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1.
Apoptosis ; 2020 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-32418059

RESUMO

Smac/Diablo is a pro-apoptotic protein via interaction with inhibitors of apoptosis proteins (IAPs) to relieve their inhibition of caspases. Smac mimetic compounds (also known as antagonists of IAPs) mimic the function of Smac/Diablo and sensitize cancer cells to TNF-induced apoptosis. However, the majority of cancer cells are resistant to Smac mimetic alone. Doxorubicin is a widely used chemotherapeutic drug and causes adverse effect of cardiotoxicity in many patients. Therefore, it is important to find strategies of combined chemotherapy to increase chemosensitivity and reduce the adverse effects. Here, we report that doxorubicin synergizes with Smac mimetic to trigger TNF-mediated apoptosis, which is mechanistically distinct from doxorubicin-induced cell death. Doxorubicin sensitizes cancer cells including human pancreatic and colorectal cancer cells to Smac mimetic treatment. The combined treatment leads to synergistic induction of TNFα to initiate apoptosis through activating NF-κB and c-Jun signaling pathways. Knockdown of caspase-8 or knockout of FADD significantly blocked apoptosis synergistically induced by Smac mimetic and doxorubicin, but had no effect on cell death caused by doxorubicin alone. Moreover, Smac mimetic and doxorubicin-induced apoptosis requires receptor-interacting protein kinase 1 (RIPK1) and its deubiquitinating enzyme cylindromatosis (CYLD), not A20. These in vitro findings demonstrate that combination of Smac mimetic and doxorubicin synergistically triggers apoptosis through the TNF/CYLD/RIPK1/FADD/caspase-8 signaling pathway. Importantly, the combined treatment induced in vivo synergistic anti-tumor effects in the xenograft tumor model. Thus, the combined therapy using Smac mimetic and doxorubicin presents a promising apoptosis-inducing strategy with great potential for the development of anti-cancer therapy.

2.
Nat Commun ; 11(1): 2186, 2020 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-32367034

RESUMO

Diabetic cardiomyopathy is a progressive disease in diabetic patients, and myocardial insulin resistance contributes to its pathogenesis through incompletely-defined mechanisms. Striated muscle preferentially expressed protein kinase (SPEG) has two kinase-domains and is a critical cardiac regulator. Here we show that SPEG is phosphorylated on Ser2461/Ser2462/Thr2463 by protein kinase B (PKB) in response to insulin. PKB-mediated phosphorylation of SPEG activates its second kinase-domain, which in turn phosphorylates sarcoplasmic/endoplasmic reticulum calcium-ATPase 2a (SERCA2a) and accelerates calcium re-uptake into the SR. Cardiac-specific deletion of PKBα/ß or a high fat diet inhibits insulin-induced phosphorylation of SPEG and SERCA2a, prolongs SR re-uptake of calcium, and impairs cardiac function. Mice bearing a Speg3A mutation to prevent its phosphorylation by PKB display cardiac dysfunction. Importantly, the Speg3A mutation impairs SERCA2a phosphorylation and calcium re-uptake into the SR. Collectively, these data demonstrate that insulin resistance impairs this PKB-SPEG-SERCA2a signal axis, which contributes to the development of diabetic cardiomyopathy.

3.
Vet Res ; 51(1): 61, 2020 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-32381067

RESUMO

Hsp40/DnaJ family proteins play important roles in the infection process of various viruses. Porcine DNAJB6 (pDNAJB6) is a major member of this family, but its role in modulating the replication of porcine circovirus type 2 (PCV2) is still unclear. In the present study, pDNAJB6 was found to be significantly upregulated by PCV2 infection, and confirmed to be interacted with PCV2 capsid (Cap) protein and co-localized at both cytoplasm and nucleus in the PCV2-infected cells. Knockout of pDNAJB6 significantly reduced the formation of autophagosomes in PCV2-infected cells or in the cells expressing Cap protein, whereas overexpression of pDNAJB6 showed an opposite effect. In addition, the domain mapping assay showed that the J domain of pDNAJB6 (amino acids (aa) 1-99) and the C terminus of Cap (162-234 aa) were required for the interaction of pDNAJB6 with Cap. Notably, the interaction of pDNAJB6 with Cap was very important to promoting the formation of autophagosomes induced by PCV2 infection or Cap expression and enhancing the replication of PCV2. Taken together, the results presented here show a novel function of pDNAJB6 in regulation of porcine circovirus replication that pDNAJB6 enhances the formation of autophagy to promote viral replication through interacting with viral capsid protein during PCV2 infection.

4.
Biomed Res Int ; 2020: 6152925, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32280692

RESUMO

A STRN-ALK fusion protein has been recently identified as a potential therapeutic target in multiple cancers; however, the role of STRN alone in regulating the biological function of hepatocellular carcinoma (HCC) remains unclear. In this study, we firstly detected an overexpression of STRN in HCC tissues compared to that in adjacent nontumour (ANT) tissues through IHC analysis, and the expression level of this protein was positively correlated with lymph node metastasis and TNM stage. In vitro, high expression of STRN was also confirmed in different HCC cell lines, and regulation of STRN expression in Huh7 cells did not significantly affect tumour cell proliferation or apoptosis but was positively correlated with tumour cell invasion and migration capacities. Moreover, both the knockdown and overexpression of STRN in Huh7 cells can lead to cell morphological changes that are accompanied with an alteration of epithelial-mesenchymal transition (EMT) molecular markers E-cadherin and Vimentin. Finally, STRN was further proved to be negatively related to E-cadherin expression but positively related to Vimentin expression in human HCC tissue samples. Taken together, STRN is upregulated in HCC and acts as a tumour promoter regulating cell invasion and migration through facilitating the EMT process.

5.
Biomed Chromatogr ; : e4857, 2020 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-32307730

RESUMO

Owing to its unpredictable side effects and efficacy, the anticancer drug docetaxel requires improved characterisation of its pharmacokinetic profiles through population pharmacokinetic (PPK) studies. A sensitive and rugged liquid chromatography-tandem mass spectrometry method for the detection of docetaxel in human plasma was developed and optimised using paclitaxel as an internal standard (IS). The plasma samples underwent rapid extraction using Hybrid solid-phase extraction-protein precipitation. The analyte and IS were separated with an isocratic system on a Zorbax Eclipse Plus C18 column using water containing 0.05% acetic acid along with 20 µM sodium acetate and methanol (30/70, v/v) as the mobile phase. Quantification was performed with a triple quadrupole mass spectrometer through multiple reaction monitoring in positive mode, using the m/z 830.3→548.8 and m/z 876.3→307.7 transitions for docetaxel and paclitaxel, respectively. The range of the calibration curve was 1-500 ng/mL for docetaxel and the linear correlation coefficient was greater than 0.99. The accuracies ranged from -4.6% to 4.2%, and the precision was no higher than 7.0% for the analytes. No significant matrix effect was observed. Both docetaxel and the IS showed considerable recovery. This method was finally applied to the establishment of a PPK model to optimise the clinical use of docetaxel.

6.
BMC Infect Dis ; 20(1): 271, 2020 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-32264839

RESUMO

BACKGROUND: Hand, foot, and mouth disease (HFMD) is a common infectious disease occurring in children under 5 years of age worldwide, and Enterovirus A71 (EV-A71) and Coxsackievirus A16 (CVA-16) are identified as the predominant pathogens. In recent years, Coxsackievirus A6 (CVA-6) and Coxsackievirus A10 (CVA-10) have played more and more important role in a series of HFMD outbreaks. This study aimed to understand the epidemic characteristics associated with HFMD outbreak in Guangzhou, 2018. METHODS: The clinical and laboratory data of 1220 enterovirus-associated HFMD patients in 2018 were analysed in this study. Molecular diagnostic methods were performed to identify its serotypes. Phylogenetic analyses were depicted based on the complete VP1 gene. RESULTS: There were 21 enterovirus serotypes detected in Guangzhou in 2018. Three serotypes of enterovirus, CVA-6 (364/1220, 29.8%), CVA-10 (305/1220, 25.0%), and CVA-16 (397/1220, 32.5%), were identified as the causative pathogens and accounted for 87.3% among all 1220 HFMD patients. In different seasons, CVA-6 was the predominant pathogen of HFMD during autumn, and CVA-10 as well as CVA-16 were more prevalent in summer. Patients infected by CVA-6, CVA-10 or CVA-16 showed similar clinical features and laboratory characteristics, and the ratios of severe HFMD were 5.8, 5.9, and 1.5% in the three serotypes. Phylogenetic analyses of VP1 sequences showed that the CVA-6, CVA-10, and CVA-16 sequences belonged to the sub-genogroup E2, genogroup E, and genogroup B1, respectively. CONCLUSIONS: CVA-6, CVA-10, and CVA-16 were the predominant and co-circulated serotypes in Guangzhou China, 2018, which should be the new target for prevention and control of HFMD. Our findings provide useful information for diagnosis, treatment, and prevention of HFMD.

7.
Nanotechnology ; 2020 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-32325440

RESUMO

Co(OH)2 nanosheets/Cu(OH)2 nanorods (Co(OH)2 Nss/Cu(OH)2 Nrs) composite electrode for non-enzymatic glucose sensing was fabricated by electrodepositing Co(OH)2 Nss on Cu(OH)2 nanorods substrate grown directly on the copper sheet via a simple one-step reaction. The Co(OH)2 Nss/Cu(OH)2 Nrs composite electrode was characterized by scanning electron microscopy, energy dispersive X-ray spectroscopy, X-ray diffraction, X-ray photoelectron spectroscopy. The performance of glucose sensing of the composite electrode was investigated by cyclic voltammetry and chronoamperometry. The composite electrode shows high sensitivity of 2254.2 µA mM-1 cm-2 up to 2 mM with a lower detection limit of 73 nM (S/N = 3). The composite electrode is highly selective to glucose in the presence of various substances always co-existed with glucose in real blood samples. The response of the composite towards human blood serum was in good agreement with that of commercially available glucose sensors, suggesting that a promising electrode material for highly sensitive and selective non enzymatic sensing of glucose can be envisioned.

8.
Curr Med Sci ; 40(2): 307-312, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32337690

RESUMO

Paeoniforin (Pae) is a monoterpenoid glycoside compound and has many biological activities, such as immunosuppression, anti-inflammation and anti-cell proliferation. However, the effects and mechanisms of Pae on chronic heart failure (CHF) remain unclear. This study was conducted to assess the effects and mechanisms of Pae on myocardial fbrosis in isoprenaline (Iso)-induced CHF rats. Pae (20 mg/kg) was intragastrically administrated to CHF rats for 6 weeks. Cardiac structure and function were assessed. The protein and mRNA levels of transforming growth factor ß1 (TGF-ß1) and p38 were detected. Compared to Iso group, Pae could alleviate myocardial fibrosis and improve cardiac function in CHF rats. The levels of collagen volume fraction (13.75%±3.77% vs. 30.97%±4.22%, P<0.001) and perivascular collagen volume area (14.32%±2.50% vs. 28.31%±3.16%, P<0.001) were signifcantly reduced in Pae group as compared with those in Iso group. The expression of TGF-ß1 protein (0.30±0.07 vs. 0.66±0.07, P<0.05) and mRNA (3.51±0.44 vs. 7.58±0.58, P<0.05) decreased signifcantly in Pae group as compared with that in Iso group. The expression of p38 protein (0.36±0.12 vs. 0.81±0.38, P<0.05) and mRNA (3.84±0.05 vs. 4.40±0.17, P<0.05) also decreased markedly in Pae group as compared with that in Iso group. Pae could attenuate myocardial fbrosis and improve cardiac function in CHF rats by down-regulating the p38 MAPK signaling pathway.

9.
J Infect Chemother ; 26(5): 523-526, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32147375

RESUMO

Transmissible gastroenteritis virus (TGEV) and porcine epidemic diarrhea virus (PEDV) are the main pathogens causing viral diarrhea in pig, mixed infections of these two viruses are very common in intensive pig rearing. However, there is a lack of a method to simultaneously detect and distinguish PEDV and TGEV in preclinical levels. In this study, we aimed to establish a dual ultrasensitive nanoparticle DNA probe-based PCR assay (dual UNDP-PCR) based on functionalized magnetic bead enrichment and specific nano-technology amplification for simultaneous detection and distinguish diagnosis of PEDV and TGEV. The detection limit of dual UNDP-PCR for single or multiple infections of PEDV and TGEV is 25 copies/g, which is 400 times more sensitive than the currently known duplex RT-PCR, showing better specificity and sensitivity without cross-reaction with other viruses. For pre-clinical fecal samples, the dual UNDP-PCR showed a markedly higher positive detection rate (52.08%) than conventional duplex RT-PCR (13.21%), can rapidly and accurately identify targeted pathogens whenever simple virus infection or co-infection. In summary, this study provides a technique for detecting and distinguishing PEDV and TGEV in preclinical levels, which is high sensitivity, specificity, repeatability, low cost and broad application prospect.

10.
Cell Transplant ; 29: 963689720913259, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32193953

RESUMO

Due to the lack of animal models and difficulty in obtaining specimens, the study of pathogenesis of moyamoya disease (MMD) almost stagnated. In recent years, endothelial progenitor cells (EPCs) have attracted more and more attention in vascular diseases due to their important role in neovascularization. With the aid of paradigms and methods in cardiovascular diseases research, people began to explore the role of EPCs in the processing of MMD. In the past decade, studies have shown that abnormalities in cell amounts and functions of EPCs were closely related to the vascular pathological changes in MMD. However, the lack of consistent criteria, such as isolation, cultivation, and identification standards, is also blocking the way forward. The goal of this review is to provide an overview of the current situation and controversial issues relevant to studies about EPCs in the pathogenesis and etiology of MMD.

11.
IEEE Trans Cybern ; 2020 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-32112687

RESUMO

Recently, the low-rank and sparse decomposition model (LSDM) has been used for anomaly detection in hyperspectral imagery. The traditional LSDM assumes that the sparse component where anomalies and noise reside can be modeled by a single distribution which often potentially confuses weak anomalies and noise. Actually, a single distribution cannot accurately describe different noise characteristics. In this article, a combination of a mixture noise model with low-rank background may more accurately characterize complex distribution. A modified LSDM, by modeling the sparse component as a mixture of Gaussian (MoG), is employed for hyperspectral anomaly detection. In the proposed framework, the variational Bayes (VB) algorithm is applied to infer a posterior MoG model. Once the noise model is determined, anomalies can be easily separated from the noise components. Furthermore, a simple but effective detector based on the Manhattan distance is incorporated for anomaly detection under complex distribution. The experimental results demonstrate that the proposed algorithm outperforms the classic Reed-Xiaoli (RX), and the state-of-the-art detectors, such as robust principal component analysis (RPCA) with RX.

12.
Cancer Lett ; 475: 14-21, 2020 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-32004573

RESUMO

The upper gastrointestinal (GI) tumors are multifactorial diseases associated with a combination of oncogenes and environmental factors. Currently, surgery, chemotherapy, radiotherapy and immunotherapy are relatively effective treatment options for the patients with these tumors. However, the asymptomatic phenotype of these tumors during the early stages poses as a significant limiting factor to diagnosis and often renders treatments ineffective. Therefore, new early diagnosis and effective therapy for upper GI tumors are urgently needed. Ca2+ is a pivotal intracellular second messenger and plays a crucial role in living cells by regulating several processes from cell division to death. The aberrant Ca2+ homeostasis is related to many human pathological conditions and diseases, including cancer, and thus the changes in the expression and function of plasma membrane Ca2+ permeable channels and sodium/calcium exchangers are frequently described in tumorigenesis and tumor development of the upper GI tract, including voltage-gated Ca2+ channels (VGCC), transient receptor potential (TRP) channels, store-operated channels (SOC) and Na+/Ca2+ exchanger (NCX). This review will summarize the current knowledge about plasma membrane Ca2+ permeable channels and sodium/calcium exchangers in the upper GI tumors and provide a synopsis of recent advancements on the role and involvement of these channels in upper GI tumors as well as a discussion of the possible strategies to target these channels and exchangers for diagnosis and therapy of the upper GI tumors.

13.
Sci Rep ; 10(1): 2961, 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-32076013

RESUMO

Sucrose has long been regarded as the most cariogenic carbohydrate. However, why sucrose causes severer dental caries than other sugars is largely unknown. Considering that caries is a polymicrobial infection resulting from dysbiosis of oral biofilms, we hypothesized that sucrose can introduce a microbiota imbalance favoring caries to a greater degree than other sugars. To test this hypothesis, an in vitro saliva-derived multispecies biofilm model was established, and by comparing caries lesions on enamel blocks cocultured with biofilms treated with sucrose, glucose and lactose, we confirmed that this model can reproduce the in vivo finding that sucrose has the strongest cariogenic potential. In parallel, compared to a control treatment, sucrose treatment led to significant changes within the microbial structure and assembly of oral microflora, while no significant difference was detected between the lactose/glucose treatment group and the control. Specifically, sucrose supplementation disrupted the homeostasis between acid-producing and alkali-producing bacteria. Consistent with microbial dysbiosis, we observed the most significant disequilibrium between acid and alkali metabolism in sucrose-treated biofilms. Taken together, our data indicate that the cariogenicity of sugars is closely related to their ability to regulate the oral microecology. These findings advance our understanding of caries etiology from an ecological perspective.

14.
Ther Drug Monit ; 2020 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-32097248

RESUMO

BACKGROUND: Vancomycin is a critical antibiotic used in important infections, and therapeutic drug monitoring is recommended. Bayesian forecasting is demonstrated to provide an approach that can improve trough concentration monitoring for dose adjustment. The objective of this study was to determine whether therapeutic drug monitoring (TDM) coupled with a Bayesian approach could increase trough concentration target attainment and prevent vancomycin-associated nephrotoxicity in patients with renal insufficiency. METHODS: A prospective study was performed using propensity score matching to provide covariate balance in renal insufficiency patients with gram-positive bacterial infections treated with vancomycin. Patients were divided into non-TDM (84 cases) and TDM (84 cases) groups, and their clinical outcomes were compared. The primary endpoints were probability of trough concentration target attainment and incidence of vancomycin-associated nephrotoxicity. A decision-tree model was developed to assess the cost-effectiveness of TDM to prevent vancomycin-associated nephrotoxicity. RESULTS: Of the 168 eligible patients, 69 from each group (non-TDM and TDM) were matched based on propensity scores. In the matched cohort, trough concentration target attainment was higher with TDM (P = 0.003). Further, reaching toxic trough concentrations was avoided (P = 0.027) in the TDM group. Multivariate logistic regression analysis confirmed that TDM practice independently reduced the incidence of vancomycin-associated nephrotoxicity in renal insufficiency patients (P = 0.021). According to this reduced nephrotoxicity, the incremental cost-effectiveness ratios of ¥22,638 per nephrotoxic episode prevented was found for vancomycin TDM. CONCLUSIONS: TDM coupled with Bayesian forecasting led to an increase in trough concentration target attainment and a decrease in the incidence of vancomycin-associated nephrotoxicity in renal insufficiency patients. In this high-risk population, TDM was demonstrated to be a cost-effective procedure.

15.
Nat Commun ; 11(1): 54, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31911579

RESUMO

The architectural protein CTCF is a mediator of chromatin conformation, but how CTCF binding to DNA is orchestrated to maintain long-range gene expression is poorly understood. Here we perform RNAi knockdown to reduce CTCF levels and reveal a shared subset of CTCF-bound sites are robustly resistant to protein depletion. The 'persistent' CTCF sites are enriched at domain boundaries and chromatin loops constitutive to all cell types. CRISPR-Cas9 deletion of 2 persistent CTCF sites at the boundary between a long-range epigenetically active (LREA) and silenced (LRES) region, within the Kallikrein (KLK) locus, results in concordant activation of all 8 KLK genes within the LRES region. CTCF genome-wide depletion results in alteration in Topologically Associating Domain (TAD) structure, including the merging of TADs, whereas TAD boundaries are not altered where persistent sites are maintained. We propose that the subset of essential CTCF sites are involved in cell-type constitutive, higher order chromatin architecture.


Assuntos
Fator de Ligação a CCCTC/metabolismo , Cromatina/metabolismo , Epigênese Genética , Sítios de Ligação , Fator de Ligação a CCCTC/genética , Cromatina/química , Cromatina/genética , DNA/genética , DNA/metabolismo , Humanos , Regiões Promotoras Genéticas , Ligação Proteica , Domínios Proteicos
16.
Vet Microbiol ; 240: 108502, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31902505

RESUMO

Porcine parvovirus (PPV) is one of the major pathogens causing reproductive failure of swine. However, its specific pathogenesis has not been fully elucidated. Infectious clone is a powerful tool for further studying the pathogenic mechanism of PPV. In the present study, a PPV infectious clone was constructed, and the clone carries His-tag and Flag-tag double-genetic marker at the end of the ns1 gene 3' terminal and vp1 gene 5' terminal, respectively. The PPV DNA fragment F1 (1-182) in 5' end and the other PPV DNA fragment F2 (4788-5074) in 3' end were synthesized and assembled to the lower copy plasmid to construct pKQLL(F1 + F2), while the PPV DNA genome as a template to amplify carrying tags sequence PPV middle DNA fragment F3 and F4 by introducing Flag and His tags sequence in primers. Subsequently, the fused fragment F3/F4 were cloned into the Stu I/Sna B I sites of pKQLL(F1 + F2) plasmid to assemble the complete full-length PPV DNA recombinant plasmids, named as pD-PPV. The pD-PPV was transfected into PK-15 cells to gain rescued PPV virus, designed as D-PPV. Moreover, D-PPV showed similar replicate capability and pathogenicity comparing to the wild-type parental PPV through in vitro and in vivo studies, and the double labels can effectively indicate the expression and localization of viral proteins. Finally, the rescued D-PPV was found to be a convenient tool for antiviral drug screening. These data indicated that the newly established reverse genetic system for PPV would be a useful tool for further studying the pathogenesis mechanisms of PPV, developing labeled vaccine and screening antiviral drug.

17.
Sensors (Basel) ; 20(2)2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31936028

RESUMO

The manual collection of eggs laid on the floor (or 'floor eggs') in cage-free (CF) laying hen housing is strenuous and time-consuming. Using robots for automatic floor egg collection offers a novel solution to reduce labor yet relies on robust egg detection systems. This study sought to develop vision-based floor-egg detectors using three Convolutional Neural Networks (CNNs), i.e., single shot detector (SSD), faster region-based CNN (faster R-CNN), and region-based fully convolutional network (R-FCN), and evaluate their performance on floor egg detection under simulated CF environments. The results show that the SSD detector had the highest precision (99.9 ± 0.1%) and fastest processing speed (125.1 ± 2.7 ms·image-1) but the lowest recall (72.1 ± 7.2%) and accuracy (72.0 ± 7.2%) among the three floor-egg detectors. The R-FCN detector had the slowest processing speed (243.2 ± 1.0 ms·image-1) and the lowest precision (93.3 ± 2.4%). The faster R-CNN detector had the best performance in floor egg detection with the highest recall (98.4 ± 0.4%) and accuracy (98.1 ± 0.3%), and a medium prevision (99.7 ± 0.2%) and image processing speed (201.5 ± 2.3 ms·image-1); thus, the faster R-CNN detector was selected as the optimal model. The faster R-CNN detector performed almost perfectly for floor egg detection under a wide range of simulated CF environments and system settings, except for brown egg detection at 1 lux light intensity. When tested under random settings, the faster R-CNN detector had 91.9-94.7% precision, 99.8-100.0% recall, and 91.9-94.5% accuracy for floor egg detection. It is concluded that a properly-trained CNN floor-egg detector may accurately detect floor eggs under CF housing environments and has the potential to serve as a crucial vision-based component for robotic floor egg collection systems.

18.
Nat Commun ; 11(1): 320, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31949157

RESUMO

Endocrine therapy resistance frequently develops in estrogen receptor positive (ER+) breast cancer, but the underlying molecular mechanisms are largely unknown. Here, we show that 3-dimensional (3D) chromatin interactions both within and between topologically associating domains (TADs) frequently change in ER+ endocrine-resistant breast cancer cells and that the differential interactions are enriched for resistance-associated genetic variants at CTCF-bound anchors. Ectopic chromatin interactions are preferentially enriched at active enhancers and promoters and ER binding sites, and are associated with altered expression of ER-regulated genes, consistent with dynamic remodelling of ER pathways accompanying the development of endocrine resistance. We observe that loss of 3D chromatin interactions often occurs coincidently with hypermethylation and loss of ER binding. Alterations in active A and inactive B chromosomal compartments are also associated with decreased ER binding and atypical interactions and gene expression. Together, our results suggest that 3D epigenome remodelling is a key mechanism underlying endocrine resistance in ER+ breast cancer.


Assuntos
Sítios de Ligação , Neoplasias da Mama/genética , Cromatina/metabolismo , Epigênese Genética , Receptores Estrogênicos/química , Receptores Estrogênicos/metabolismo , Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/metabolismo , Fator de Ligação a CCCTC/química , Fator de Ligação a CCCTC/metabolismo , Cromatina/química , Cromatina/genética , Metilação de DNA , Epigênese Genética/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Células MCF-7 , Proteínas de Neoplasias/genética , Regiões Promotoras Genéticas/efeitos dos fármacos , Domínios e Motivos de Interação entre Proteínas , Sequenciamento Completo do Genoma
19.
J Clin Pharm Ther ; 45(1): 72-80, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31468555

RESUMO

WHAT IS KNOWN AND OBJECTIVE: Caspofungin is commonly used in kidney transplant patients for prophylaxis or treatment of invasive fungal infections (IFIs) caused by Candida spp. and Aspergillus spp. Factors such as concomitant medications, co-morbidity and rejection often cause caspofungin pharmacokinetic parameters alterations in kidney transplant patients. Here, we aimed to investigate factors influencing caspofungin plasma concentrations and evaluate its prophylaxis and treatment efficiency for IFIs in kidney transplant patients. METHODS: The prophylaxis and treatment efficiency of caspofungin for IFIs were assessed in 164 kidney transplant patients in the study. Six hundred and fifty-two caspofungin trough concentrations (Cmin ) from the 164 patients were monitored by the liquid chromatography-tandem mass spectrometry method. Basic demographic variables, baseline disease, surgery, rejection, indwelling catheter, coinfection, concomitant medication and other caspofungin-related factors were collected. Univariate and multivariate analyses were used to assess factors influencing caspofungin plasma concentrations. RESULTS AND DISCUSSION: The success rates were 94.96% (132/139) for caspofungin prevention and 80% (20/25) for caspofungin for IFIs. Caspofungin Cmin in the kidney recipients varied largely compared with healthy volunteers (0.10-12.25 mg/L vs. 1.12-1.78 mg/L). Caspofungin Cmin significantly increased in patients with continuous renal replacement therapy before transplantation (P = .001), concomitant medication of cyclosporine A (CsA, P = .009), ALB concentration of > 30 g/L (P = .019). WHAT IS NEW AND CONCLUSION: This is an uncontrolled observational study of caspofungin as prophylaxis or treatment for IFIs in kidney transplant patients. Caspofungin could be an effective and well-tolerated option for antifungal prophylaxis and treatment in kidney transplant patients, and a number of factors could influence caspofungin Cmin in these patients.

20.
World Neurosurg ; 133: 135-141, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31505277

RESUMO

BACKGROUND: The occurrence rate of thoracic spinal stenosis caused by ossification of the ligamentum flavum combined with disk herniation is lower than that of ossified ligamentum flavum in the thoracic spine, and the treatment method has rarely been reported. In this paper, we applied an endoscopic technique to a patient with thoracic spinal stenosis caused by ossification of the ligamentum flavum combined with disk herniation at the T10-11 level. METHODS: We performed surgical decompression of the thoracic spinal cord for a patient diagnosed with thoracic spinal stenosis at the T10-11 level caused by ossification of the ligamentum flavum combined with disk herniation using percutaneous endoscopic surgery via the bilateral translaminar osseous channel approach. Pre- and postoperative computed tomography (CT) scan and magnetic resonance imaging (MRI) examinations were performed, and pre- and postoperative neurologic status was evaluated using the Modified Japanese Orthopaedic Association and visual analog scale scores. RESULTS: The ossified ligamentum flavum and herniated disk material were removed through this osseous channel. Postoperative CT and MRI scanning revealed adequate decompression of the spinal cord at the T10-11 level. The patient was discharged home on postoperative day 3. At 6-month postoperative follow-up, the patient experienced complete resolution of T12 dermatomal numbness. The strength in her bilateral lower extremities improved slightly to grade 5. CONCLUSIONS: We have applied percutaneous endoscopic surgery via bilateral translaminar osseous channels for the treatment of thoracic spinal stenosis caused by ossification of the ligamentum flavum combined with disk herniation. This surgery could provide sufficient decompression for thoracic spinal cord with minimum trauma.


Assuntos
Descompressão Cirúrgica/métodos , Endoscopia/métodos , Deslocamento do Disco Intervertebral/cirurgia , Ligamento Amarelo/patologia , Ossificação Heterotópica/cirurgia , Estenose Espinal/cirurgia , Vértebras Torácicas/cirurgia , Feminino , Humanos , Deslocamento do Disco Intervertebral/complicações , Deslocamento do Disco Intervertebral/patologia , Pessoa de Meia-Idade , Ossificação Heterotópica/complicações , Ossificação Heterotópica/patologia , Estenose Espinal/etiologia , Estenose Espinal/patologia , Resultado do Tratamento
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