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1.
Am J Nephrol ; : 1-9, 2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-33596571

RESUMO

BACKGROUND: The relation of tissue and circulating advanced glycation end products (AGEs) with mortality in hemodialysis (HD) patients remains inconclusive. We aimed to investigate the association of serum AGEs (CML) and tissue AGEs estimated by skin autofluorescence (SAF) with all-cause and cardiovascular disease (CVD) mortality, and examine the possible modifiers for the association in HD patients with by far the largest sample size in any similar studies. METHODS: A total of 1,634 HD patients were included from the China Cooperative Study on Dialysis (CCSD), a multicenter prospective cohort study. The primary and secondary outcomes were all-cause mortality and CVD mortality, respectively. RESULTS: The median follow-up duration was 5.2 years. Overall, there was a positive relation of baseline SAF levels with the risk of all-cause mortality (per 1 AU increment, adjusted hazard ratio (HR), 1.30; 95% confidence interval (CI): 1.12, 1.50) and CVD mortality (per 1 AU increment, adjusted HR, 1.36; 95% CI: 1.14, 1.62). Moreover, a stronger positive association between baseline SAF (per 1 AU increment) and all-cause mortality was found in participants with shorter dialysis vintage, or lower C-reactive protein levels (Both p interactions <0.05). Nevertheless, there was no significant association between serum CML and the risk of mortality. CONCLUSIONS: In patients undergoing long-term HD, baseline SAF, but not serum CML, was significantly associated with the risk of all-cause and CVD death.

2.
Biomater Sci ; 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33605949

RESUMO

Non-viral gene delivery vectors with high transfection efficiency both in vitro and in vivo and low cytotoxicity are highly desirable for clinical applications. Herein, a series of guanidine-rich polypeptides bearing hydrophobic amino acid pendants was efficiently prepared via the 1,3-dipolar cycloaddition between azido decorated polypeptide and propargyl functionalized guanidinium and N-acetylamino acids. CD analysis indicated α-helical conformations of all resulting polypeptides in aqueous solution. The guanidine-rich polypeptide/DNA complexes showed significantly enhanced cellular internalization and high cell viability (>90%) in different mammalian cell lines (i.e., HeLa and RAW 264.7) at concentrations of the best performance. The top-performing guanidine-rich polypeptide containing 10% N-acetyl-l-valine pendants outperformed the commercial transfection reagent PEI by 400 times in vitro and 6 times in vivo. This study provides a new guidance for future molecular design of non-viral gene vectors with high delivery efficiency and low cytotoxicity.

3.
PLoS One ; 16(1): e0244606, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33406090

RESUMO

The assessment and prediction of regional water quality are fundamental inputs to environmental planning and watershed ecological management. This paper explored spatiotemporal changes in the correlation of water quality parameters (WQPs) and land-use types (LUTs) in a reticular river network area. Water samples of 44 sampling sites were collected every quarter from 2016 to 2018 and evaluated for dissolved oxygen (DO), total phosphorus (TP), ammonia nitrogen (NH3-N), and permanganate index (CODMn). A redundancy analysis (RDA) and stepwise multiple linear regression (SMLR) were applied to analyze the land-use type impacts on seasonal WQPs at five buffer scales (100, 200, 500, 800, and 1000 m). The Kruskal-Wallis test results revealed significant seasonal differences in NH3-N, TP, CODMn, and DO. The area percentages of farmland, water area and built-up land in the study area were 38.96%, 22.75% and16.20%, respectively, for a combined total area percentage of nearly 80%. Our study showed that orchard land had an especially favorable influence on WQPs. Land-use type impacts on WQPs were more significant during the dry season than the wet season. The total variation explained by LUTs regarding WQPs at the 1 km buffer scale was slightly stronger than at smaller buffer scales. Built-up land had a negative effect on WQPs, but orchard and forest-grassland had a positive effect on WQPs. The effects of water area and farmland on WQPs were complex on different buffer scales. These findings are helpful for improving regional water resource management and environmental planning.

4.
Anal Chem ; 93(4): 2200-2206, 2021 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-33406817

RESUMO

The predicted liquid chromatographic retention times (RTs) of small molecules are not accurate enough for wide adoption in structural identification. In this study, we used the graph neural network to predict the retention time (GNN-RT) from structures of small molecules directly without the requirement of molecular descriptors. The predicted accuracy of GNN-RT was compared with random forests (RFs), Bayesian ridge regression, convolutional neural network (CNN), and a deep-learning regression model (DLM) on a METLIN small molecule retention time (SMRT) dataset. GNN-RT achieved the highest predicting accuracy with a mean relative error of 4.9% and a median relative error of 3.2%. Furthermore, the SMRT-trained GNN-RT model can be transferred to the same type of chromatographic systems easily. The predicted RT is valuable for structural identification in complementary to tandem mass spectra and can be used to assist in the identification of compounds. The results indicate that GNN-RT is a promising method to predict the RT for liquid chromatography and improve the accuracy of structural identification for small molecules.

5.
Nat Commun ; 12(1): 476, 2021 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-33473107

RESUMO

Endonuclease G (ENDOG), a mitochondrial nuclease, is known to participate in many cellular processes, including apoptosis and paternal mitochondrial elimination, while its role in autophagy remains unclear. Here, we report that ENDOG released from mitochondria promotes autophagy during starvation, which we find to be evolutionally conserved across species by performing experiments in human cell lines, mice, Drosophila and C. elegans. Under starvation, Glycogen synthase kinase 3 beta-mediated phosphorylation of ENDOG at Thr-128 and Ser-288 enhances its interaction with 14-3-3γ, which leads to the release of Tuberin (TSC2) and Phosphatidylinositol 3-kinase catalytic subunit type 3 (Vps34) from 14-3-3γ, followed by mTOR pathway suppression and autophagy initiation. Alternatively, ENDOG activates DNA damage response and triggers autophagy through its endonuclease activity. Our results demonstrate that ENDOG is a crucial regulator of autophagy, manifested by phosphorylation-mediated interaction with 14-3-3γ, and its endonuclease activity-mediated DNA damage response.


Assuntos
Autofagia/fisiologia , Dano ao DNA/fisiologia , Endodesoxirribonucleases/genética , Endodesoxirribonucleases/metabolismo , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Proteínas 14-3-3/metabolismo , Animais , Apoptose , Caenorhabditis elegans , Linhagem Celular , Classe III de Fosfatidilinositol 3-Quinases/metabolismo , Drosophila , Técnicas de Inativação de Genes , Células Hep G2 , Humanos , Fígado/metabolismo , Fígado/patologia , Camundongos , Camundongos Knockout , Mitocôndrias/metabolismo , Fosforilação , Transcriptoma , Proteína 2 do Complexo Esclerose Tuberosa/metabolismo
6.
Sci Rep ; 11(1): 2505, 2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33510312

RESUMO

Red blood cells (RBCs) stressed by high temperature are similar to senescent or damaged RBCs in pathological conditions. RBCs can be efficiently labelled with 18F-fluorodeoxyglucose (FDG). The aim of this study was to assess stressed RBCs erythrophagocytosis and organ distribution in vivo with the application of 18F-FDG PET/CT. RBCs were induced under high temperature (48 °C) to prepare stressed RBCs. Fluorescence-activated cell sorting (FACS) was used to analyse reactive oxygen species (ROS) generation, intracellular Ca2+ concentration and membrane phosphatidylserine (PS) externalization of RBCs. 18F-FDG was used to label RBCs and assess the erythrophagocytosis. Finally, 18F-FDG PET/CT was applied to reveal and measure the organ distribution of stressed RBCs in mice. Compared with untreated RBCs, stressed RBCs decreased in cell volume and increased in ROS level, intracellular Ca2+ concentration, and PS exposure. RBCs could be labelled by 18F-FDG. Stressed RBCs tended to be phagocytosed by macrophages via assessment of FACS and radioactivity. 18F-FDG PET/CT imaging showed that stressed RBCs were mainly trapped in spleen, while untreated RBCs remained in circulation system. Thus, stressed RBCs can be effectively labelled by 18F-FDG and tend to be trapped in spleen of mice as assessed by PET/CT.

7.
Medicine (Baltimore) ; 100(1): e24014, 2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33429764

RESUMO

INTRODUCTION: As a hematopoietic carcinogen, benzene induces human leukemia through its active metabolites such as benzoquinone, which may cause oxidative damage to cancer-related nuclear genes by increasing reactive oxygen species (ROS). Mitochondrion is the main regulatory organelle of ROS, genetic abnormality of mitochondrion can impede its regulation of ROS, leading to more severe oxidative damage. Mutations have been related to certain types of cancer in several mitochondrial genes, but they have never been completely analyzed genome-wide in leukemia. PATIENT CONCERNS: The patient was a 52-year-old female who had chronic exposure to benzene for several years. Her symptoms mainly included recurrent dizziness, fatigue, and they had lasted for nearly 8 years and exacerbated in recent weeks before diagnosis. DIAGNOSIS: Samples of peripheral blood were taken from the patient using evacuated tubes with EDTA anticoagulant on the second day of her hospitalization. At the same time blood routine and BCR/ABL genes of leukemic phenotype were tested. Platelets were isolated for mitochondrial DNA (mtDNA) extraction. The genetic analysis of ATP synthase Fo subunit 8 (complex V), ATP synthase Fo subunit 6 (complex V), cytochrome c oxidase subunit 1 (complex IV), cytochrome c oxidase subunit 2 (complex IV), cytochrome c oxidase subunit 3, Cytb, NADH dehydrogenase subunit 1 (complex I) (ND) 1, ND2, ND3, ND4, ND5, ND6, 12S-RNA, 16S-RNA, tRNA-Cysteine, A, N, tRNA-Leucine, E, displacement loop in platelet mtDNA were performed. All the detected gene mutations were validated using the conventional Sanger sequencing method. INTERVENTIONS: The patient received imatinib, a small molecule kinase inhibitor, and symptomatic treatments. OUTCOMES: After 3 months treatment her blood routine test indicators were restored to normal. CONCLUSION: A total of 98 mutations were found, and 25 mutations were frame shift. The ND6 gene mutation rate was the highest among all mutation points. Frame shifts were identified in benzene-induced leukemia for the first time. Many mutations in the platelet mitochondrial genome were identified and considered to be potentially pathogenic in the female patient with benzene-induced leukemia. The mutation rate of platelet mitochondrial genome in the benzene-induced leukemia patient is relatively high, and the complete genome analysis is helpful to fully comprehend the disease characteristics.


Assuntos
Plaquetas/patologia , Leucemia/etiologia , Leucemia/genética , Mitocôndrias/genética , Antineoplásicos/uso terapêutico , Benzeno/efeitos adversos , Exposição Ambiental/efeitos adversos , Feminino , Genoma Mitocondrial/genética , Genoma Mitocondrial/fisiologia , Humanos , Mesilato de Imatinib/uso terapêutico , Pessoa de Meia-Idade , Mitocôndrias/fisiologia
8.
Biomater Sci ; 9(4): 1301-1312, 2021 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-33350407

RESUMO

The discrepancy of surface receptors on cancerous and non-cancerous cells has been regarded as the mainstay of cancer-targeted therapy. However, due to the heterogeneity of tumor cells and the insufficient levels of receptors on the tumor cell surface, the success of cancer cell-targeted therapies is largely limited. Histone deacetylase/cathepsin l-responsive acetylated azidomannose (DCL-AAM) was previously developed to effectively and selectively label cancer cell surfaces with reactive azido groups via sugar metabolism. Herein, the labeling kinetics and generality of DCL-AAM were systematically investigated in varieties of tumor cells in vitro and in SKOV3 xenograft tumors in vivo. Based on this, dibenzocyclooctyne-cisplatin (DBCO-Pt) prodrug was developed, and DCL-AAM-mediated metabolic labeling of SKOV3 cells enhanced the tumor accumulation of DBCO-Pt ∼2 fold via bioorthogonal click chemistry, potentiating the anti-tumor efficacy of cisplatin yet alleviating the systemic toxicity. This work, therefore, provides the experimental and theoretical support for the future design of sugar metabolism-based targeted delivery systems and may provide a promising candidate for the treatment of cancers lacking appropriate biomarkers.

9.
Medicine (Baltimore) ; 99(49): e23380, 2020 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-33285722

RESUMO

BACKGROUND: Heart failure (HF) is one of the primary causes of the increasing public health costs, incidence rate and mortality of heart disease. As treatment options for the HF have evolved, people have a better understanding of overall burden of HF, resulting a more centralized method for the treatment of these patients with chronic diseases. At present, with the rapid progress of medical technology, the nursing mode must be updated accordingly. The objective of this trial is to investigate the effects of the program of nursing care and follow-up on life quality, self-care, and the rehospitalization of patients with HF. METHOD: This is a randomized controlled study to be carried out from November 2020 to March 2021 and was granted through the Ethics Committee of Changshan County People's Hospital (CCPH002376). The patients meet the following criteria will be included: the age of the patients is 18 years and above, and the functional classification is NYHA II or NYHA III. The patients with the following criteria will be excluded: patients who have received the by-pass surgery in the last 6 months; cancer patients are given radiotherapy or chemotherapy; patients with severe renal failure requiring dialysis; patients with chronic obstructive pulmonary disease who need ventilation; and patients with hearing or visual impairment. In our experiment, patient information scale, the life quality scale (The Left Ventricular Dysfunction Scale) and Self-Care of HF Index are utilized for the assessment. All the analyses are implemented with SPSS for Windows Version 20.0. RESULTS: Impact of experimental programs on outcomes will be illustrated in the Table. CONCLUSION: We hypothesize that the nursing care conducted for the HF patients may improve the life quality and self-care. TRIAL REGISTRATION NUMBER: researchregistry 6129.

10.
Sci Rep ; 10(1): 20924, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33262410

RESUMO

Resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) has become the main clinical challenge of advanced lung cancer. This research aimed to explore the role of PARP1-mediated autophagy in the progression of TKI therapy. PARP1-mediated autophagy was evaluated in vitro by CCK-8 assay, clonogenic assay, immunofluorescence, and western blot in the HCC-827, H1975, and H1299 cells treated with icotinib (Ico), rapamycin, and AZD2281 (olaparib) alone or in combination. Our results and GEO dataset analysis confirmed that PARP1 is expressed at lower levels in TKI-sensitive cells than in TKI-resistant cells. Low PARP1 expression and high p62 expression were associated with good outcomes among patients with NSCLC after TKI therapy. AZD2281 and a lysosomal inhibitor reversed resistance to Ico by decreasing PARP1 and LC3 in cells, but an mTOR inhibitor did not decrease Ico resistance. The combination of AZD2281 and Ico exerted a markedly enhanced antitumor effect by reducing PARP1 expression and autophagy in vivo. Knockdown of PARP1 expression reversed the resistance to TKI by the mTOR/Akt/autophagy pathway in HCC-827IR, H1975, and H1299 cells. PARP1-mediated autophagy is a key pathway for TKI resistance in NSCLC cells that participates in the resistance to TKIs. Olaparib may serve as a novel method to overcome the resistance to TKIs.

11.
Mol Med ; 26(1): 112, 2020 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-33225891

RESUMO

BACKGROUND: The oncogenic role of the newly identified lncRNA LUADT1 has been revealed in lung adenocarcinoma. It was reported that LUADT1 plays a critical role in multiple human diseases. This study was carried out to investigate the role of LUADT1 in sepsis. METHODS: Sixty patients with sepsis and sixty healthy volunteers were recruited for this study. Plasma samples were collected from all participants. Human primary coronary artery endothelial cells were also used in this study. The expression of Pim-1, miR-195 and LUADT1 were detected by RT-qPCR. The interaction between miR-195 and LUADT1 was determined by overexpression experiments and luciferase activity assay. Cell apoptosis was detected by flow cytometry. The expression of apoptosis-related protein was detected by Western blotting. RESULTS: Bioinformatics analysis revealed the potential interaction between LUADT1 and miR-195, which was confirmed by dual luciferase reporter assay. LUADT1 was downregulated in patients with sepsis. Moreover, LPS treatment downregulated the expression of LUADT1 in primary cardiac endothelial cells. Overexpression of LUADT1 and miR-195 did not affect the expression of each other in primary cardiac endothelial cells. Interestingly, overexpression of LUADT1 was found to upregulate the expression of Pim-1, a target of miR-195. In addition, it was found that overexpression of LUADT1 and Pim-1 reduced the enhancement effects of miR-195 on LPS-induced cardiac endothelial cell apoptosis. CONCLUSION: In summary, LUADT1 may protect cardiac endothelial cells against apoptosis in sepsis by regulating the miR-195/Pim-1 axis.

12.
J Chromatogr A ; : 461713, 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33229011

RESUMO

Gas chromatography-mass spectrometry (GC-MS) is one of the major platforms for analyzing volatile compounds in complex samples. However, automatic and accurate extraction of qualitative and quantitative information is still challenging when analyzing complex GC-MS data, especially for the components incompletely separated by chromatography. Deep-Learning-Assisted Multivariate Curve Resolution (DeepResolution) was proposed in this study. It essentially consists of convolutional neural networks (CNN) models to determine the number of components of each overlapped peak and the elution region of each compound. With the assistance of the predicted elution regions, the informative regions (such as selective region and zero-concentration region) of each compound can be located precisely. Then, full rank resolution (FRR), multivariate curve resolution-alternating least squares (MCR-ALS) or iterative target transformation factor analysis (ITTFA) can be chosen adaptively to resolve the overlapped components without manual intervention. The results showed that DeepResolution has superior compound identification capability and better quantitative performances when comparing with MS-DIAL, ADAP-GC and AMDIS. It was also found that baseline levels, interferents, component concentrations and peak tailing have little influences on resolution result. Besides, DeepResolution can be extended easily when encountering unknown component(s), due to the independence of each CNN model. All procedures of DeepResolution can be performed automatically, and adaptive selection of resolution methods ensures the balance between resolution power and consumed time. It is implemented in Python and available at https://github.com/XiaqiongFan/DeepResolution.

13.
Eur J Med Chem ; : 112981, 2020 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-33160761

RESUMO

Proteolysis targeting chimera (PROTAC), hijacking protein of interest (POI) and recruiting E3 ligase for target degradation via the ubiquitin-proteasome pathway, is a novel drug discovery paradigm which has been widely used as biological tools and medicinal molecules with the potential of clinical application value. Currently, ARV-110, an orally small molecule PROTAC was designed to specifically target Androgen receptor (AR), firstly enters clinical phase I trials for the treatment of metastatic castration-resistant prostate cancer, which turns a new avenue for the development of PROTAC. We herein provide a detail summary on the latest one year progress of PROTAC target various proteins and elucidate the advantages of PROTAC technology. Finally, the potential challenges of this vibrant field are also discussed.

14.
Materials (Basel) ; 13(21)2020 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-33153012

RESUMO

Reciprocating Upsetting-Extrusion (RUE) deformation process can significantly refine the grains size and weaken the basal plane texture by applying a large cumulative strain to the alloy, which is of great significance to weaken the anisotropy of magnesium (Mg) alloys and increase the application range. In this paper, the Mg-8.27Gd-3.18Y-0.43Zr (wt %) alloy was subjected to isothermal multi-passes RUE. The microstructure and texture evolution, crystal orientation-dependent deformation mechanism of the alloy after deformation were investigated. The results clearly show that with the increase of RUE process, the grains are significantly refined through continuous dynamic recrystallization (CDRX) and discontinuous dynamic recrystallization (DDRX) mechanisms, the uniformity of the microstructure is improved, and the texture intensity is reduced. At the same time, a large number of particle phases are dynamically precipitated during the deformation process, promoting grain refinement by the particle-stimulated nucleation (PSN) mechanism. The typical [10-10] fiber texture is produced after one pass due to the basal plane of the deformed grains with a relatively high proportion is gradually parallel to the ED during extrusion process. However, the texture concentration is reduced compared with the traditional extrusion deformation, indicating that the upsetting deformation has a certain delay effect on the subsequent extrusion texture generation. After three or four passes deformation, the grain orientation is randomized due to the continuous progress of the dynamic recrystallization process.

15.
J Proteomics ; : 104028, 2020 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-33129985

RESUMO

Prunella vulgaris L., better known as 'self-heal', has been extensively used in the traditional system of medicines. To reveal the regulatory mechanism of its development, TMT-based quantitative proteome analysis was performed in the Prunella vulgaris L. spica before and during ripening (Group A and Group B, respectively). This analysis resulted in the identification of 7655 proteins, of which 1910 showed differential abundance between the two groups. Pronounced changes in the proteomic profile included the following: 1) Stress-responsive proteins involved in protecting cells and promoting fruit ripening and seed development were highly abundant during ripening. 2) The degradation of chlorophyll, inhibition of chlorophyll biosynthesis and increased abundance of transketolase occurred simultaneously in the spica of Prunella vulgaris L., resulting in the spica changing color from green to brownish red. 3) The abundance of protein species related to phenylpropanoid biosynthesis mainly increased during ripening, while flavonoid and terpenoid backbone biosynthesis mostly occurred before ripening. SIGNIFICANCE: This study establishes a link between protein profiles and mature phenotypes, which will help to improve our understanding of the molecular mechanisms involved in the maturation of Prunella vulgaris L. at the proteome level and reveal the scientific connotation for the best time to harvest Prunella vulgaris L. This work provides a scientific basis for the production of high-quality medicinal Prunella vulgaris L., as well as a typical demonstration of molecular research used for the harvest period of traditional Chinese medicine. BIOLOGICAL SIGNIFICANCE: This work provided a comprehensive overview on the functional protein profile changes of Prunella vulgaris L. spica at different growing stages, as well as the scientific rationale of Prunella vulgaris L. harvested in summer after brownish red, thus laid an intriguing stepping stone for elucidating the molecular mechanisms of quality development.

16.
Nat Genet ; 52(12): 1384-1396, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33139953

RESUMO

Trimethylated histone H3 lysine 27 (H3K27me3) regulates gene repression, cell-fate determination and differentiation. We report that a conserved bromo-adjacent homology (BAH) module of BAHCC1 (BAHCC1BAH) 'recognizes' H3K27me3 specifically and enforces silencing of H3K27me3-demarcated genes in mammalian cells. Biochemical, structural and integrated chromatin immunoprecipitation-sequencing-based analyses demonstrate that direct readout of H3K27me3 by BAHCC1 is achieved through a hydrophobic trimethyl-L-lysine-binding 'cage' formed by BAHCC1BAH, mediating colocalization of BAHCC1 and H3K27me3-marked genes. BAHCC1 is highly expressed in human acute leukemia and interacts with transcriptional corepressors. In leukemia, depletion of BAHCC1, or disruption of the BAHCC1BAH-H3K27me3 interaction, causes derepression of H3K27me3-targeted genes that are involved in tumor suppression and cell differentiation, leading to suppression of oncogenesis. In mice, introduction of a germline mutation at Bahcc1 to disrupt its H3K27me3 engagement causes partial postnatal lethality, supporting a role in development. This study identifies an H3K27me3-directed transduction pathway in mammals that relies on a conserved BAH 'reader'.

17.
Eur J Med Chem ; : 113023, 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-33248853

RESUMO

A series of pyrido [2, 3-d]pyrimidin-7(8H)-ones were designed and synthesized as new selective orally bioavailable Threonine Tyrosine Kinase (TTK) inhibitors. One of the representative compounds, 5o, exhibited strong binding affinity with a Kd value of 0.15 nM, but was significantly less potent against a panel of 402 wild-type kinases at 100 nM. The compound also potently inhibited the kinase activity of TTK with an IC50 value of 23 nM, induced chromosome missegregation and aneuploidy, and suppressed proliferation of a panel of human cancer cell lines with low µM IC50 values. Compound 5o demonstrated good oral pharmacokinetic properties with a bioavailability value of 45.3% when administered at a dose of 25 mg/kg in rats. Moreover, a combination therapy of 5o with paclitaxel displayed promising in vivo efficacy against the HCT-116 human colon cancer xenograft model in nude mice with a Tumor Growth Inhibition (TGI) value of 78%. Inhibitor 5o may provide a new research tool for further validating therapeutic potential of TTK inhibition.

18.
Bioorg Chem ; 105: 104377, 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33091668

RESUMO

Bruton's tyrosine kinase (BTK), a non-receptor tyrosine kinase, is a member of the Tec kinases family and is essential for B cell receptor (BCR) mediated signaling. BTK inhibitors such as ibrutinib hold a prominent role in the treatment of B cell malignancies. Here we disclose a potent, selective, and covalent BTK inhibitor, HZ-A-005, currently in preclinical development. HZ-A-005 demonstrated dose-dependent activity in two xenograft models of lymphoma in vivo. It showed highly favourable safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles in preclinical studies. On the basis of its potency, selectivity, and covalent mode of inhibition, HZ-A-005 reveals the potential to be a promising BTK inhibitor for a wide range of cancer indications.

19.
Medicine (Baltimore) ; 99(43): e22866, 2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33120826

RESUMO

BACKGROUND: Acute myocardial infarction is a very common disease in the emergency room. Emergency percutaneous coronary intervention (PCI) is the first choice to open infarct-related artery in time to regain the active blood flow of myocardial tissue. Clinical nursing pathway (CNP), namely clinical project, is an original nursing mode with good quality, outstanding efficiency, and low treatment spending, so it has attracted more and more attention. However, few studies have reported the implementation of a CNP in PCIs. The purpose of the protocol is to assess the impact of CNP on the clinical efficacy of transradial emergency PCI. METHODS: This is a randomized controlled, single center trial which will be implemented from January 2021 to June 2021. Hundred samples diagnosed with acute myocardial infarction will be included in this study. It was authorized via the Ethics Committee of Changshan County People's Hospital (CCPH002348). Patients are assigned to the following groups: control group, given normal routine care; CNP group, treated with CNP plan. The time from door to balloon, hospitalization expenses, length of stay, postoperative complications, patients' satisfaction with treatment are compared and analyzed. All data are collected and analyzed by Social Sciences software version 21.0 (SPSS, Inc., Chicago, IL) program. RESULTS: Differences of clinical outcomes between groups (). CONCLUSION: This original evidence-based nursing model can be used as the foundation for further research. TRIAL REGISTRATION NUMBER: researchregistry6030.


Assuntos
Procedimentos Clínicos/estatística & dados numéricos , Infarto do Miocárdio/cirurgia , Intervenção Coronária Percutânea/métodos , Artéria Radial/cirurgia , Doença Aguda , Estudos de Casos e Controles , Serviço Hospitalar de Emergência/estatística & dados numéricos , Feminino , Hospitalização/economia , Humanos , Tempo de Internação , Masculino , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/fisiopatologia , Satisfação do Paciente , Complicações Pós-Operatórias/epidemiologia , Fatores de Tempo , Resultado do Tratamento
20.
BMC Infect Dis ; 20(1): 779, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33081702

RESUMO

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has become a public health emergency of international concern. SARS-CoV-2 RNA detection is the diagnostic criterion for coronavirus disease 2019 (COVID-19). Nevertheless, RNA detection has many limitations, such as being time-consuming and cost-prohibitive, and it must be performed in specialized laboratories. Virus antibody detection is a routine method for screening for multiple viruses, but data about SARS-CoV-2 antibody detection are limited. METHOD: Throat swabs and blood were collected from 67 suspected SARS-CoV-2 infection patients at the Affiliated Hospital of Zunyi Medical University and Zunyi Fourth People's Hospital isolated observation departments. Throat swab samples were subjected to SARS-CoV-2 RNA detection by real-time PCR. Blood was used subjected to SARS-CoV-2 IgG/IgM detection by an enzyme-linked immunosorbent assay (ELISA) and gold immunochromatography assay (GICA). Blood underwent C-reactive protein detection by immunoturbidimetry, and white blood cells, neutrophil percentages and lymphocyte percentages were counted and calculated, respectively. Clinical symptoms, age and lifestyle habits (smoking and drinking) in all patients were recorded. Data were analysed using SPSS version 19. The results were confirmed by T and χ2 tests; correlations with detection results were analysed by kappa coefficients. Odds ratio (OR) and corrected OR values were analysed by logistic regression. P < 0.05 was considered statistically significant. RESULTS: Of the 67 patients included in this study, 26 were SARS-CoV-2 RNA-positive. GICA IgM sensitivity was 50.9% (13/26), and specificity was 90.2% (37/41). ELISA IgM sensitivity was 76.9% (20/26), and specificity was 90.2% (37/41). ELISA IgG sensitivity was 76.9% (20/26), and specificity was 95.1% (39/41). The kappa coefficients between RNA detection and ELISA IgG, ELISA IgM, and GICA IgM results were 0.741 (P < 0.01), 0.681 (P < 0.01) and 0.430 (P < 0.01), respectively. CONCLUSION: Among the candidate blood indicators, serum IgG and IgM detected by ELISA had the best consistency and validity when compared with standard RNA detection; these indicators can be used as potential preliminary screening tools to identify those who should undergo nucleic acid detection in laboratories without RNA detection abilities or as a supplement to RNA detection.


Assuntos
Betacoronavirus/genética , Betacoronavirus/imunologia , Técnicas de Laboratório Clínico , Infecções por Coronavirus/diagnóstico , Ensaio de Imunoadsorção Enzimática/métodos , Pneumonia Viral/diagnóstico , RNA Viral/genética , Reação em Cadeia da Polimerase em Tempo Real/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antivirais/sangue , Estudos de Coortes , Infecções por Coronavirus/virologia , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/virologia , Sensibilidade e Especificidade
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