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1.
Curr Med Res Opin ; : 1, 2020 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-33085514

RESUMO

Objective: The Gout Impact Scale (GIS) is a disease-specific health-related quality of life (HR-QoL) measurement for patients with gout. This study aimed to investigate the quality of life in Chinese patients with gout and potential risk factors for poorer HR-QoL by GIS. Methods: Adults with gout from February 2017 to February 2019 were invited to complete a questionnaire containing the GIS, social demographic characteristics, clinical information and gout-specific questions. Pearson/Spearman correlation and linear regression were used to analyze the data. Results: A total of 413 patients were included in the analysis (mean age, 51.85 years; 96.4% male). The mean (SD) score of GIS total was 56.79 ± 15.45. Worse gout-specific HR-QoL was associated with anxiety (P < 0.05), depression (P < 0.05) and fatigue (P < 0.05). The effectiveness and global satisfaction of Treatment Satisfaction Questionnaire for Medication (TSQM) were negatively related to each dimension of GIS. Age (B=-0.251, P = 0.013), fatigue (B = 1.850, P < 0.001) and depression (B = 9.068, P = 0.042) were independent predictors of GIS total score. Conclusion: Gout-specific HR-QoL is impaired by social demographic and clinical characteristics, highlighting the importance of psychological factors (fatigue and depression) and patient-reported outcomes (patients' satisfaction and confidence in gout treatment). These findings suggest that more studies should focus on disease-specific HR-QoL.

2.
J Diabetes Investig ; 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33035409

RESUMO

AIM: This study aimed to explore the association between glycemic control prior to admission with severity and mortality of COVID-19, and tried to reveal the mechanism. METHODS: 77 inpatients were grouped into sufficient control group (HbA1c<6.5%, n=49) and insufficient control group (HbA1c ≥ 6.5%, n=28). Regression models were used to analyze the clinical data. RESULTS: Compared with patients with HbA1C < 6.5, patients with HbA1C ≥ 6.5 showed higher heart rate (101 vs. 89 beats per min, P=0.012), lower percutaneous oxygen saturation (93% vs. 97%, P=0.001), higher levels of multiple indicators of inflammation, such as white blood cell count (7.9 vs. 5.9 ×109/L, P=0.019), neutrophil count (6.5 vs. 4.1 ×109/L, P=0.001), high-sensitivity C-reactive protein (52 vs. 30 mg/L, P=0.025), and serum ferritin (1287 vs. 716 µg/L, P=0.023), as well as lower level of lymphocyte count (0.7 vs. 0.8 ×109/L P=0.049) at hospital admission. Thus, patients with HbA1C ≥ 6.5 were more likely to develop secondary respiratory infections (25 [89%] vs. 33 [67%], P=0.032) and acute respiratory distress syndrome (ARDS) (17 [61%] vs. 14 [29%], P=0.006) than patients with HbA1C < 6.5, resulting in a higher proportion of critically ill cases (19 [68%] vs. 18 [37%], P=0.009) and non-survivors (13 [46%] vs. 11 [22%], P=0.029). After adjustment for potential risk factors, HbA1C was independently associated with in-hospital death. CONCLUSION: HbA1c was an independent risk factor for poor outcomes in COVID-19 patients. Severe pulmonary infection and consequent ARDS might be the primary causes of death in insufficient glycemic control patients.

3.
Cell Mol Immunol ; 2020 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-32963355

RESUMO

Rheumatoid arthritis (RA) is exacerbated by TNF-alpha signaling. However, it remains unclear whether TNF-α-activated TNFR1 and TNFR2 are regulated by extracellular factors. Here, we showed that soluble glycosylated interleukin-17 receptor D (sIL-17RD), which was produced by proteolytic cleavage, enhanced TNF-α-induced RA. We revealed that IL-17RD shedding was induced by the proteolytic enzyme TACE and enhanced by TNF-α expression in macrophages. Intriguingly, sIL-17RD was elevated in the sera of arthritic mice and rats. Recombinant sIL-17RD significantly enhanced the TNF-α-induced proinflammatory response by promoting TNF-α-TNFR-sIL-17RD complex formation and receptor clustering, leading to the accelerated development of collagen-induced arthritis. Our observations revealed that ectodomain shedding of IL-17RD occurred in RA to boost the TNF-α-induced inflammatory response. Targeting sIL-17RD may provide a new strategy for the therapy of RA.

4.
Sci Total Environ ; 753: 141950, 2020 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-32906044

RESUMO

2,4-dichlorophenoxyacetic acid (2,4-D), a widely used herbicide, is a small organic chemical pollutant in the environment. To develop a nanobody-based immunoassay for monitoring trace levels of 2,4-D, a step-wise strategy for the generation of nanobodies highly specific against this small chemical was employed. Firstly, we synthesized three novel haptens mimicking 2,4-D and assessed their influence on the sensitivity and specificity of the existing antibody-based assay. Polyclonal antibodies (pAb) from rabbits showed good sensitivity and moderate specificity for 2,4-D, pAb from llama based on selected haptens showed similar performance when compared to those from rabbits. Secondly, nanobodies derived from llama were generated for 2,4-D by an effective procedure, including serum monitoring and one-step library construction. One nanobody, NB3-9, exhibited good sensitivity against 2,4-D (IC50 = 29.2 ng/mL) had better specificity than the rabbit pAb#1518, with no cross-reactivities against the 2,4-D analogs tested. Thirdly, one-step fluorescent enzyme immunoassay (FLEIA) for 2,4-D based on a nanobody-alkaline phosphatase (AP) fusion was developed with IC50 of 1.9 ng/mL and a linear range of 0.4-8.6 ng/mL. Environmental water samples were analyzed by FLEIA and LC-MS/MS for comparison, and the results were consistent between both methods. Therefore, the proposed step-wise strategy from hapten design to nanobody-AP fusion production was successfully conducted, and the resulting nanobody based FLEIA was demonstrated as a convenient tool to monitor 2,4-D residuals in the environment.

7.
Sensors (Basel) ; 20(18)2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32927772

RESUMO

Diverse and wide-range applications of integrated circuits (ICs) and the development of Cyber Physical System (CPS), more and more third-party manufacturers are involved in the manufacturing of ICs. Unfortunately, like software, hardware can also be subjected to malicious attacks. Untrusted outsourced manufacturing tools and intellectual property (IP) cores may bring enormous risks from highly integrated. Attributed to this manufacturing model, the malicious circuits (known as Hardware Trojans, HTs) can be implanted during the most designing and manufacturing stages of the ICs, causing a change of functionality, leakage of information, even a denial of services (DoS), and so on. In this paper, a survey of HTs is presented, which shows the threatens of chips, and the state-of-the-art preventing and detecting techniques. Starting from the introduction of HT structures, the recent researches in the academic community about HTs is compiled and comprehensive classification of HTs is proposed. The state-of-the-art HT protection techniques with their advantages and disadvantages are further analyzed. Finally, the development trends in hardware security are highlighted.

8.
Nat Immunol ; 2020 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-32884131

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

9.
Math Biosci Eng ; 17(4): 2923-2935, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32987507

RESUMO

Breast cancer is a commonly diagnosed cancer in women, and one of the leading causes of cancer-related death among female patients However, the key microRNAs involved in its tumorigenesis and microRNAs of prognostic values have not been fully understood. In the present study, we aimed to perform a systematic analysis of microRNA expression profiles to identify some key microRNAs associated with tumor initiation and prognosis. Using TCGA breast cancer datasets, we identified 110 differentially expressed microRNAs. The functional enrichment analysis of the upregulated microRNAs revealed signaling transduction pathways, such as Notch and Wnt signaling pathway, and metabolism-related pathways such as sugar and nucleotide sugar metabolism, and oxidative stress response. Moreover, multivariable Cox model based on three variables of hsa-mir-130a, hsa-mir-3677, and hsa-mir-1247 stratified patients into high-risk and low-risk groups, which showed significant prognostic difference. In addition, we also tested the performance of this model in patient cohorts of any specific breast cancer subtypes or different TNM stages. The high performance in risk prediction was also observed in all of breast cancer subtypes and TNM stages. We also observed that there were highly possible interactions between hsa-mir-130a and seven target genes. Among these target genes, VAV3 and ESR1 were predicted as the target genes of hsa-mir-130a, suggesting that hsa-mir-130a may function by regulating the expression of VAV3 and ESR1 in breast cancer. In conclusion, the stratification based on the multivariable Cox model showed high performance in risk prediction. The dysregulated microRNAs and prognostic microRNAs greatly improved our understanding of the microRNA-related molecular mechanism underlying breast cancer.

10.
Science ; 369(6506): 984-988, 2020 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-32820125

RESUMO

Germinal center (GC) responses potentiate the generation of follicular regulatory T (TFR) cells. However, the molecular cues driving TFR cell formation remain unknown. Here, we show that sclerostin domain-containing protein 1 (SOSTDC1), secreted by a subpopulation of follicular helper T (TFH) cells and T-B cell border-enriched fibroblastic reticular cells, is developmentally required for TFR cell generation. Fate tracking and transcriptome assessment in reporter mice establishes SOSTDC1-expressing TFH cells as a distinct T cell population that develops after SOSTDC1- TFH cells and loses the ability to help B cells for antibody production. Notably, Sostdc1 ablation in TFH cells results in substantially reduced TFR cell numbers and consequently elevated GC responses. Mechanistically, SOSTDC1 blocks the WNT-ß-catenin axis and facilitates TFR cell differentiation.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Linfócitos B/imunologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Centro Germinativo/imunologia , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Contagem de Linfócitos , Camundongos , Camundongos Mutantes , Proteínas Wnt/metabolismo , beta Catenina/metabolismo
11.
Chin J Integr Med ; 26(9): 663-669, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32740825

RESUMO

OBJECTIVE: To select potential molecules that can target viral spike proteins, which may potentially interrupt the interaction between the human angiotension-converting enzyme 2 (ACE2) receptor and viral spike protein by virtual screening. METHODS: The three-dimensional (3D)-coordinate file of the receptor-binding domain (RBD)-ACE2 complex for searching a suitable docking pocket was firstly downloaded and prepared. Secondly, approximately 15,000 molecular candidates were prepared, including US Food and Drug Administration (FDA)-approved drugs from DrugBank and natural compounds from Traditional Chinese Medicine Systems Pharmacology (TCMSP), for the docking process. Then, virtual screening was performed and the binding energy in Autodock Vina was calculated. Finally, the top 20 molecules with high binding energy and their Chinese medicine (CM) herb sources were listed in this paper. RESULTS: It was found that digitoxin, a cardiac glycoside in DrugBank and bisindigotin in TCMSP had the highest docking scores. Interestingly, two of the CM herbs containing the natural compounds that had relatively high binding scores, Forsythiae fructus and Isatidis radix, are components of Lianhua Qingwen (), a CM formula reportedly exerting activity against severe acute respiratory syndrome (SARS)-Cov-2. Moreover, raltegravir, an HIV integrase inhibitor, was found to have a relatively high binding score. CONCLUSIONS: A class of compounds, which are from FDA-approved drugs and CM natural compounds, that had high binding energy with RBD of the viral spike protein. Our work provides potential candidates for other researchers to identify inhibitors to prevent SARS-CoV-2 infection, and highlights the importance of CM and integrative application of CM and Western medicine on treating COVID-19.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos/métodos , Medicamentos de Ervas Chinesas/farmacologia , Glicoproteínas/efeitos dos fármacos , Imageamento Tridimensional , Simulação de Acoplamento Molecular/métodos , Pneumonia Viral/tratamento farmacológico , China , Simulação por Computador , Infecções por Coronavirus/diagnóstico , Glicoproteínas/metabolismo , Humanos , Programas de Rastreamento/métodos , Pandemias , Peptidil Dipeptidase A/efeitos dos fármacos , Pneumonia Viral/diagnóstico , Ligação Proteica , Estados Unidos , United States Food and Drug Administration
12.
J Chin Med Assoc ; 2020 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-32773589

RESUMO

BACKGROUND: To explore the potential role of the platelet/lymphocyte ratio as a prognostic marker in septic patients with acute kidney injury and to provide theoretical evidence for the epidemiological study of the prognosis of patients with septic acute kidney injury in its early stage. METHODS: A pilot study was conducted. A logistic regression analysis was conducted to screen the risk factors, and the selected factors were performed using multiple logistic regression analysis; a Receiver Operating Characteristic curve was used to determine the optimal cutoff value of the platelet/lymphocyte ratio and then to calculate the sensitivity and specificity of the platelet/lymphocyte ratio. RESULTS: Mechanical ventilation, platelet count, platelet/lymphocyte ratio, and arterial blood lactate concentration have a correlation with sepsis (P < 0.05). An elevated platelet/lymphocyte ratio is significantly associated with a worse prognosis of sepsis-induced acute kidney injury (higher mortality). CONCLUSION: The platelet/lymphocyte ratio might be an effective factor in predicting a worse prognosis of septic acute kidney injury patients.

13.
Postgrad Med ; : 1-9, 2020 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-32758047

RESUMO

OBJECTIVES: A questionnaire which provides desirable reliability and validity has been previously developed to assess the disease awareness of diagnosed chronic kidney disease (CKD) patients. However, conventional paper questionnaires often have disadvantages, including recall bias. To substantially improve this, we therefore aimed to explore the feasibility of developing a smartphone-based electronic version (e-version) based upon its original paper version and subsequently tested its validity, reliability, and applicability. METHODS: A pilot study was conducted at Guangdong Provincial Hospital of Chinese Medicine in Guangzhou, China, during August 2019. The e-version had identical content to the paper version and was adapted in terms of layout and assisted functions via the Wechat-incorporated Wen-Juan-Xing platform. Eligible patients with diagnosed CKD were invited to participate and were assigned the e-version. Randomly selected respondents received a test-retest of the same e-version 2 weeks after their first completion. In some instances, psychometric properties, including validity and reliability of the e-version, were examined. In others, its clinical application was also tested, which included comparisons among the clinical profiles of patients who had/had not responded to the questionnaire as well as patients with above or below average questionnaire scores. RESULTS: Of the 225 patients screened, 217 were enrolled to participate, with a response rate of 52.5%. Desirable reliability (Cronbachα = 0.962, ICC for total scores = 0.948), while good convergent validity (Cronbachα = 0.962) and low discriminant validity (one extracted component), of the e-version were detected. Performing inter-group comparisons highlighted statistical differences in terms of higher education level (z = -2.436, P = 0.015) and earlier CKD stages (z = -1.978, P = 0.048), with these patients often preferring to respond. No significant differences were detected in the clinical profiles between respondents who obtained an above or below average questionnaire score. CONCLUSION: The e-version is reliable but was not shown to be a valid approach. Audiences with higher education levels and less advanced disease condition may prefer to respond to the e-version. Adaptation of this e-questionnaire, from its original paper version, may not be a direct transition and meticulous modifications may be required during the transition process. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR1900024633).

15.
Sci Adv ; 6(33): eaaz6477, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32851157

RESUMO

Mutations in the polycomb repressive complex 2 (PRC2) can cause Weaver-like syndrome, wherein a patient cohort exhibits abnormal white matter; however, PRC2 functions in CNS myelination and regeneration remain elusive. We show here that H3K27me3, the PRC2 catalytic product, increases during oligodendrocyte maturation. Depletion of embryonic ectoderm development (EED), a core PRC2 subunit, reduces differentiation of oligodendrocyte progenitors (OPCs), and causes an OPC-to-astrocyte fate switch in a region-specific manner. Although dispensable for myelin maintenance, EED is critical for oligodendrocyte remyelination. Genomic occupancy and transcriptomic analyses indicate that EED establishes a chromatin landscape that selectively represses inhibitory WNT and bone morphogenetic protein (BMP) signaling, and senescence-associated programs. Blocking WNT or BMP pathways partially restores differentiation defects in EED-deficient OPCs. Thus, our findings reveal that EED/PRC2 is a crucial epigenetic programmer of CNS myelination and repair, while demonstrating a spatiotemporal-specific role of PRC2-mediated chromatin silencing in shaping oligodendrocyte identity and lineage plasticity.

16.
Nat Rev Immunol ; 2020 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-32788707

RESUMO

IL-9-producing CD4+ T cells have been considered to represent a distinct T helper cell (TH cell) subset owing to their unique developmental programme in vitro, their expression of distinct transcription factors (including PU.1) and their copious production of IL-9. It remains debatable whether these cells represent a truly unique TH cell subset in vivo, but they are closely related to the T helper 2 (TH2) cells that are detected in allergic diseases. In recent years, increasing evidence has also indicated that IL-9-producing T cells may have potent abilities in eradicating advanced tumours, particularly melanomas. Here, we review the latest literature on the development of IL-9-producing T cells and their functions in disease settings, with a particular focus on allergy and cancer. We also discuss recent ideas concerning the therapeutic targeting of these cells in patients with chronic allergic diseases and their potential use in cancer immunotherapy.

17.
Immunity ; 53(3): 614-626.e4, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32827457

RESUMO

RORγt is the lineage-specific transcription factor for T helper 17 (Th17) cells whose upregulation in developing Th17 cells is critically regulated by interleukin-6 (IL-6) and TGF-ß, the molecular mechanisms of which remain largely unknown. Here we identified conserved non-coding sequences (CNSs) 6 and 9 at the Rorc gene, essential for its expression during Th17 cell differentiation but not required for RORγt expression in innate lymphocytes and γδ T cells. Mechanistically, the IL-6-signal transducer and activator of transcription 3 (STAT3) axis appeared to be largely dependent on CNS9 and only partially on CNS6 in controlling RORγt expression and epigenetic activation of the Rorc locus. TGF-ß alone was sufficient to induce RORγt expression in a CNS6- but not CNS9-dependent manner through CNS6 binding by SMAD proteins. Our study reveals an important synergistic mechanism downstream of IL-6 and TGF-ß in regulation of RORγt expression and Th17 cell commitment via distinct cis-regulatory elements.

18.
Kidney Blood Press Res ; 45(4): 497-509, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32623432

RESUMO

BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL) is a promising marker for the diagnosis of diabetic kidney disease (DKD), but its utility is currently debated. This meta-analysis aims to evaluate the diagnostic value of NGAL for DKD. METHOD: MEDLINE, Embase, -Cochrane Library, CNKI, and CBM databases were searched up to April 13, 2019. In bivariate random-effect models, the diagnostic performance of NGAL for DKD was assessed using pooled estimates of sensitivity, specificity, likelihood ratio, diagnostic odds ratio, and hierarchical summary receiver-operating characteristic analysis. RESULTS: Nineteen studies were eligible for the meta-analysis. Serum NGAL had a pooled sensitivity and specificity of 0.79 (95% confidence intervals [CI] 0.60-0.91) and 0.87 (0.75-0.93) (7 studies, 1,238 patients). The pooled positive likelihood ratio (LR+) and negative likelihood ratio (LR-) were 5.97 (3.03-11.76) and 0.24 (0.11-0.51). For urine NGAL, the pooled sensitivity, specificity, LR+, and LR- were 0.85 (0.74-0.91), 0.74 (0.57-0.86), 3.26 (1.87-5.67), and 0.21 (0.12-0.35), respectively (10 studies, 1,369 patients). The pooled sensitivity and specificity for kidney disease in normoalbuminuric patients with diabetes was 0.90 (0.82-0.95) and 0.97 (0.90-0.99) for both serum NGAL and 0.94 (0.87-0.98) and 0.90 (0.81-0.96) for urine NGAL (4 studies, 221 patients). NGAL appeared to perform similarly in subgroup analysis. CONCLUSION: The meta-analysis has shown that NGAL may be useful for DKD classification and also has a potential diagnostic value for normoalbuminuric kidney disease. Large-scale prospective studies are required to clarify its role in the diagnosis and risk stratification of patients with DKD.

19.
Mol Med Rep ; 22(2): 1558-1566, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32626967

RESUMO

Siva­1 is a well­known anti­apoptosis protein that serves a role in multiple types of cancer cells. However, whether Siva­1 affects multidrug resistance via the NF­κB pathway in gastric cancer is currently unknown. The present study aimed to determine the possible involvement of Siva­1 in gastric cancer anticancer drug resistance in vitro. A vincristine (VCR)­resistant KATO III/VCR gastric cancer cell line with stable Siva­1 overexpression was established. The protein expression levels of Siva­1, NF­κB, multidrug resistance 1 (MDR1) and multidrug resistance protein 1 (MRP1) were detected via western blotting. The effect of Siva­1 overexpression on anticancer drug resistance was assessed by measuring the 50% inhibitory concentration of KATO III/VCR cells to VCR, 5­fluorouracil and doxorubicin. The rate of doxorubicin efflux and apoptosis were detected by flow cytometry. Additionally, colony formation, wound healing and Transwell assays were used to detect the proliferation, migration and invasion of cells, respectively. The results of the current study revealed that the Siva­1­overexpressed KATO III/VCR gastric cancer cells exhibited a significantly decreased sensitivity to VCR, 5­fluorouracil and doxorubicin. The results of flow cytometry revealed that the percentage of apoptotic cells decreased following overexpression of Siva­1. The colony formation assay demonstrated that cell growth and proliferation were significantly promoted by Siva­1 overexpression. Additionally, Siva­1 overexpression increased the migration and invasion of KATO III/VCR cells in vitro. Western blot analysis determined that Siva­1 overexpression increased NF­κB, MDR1 and MRP1 levels. The current study demonstrated that overexpression of Siva­1, which functions as a regulator of MDR1 and MRP1 gene expression in gastric cancer cells via promotion of NF­κB expression, inhibited the sensitivity of gastric cancer cells to certain chemotherapies. These data provided novel insight into the molecular mechanisms of gastric cancer, and may be of significance for the clinical diagnosis and therapy of patients with gastric cancer.

20.
Nat Immunol ; 21(8): 821-822, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32616860
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