elaborate synthetic efforts. Computational studies with density functional theory elucidate the mechanism and origins of the observed regio- and diastereoselectivities.


Assuntos
Alcenos/química , Reação de Cicloadição , Hidrocarbonetos Aromáticos/química , Catálise , Transferência de Energia , Estrutura Molecular , Quinolinas/química , Estereoisomerismo
15.
Appl Ergon ; 94: 103400, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33735812

RESUMO

In immersive virtual reality (VR) environments, users rely on the vision channel to search for objects. Such eyes-engaged interactive techniques may significantly degrade the interaction efficiency and user experience, particularly when users have to turn their head frequently to search for a target object in the limited field of view (FOV) of a head-mounted display (HMD). In this study, we systematically investigated user capabilities in eyes-free spatial target acquisition considering different horizontal angles, vertical angles, distances from the user's body, and body sides. Our results show that high acquisition accuracy and low task load are achieved for target locations at front and middle horizontal angles as well as those at middle vertical angles. Meanwhile, a trade-off cannot be achieved between the acquisition accuracy and the task load for target locations at long distances from the user's body. In addition, the acquisition accuracy and task load for the target locations vary with the body side. Our research findings can provide a deeper understanding of user capability in eyes-free target acquisition and offer concrete design guidelines for appropriate target arrangement for eyes-free target acquisition in immersive VR environments.

16.
Molecules ; 26(4)2021 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-33672380

RESUMO

In the present study, a sunflower-like nanostructure array composed of a series of synaptic nanoparticles and nanospheres was manufactured through an efficient and low-cost colloidal lithography technique. The primary electromagnetic field contribution generated by the synaptic nanoparticles of the surface array structures was also determined by a finite-difference time-domain software to simulate the hotspots. This structure exhibited high repeatability and excellent sensitivity; hence, it was used as a surface-enhanced Raman spectroscopy (SERS) active substrate to achieve a rapid detection of ultra-low concentrations of Alpha-fetoprotein (AFP). This study demonstrates the design of a plasmonic structure with strong electromagnetic coupling, which can be used for the rapid detection of AFP concentration in clinical medicine.


Assuntos
Nanoestruturas/química , alfa-Fetoproteínas/análise , Coloides/química , Campos Eletromagnéticos , Tamanho da Partícula , Software , Análise Espectral Raman , Propriedades de Superfície
17.
Adv Healthc Mater ; : e2002036, 2021 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-33644987

RESUMO

Hepatocellular carcinoma (HCC) is one of the most common and deadliest malignancy cancers, which remains a major global health problem. At present, over 50% of patients with HCC have implemented systemic therapies, such as interventional therapy or local chemotherapy that are scarcely effective and induce serious side effects to the remaining normal liver, further limiting their clinical outcomes. Herein, a tumor microenvironment triggered cascade-activation nanoplatform (A-NPLap/TPZ ) is prepared based on ß-lapachone (ß-Lap) and tirapazamine (TPZ) for the synergistic therapy of HCC. The A-NPLap/TPZ exerts its targeting effect by binding to the receptor of tumor cells with an external aptamer. In the tumor microenvironment, the nanoplatform can realize H2 O2 -triggered disassembly to release ß-Lap and TPZ. The released ß-Lap generates ROS to induce tumor cell apoptosis under the catalysis of the tumor cell over-expressed NAD(P)H-quinone oxidoreductase-1 (NQO1) enzyme. In this process, oxygen is consumed to intensify tumor hypoxia, and eventually cascade activates TPZ to exert the anti-tumor effect. The studies in vitro and in vivo consistently demonstrate that the as-prepared A-NPLap/TPZ nanoplatform possesses an excellent synergistic anti-tumor effect. This design of nanoplatform with cascade activation effect provides a promising strategy for HCC treatment.

18.
Interv Neuroradiol ; 27(2): 181-190, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33641496

RESUMO

BACKGROUND: Straightening of parent vessels happens for stent-assisted coiling embolization (SACE) treatment of intracranial aneurysms. This study aims to investigate aneurysmal hemodynamic modifications caused by stent-induced vessel straightening. METHODS: Stent and coil deployments of a SACE-treated distal bifurcation aneurysm by finite element method were performed first with the preoperative (not straightened, NS) and postoperative (straightened, S) vessel models respectively. Computational fluid dynamics were then performed for eight models, including (I) NS only model, (II) NS+stent model, (III) NS+coils model, (IV) NS+stent+coils model, (V) S only model, (VI) S+stent model, (VII) S+coils model, and (VIII) S+stent+coils model. Finally, changes in aneurysmal flow velocity, isovelocity surface and wall shear stress (WSS) were analyzed qualitatively and quantitatively. RESULTS: The flow was less in the S models than that in the corresponding NS models. Coils blocked most of the flow into the aneurysm sac in both NS models and S models and vessel straightening had more profound effect on the high aneurysmal flow volume reduction than coiling, while stenting generated adverse effect on flow reduction. Taking the NS only model as baseline (100%), the sac-averaged velocities of models II to VIII were 112%, 36%, 42%, 45%, 39%, 12%, 13%, and high flow volumes were 119%, 21%, 30%, 10%, 8%, 3%, 3%, while the sac-averaged WSSs were 106%, 37%, 44%, 41%, 35%, 17% and 24%, respectively. CONCLUSIONS: Stent-induced vessel straightening combined coil embolization has the best performance in hemodynamic modifications and may reduce the recurrence rate, whereas stenting may generate adverse effect on hemodynamic alterations.

19.
J Immunother Cancer ; 9(2)2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33637599

RESUMO

BACKGROUND: The advent of immune checkpoint therapy has been a tremendous advance in cancer treatment. However, the responses are still insufficient in patients with soft tissue sarcoma (STS). We aimed to identify rational combinations to increase the response to immune checkpoint therapy and improve survival. METHODS: Whole-exome sequencing (WES) was performed in 11 patients with liposarcoma. Somatic copy number alterations (SCNAs) were analyzed at the gene level to identify obvious amplification patterns in drug-target genes. The expression and prognostic value of class I histone deacetylases (HDACs) was evaluated in 49 patients with sarcoma in our center and confirmed in 263 sarcoma samples from The Tumor Cancer Genome Atlas (TCGA) database. Q-PCR, flow cytometry and RNA-seq were performed to determine the correlations between class I HDACs, chidamide and PD-L1 in vitro and in vivo. The efficacy of combining chidamide with PD-1 blockade was explored in an immunocompetent murine model and a small cohort of patients with advanced sarcoma. Western blot, ChIP assay and dual luciferase assessment were applied in the mechanistic study. RESULTS: The HDAC gene family was frequently amplified in STS. SCNAs in the HDAC gene family were extensively amplified in 8 of 11 (73%) patients with liposarcoma, based on a drug-target gene set, and we verified amplification in 76.65% (197/257) of cases by analyzing TCGA sarcoma cohort. Class I HDAC expression is associated with a poor prognosis for patients with STS, and its inhibition is responsible for promoting apoptosis and upregulating of programmed cell death ligand 1 (PD-L1). The HDAC class I inhibitor chidamide significantly increases PD-L1 expression, increased the infiltration of CD8+ T cells and reduced the number of MDSCs in the tumor microenvironment. The combination of chidamide with an anti-PD-1 antibody significantly promotes tumor regression and improves survival in a murine model. Moreover, chidamide combined with the anti-PD-1 antibody toripalimab is effective in patients with advanced and metastatic sarcoma, and the side effects are tolerable. Mechanistically, chidamide increases histone acetylation at the PD-L1 gene through the activation of the transcriptional factor STAT1. CONCLUSIONS: The combination of chidamide and anti-programmed cell death 1 (PD-1) therapy represents a potentially important strategy for STS.

20.
Angew Chem Int Ed Engl ; 60(12): 6553-6560, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33438257

RESUMO

Although the Turing structures, or stationary reaction-diffusion patterns, have received increasing attention in biology and chemistry, making such unusual patterns on inorganic solids is fundamentally challenging. We report a simple cation exchange approach to produce Turing-type Ag2 Se on CoSe2 nanobelts relied on diffusion-driven instability. The resultant Turing-type Ag2 Se-CoSe2 material is highly effective to catalyze the oxygen evolution reaction (OER) in alkaline electrolytes with an 84.5 % anodic energy efficiency. Electrochemical measurements show that the intrinsic OER activity correlates linearly with the length of Ag2 Se-CoSe2 interfaces, determining that such Turing-type interfaces are more active sites for OER. Combing X-ray absorption and computational simulations, we ascribe the excellent OER performance to the optimized adsorption energies for critical oxygen-containing intermediates at the unconventional interfaces.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...