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1.
Artigo em Inglês | MEDLINE | ID: mdl-32014387

RESUMO

AIM: The aim of the study was to determine the clinical value of in vitro high-throughput drug sensitivity screening with primary hepatocellular carcinoma cells to select drugs for adjuvant chemotherapy. METHODS: This study included 162 patients who underwent hepatectomy from September 2013 to December 2016. The patients were divided into a drug sensitivity screening group and an empirical treatment group. High-throughput drug sensitivity screening using primary HCC cells was carried out and, based on the test results, effective drugs were selected for treatment. Patients in the empirical group were treated with commonly used drugs, according to the clinicians' preferences. Clinical efficacy, i.e., disease-free survival (DFS) time, was compared between the two groups. RESULTS: Most patients with HCC showed extensive resistance to known chemotherapeutic drugs. However, bortezomib, regorafenib, sorafenib, romidepsin, hydroxycamptothecin and adriamycin+oxaliplatin showed strong anti-HCC activity in the sensitivity assay. Comparing clinical efficacy, the overall median DFS of patients in the drug sensitivity screening group was significantly better than that of patients in the empirical treatment group (17.00±3.80 months vs. 9.00±1.18 months, P=0.001). Median DFS times in the TACE group were 9.00±4.07 months vs. 7.00±1.06 months (P=0.014) and median DFS times in the oral drugs group were 16.80±3.98 months vs. 10.00±0.81 months (P=0.024). Patients DFS was 69.4%, 62.5% at 1-, 2- years, respectively, for patients with drug sensitivity screening, and 48.5%, 37.8% at 1-, 2- years, respectively, for patients with empirical treatment. CONCLUSION: High-throughput drug sensitivity screening can be successfully used to screen chemotherapeutic drugs for efficacy against HCC and the efficacious drugs can be used in postoperative adjuvant chemotherapy of HCC patients. This treatment paradigm is safe and reliable, and improves survival compared with empirical chemotherapy.

2.
Dev Comp Immunol ; 106: 103631, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31991164

RESUMO

The APOBEC proteins play significant roles in the innate and adaptive immune system, probably due to their deaminase activities. Because APOBEC1 (A1) and APOBEC3 (A3) are absent in the chicken genome, we were interested in determining whether chicken APOBEC4 (A4) possessed more complex functions than its mammalian homologs. In this study, chicken A4 (chA4) mRNA was identified and cloned for the first time. Based on bioinformatics analyses, the conserved zinc-coordinating motif (HXE … PC(X)2-6C) was identified on the surface of chA4 and contained highly conserved His97, Glu99, Pro130, Cys131 and Cys138 active sites. The highest expression levels of constitutive chA4 were detected in primary lymphocytes and bursa of Fabricius. Newcastle Disease (ND) is one of the most serious infectious diseases in birds, causing major economic losses to the poultry industry. In vitro, Newcastle Disease Virus (NDV) early infection induced significant increases in chA4 expression in the chicken B cell line, DT40, the macrophage cell line, HD11 and the CD4+ T cell line, MSB-1, but not the fibroblast cell line, DF-1. In vivo, the expression levels of chA4 were up-regulated in several tissues from NDV-infected chickens, especially the thymus, testicles, duodenum and kidney. The high level expression of exogenous chA4 displayed inhibitory effects on NDV and reduced viral RNA in infected cells. Taken together, these data demonstrate that chA4 is involved in the chicken immune system and may play important roles in host anti-viral responses.

3.
Int J Oncol ; 56(2): 470-479, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31894264

RESUMO

microRNAs (miRNAs or miRs) are endogenous noncoding single­stranded RNA molecules that can regulate gene expression by targeting the 3'­untranslated region and play an important role in many biological and pathological processes, such as inflammation and cancer. In this study, we found that miR­20b was significantly increased in human non­small cell lung cancer (NSCLC) cell lines and patient tissues, suggesting that it may possess a carcinogenic role in lung cancer. This miRNA promoted the proliferation, migration and invasion of NSCLC cells by targeting and downregulating the expression of adenomatous polyposis coli (APC), which is a negative regulator of the canonical Wnt signaling pathway. Wnt signaling activation may increase transcription of miR­20b. Therefore, miR­20b and canonical Wnt signaling were coupled through a feed­forward positive feedback loop, forming a biological regulatory circuit. Finally, an in vivo investigation further demonstrated that an increase in miR­20b promoted the growth of cancer cells. Overall, our findings offer evidence that miR­20b may contribute to the development of NSCLC by inhibiting APC via the canonical Wnt signaling pathway.

4.
EMBO Mol Med ; 12(1): e10233, 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31782624

RESUMO

Severe pulmonary infection is a major threat to human health accompanied by substantial medical costs, prolonged inpatient requirements, and high mortality rates. New antimicrobial therapeutic strategies are urgently required to address the emergence of antibiotic resistance and persistent bacterial infections. In this study, we show that the constitutive expression of a native antimicrobial peptide LL-37 in transgenic mice aids in clearing Pseudomonas aeruginosa (PAO1), a major pathogen of clinical pulmonary infection. Orthotopic transplantation of adult mouse distal airway stem cells (DASCs), genetically engineered to express LL-37, into injured mouse lung foci enabled large-scale incorporation of cells and long-term release of the host defense peptide, protecting the mice from bacterial pneumonia and hypoxemia. Further, correlates of DASCs in adult humans were isolated, expanded, and genetically engineered to demonstrate successful construction of an anti-infective artificial lung. Together, our stem cell-based gene delivery therapeutic platform proposes a new strategy for addressing recurrent pulmonary infections with future translational opportunities.

5.
Transbound Emerg Dis ; 67(1): 159-170, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31432620

RESUMO

Although Newcastle disease virus (NDV) has a worldwide distribution, some NDV genotypes have more regional geographical ranges within continents. In this study, we isolated a subgenotype XIIb NDV strain, Goose/CH/GD/E115/2017 (E115), from geese in Guangdong province, Southern China, in 2017. Phylogenetic analysis showed that E115 and six other NDVs from geese in China were grouped under subgenotype XIIb and were distinct from subgenotype XIIa, isolated from chickens in South Africa, and subgenotype XIId, isolated from chickens in Vietnam. To better understand the pathogenicity and transmission of the subgenotype XIIb NDVs from geese in Guangdong province, we inoculated chickens and geese with 106 EID50 of the E115 virus. Eight hours after inoculation, three naïve chickens and three naïve geese were co-housed with the infected chickens or geese to assess intraspecific and interspecific horizontal transmission of the E115 virus. The E115 virus induced significant clinical signs without mortality in chickens, while it was not pathogenic to geese. Intraspecific and interspecific horizontal transmission of the E115 virus was observed among chickens and geese via direct contact. Furthermore, although the current vaccines provided complete protection against disease in chickens after challenging them with the E115 virus, the virus could also be transmitted from vaccinated chickens to naïve contact chickens. Collectively, our findings highlight the need for avoiding the mixing of different bird species to reduce cross-species transmission and for surveillance of NDV in waterfowl.

6.
Biomed Res Int ; 2019: 5240898, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31815144

RESUMO

The aim of our study was to assess the effects of mitochondrial coenzyme Q (MitoQ) on sepsis-induced acute lung injury (ALI) and investigate its possible mechanisms. The cecal ligation and puncture (CLP) method was used to establish a septic ALI model. Rats were randomly divided into Con group, CLP group, MitoQ group, and MitoQ + LY294002 group. The survival rate of the rats was recorded, and the survival rate curve was plotted. Moreover, the ratio of wet/dry weight (W/D) in lung tissue was measured. The activity of myeloperoxidase (MPO) was measured by using the MPO colorimetric activity assay kit. The levels of high-mobility group box 1 (HMGB1) and interleukin-6 (IL-6), macrophage inflammatory protein 2 (MIP2), and keratinocyte chemoattractant (KC) were analyzed by ELISA. The histopathological changes were measured by HE staining, and the lung injury was scored. TUNEL assay was applied to detect the apoptotic cells in lung tissue. The protein expressions were detected by western blot. MitoQ increased the survival rate and alleviated pulmonary edema in septic ALI rats. In addition, MitoQ inhibited the MPO activity and decreased the levels of HMGB1 and IL-6. After treatment with MitoQ, alveolar wall edema, inflammatory cell infiltration, and red blood cell exudation were relieved. MitoQ inhibited cell apoptosis in lung tissue of septic ALI rats. Meanwhile, MitoQ treatment remarkedly increased the expression of p-Akt, p-GSK-3ß, and p-mTOR but decreased Bax, caspase-3, caspase-9, Beclin-1, and LC-3II/LC-3I. The effects of MitoQ were significantly reversed by the PI3K inhibitor (LY294002). Our study demonstrated that MitoQ could protect sepsis-induced acute lung injury by activating the PI3K/Akt/GSK-3ß/mTOR pathway in rats.

7.
Ying Yong Sheng Tai Xue Bao ; 30(11): 3931-3941, 2019 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-31833707

RESUMO

We investigated the community structure of ground-active arthropods as well as vegetation and soil properties in Caragana shrub plantations under grazing and exclosure management across spring, summer and autumn in Yanchi County of Ningxia in northern China. The aim of this study was to uncover the responses of ground-active arthropods in shrub plantations to grazing management in desertified regions. The results showed that: 1) plant height, soil fine sand content, and soil electrical conductivity were significantly lower, whereas soil bulk density and coarse sand were significantly higher in shrub plantations under grazing than exclosure. 2) There were 40 families from 13 orders captured. The dominant groups included Formicidae and Tenebrionidae families, which comprised 68.75% of the total individuals. There were four common groups occupying 20.82% of the total individuals. The remaining 34 groups were relatively rare, only accounting for 10.44% of the total. Across the three seasons, the composition of ground-active arthropod community was significantly different between grazing and exclosure, which indicates the sensitivity and adaptability of ground-active arthropods to environmental changes including grazing management and seasonal changes. 3) There was a significant effect of grazing on total abundance of ground-active arthropods in shrub plantations, with significantly higher values under grazing than under exclosure. There was no significant effect of grazing management on group richness and diversity of ground-active arthropods in shrub plantations. 4) There was a correlation of total abundance, evenness index and the Simpson index with plant abundance, vegetation height, soil moisture, soil pH and electrical conductivity. There was a significant correlation of the Shannon index with vegetation height, soil moisture and soil fine sand. Plant density, and soil pH, soil moisture and soil temperature were the key factors driving the structure of ground-active arthropod communities in shrub plantations under gra-zing management across seasons based on the partial RDA results. It was concluded that the variations of plant height, soil pH, soil moisture and soil temperature under grazing management could result in different ground-active arthropod taxon to changing habitats. The conservation effect of shrub on ground-active arthropod could reduce the negative impacts of grazing. Spring grazing could enhance ground-active arthropod abundances in shrub plantations. It was necessary to pay attention to prevention of insects which are caused by spring grazing in shrub plantations.


Assuntos
Artrópodes , Caragana , Animais , China , Ecossistema , Solo
8.
Biomed Res Int ; 2019: 5049248, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31886221

RESUMO

Background: Rapid on-site evaluation (ROSE) is commonly used to evaluate the adequacy of biopsy materials in fine-needle aspiration; however, the diagnostic performance of ROSE during fiber optic bronchoscopy (FOB) biopsy under direct vision is rarely reported. Here, we evaluated the role of ROSE during FOB biopsy of visible lesion in trachea or bronchi. Methods: The role of ROSE was prospectively evaluated in consecutive bronchoscopy specimens obtained between January 2016 and January 2018. The agreement and accuracy between ROSE and final histopathological interpretation were assessed. The frequency and possible reasons for discrepancy between ROSE and definitive histopathology results were identified. Histological and cytological classification was performed according to the International Association for the Study of Lung Cancer, the American Thoracic Society, and the European Respiratory Society (IASLC/ATS/ERS) criteria of lung ADCs classification. Results: The study enrolled 651 patients, of which 33 were excluded because of insufficient cells. Final diagnosis of malignancy was achieved in 462 cases (74.8%), whereas 156 cases (25.2%) were nonmalignant. ROSE and pathology were well correlated for the diagnosis of squamous cell carcinoma (SCC) (Kappa = 0.718, p < 0.05), adenocarcinoma (AdC) (Kappa = 0.662; p < 0.05) and small cell lung cancer (SCLC) (Kappa = 0.955; p < 0.05). In 24 cases diagnosed as malignant by ROSE and nonmalignant by pathology, the lesion tissues were surgically excised and re-analyzed, and the 24 cases were finally confirmed as malignant by pathology. Conclusions: ROSE technique allows bronchoscopists to obtain viable and adequate material for the diagnosis of histopathology, and provides them with an onsite preliminary diagnosis especially in cases with inconclusive macroscopic appearance. ROSE and pathology should be used in combination to increase the accuracy of diagnosis.

9.
Soft Robot ; 2019 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-31584322

RESUMO

Soft actuators and robotics have been widely researched in recent years mainly due to their compliance to environments and safe interaction with humans. However, the need of tether and low energy efficiency of such actuators/robots has limited their practical applications. This article presents a novel tendon-driven soft actuator concept that has the property of self-pumping, called soft self-pumping actuator (SSPA) in this research. A SSPA is designed by assembling two soft pneumatic actuators (SPAs) face-to-face, whose air chambers are connected by two check valves. Actuation of the SSPA is achieved by tendons that allows precise and untethered control compared with traditional SPAs. The two chambers in the proposed actuators are precharged with air to a desired pressure to enlarge self-stiffness and to facilitate bending. When actuated, one chamber will be compressed and serve as a pump to inject its air into the other chamber, resulting in further bending of the actuator. The airflow involves energy transmission to help the intended actuation, thus improving energy efficiency. In experimental studies, differential chamber air pressure is found to reduce the force in initiating actuator bending. Experimental results have also shown that energy efficiency increase of up to 45% has been achieved compared with the same design but without air transmission. We believe that the proposed concept could lead to more novel designs of controllable and energy saving soft robots.

10.
Biomolecules ; 9(10)2019 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-31547161

RESUMO

The herbicide fomesafen has the advantages of low toxicity and high selectivity, and the target of this compound is protoporphyrinogen IX oxidase (PPO, EC 1.3.3.4). However, this herbicide has a long residual period and can have phytotoxic effects on succeeding crops. To protect maize from fomesafen, a series of thiazole phenoxypyridines were designed based on structure-activity relationships, active substructure combinations, and bioisosterism. Bioassays showed that thiazole phenoxypyridines could improve maize tolerance under fomesafen toxicity stress to varying degrees at a dose of 10 mg·kg-1. Compound 4i exhibited the best effects. After being treated by compound 4i, average recovery rates of growth index exceeded 72%, glutathione content markedly increased by 167% and glutathione S-transferase activity was almost 163% of fomesafen-treated group. More importantly, after being treated by compound 4i, the activity of PPO, the main target enzyme of fomesafen, recovered to 93% of the control level. The molecular docking result exhibited that the compound 4i could compete with fomesafen to bind with the herbicide target enzyme, which consequently attained the herbicide detoxification. The present work suggests that compound 4i could be developed as a potential safener to protect maize from fomesafen.

11.
Ying Yong Sheng Tai Xue Bao ; 30(8): 2691-2698, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31418194

RESUMO

Using an approach of spatial sequence instead of temporal succession, we investigated the variation and driving factors of soil microbial biomass and microbial entropy in desert grasslands across four different desertification stages (grassland, fixed dune, semi-fixed dune and mobile dune) in Yanchi County, Ningxia, China. The results showed that soil microbial biomass carbon, nitrogen and phosphorus reduced by 46.1%, 80.8% and 30.0% from grassland to mobile dunes, respectively. The soil microbial entropy (qMBC, qMBN, and qMBP) decreased but soil-microbial stoichiometry imbalance (C:Nimb, C:Pimb and N:Pimb) generally increased with the development of desertification. There were significantly positive relationship between soil microbial biomass nitrogen and C:Nimb, soil microbial biomass phosphorus and C:Pimb, while negative relationship between soil microbial biomass nitrogen and N:Pimb. The RDA result showed that soil ecological stoichiometry (C:N, C:P) had the strongest negative effect on soil microbial entropy carbon (qMBC). Soil microbial biomass and microbial entropy were significantly affected by desertification in desert grassland.


Assuntos
Pradaria , Microbiologia do Solo , Solo , Biomassa , Carbono , China , Conservação dos Recursos Naturais , Clima Desértico , Entropia , Nitrogênio
12.
Bioinspir Biomim ; 14(6): 066008, 2019 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-31430730

RESUMO

Research on quadrupedal robots inspired by canids or felids have been widely reported and demonstrated. However, none of these legged robots can deal with difficult environments that include water, such as small lakes, streams, rain, mud, flooded terrain, etc. In this paper, we present for the first time a kinematic analysis and a hydrodynamic model of dog paddling motion in a robotic system. The quadrupedal paddling gait of dogs was first analyzed based on underwater video recording. Hydrodynamic drag force analysis in a paddling gait cycle was conducted for a prototype robotic dog. The prototype robotic dog was developed using four pre-charged pneumatics soft actuators with consideration of relative positions of CG (center of gravity) and CB (center of buoyancy) and their dynamic variation in paddling. It was found that such soft actuators have great potential in developing amphibious legged robots, because they are inherently water-tight, anti-rusty, simple in structural design, and have large hydrodynamic advantage due to their mostly hemi-cylindrical shape design. Trotting and paddling of the prototype robotic dog was also demonstrated. It is believed that our findings reported in this research will provide useful guidance in future development of amphibious robotic dogs.

13.
Stem Cells Int ; 2019: 7123078, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281383

RESUMO

Background: This study is aimed at characterizing the human distal airway stem cells (DASCs) and assessing their therapeutic potential in patients with chronic, degenerative lung diseases. These findings will provide a comprehensive understanding for further clinical applications utilizing autologous airway stem cells as therapeutic intervention in respiratory diseases. Methods: DASCs were isolated from healthy subjects or patients diagnosed with bronchiectasis, chronic obstructive pulmonary diseases (COPD), or interstitial lung disease (ILD). Differentiation capacity, a key property of the stem cells, was studied using a novel monolayer differentiation system. The differentiated cells were evaluated for alveolar and bronchial cell marker expression, and the quantified expression level of differentiated cells was further examined for their relationship with age and pulmonary function of the subjects. Results and Conclusions: Differentiation of DASCs and tracheal stem cells (TSCs) yielded an alveolus-like structure and a tube-shaped structure, respectively, with distinct marker gene expression. Additionally, single-cell-derived clones showed diverse differentiation fates, even if the clones arise from identical or different individuals. More importantly, the alveolar differentiation potency was higher in DASCs derived from patients than from healthy people. The differentiation efficiency of DASCs also correlates with age in patients with bronchiectasis and ILD.

14.
J Vis Exp ; (149)2019 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-31329179

RESUMO

Direct control of cellular defined molecular events is important to life science. Recently, studies have demonstrated that femtosecond laser stimulation can simultaneously activate multiple cellular molecular signaling pathways. In this protocol, we show that through coupling femtosecond laser into a confocal microscope, cells can be stimulated precisely by the tightly-focused laser. Some molecular processes that can be simultaneously observed are subsequently activated. We present detailed protocols of the photostimulation to activate extracellular signal regulated kinase (ERK) signaling pathway in Hela cells. Mitochondrial flashes of reactive oxygen species (ROS) and other mitochondrial events can be also stimulated if focusing the femtosecond laser pulse on a certain mitochondrial tubular structure. This protocol includes pretreating cells before photostimulation, delivering the photostimulation by a femtosecond laser flash onto the target, and observing/identifying molecular changes afterwards. This protocol represents an all-optical tool for related biological researches.

15.
BMC Plant Biol ; 19(1): 302, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31291890

RESUMO

BACKGROUND: Nitrogen (N) and potassium (K) are two important mineral nutrients in regulating leaf photosynthesis. Studying the interactive effects of N and K on regulating N allocation and photosynthesis (Pn) of rice leaves will be of great significance for further increasing leaf Pn, photosynthetic N use efficiency (PNUE) and grain yield. We measured the gas exchange of rice leaves in a field experiment and tested different kinds of leaf N based on N morphology and function, and calculated the interactive effects of N and K on N allocation and the PNUE. RESULTS: Compared with N0 (0 kg N ha- 1) and K0 (0 kg K2O ha- 1) treatments, the Pn was increased by 17.1 and 12.2% with the supply of N and K. Compared with N0K0 (0 kg N and 0 kg K2O ha- 1), N0K120 (0 kg N and 120 kg K2O ha- 1) and N0K180 (0 kg N and 180 kg K2O ha- 1), N supply increased the absolute content of photosynthetic N (Npsn) by 15.1, 15.5 and 10.5% on average, and the storage N (Nstore) was increased by 32.7, 64.9 and 72.7% on average. The relative content of Npsn was decreased by 5.6, 12.1 and 14.5%, while that of Nstore was increased by 8.7, 27.8 and 33.8%. Supply of K promoted the transformation of Nstore to Npsn despite the leaf N content (Na) was indeed decreased. Compared with N0K0, N180K0 (180 kg N and 0 kg K2O ha- 1) and N270K0 (270 kg N and 0 kg K2O ha- 1), K supply increased the relative content of Npsn by 17.7, 8.8 and 7.3%, and decreased the relative content of Nstore by 24.2, 11.4 and 8.7% respectively. CONCLUSIONS: This study indicated the mechanism that K supply decreased the Na but increased the Npsn content and then increased leaf Pn and PNUE from a new viewpoint of leaf N allocation. The supply of K promoted the transformation of Nstore to Npsn and increased the PNUE. The decreased Nstore mainly resulted from the decrease of non-protein N. Combined use of N and K could optimize leaf N allocation and maintain a high leaf Npsn content and PNUE.


Assuntos
Nitrogênio/metabolismo , Oryza/fisiologia , Potássio/metabolismo , Grão Comestível/genética , Grão Comestível/crescimento & desenvolvimento , Grão Comestível/fisiologia , Oryza/genética , Oryza/crescimento & desenvolvimento , Fotossíntese , Folhas de Planta/genética , Folhas de Planta/crescimento & desenvolvimento , Folhas de Planta/fisiologia
16.
Ther Adv Med Oncol ; 11: 1758835919849757, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31205508

RESUMO

Background: cKIT kinase overexpression and gain-of-function mutations are the critical pathogenesis of gastrointestinal stromal tumors (GISTs). Although the multiple kinase inhibitors such as imatinib, sunitinib, and regorafenib have been approved for GISTs, the acquisition of polyclonal secondary resistance mutations in KIT is still a limitation for GIST treatment. Here we explored the KIT inhibitory activity of axitinib in preclinical models and describe initial characterization of its activity in GIST patient-derived primary cells. Methods: The activities of axitinib against mutant KIT were evaluated using protein-based assay and a panel of engineered and GIST-derived cell lines. The binding modes of axitinib-KIT/KIT mutants were analyzed. Four primary cells derived from GIST patients were also used to assess the drug response of axitinib. Results: Axitinib exhibited potent activities against a variety of cKIT associated primary and secondary mutations. It displayed better activity against cKIT wild-type, cKIT V559D/A/G, and L576P primary gain-of-function mutations than imatinib, sunitinib, and regorafenib. In addition, it could inhibit imatinib resistant cKIT T670I and V654A mutants in vitro and in vivo GIST preclinical models. Conclusion: Our results provide the basis for extending the application of axitinib to GISTs patients who are unresponsive or intolerant to the current therapies.

17.
Colloids Surf B Biointerfaces ; 181: 379-388, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31170644

RESUMO

The study developed a simple, effective and inexpensive strategy for capturing, enriching and detecting circulating tumor cells (CTCs) by using folic acid (FA) as the targeting molecule instead of antibodies. This work constructed magnetic halloysite nanotubes (MHNTs) coated with biocompatible ß-cyclodextrin (CD), and conjugated to FA via a PEG-Ad linker, to specifically capture the FA receptor (FR)-overexpressing cancer cells. The capture efficiencies of MHNTs@ß-CD@Ad-PEG-FA for the Skov3, Hela and A549 cancer cells were 96.3%, 97.0% and 95.6% respectively. In addition, the nanoparticles were able to capture very low numbers of the cancer cells (25-500 cells/mL) from PBS and whole blood, as well as selectively capture the cancer cells over normal HEK 293 T cells. Furthermore, the captured cells were viable and grew normally in vitro, indicating the future potential of downstream analyses. This approach can be adapted for different CTCs, once the tumor-specific surface markers are identified and the efficacy of targeting ligands is established. Taken together, FA-conjugated MHNTs nanoparticles are a highly promising tool for isolating CTCs for the diagnosis and treatment of cancer.

18.
Sci Rep ; 9(1): 8387, 2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31182773

RESUMO

Identifying influential spreaders in complex networks is crucial in understanding, controlling and accelerating spreading processes for diseases, information, innovations, behaviors, and so on. Inspired by the gravity law, we propose a gravity model that utilizes both neighborhood information and path information to measure a node's importance in spreading dynamics. In order to reduce the accumulated errors caused by interactions at distance and to lower the computational complexity, a local version of the gravity model is further proposed by introducing a truncation radius. Empirical analyses of the Susceptible-Infected-Recovered (SIR) spreading dynamics on fourteen real networks show that the gravity model and the local gravity model perform very competitively in comparison with well-known state-of-the-art methods. For the local gravity model, the empirical results suggest an approximately linear relation between the optimal truncation radius and the average distance of the network.

19.
J Med Chem ; 62(13): 6083-6101, 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31250638

RESUMO

Starting from our previously developed c-KIT kinase inhibitor CHMFL-KIT-8140, through a type II kinase inhibitor binding element hybrid design approach, we discovered a novel c-KIT kinase inhibitor compound 18 (CHMFL-KIT-64), which is potent against c-KIT wt and a broad spectrum of drug-resistant mutants with improved bioavailability. 18 exhibits single-digit nM potency against c-KIT kinase and c-KIT T670I mutants in the biochemical assay and displays great potencies against most of the gain-of-function mutations in the juxtamembrane domain, drug-resistant mutations in the ATP binding pocket (except V654A), and activation loops (except D816V). In addition, 18 exhibits a good in vivo pharmacokinetic (PK) profile in different species including mice, rats, and dogs. It also displays good in vivo antitumor efficacy in the c-KIT T670I, D820G, and Y823D mutant-mediated mice models as well as in the c-KIT wt patient primary cells which are known to be imatinib-resistant. The potent activity against a broad spectrum of clinically important c-KIT mutants combining the good in vivo PK/pharmacodynamic properties of 18 indicates that it might be a new potential therapeutic candidate for gastrointestinal stromal tumors.

20.
Infect Genet Evol ; 75: 103928, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31226331

RESUMO

Increasing numbers of hepatitis-hydropericardium syndrome (HHS) outbreaks associated with Fowl adenovirus 4 (FAdV-4) have been confirmed in several provinces of China since 2015, mainly affecting 3-5-week-old broiler chicks, resulting in significant losses to the poultry industry. However, little is currently known regarding the molecular epidemiology and host specificity of FAdV-4 associated with HHS in Southern China. In the present study, we isolated 37 FAdV-4 strains from 52 suspected cases of HHS (33 from broilers, one from a layer, two from ducks, and one from a mandarin duck) from Guangdong province during 2016 to 2017. All 37 FAdV-4 strains obtained showed 100% identity of hexon genes at the nucleotide level, and also showed 100% nucleotide sequence identities with strains obtained from other provinces such as Shandong, Zhejiang, and Anhui, which grouped into a FAdV-C cluster. To our knowledge, this represents the first report of an FAdV-4 strain (GZ1) from a mandarin duck with HHS. Experimental infection of the GZ1 strain via intramuscular injection led to a 100% mortality rate in 21-day-old specific pathogen-free chickens. These data indicate the possibility of the cross-species transmission of FAdV-4, highlighting the need for implementing strict biosecurity measures to avoid the mixing of different bird species.

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