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Front Cell Dev Biol ; 9: 768970, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34820384

RESUMO

Cadherins play an important role in tissue homeostasis, as they are responsible for cell-cell adhesion during embryogenesis, tissue morphogenesis, and differentiation. In this study, we identified Cadherin-12 (CDH12), which encodes a type II classical cadherin, as a gene that promotes neurite outgrowth in an in vitro model of neurons with differentiated intrinsic growth ability. First, the effects of CDH12 on neurons were evaluated via RNA interference, and the results indicated that the knockdown of CDH12 expression restrained the axon extension of E18 neurons. The transcriptome profile of neurons with or without siCDH12 treatment revealed a set of pathways positively correlated with the effect of CDH12 on neurite outgrowth. We further revealed that CDH12 affected Rac1/Cdc42 phosphorylation in a PKA-dependent manner after testing using H-89 and 8-Bromo-cAMP sodium salt. Moreover, we investigated the expression of CDH12 in the brain, spinal cord, and dorsal root ganglia (DRG) during development using immunofluorescence staining. After that, we explored the effects of CDH12 on neurite outgrowth in vivo. A zebrafish model of CDH12 knockdown was established using the NgAgo-gDNA system, and the vital role of CDH12 in peripheral neurogenesis was determined. In summary, our study is the first to report the effect of CDH12 on axonal extension in vitro and in vivo, and we provide a preliminary explanation for this mechanism.

3.
Molecules ; 26(22)2021 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-34833949

RESUMO

An ionic porous aromatic framework is developed as a self-degraded template to synthesize the magnetic heterostructure of γ-Fe2O3/WO3·0.5H2O. The Fe3O4 polyhedron was obtained with the two-phase method first and then reacted with sodium tungstate to form the γ-Fe2O3/WO3·0.5H2O hybrid nanostructure. Under the induction effect of the ionic porous network, the Fe3O4 phase transformed to the γ-Fe2O3 state and complexed with WO3·0.5H2O to form the n-n heterostructure with the n-type WO3·0.5H2O on the surface of n-type γ-Fe2O3. Based on a UV-Visible analysis, the magnetic photocatalyst was shown to have a suitable band gap for the catalytic degradation of organic pollutants. Under irradiation, the resulting γ-Fe2O3/WO3·0.5H2O sample exhibited a removal efficiency of 95% for RhB in 100 min. The charge transfer mechanism was also studied. After the degradation process, the dispersed powder can be easily separated from the suspension by applying an external magnetic field. The catalytic activity displayed no significant decrease after five recycles. The results present new insights for preparing a hybrid nanostructure photocatalyst and its potential application in harmful pollutant degradation.

4.
Plant Dis ; 2021 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-34763518

RESUMO

Scarlet Beebalm (Monarda didyma) is a perennial ornamental flowering plant in the mint family, Labiatae. Due to low-maintenance, and a long blooming period, it is commonly cultivated in gardens as an ornamental plant in China. In May 2021, a disease was observed on the leaves of a capitals beebalm plant in a Ten Mile Flower Sea in Xiayi county (116°13'8″E, 34°14'45″N), Henan province of China. Symptoms first appeared as nearly circular, small, white, powdery mildew-like spots on the leaves which gradually expand, covering the entire leaves. The lesions spread from the lower leaves to the upper canopy, and the stems were also covered by white mycelia. In severe cases, early defoliation occured. About 30% plants were affected. Representative voucher specimens (SQNUMd04, SQNUDn4) were deposited in the herbarium of Shangqiu Normal University (SQNU), Shangqiu, China. Conidiophores (n = 30) were cylindrical, 92.0 to 142.2 µm long and 10.8 to 14.2 µm wide, and produced 5 to 7 immature conidia in a chain. Foot-cells of conidiophores were mostly curved at the base. Conidia (n = 30) were hyaline, ellipsoid, 23.3 to 29.8 µm (avg. 26.6 µm) long, and 11.2 to 16.9 µm (avg. 14.5µm) width, a length/width ratio of 1.5 to 2.1, and germ tubes were produced at the perihilar position. No chasmothecia were observed. Based on morphological comparison using the description by Scholler et al. (2016) description the fungus was tentatively identified as Golovinomyces monardae (G.S. Nagy) M. Scholler, U. Braun & Anke Schmidt. For molecular identification, DNA was extracted from mycelia and conidia, which were collected by scraping symptomatic leaves.The ITS regions and LSU were amplified using primers ITS1/ITS4 (White et al. 1990) and NL1/NL4 (Horisawa et al. 2013). BLASTn analysis of the (MZ303741) and LSU (MZ305434) sequences showed 100% identity with those of G. monardae (AB307667, LC076800, LC076802, LC076808, and AB077691) reported on Monarda species (Matsuda et al. 2003; Takamatsu et al. 2013; Scholler et al. 2016). Pathogenicity tests were carried out by gently dusting conidia from infected leaves onto healthy leaves of five M. didyma plants and five non-inoculated plants used as controls. After 9 days, typical powdery mildew colonies started to appear on the inoculated leaves while control plants remained disease free. All plants were placed in a greenhouse without temperature and humidity control. Based on morphology, fungus was identified as the same as that used for inoculum, fulfilling Koch's postulates. Although G. monardae has been reported on various genera in the Labiatae and Verbenaceae (Farr and Rossman 2021), to our knowledge, this is the first report of G. monardae causing powdery mildew of Scarlet Beebalm(M. didyma) in China.

5.
Artigo em Inglês | MEDLINE | ID: mdl-34767173

RESUMO

To analyze the association of long-term exposure to air pollution and its attributable risks with the number of tuberculosis (TB) cases notified, a quasi-Poisson regression model combined with a distributed lag nonlinear model (DLNM) was constructed using monthly data on air pollution and TB cases notified in Hong Kong from 1999 to 2018. Nonlinear relationships between PM10, PM2.5, and CO and TB cases notified were identified. The concentrations of PM10, PM2.5, and CO corresponding to the minimum numbers of TB cases notified (the minimum TB notification concentrations, MTNCs) were 58.3 µg/m3, 41.7 µg/m3, and 0.1 mg/m3, respectively. Compared with the MTNCs, the overall cumulative numbers of TB cases notified increased by 76.93% (95% CI: 13.08%, 176.83%), 88.81% (95% CI: 26.09%, 182.71%), and 233.43% (95% CI: 13.56%, 879.03%) for the 95th percentiles of PM10 and PM2.5 and for the 97.5th percentiles of CO, respectively. The TB notification rate attributed to concentration ranges above the 97.5th percentile of PM10, PM2.5, and CO was 3.38% (95% empirical confidence intervals [eCI]: 0.93%, 5.61%), 4.73% (95% eCI: 1.87%, 7.15%), and 3.34% (95% eCI: 0.29%, 5.83%), respectively. Long-term exposure to high concentrations of air pollution in Hong Kong may be associated with increases in the number of TB cases notified for this area.

6.
J Clin Transl Hepatol ; 9(5): 626-634, 2021 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-34722177

RESUMO

Background and Aims: Acute-on-chronic liver failure (ACLF) is acute decompensation of liver function in the setting of chronic liver disease, and characterized by high short-term mortality. In this study, we sought to investigate the clinical course of patients at specific time points, and to propose dynamic prognostic criteria. Methods: We assessed the clinical course of 453 patients with ACLF during a 12-week follow-up period in this retrospective multicenter study. The clinical course of patients was defined as disease recovery, improvement, worsening or steady patterns based on the variation tendency in prothrombin activity (PTA) and total bilirubin (TB) at different time points. Results: Resolution of PTA was observed in 231 patients (51%) at 12 weeks after the diagnosis of ACLF. Among the remaining patients, 66 (14.6%) showed improvement and 156 (34.4%) showed a steady or worsening course. In patients with resolved PTA, the clinical course of TB exhibited resolved pattern in 95.2%, improved in 3.9%, and steady or worse in 0.8%. Correspondingly, in patients with improved PTA, these values for TB were 28.8%, 27.3%, and 43.9%, respectively. In patients with steady or worsening PTA, these values for TB were 5.7%, 32.3%, and 65.6%, respectively. Dynamic prognostic criteria were developed by combining the clinical course of PTA/TB and the clinical outcomes at 4 and 12 weeks after diagnosis in ACLF patients. Conclusions: We propose the following dynamic prognostic criteria: rapid progression, slow progression, rapid recovery, slow recovery, and slow persistence, which lay the foundation for precise prediction of prognosis and the improvement of ACLF therapy.

7.
J Mol Histol ; 52(6): 1189-1204, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34676488

RESUMO

Many species of lizards are capable of tail regeneration. There has been increased interest in the study of lizard tail regeneration in recent years as it is an amenable regeneration model for amniotes. In this study, Gekko japonicus was used as a model to investigate the initiation of vascularization, innervation and myogenesis during tail regeneration. We found that angiogenesis and axon regeneration occurred almost simultaneously within 4 days post amputation. The results showed that the endothelial cells of the original vasculature proliferated and extended into the blastema as capillary vessels, which inter-connected to form a capillary network. The nerve fibers innervated the regenerated tissue from the original spinal cord and dorsal root ganglia, and the fiber bundles increased during 14 days. Regenerating muscle tissues emerged 2 weeks after amputation. PAX3 and PAX7 expression were detected during myogenesis, with PAX7 showing a continuous increase in expression from day 3 until the day 14, whereas PAX3 reached a peak level on day 10 day post amputation, and then declined quickly to level as normal control on day 14. PCNA and PAX3 double-positive satellite cells were observed in the original rostral tissues, indicating the involvement of satellite cell proliferation during tail regeneration. Taken together, these data suggest that tail regeneration in Gekko japonicus involved rapid angiogenesis from the beginning to the day 10 and followed by capillary remodeling. The innervation of regenerated tail was significant on day 4 and increased gradually during regeneration, while the regenerated muscle tissues was obvious on day 14 after amputation.

8.
Comput Methods Programs Biomed ; 211: 106444, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34614451

RESUMO

BACKGROUND: As blood testing is radiation-free, low-cost and simple to operate, some researchers use machine learning to detect COVID-19 from blood test data. However, few studies take into consideration the imbalanced data distribution, which can impair the performance of a classifier. METHOD: A novel combined dynamic ensemble selection (DES) method is proposed for imbalanced data to detect COVID-19 from complete blood count. This method combines data preprocessing and improved DES. Firstly, we use the hybrid synthetic minority over-sampling technique and edited nearest neighbor (SMOTE-ENN) to balance data and remove noise. Secondly, in order to improve the performance of DES, a novel hybrid multiple clustering and bagging classifier generation (HMCBCG) method is proposed to reinforce the diversity and local regional competence of candidate classifiers. RESULTS: The experimental results based on three popular DES methods show that the performance of HMCBCG is better than only use bagging. HMCBCG+KNE obtains the best performance for COVID-19 screening with 99.81% accuracy, 99.86% F1, 99.78% G-mean and 99.81% AUC. CONCLUSION: Compared to other advanced methods, our combined DES model can improve accuracy, G-mean, F1 and AUC of COVID-19 screening.


Assuntos
COVID-19 , Contagem de Células Sanguíneas , Análise por Conglomerados , Humanos , Aprendizado de Máquina , SARS-CoV-2
9.
Neurosci Bull ; 2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34611829

RESUMO

Deficits in the clearance of amyloid ß protein (Aß) by the peripheral system play a critical role in the pathogenesis of sporadic Alzheimer's disease (AD). Impaired uptake of Aß by dysfunctional monocytes is deemed to be one of the major mechanisms underlying deficient peripheral Aß clearance in AD. In the current study, flow cytometry and biochemical and behavioral techniques were applied to investigate the effects of polysaccharide krestin (PSK) on AD-related pathology in vitro and in vivo. We found that PSK, widely used in therapy for various cancers, has the potential to enhance Aß uptake and intracellular processing by human monocytes in vitro. After administration of PSK by intraperitoneal injection, APP/PS1 mice performed better in behavioral tests, along with reduced Aß deposition, neuroinflammation, neuronal loss, and tau hyperphosphorylation. These results suggest that PSK holds promise as a preventive agent for AD by strengthening the Aß clearance by blood monocytes and alleviating AD-like pathology.

10.
Tumour Biol ; 43(1): 249-259, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34602506

RESUMO

BACKGROUND: The etiology of salivary gland tumors is mainly unknown. The anatomical location of the salivary glands, with the mucosal pathway to the oral cavity and its rich microbiome, raises the question of potential viral background. OBJECTIVE: This study focuses on the potential presence of herpes-, polyoma- and parvoviruses in pleomorphic adenoma (PA), recurrent pleomorphic adenoma (RPA) and carcinoma ex pleomorphic adenoma (CaxPA). METHODS: Thirty different viruses were analyzed by PCR-based assays in 68 formalin-fixed paraffin-embedded salivary gland tumors (25 PA, 31 RPA and 12 CaxPA). RESULTS: Virus DNA was detected altogether in 19/68 (28%) tumor samples. Human herpesviruses 6B and 7 (HHV-6B and HHV-7) and Epstein-Barr virus (EBV) were frequently and almost exclusively found in CaxPA (5/12, 7/12, and 3/12, respectively). Within the 7 CaxPA that were virus-positive, 3 samples contained 3, and 1 sample even 4, different viruses. Infrequent viral positivity was shown for parvovirus B19 and cutavirus, as well as Merkel cell and Malawi polyomaviruses. CONCLUSIONS: Our unexpected finding of herpesvirus DNA almost exclusively in CaxPA tissues deserves further in-depth studies.


Assuntos
Adenoma Pleomorfo/virologia , Neoplasias das Glândulas Salivares/virologia , DNA Viral/genética , Infecções por Vírus Epstein-Barr/virologia , Feminino , Herpesviridae/genética , Infecções por Herpesviridae/virologia , Herpesvirus Humano 4/genética , Humanos , Masculino , Pessoa de Meia-Idade , Glândulas Salivares/virologia
11.
Int J Gen Med ; 14: 6787-6793, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34703284

RESUMO

Objective: To investigate the effect of comprehensive treatment on ocular surface function and the visual quality of online teachers with a mild-to-moderate dry eye condition during the early phase of coronavirus disease 2019 (COVID-19). Methods: Secondary school online teachers diagnosed with a mild-to-moderate dry eye disease in our outpatient clinic from February to May 2020 were enrolled in this retrospective cross-section study, and all patients received dry eye comprehensive treatment. A questionnaire survey on eye-use habits, visual quality and dry eye-related indicators was collected before and after treatment (2 and 4 weeks). The changes and the correlations between indicators before and after treatment were compared. Results: A total of 30 patients (15 females and 15 males) were included. After comprehensive treatment, patients had significantly higher central tear meniscus height (TMH), non-invasive first tear film breakup time (NIBUTf) and non-invasive average tear film breakup time (NIBUTav) than those before with statistical significance (P < 0.05). Lower ocular surface disease index (OSDI) and Meibomian gland scores were observed after treatment with statistical significance (P < 0.05). Objective scatter index (OSI), modulation transfer function (MTF) cutoff, strehl ratio (SR), and tear film objective scatter index (TF-OSI) were significantly improved after treatment (P < 0.05). Besides, TF-OSI was positively correlated with the changes in OSDI, Meibomian gland score, eye-use duration and OSI with statistical significance (P < 0.05), while it was negatively correlated with NIBUTf, NIBUTav, the TMH of the central lower eyelid, SR, sleep duration, conjunctival congestion and the MTF cutoff (P < 0.05), respectively. No correlation between TF-OSI and ciliary congestion was found (P > 0.05). Conclusion: Comprehensive treatment could effectively improve the symptoms and visual quality of online teachers with a mild-to-moderate dry eye condition during the early stage of COVID-19 pandemic.

12.
Huan Jing Ke Xue ; 42(11): 5491-5499, 2021 Nov 08.
Artigo em Chinês | MEDLINE | ID: mdl-34708988

RESUMO

The purple soil sloping field is the main cultivated land type in the Three Gorges area, and the soil fertility directly determines crop yield. In order to explore the effects of different fertilization treatments on the soil organic carbon content at different slope positions, field experiments were carried out at the Three Gorges Reservoir Test Station of Chengdu Institute of Mountain and Disasters, Chinese Academy of Sciences. A total of five treatments were set up:no fertilization(CK), conventional fertilization(T1), optimum fertilization(T2), biochar combined with 85% of T2(T3), and straw combined with 85% of T2(T4), to study the differences in soil aggregate composition, soil total organic carbon, soluble organic carbon, and microbial carbon content at different slope positions under different fertilization treatments. The results showed that:①Fertilization increased the content of soil mass and improved the organic carbon content of soil, especially with T3 and T4 treatments. ②The sequence of distribution of soil organic carbon content with CK, T1, and T2 treatments in different slope positions was downslope position>middle slope position>upslope position, while the soil organic carbon content of T3 and T4 treatments was the highest at the middle slope position. ③With the decrease of slope, the soluble organic carbon content of CK, T1, T2, and T3 treated soil showed an increasing trend; the carbon content of CK, T1, T2, and T4 treated soil microorganisms increased; while the distribution of T3 treated soil microbial carbon on the slope was highest at the middle slope followed by the lower slope. In general, both biochar and straw treatments can significantly increase soil carbon content and delay the migration of soil carbon on slopes, which provides guidance for improving the soil quality and reducing water pollution of purple soil dry slopes in the Three Gorges reservoir area.


Assuntos
Carbono , Solo , Fertilização , Fertilizantes/análise
13.
Artigo em Inglês | MEDLINE | ID: mdl-34693603

RESUMO

Ring-opening metathesis polymerization (ROMP) has been regarded as a powerful tool for sequence-controlled polymerization. However, the traditional entropy-driven ROMP of macrocyclic olefins suffers from the lack of ring strain and poor regioselectivity, whereas the relay-ring-closing metathesis polymerization inevitably brings some unnecessary auxiliary structure into each monomeric unit. We developed a macrobicyclic olefin system bearing a sacrificial silyloxide bridge on the α,ß'-positions of the double bond as a new class of sequence-defined monomer for regioselective ROMP. The monomeric sequence information is implanted in the macro-ring, while the small ring, a 3-substituted cyclooctene structure with substantial ring tension, can provide not only narrow polydispersity, but also high regio-/stereospecificity. Besides, the silyloxide bridge can be sacrificially cleaved by desilylation and deoxygenation reactions to provide clean-structured, non-auxiliaried polymers.

14.
Environ Microbiol Rep ; 13(6): 852-861, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34494716

RESUMO

Ectomycorrhiza-associated bacteria, especially endofungal bacterial microbiota (EBM) in the fruiting body, play important roles in driving the establishment and function of ectomycorrhizae. However, the influence of ectomycorrhizal fungus bolete identity on their EBM is still unclear. We analysed the EBM of three different bolete fruiting body species on Thousand Island Lake, including Tylopilus felleus, Tylopilus areolatus and Boletus queletii, and compared them with their corresponding mycosphere soil bacterial microbiota by high-throughput sequencing. The EBM was classified into Bacillus, Pseudomonas, Burkholderia and Stenotrophomonas genera. Proteobacteria, Bacteroidetes and Acidobacteria were predominant in the EBM of bolete fruiting bodies as well as their mycosphere soil, while Firmicutes was significantly higher in the EBM. Moreover, the core microbiome (342 operational taxonomic units) of the EBM was shared among the three bolete fungal species. The relative abundances of gene families related to cell cycle control and nucleotide, coenzyme and lipid metabolism were significantly higher in the EBM than in the corresponding mycosphere soil bacterial microbiota, but there was no difference among the three different boletes. The results suggested that the host identity of ectomycorrhizal fungus boletes could affect the EBM, which might be mainly due to the selection of host fungi for the different functional EBM needed.

16.
Front Pharmacol ; 12: 721988, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34531747

RESUMO

Dihydrotanshinone I (DHT) is a natural component in Salvia miltiorrhiza and has been widely researched for its multiple bioactivities. However, poor solubility and biocompatibility of DHT limit its desirable application for clinical purposes. Herein, DHT was encapsulated with bovine serum albumin (BSA) to enhance bioavailability. Compared to free DHT, DHT-BSA NPs (nanoparticles) showed an improved solubility in normal saline and increased protection against hydrogen peroxide-induced oxidative damage in PC12 cells. In addition, DHT-BSA NPs administered by intravenous injection displayed a significant efficacy in the middle cerebral artery occlusion/reperfusion models, without any impact on the cerebral blood flow. In summary, DHT-BSA NPs show an enhanced bioavailability compared with free DHT and a successful penetration into the central nervous system for stroke therapy, demonstrating their application potential in cardio-cerebrovascular diseases.

17.
Oxid Med Cell Longev ; 2021: 9979706, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34504645

RESUMO

Angiotensin II- (Ang II-) induced cardiac hypertrophy and apoptosis are major characteristics of early-stage heart failure. Choline exerts cardioprotective effects; however, its effects on Ang II-induced cardiomyocyte apoptosis are unclear. In this study, the role and underlying mechanism of choline in regulating Ang II-induced cardiomyocyte apoptosis were investigated using a model of cardiomyocyte apoptosis, which was induced by exposing neonatal rat cardiomyocytes to Ang II (10-6 M, 48 h). Choline promoted heat shock transcription factor 1 (HSF1) nuclear translocation and the intracellular domain of Notch1 (NICD) expression. Consequently, choline attenuated Ang II-induced increases in mitochondrial reactive oxygen species (mtROS) and promotion of proapoptotic protein release from mitochondria, including cytochrome c, Omi/high-temperature requirement protein A2, and second mitochondrial activator of caspases/direct inhibitor of apoptosis-binding protein with low P. The reversion of these events attenuated Ang II-induced increases in cardiomyocyte size and numbers of terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling-positive cells, presumably via type 3 muscarinic acetylcholine receptor (M3AChR). Indeed, downregulation of M3AChR or Notch1 blocked choline-mediated upregulation of NICD and nuclear HSF1 expression, as well as inhibited mitochondrial apoptosis pathway and cardiomyocyte apoptosis, indicating that M3AChR and Notch1/HSF1 activation confer the protective effects of choline. In vivo studies were performed in parallel, in which rats were infused with Ang II for 4 weeks to induce cardiac apoptosis. The results showed that choline alleviated cardiac remodeling and apoptosis of Ang II-infused rats in a manner related to activation of the Notch1/HSF1 pathway, consistent with the in vitro findings. Taken together, our results reveal that choline impedes oxidative damage and cardiomyocyte apoptosis by activating M3AChR and Notch1/HSF1 antioxidant signaling, and suggest a novel role for the Notch1/HSF1 signaling pathway in the modulation of cardiomyocyte apoptosis.

18.
Comput Math Methods Med ; 2021: 2213194, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34545291

RESUMO

Predicting postoperative survival of lung cancer patients (LCPs) is an important problem of medical decision-making. However, the imbalanced distribution of patient survival in the dataset increases the difficulty of prediction. Although the synthetic minority oversampling technique (SMOTE) can be used to deal with imbalanced data, it cannot identify data noise. On the other hand, many studies use a support vector machine (SVM) combined with resampling technology to deal with imbalanced data. However, most studies require manual setting of SVM parameters, which makes it difficult to obtain the best performance. In this paper, a hybrid improved SMOTE and adaptive SVM method is proposed for imbalance data to predict the postoperative survival of LCPs. The proposed method is divided into two stages: in the first stage, the cross-validated committees filter (CVCF) is used to remove noise samples to improve the performance of SMOTE. In the second stage, we propose an adaptive SVM, which uses fuzzy self-tuning particle swarm optimization (FPSO) to optimize the parameters of SVM. Compared with other advanced algorithms, our proposed method obtains the best performance with 95.11% accuracy, 95.10% G-mean, 95.02% F1, and 95.10% area under the curve (AUC) for predicting postoperative survival of LCPs.

19.
Cancer Res ; 2021 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-34548332

RESUMO

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) are the standard-of-care treatment for EGFR-mutant non-small cell lung cancers (NSCLC). However, most patients develop acquired drug resistance to EGFR TKIs. HER3 is a unique pseudokinase member of the ERBB family that functions by dimerizing with other ERBB family members (EGFR and HER2) and is frequently overexpressed in EGFR-mutant NSCLC. Although EGFR TKI resistance mechanisms do not lead to alterations in HER3, we hypothesized that targeting HER3 might improve efficacy of EGFR TKI. HER3-DXd is an antibody-drug conjugate (ADC) comprised of HER3-targeting antibody linked to a topoisomerase I inhibitor currently in clinical development. In this study, we evaluated the efficacy of HER3-DXd across a series of EGFR inhibitor-resistant, patient-derived xenografts and observed it to be broadly effective in HER3-expressing cancers. We further developed a preclinical strategy to enhance the efficacy of HER3-DXd through osimertinib pre-treatment, which increased membrane expression of HER3 and led to enhanced internalization and efficacy of HER3-DXd. The combination of osimertinib and HER3-DXd may be an effective treatment approach and should be evaluated in future clinical trials in EGFR-mutant NSCLC patients.

20.
Front Microbiol ; 12: 700142, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34512576

RESUMO

Continuous monoculture of cucumber (Cucumis sativus L.) typically leads to the frequent incidence of Fusarium wilt caused by Fusarium oxysporum f. sp. cucumerinum (FOC). As potent allelochemicals, phenolic acids are believed to be associated with soilborne diseases. This study aimed to investigate the effect of single or co-inoculation of antagonistic bacteria Bacillus amyloliquefaciens B2 and phenolic acid-degrading fungus Pleurotus ostreatus P5 on the suppression of cucumber Fusarium wilt. The strain B2 was identified as B. amyloliquefaciens based on biochemical, physiological, and 16S rDNA and gyrB gene sequence analyses. Strain B2 showed indole-3-acetic acid (IAA) and siderophore production and phosphate solubilization in in vitro assays. Scanning electron microscope (SEM) imaging showed the ability of strain B2 to adhere to the root surface of cucumber. P. ostreatus P5 could effectively degrade mixed phenolic acids as its sole source of carbon and energy for growth in liquid medium. In a pot experiment, four treatments were established as follows: (1) CK, uninoculated control; (2) B2, inoculation of strain B2; (3) P5, inoculation of strain P5; and (4) B2 + P5, co-inoculation of strain B2 and strain P5. At the end of the 60-day pot experiment, the B2, P5, and B2 + P5 treatments significantly reduced disease incidence by 48.1, 22.2, and 63.0%, respectively, compared to the CK treatment (p < 0.05). All three inoculation treatments significantly increased the growth of cucumber seedlings and suppressed the FOC population compared to the control (p < 0.05). High-performance liquid chromatography (HPLC) analysis showed that total phenolic acids were decreased by 18.9, 35.9, and 63.2% in the B2, P5, and B2 + P5 treatments, respectively. The results from this study suggest that combined application of B. amyloliquefaciens B2 and P. ostreatus P5 could be a promising strategy for suppressing Fusarium wilt and improving plant growth of cucumber seedlings under continuous cropping conditions.

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