Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 601
Filtrar
1.
BMJ ; 368: m1091, 2020 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-32217556

RESUMO

OBJECTIVE: To delineate the clinical characteristics of patients with coronavirus disease 2019 (covid-19) who died. DESIGN: Retrospective case series. SETTING: Tongji Hospital in Wuhan, China. PARTICIPANTS: Among a cohort of 799 patients, 113 who died and 161 who recovered with a diagnosis of covid-19 were analysed. Data were collected until 28 February 2020. MAIN OUTCOME MEASURES: Clinical characteristics and laboratory findings were obtained from electronic medical records with data collection forms. RESULTS: The median age of deceased patients (68 years) was significantly older than recovered patients (51 years). Male sex was more predominant in deceased patients (83; 73%) than in recovered patients (88; 55%). Chronic hypertension and other cardiovascular comorbidities were more frequent among deceased patients (54 (48%) and 16 (14%)) than recovered patients (39 (24%) and 7 (4%)). Dyspnoea, chest tightness, and disorder of consciousness were more common in deceased patients (70 (62%), 55 (49%), and 25 (22%)) than in recovered patients (50 (31%), 48 (30%), and 1 (1%)). The median time from disease onset to death in deceased patients was 16 (interquartile range 12.0-20.0) days. Leukocytosis was present in 56 (50%) patients who died and 6 (4%) who recovered, and lymphopenia was present in 103 (91%) and 76 (47%) respectively. Concentrations of alanine aminotransferase, aspartate aminotransferase, creatinine, creatine kinase, lactate dehydrogenase, cardiac troponin I, N-terminal pro-brain natriuretic peptide, and D-dimer were markedly higher in deceased patients than in recovered patients. Common complications observed more frequently in deceased patients included acute respiratory distress syndrome (113; 100%), type I respiratory failure (18/35; 51%), sepsis (113; 100%), acute cardiac injury (72/94; 77%), heart failure (41/83; 49%), alkalosis (14/35; 40%), hyperkalaemia (42; 37%), acute kidney injury (28; 25%), and hypoxic encephalopathy (23; 20%). Patients with cardiovascular comorbidity were more likely to develop cardiac complications. Regardless of history of cardiovascular disease, acute cardiac injury and heart failure were more common in deceased patients. CONCLUSION: Severe acute respiratory syndrome coronavirus 2 infection can cause both pulmonary and systemic inflammation, leading to multi-organ dysfunction in patients at high risk. Acute respiratory distress syndrome and respiratory failure, sepsis, acute cardiac injury, and heart failure were the most common critical complications during exacerbation of covid-19.

2.
Genes Brain Behav ; : e12649, 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32129566

RESUMO

According to traditional Chinese medicine, lily bulb and Rehmannia decoction (LBRD) is a specialized formula for the treatment of "lily disease", the symptoms of which resemble the clinical manifestations of major depression. However, the molecular basis of the antidepressant mechanism of LBRD and the quality marker ingredients of LBRD remain unclear. This study aimed to investigate the quality marker ingredients of LBRD and to show the molecular mechanism of its antidepressant activities. In this study, we adopted the chronic unpredicted mild stress paradigm to construct a depression model. High-performance liquid chromatography (HPLC) was used to determine the levels of the main markers in LBRD. The underlying mechanism of LBRD was explored by measuring neurotransmitter and cytokine levels using enzyme-linked immunosorbent assay, and by quantifying differentially expressed gene (DEG) of transcriptome in the medial prefrontal cortex (mPFC) tissue through RNA sequencing. HPLC results showed that the average levels of quality marker ingredients of LBRD (ferulic acid, dioscin, verbascoside and catalpol) were 0.00079%, 0.00039%, 0.7% and 1.6% (w/w), respectively. LBRD intervention significantly attenuated the depressive phenotype compared with that in the depressed group. LBRD treatment altered the enriched DEGs in the signaling pathways of γ-aminobutyric acid (GABA) and glutamate neurotransmitter, synaptic plasticity and axon guidance, circadian rhythm and neural-immunity. GABAergic and glutamatergic synapses as well as brain-derived neurotrophic factor (BDNF)/TrkB-dependent phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin-1 (mTOR1), might be the main signaling pathways underlying the multi-target therapeutic effects of LBRD against depression.

3.
J Cell Mol Med ; 2020 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-32125766

RESUMO

Hepatocellular carcinoma (HCC) is a main cause of cancer-related deaths globally. Long non-coding RNAs (lncRNAs) play important roles in diverse cancers. Our previous microarray-based lncRNA profiling showed that LINC00467 was highly expressed in HCC. Here, we further explored the expression, role and functional mechanism of lncRNA LINC00467 in HCC. Our findings revealed that LINC00467 was up-regulated in HCC tissues and HCC cell lines. Increased expression of LINC00467 was positively associated with tumour size and vascular invasion. In vitro functional experiments revealed that LINC00467 accelerated HCC cell proliferation, cell cycle progression and migration and reduced HCC cell apoptosis. In vivo functional assays revealed that LINC00467 drove HCC xenograft growth and HCC cell proliferation and repressed HCC cell apoptosis in vivo. Moreover, LINC00467 inhibited NR4A3 post-transcriptionally via interacting with NR4A3 mRNA to form double-stranded RNA, which was further degraded by Dicer. The expression of NR4A3 was inversely associated with LINC00467 in HCC tissues. Functional rescue assays found that restore of NR4A3 expression blocked the oncogenic roles of LINC00467 in HCC. Taken together, our results demonstrated that lncRNA LINC00467 was a novel highly expressed and oncogenic lncRNA in HCC via inhibiting NR4A3. Targeting LINC00467 or enhancing NR4A3 may be potential therapeutic strategies against HCC.

4.
Clin Infect Dis ; 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32161940

RESUMO

BACKGROUND: In December 2019, coronavirus disease 2019 (COVID-19) emerged in Wuhan and rapidly spread throughout China. METHODS: Demographic and clinical data of all confirmed cases with COVID-19 on admission at Tongji Hospital from January 10 to February 12, 2020, were collected and analyzed. The data of laboratory examinations, including peripheral lymphocyte subsets, were analyzed and compared between severe and non-severe patients. RESULTS: Of the 452 patients with COVID-19 recruited, 286 were diagnosed as severe infection. The median age was 58 years and 235 were male. The most common symptoms were fever, shortness of breath, expectoration, fatigue, dry cough and myalgia. Severe cases tend to have lower lymphocytes counts, higher leukocytes counts and neutrophil-lymphocyte-ratio (NLR), as well as lower percentages of monocytes, eosinophils, and basophils. Most of severe cases demonstrated elevated levels of infection-related biomarkers and inflammatory cytokines. The number of T cells significantly decreased, and more hampered in severe cases. Both helper T cells and suppressor T cells in patients with COVID-19 were below normal levels, and lower level of helper T cells in severe group. The percentage of naïve helper T cells increased and memory helper T cells decreased in severe cases. Patients with COVID-19 also have lower level of regulatory T cells, and more obviously damaged in severe cases. CONCLUSIONS: The novel coronavirus might mainly act on lymphocytes, especially T lymphocytes. Surveillance of NLR and lymphocyte subsets is helpful in the early screening of critical illness, diagnosis and treatment of COVID-19.

5.
Am J Transplant ; 2020 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-32181990

RESUMO

The current outbreak of Coronavirus Disease 2019 (COVID-19) has raised great concern worldwide, but its impact on transplant recipients is unknown. We report here the clinical features and therapeutic course of the first reported renal transplant recipient with confirmed COVID-19 pneumonia. This is a 52-year-old man who received kidney transplantation 12 years ago. His overall clinical characteristics (symptoms, laboratory examinations, and chest CT) were similar to those of non-transplanted COVID-19 patients. Following a treatment regimen consisting of reduced immunosuppressant use and low dose methylprednisolone-based therapy, the COVID-19 pneumonia in this long-term immunosuppressive patient was successfully recovered. This effectively treated case has reference value for the future treatment of other transplant patients with COVID-19 pneumonia.

6.
Cell Biochem Funct ; 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-32196715

RESUMO

According to statistics, abnormal regulation of lncRNAs pivotally influences multiple malignant tumours. DLEU2, as one of these lncRNAs, is detected to be related to growth and development of tumours. The molecular mechanisms of DLEU2 in osteosarcoma, however, are still unknown. QRT-PCR was adopted to analyse the correlations of clinicopathological features and prognosis of osteosarcoma cases with DLEU2. The influences of DLEU2 on cell migration and viability were evaluated independently by experiments in vitro and in vivo. Bioinformatics analysis, RNA immunoprecipitation (RIP) assay, and dual luciferase reporter gene assay confirmed the specific binding of DLEU2 to miR-337-3p. Moreover, rescue experiments were carried out to further evaluate the regulatory association between miR-337-3p expression and DLEU2. In osteosarcoma tissues and cells, DLEU2 expression level was raised remarkably in comparison with that in para-carcinoma normal tissues, and DLEU2 high expression had associations with poor prognosis, tumour stages, and TS of osteosarcoma cases. Cell migration ability and viability were blocked by DLEU2 knockdown but enhanced by ectopic DLEU2 expression in vitro and in vivo. Additionally, DLEU2 was found to sponge miR-337-3p and trigger the stimulating effect in osteosarcoma cells, which would be suppressed by miR-337-3p mimics. Furthermore, a negative correlation existed between miR-337-3p expression and DLEU2 in osteosarcoma tissues. This study manifests that DLEU2 sponges miR-337-3p to accelerate tumour growth and is confirmed to be a factor for poor prognosis of osteosarcoma cases. SIGNIFICANCE OF THE STUDY: LncRNA DLEU2 has been reported to be dysregulated in many tumours; however, the functions and underlying mechanism of DLEU2 in osteosarcoma pathogenesis are still unknown. This study is the first to demonstrate the roles of DLEU2 in osteosarcoma and revealed that DLEU2 may serve as a ceRNA to sponge miR-337-3p and then promote the progression of osteosarcoma, providing a potential therapeutic target for osteosarcoma.

7.
Med Sci Monit ; 26: e920855, 2020 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-32150531

RESUMO

BACKGROUND Transplantation of exosomes derived from mesenchymal stem cells (MSCs-Exo) can improve the recovery of neurological function in rats after traumatic brain injury (TBI). We tested a new hypothesis that BDNF-mediated MSCs-Exo could effectively promote functional recovery and neurogenesis of rats after TBI. MATERIAL AND METHOD BMSCs of rats were extracted by whole bone marrow culture, BDNF was added to BMSCs for intervention, supernatant was collected, and exosomes were separated and purified by hypercentrifugation. Exosomes were identified by WB, TEM and particle size analysis and subsequently used in cell and animal experiments. We investigated the recovery of sensorimotor function and spatial learning ability, inflammation inhibition and neuron regeneration in rats after TBI. RESULTS Compared with group MSCs-Exo, group BDNF-mediated MSCs-Exo showed better effects in promoting the recovery of sensorimotor function and spatial learning ability. BDNF-mediated MSCs-Exo successfully inhibited inflammation and promoted neuronal regeneration in vivo and in vitro. We further analyzed miRNA in BDNF-mediated MSCs-Exo and MSCs-Exo, and found that the expression of miR-216a-5p in BDNF-mediated MSCs-Exo was significantly higher than that in MSCs-Exo by qRT-PCR. Rescue experiment indicated that miR-216a-5p has a similar function to BDNF-mediated MSCs-Exo. CONCLUSIONS In conclusion, we found that BDNF-mediated MSCs-Exo can better promote neurogenesis and inhibit apoptosis than MSCs-Exo in rats after TBI, and the mechanism may be related to the high expression of miR-216a-5p.

8.
FASEB J ; 2020 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-32212194

RESUMO

Circadian clock confers temporal control in metabolism, with its disruption leading to the development of insulin resistance. Metabolic substrate utilization in skeletal muscle is coordinated with diurnal nutrient cycles. However, whether the molecular clock is involved in this coordination is largely unknown. Using a myocyte-selective genetic ablation mouse model of the essential clock activator Bmal1, here we identify muscle-intrinsic clock as a sensor of feeding cues to orchestrate skeletal muscle oxidation required for global nutrient flux. Bmal1 in skeletal muscle responds robustly to feeding in vivo and insulin induces its expression. Muscle Bmal1 deficiency impaired the transcriptional control of glucose metabolic pathway, resulting in markedly attenuated glucose utilization and fasting hyperglycemia. Notably, the loss of Bmal1 response to feeding abolished fasting-to-feeding metabolic fuel switch from fatty acids to glucose in skeletal muscle, leading to the activation of energy-sensing pathways for fatty acid oxidation. These altered metabolic substrate oxidations in Bmal1-deficient muscle ultimately depleted circulating lipid levels that prevented hepatic steatosis. Collectively, our findings highlight the key role of the metabolic-sensing function of skeletal muscle clock in partitioning nutrient flux between muscle and liver to maintain whole-body lipid and glucose homeostasis.

9.
Arch Oral Biol ; 113: 104711, 2020 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-32220804

RESUMO

OBJECTIVE: This study aimed to explore the prognostic value and functional role of Prolyl 4-Hydroxylase Subunit Alpha 3 (P4HA3) in head and neck squamous cell carcinoma. METHODS: We downloaded the RNA-Seq dataset of head and neck squamous cell carcinoma for analyzing the expression of P4HA3 and determining its prognostic value. Head and neck squamous cell carcinoma cell lines CAL27 and FaDu were chose for gain- and loss-of-function of P4HA3 tests. mRNA and protein levels of P4HA3 in head and neck squamous cell carcinoma cells were tested by quantitative real-time PCR and western blot respectively. Cell counting Kit-8, clone formation assay, Transwell assay were used to determine the effect of P4HA3 on the proliferative, invasive and migratory capacities of head and neck squamous cell carcinoma cells. RESULTS: Bioinformatics analysis showed that P4HA3 was up-regulated in head and neck squamous cell carcinoma tissues, and had an independent prognostic value for head and neck squamous cell carcinoma patients. The outcomes of gain- and loss-of-function tests illustrated that P4HA3 significantly boosted head and neck squamous cell carcinoma cell proliferative, invasive and migratory abilities. Besides, western blot assay demonstrated that P4HA3 could remarkably activate the epithelial-mesenchymal transition process, with reduced the level of E-cadherin and up-regulated the levels of N-cadherin, Vimentin and Snail. CONCLUSION: We deduce that P4HA3 acts as an oncogene that raises tumor cell viability and metastasis partly by inducing the epithelial-mesenchymal transition process, suggesting that P4HA3 may be considered as a valuable biomarker for head and neck squamous cell carcinoma treatment.

10.
Ecotoxicology ; 2020 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-32088881

RESUMO

As the top-selling herbicide in the world, glyphosate distributes widely in natural environment and its influence on the ecological security and human health has attracted more and more concern. Glutathione S-transferases (GSTs) are a well-characterized superfamily of isoenzymes for cellular defense against exogenous toxic substances and therefore protect organisms from injury. In this study, the complete cDNA sequence of GST gene (named as Dja-GST) in freshwater planarian Dugesia japonica was firstly cloned by means of RACE method. The full-length Dja-GST comprises of 706 nucleotides which encodes a polypeptide of 200 amino acids. Dja-GST has two representative GST domains at the N- and C-termini. The conservative GST-N domain includes G-site Y8, F9, R14, W39, K43, P52 and S64, while the variable GST-C domain contains H-site K104, V156, D159 and L161. Sequence analysis, phylogenetic tree reconstruction and multiple alignment collectively indicate that Dja-GST belongs to the Sigma class of GST superfamily. Also, GST gene expression profile, GST enzymatic activity and MDA content in response to glyphosate exposure were systematically investigated and the correlations among them were analyzed. The results suggest that glyphosate exposure modified the mRNA transcription and enzymatic activity of GST, as well as the MDA content in planarians, indicating that Dja-GST might play an important part in organisms defending against oxidative stress induced by glyphosate. This work lays a molecular foundation for further exploring the exact functions of Dja-GST and gives an important implication for evaluating the ecological environment effects of herbicide glyphosate.

11.
Sci Rep ; 10(1): 1728, 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32015442

RESUMO

Impairment of renal phosphate elimination in chronic kidney disease (CKD) leads to enhanced plasma and tissue phosphate concentration, which in turn up-regulates transcription factor NFAT5 and serum & glucocorticoid-inducible kinase SGK1. The kinase upregulates ORAI1, a Ca2+-channel accomplishing store-operated Ca2+-entry (SOCE). ORAI1 is stimulated following intracellular store depletion by Ca2+-sensors STIM1 and/or STIM2. In megakaryocytes and blood platelets SOCE and thus ORAI1 are powerful regulators of activity. The present study explored whether the phosphate-donor ß-glycerophosphate augments NFAT5, ORAI1,2,3 and/or STIM1,2 expressions and thus SOCE in megakaryocytes. Human megakaryocytic Meg01cells were exposed to 2 mM of phosphate-donor ß-glycerophosphate for 24 hours. Platelets were isolated from blood samples of patients with impaired kidney function or control volunteers. Transcript levels were estimated utilizing q-RT-PCR, cytosolic Ca2+-concentration ([Ca2+]i) by Fura-2-fluorescence, and SOCE from increase of [Ca2+]i following re-addition of extracellular Ca2+ after store depletion with thapsigargin (1 µM). NFAT5 and ORAI1 protein abundance was estimated with Western blots. As a result, ß-glycerophosphate increased NFAT5, ORAI1/2/3, STIM1/2 transcript levels, as well as SOCE. Transcript levels of NFAT5, SGK1, ORAI1/2/3, and STIM1/2 as well as NFAT5 and ORAI1 protein abundance were significantly higher in platelets isolated from patients with impaired kidney function than in platelets from control volunteers. In conclusion, phosphate-donor ß-glycerophosphate triggers a signaling cascade of NFAT5/SGK1/ORAI/STIM, thus up-regulating store-operated Ca2+-entry.

12.
Fish Shellfish Immunol ; 99: 274-283, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32058098

RESUMO

luxS-mediated autoinducer 2 (AI-2)-dependent quorum sensing (QS) has been demonstrated to affect many bacterial phenotypes, including virulence. Streptococcus agalactiae harbors a functional luxS gene required for the biosynthesis of AI-2. In this study, we investigated the regulation effect and mechanism of the luxS/AI-2 QS system in the pathogenicity of the piscine S. agalactiae strain GD201008-001. We found that inactivation of luxS caused a marked decrease in biofilm formation, hemolytic activity, antiphagocytosis and intracellular survival of S. agalactiae. Except for hemolytic activity, the altered phenotypes due to the luxS deletion were AI-2-independent. Further investigation indicated that high levels of the proinflammatory cytokines IL-1ß and IL-6 could be induced in macrophages co-incubated with the luxS deletion mutant and synthetic AI-2, single or combined. Also, the results of tilapia infection showed that inactivation of luxS significantly decreased the virulence of S. agalactiae but upregulated the expression of cytokines in spleens and brains. Increased proinflammatory effects of the luxS mutant were restored in the luxS complemented strain but could not be restored by AI-2 addition. All the findings suggest that luxS is involved in virulence-associated phenotypes and immunological evasion of S. agalactiae, and furthermore, this involvement is mostly AI-2-independent. This study will provide valuable insights into our understanding of the role of the LuxS/AI-2 QS system in the pathogenesis of S. agalactiae.

13.
Sci Rep ; 10(1): 709, 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31959797

RESUMO

Recent evidence suggests that SNARE fusion machinery play critical roles in postsynaptic neurotransmitter receptor trafficking, which is essential for synaptic plasticity. However, the key SNAREs involved remain highly controversial; syntaxin-3 and syntaxin-4 are leading candidates for the syntaxin isoform underlying postsynaptic plasticity. In a previous study, we showed that pyramidal-neuron specific conditional knockout (cKO) of syntaxin-4 significantly reduces basal transmission, synaptic plasticity and impairs postsynaptic receptor trafficking. However, this does not exclude a role for syntaxin-3 in such processes. Here, we generated and analyzed syntaxin-3 cKO mice. Extracellular field recordings in hippocampal slices showed that syntaxin-3 cKO did not exhibit significant changes in CA1 basal neurotransmission or in paired-pulse ratios. Importantly, there were no observed differences during LTP in comparison to control mice. Syntaxin-3 cKO mice performed similarly as the controls in spatial and contextual learning tasks. Consistent with the minimal effects of syntaxin-3 cKO, syntaxin-3 mRNA level was very low in hippocampal and cortex pyramidal neurons, but strongly expressed in the corpus callosum and caudate axon fibers. Together, our data suggest that syntaxin-3 is dispensable for hippocampal basal neurotransmission and synaptic plasticity, and further supports the notion that syntaxin-4 is the major isoform mediating these processes.

14.
Thorac Cancer ; 11(3): 659-671, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31968395

RESUMO

BACKGROUND: Lung adenocarcinoma (LAD) is a highly aggressive malignant tumor which threatens the health and life of the population. Long non-coding RNA X-inactive specific transcript (XIST) and mouse double minute clone 2 (MDM2) are connected with the tumorigenesis of LAD. Nevertheless, whether MDM2 is regulated by XIST has not previously been reported in LAD. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to detect the expression of XIST, microRNA-363-3p (miR-363-3p) and MDM2 in LAD tissues and cells. The proliferation, migration, invasion and apoptosis of LAD cells were determined by 3-(4, 5-dimethylthiazol-2-YI)-2, 5-diphenyltetrazolium bromide (MTT), transwell or flow cytometry assay, respectively. MDM2 protein level was detected using western blot analysis. Dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay and RNA pulldown assay were performed to determine the interaction among XIST, miR-363-3p and MDM2. A xenograft tumor model was constructed to validate the effect of XIST on LAD cells in vivo. RESULTS: We found that XIST and MDM2 were remarkably elevated while miR-363-3p was reduced in LAD tissues and cells. Both XIST and MDM2 downregulation restrained proliferation, migration and invasion, and facilitated apoptosis of LAD cells in vitro. Importantly, XIST bound to miR-363-3p to modulate MDM2 expression in LAD cells. Moreover, miR-363-3p knockdown or MDM2 elevation reversed the effects of XIST downregulation on the proliferation, migration, invasion and apoptosis of LAD cells. Furthermore, XIST knockdown constrained tumor growth on LAD cells in vivo. CONCLUSIONS: XIST knockdown repressed proliferation, migration and invasion, and accelerated apoptosis of LAD cells by downregulating MDM2 expression via binding to miR-363-3p. KEY POINTS: Significant findings of the study XIST and MDM2 were abnormally enhanced in LAD tissues and cells. Both downregulation of XIST and MDM2 repressed proliferation, migration and invasion, and boosted apoptosis of LAD cells in vitro. XIST bound to miR-363-3p to regulate MDM2 expression in LAD cells. Downregulation of XIST impeded tumor growth on LAD cells in vivo. What this study adds This study confirmed that XIST was a potential target for inhibiting the development of LAD, and affords a possible strategy for the treatment of LAD in the future.

15.
Artigo em Inglês | MEDLINE | ID: mdl-31902785

RESUMO

OBJECTIVES: Compensations are commonly employed by patients with stroke during rehabilitation without therapist supervision, leading to suboptimal recovery outcomes. This study investigated the feasibility of the real-time monitoring of compensation in patients with stroke by using pressure distribution data and machine learning algorithms. Whether trunk compensation can be reduced by combining the online detection of compensation and haptic feedback of a rehabilitation robot was also investigated. METHODS: Six patients with stroke did three forms of reaching movements while pressure distribution data were recorded as Dataset1. A support vector machine (SVM) classifier was trained with features extracted from Dataset1. Then, two other patients with stroke performed reaching tasks, and the SVM classifier trained by Dataset1 was employed to classify the compensatory patterns online. Based on the real-time monitoring of compensation, a rehabilitation robot provided an assistive force to patients with stroke to reduce compensations. RESULTS: Good classification performance (F1 score>0.95) was obtained in both offline and online compensation analysis using the SVM classifier and pressure distribution data of patients with stroke. Based on the real-time detection of compensatory patterns, the angles of trunk rotation, trunk lean-forward and trunk-scapula elevation decreased by 46.95%, 32.35% and 23.75%, respectively. CONCLUSION: High classification accuracies verified the feasibility of detecting compensation in patients with stroke based on pressure distribution data. Since the validity and reliability of the online detection of compensation has been verified, this classifier can be incorporated into a rehabilitation robot to reduce trunk compensations in patients with stroke.

16.
Life Sci ; 247: 117334, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-31962131

RESUMO

AIMS: The role of long noncoding RNA ZEB1 antisense 1 (lncRNA ZEB1-AS1) in carotid artery atherosclerosis remains barely explored. MATERIALS AND METHODS: The viability and apoptosis of HCtAEC cells were measured by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), Caspase-3 activity detection assay and flow cytometry. The oxidative stress status and inflammation of THP-1 cells were detected by oxidative stress indicator detection kit and Enzyme-linked immunosorbent assay (ELISA). The abundance of ZEB1-AS1, miR-942 and high-mobility group box 1 (HMGB1) was measured by quantitative real time polymerase chain reaction (qRT-PCR). The targets of ZEB1-AS1 and miR-942 in HCtAEC and THP-1 cells were predicted by DIANA tool, and the combination was confirmed by dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay and RNA-pull down assay. Western blot was conducted to examine the protein expression of HMGB1. KEY FINDINGS: ZEB1-AS1 promoted ox-LDL-mediated injury in HCtAEC and THP-1 cells. MiR-942 was a direct target of ZEB1-AS1, and it was negatively modulated by ZEB1-AS1 in HCtAEC and THP-1 cells. HMGB1 could bind to miR-942, and it was regulated by ZEB1-AS1/miR-942 axis in HCtAEC and THP-1 cells. HMGB1 overexpression or miR-942 depletion reversed the inhibitory effects of ZEB1-AS1 intervention on the injury and apoptosis of HCtAEC cells and the oxidative stress and inflammation of THP-1 cells. SIGNIFICANCE: LncRNA ZEB1-AS1 contributed to ox-LDL-mediated injury and apoptosis of HCtAEC cells and the oxidative stress and inflammation of THP-1 cells through up-regulating HMGB1 via sponging miR-942. ZEB1-AS1/miR-942/HMGB1 axis might provide a new direction to treatment carotid artery atherosclerosis.

17.
Clin Cancer Res ; 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31911545

RESUMO

BACKGROUND: Tumor genomic features have been of particular interest because of their potential impact on the tumor immune microenvironment and response to immunotherapy. Due to the substantial heterogeneity, an integrative approach incorporating diverse molecular features is needed to characterize immunological features underlying primary resistance to immunotherapy and for the establishment of novel predictive biomarkers. METHODS: We developed a pan-cancer deep machine-learning model integrating tumor mutation burden, microsatellite instability and somatic copy number alterations to classify tumors of different types into different genomic clusters, assessed the immune microenvironment in each genomic cluster and the association of each genomic cluster with response to immunotherapy. RESULTS: Our model grouped 8,646 tumors of 29 cancer types from the Cancer Genome Atlas into four genomic clusters. Analysis of RNA-sequencing data revealed distinct immune microenvironment in tumors of each genomic class. Furthermore, applying this model to tumors from two melanoma immunotherapy clinical cohorts demonstrated that patients with melanoma of different genomic classes achieved different benefit from immunotherapy. Interestingly, tumors in cluster 4 demonstrated a cold immune microenvironment and lack of benefit from immunotherapy despite high microsatellite instability burden. CONCLUSION: Our study provides a proof-for-principle that deep learning modeling may have the potential to discover intrinsic statistical cross-modality correlations of multifactorial input data to dissect the molecular mechanisms underlying primary resistance to immunotherapy, which likely involves multiple factors from both the tumor and host at different molecular levels.

18.
Cancer Med ; 9(2): 517-529, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31769218

RESUMO

BACKGROUND: Primary pure mucinous adenocarcinoma of the lung (PMA) is a rare subtype. However, correlations between clinicopathological features and genetic phenotypes with survival have not been described comprehensively. METHODS: Pure mucinous adenocarcinoma patient information collected from the Surveillance, Epidemiology, and End Results (SEER) database, the Department of Thoracic Surgery, Zhongshan Hospital, Fudan University (FDZSH), and the Cancer Genome Atlas (TCGA) were extracted, evaluated, and compared with other lung adenocarcinomas (LUAD) patient data. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed to explore the functional importance of underlying molecular changes. Overall survival (OS) was evaluated with the Kaplan-Meier method. Univariate and multivariate analysis through Cox proportional hazard regression identified risk factors that predicted OS, and the results were used to construct a nomogram to predict OS for PMA patients. RESULTS: Overall, 3622 patients, 41 patients, and 15 patients with PMA were identified from the SEER, FDZSH, and TCGA databases, respectively. There were 345 differentially expressed genes, 30 differentially mutated genes and 72 differentially methylated genes were identified between PMA and other LUAD samples. In the SEER database, PMA had a better prognosis compared to other LUAD. Compared with patients with other LUAD, patients with PMA exhibited unique clinicopathological features, including fewer grade III/IV tumors, less pleural invasion, more early-stage cancer, and more lower lobe carcinomas. Multivariate analyses showed that age, race, T stage, N stage, surgery, and chemotherapy were independent risk factors. The nomogram had a calibration index of 0.724. CONCLUSIONS: Our research identified unique clinicopathological characteristics and genetic phenotypes for PMA and other LUAD. The nomogram accurately predicted OS.

19.
Int J Mol Med ; 45(1): 81-92, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31746364

RESUMO

The adaptive immune response mediated by T lymphocytes is a well­established factor in the pathogenesis of pulmonary inflammation. Changes in the expression of various connexins (Cxs) or disruption of connexin­mediated cellular communication in T lymphocytes contribute to inflammation or tissue remodeling. The aim of the present study was to investigate the potential therapeutic value of blocking Cxs in a monocrotaline (MCT)­induced pulmonary inflammation rat model. Carbenoxolone (CBX) was used to inhibit connexin­mediated cellular communication. An MCT rat model was established by intraperitoneal (i.p.) injection of a single dose of MCT (60 mg/kg), and CBX treatment (20 µg/kg/day, i.p.) was initiated on the day following MCT treatment for 28 days. Vehicle­treated male Sprague­Dawley rats were used as the negative control. The MCT rat model was evaluated by measuring the pulmonary artery flow acceleration time and right ventricular hypertrophy index (RVHI). Histopathological features of the lung tissues and pulmonary arteriolar remodeling were assessed. The proportions of T lymphocyte subtypes, Cx40/cx43 expression in the T cell subtypes and the cytokine levels in the plasma and the lung tissues were also analyzed. Pharmacological inhibition of Cxs using CBX attenuated MCT­induced right ventricular hypertrophy, pulmonary arteriolar remodeling, lung fibrosis and inflammatory cell infiltration by decreasing the RVHI, pulmonary arterial wall thickening, collagen deposition and pro­inflammatory cytokines production as well as CD3+ and CD4+ T cell accumulation in lung tissues of MCT­treated rats. Furthermore, flow cytometry analysis revealed that CBX may inhibit MCT­induced Cx40 and Cx43 expression in CD4+ and CD8+ T lymphocytes in lung tissues. The present study provides evidence that pharmacological inhibition of Cxs may attenuate MCT­induced pulmonary arteriolar remodeling and pulmonary inflammatory response, at least in part, by decreasing Cx expression. The results highlight the critical role of Cxs in T lymphocytes in the MCT­induced pulmonary inflammatory response and that targeting of Cxs may be a potential therapeutic method for treating pulmonary inflammatory diseases.

20.
Biochem Biophys Res Commun ; 523(1): 18-24, 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-31831178

RESUMO

In chronic kidney disease, renal phosphate retention leads to hyperphosphatemia with subsequent vascular osteogenic signaling and calcification. Osteogenic signaling involves up-regulation of the transcription factors CBFA1, MSX2, and SOX9, as well as alkaline phosphatase (ALP), an enzyme stimulating calcification by degrading the calcification inhibitor pyrophosphate. Stimulation of osteogenic signaling and calcification by phosphate donor ß-glycerophosphate in human aortic smooth muscle cells (HAoSMCs) is attenuated by MgCl2, an effect mimicked by Ca2+-sensing receptor agonist GdCl3. Most recent observations revealed that the effect of ß-glycerophosphate on osteogenic signaling requires ORAI1, a Ca2+-channel accomplishing store-operated Ca2+-entry (SOCE), which is stimulated by Ca2+-sensor STIM1. The present study explored whether ORAI1 and/or STIM1 expression and, thus, SOCE and osteogenic signaling in HAoSMCs are sensitive to MgCl2 and/or GdCl3. To this end, transcript levels were estimated using q-RT-PCR, protein abundance with western blotting, cytosolic Ca2+-concentration ([Ca2+]i) by Fura-2-fluorescence, and SOCE from increase of [Ca2+]i following re-addition of extracellular Ca2+ after store depletion with thapsigargin (1  µM). As a result, 24 h exposure to ß-glycerophosphate (2 mM) significantly enhanced transcript levels of ORAI1 and STIM1 as well as SOCE, effects significantly blunted or virtually abrogated by 1.5 mM MgCl2 and by 50  µM GdCl3. In conclusion, MgCl2 and GdCl3 are powerful inhibitors of ORAI1 and STIM1 expression and store-operated Ca2+-entry, effects affecting osteogenic signalling in vascular smooth muscle cells.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA