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1.
Artigo em Inglês | MEDLINE | ID: mdl-32393496

RESUMO

Background. For patients hospitalized with severe influenza A, morbidity and mortality remain high. MHAA4549A, a human monoclonal antibody targeting the influenza A hemagglutinin stalk, has demonstrated pharmacological activity in animal studies and in a human influenza A challenge study. We evaluated the safety and efficacy of MHAA4549A plus oseltamivir against influenza A infection in hospitalized patients.Methods. The CRANE trial was a phase 2b, randomized, double-blind, placebo-controlled study of single intravenous (IV) doses of placebo, 3600-mg, or 8400-mg MHAA4549A together with oral oseltamivir (+OTV), in patients hospitalized with severe influenza A. Patients, enrolled across 68 clinical sites in 18 countries, were randomized 1:1:1. The primary outcome was the median time to normalization of respiratory function defined as the time to removal of supplemental oxygen support to maintain a stable SpO2 ≥ 95%. Safety, pharmacokinetics, and effects on influenza viral load were also assessed.Results. 166 patients were randomized and analyzed during a preplanned interim analysis. Compared to placebo+OTV, MHAA4549A+OTV did not significantly reduce the time to normalization of respiratory function (placebo+OTV: 4.28 days; 3600-mg MHAA4549A+OTV: 2.78 days; 8400-mg MHAA4549A+OTV: 2.65 days), nor did it improve other secondary clinical outcomes. Adverse event frequency was balanced across cohorts. MHAA4549A+OTV did not further reduce viral load versus placebo+OTV.Conclusions. In hospitalized patients with influenza A, MHAA4549A did not improve clinical outcomes over OTV alone. Variability in patient removal from oxygen supplementation limited the utility of the primary endpoint. Validated endpoints are needed to assess novel treatments for severe influenza A.

2.
Nan Fang Yi Ke Da Xue Xue Bao ; 40(1): 118-124, 2020 Jan 30.
Artigo em Chinês | MEDLINE | ID: mdl-32376553

RESUMO

OBJECTIVE: To investigate the effects of total glucosides of paeony (TGP) on the proliferation and activation-induced cell death of mouse T cells and the mechanism underlying the immunosuppressive effects of TGP. METHODS: Purified total T cells isolated from the spleen of C57BL/6 mice were treated with TGP at 0, 50, 100, or 200 µg/mL and stimulated by anti-CD3/ CD28. Flow cytometry was performed to detect the cell death and the proliferation of CFSE-labeled T cells. The expression of Fas/FasL mRNA was detected using RT-PCR, and flow cytometry was used to analyze the expression of Fas/FasL proteins on activated T cells. Western blotting was used to detect the expression of Bcl-2 in the cells. RESULTS: TGP treatment for 48 h significantly reduced the total number and percentage of viable T cells and dose-dependently lowered the percentage of divided T cells. TGP treatment obviously up-regulated the cellular expression of Fas mRNA, enhanced Fas expression on the surface of the T cells, and decreased the expression level of Bcl-2 protein in the cells. CONCLUSIONS: TGP significantly inhibits proliferation and promotes activation-induced cell death of mouse T cell by increasing the expression of Fas and downregulating the expression of Bcl-2.

3.
Artigo em Inglês | MEDLINE | ID: mdl-32438797

RESUMO

Organic solar cells (OSCs) have again become a hot research topic in recent years. The record power conversion efficiency (PCE) of OSCs has boosted to over 17% in 2020. Apart from the high PCE, the stability of OSCs is also critical for its future applications and commercialization. Recently, many studies have proposed that burn-in degradation can be considered as an ineluctable barrier to long-term stable OSCs. However, there is still lack of studies to explain the detailed mechanism of this burn-in process. In this work, we firstly investigated the mechanism of the burn-in process in the high-efficiency PM6:N3 based non-fullerene organic solar cells. The PM6:N3 based device achieved a profound average PCE of 14.10% but also showed a significant performance loss after the burn-in degradation. Following characterizations such as dark J-V, PL, TRPL, Urbach energy estimation, and EIS reveal that the burn-in degradation observed is closely related to the current extraction, energy transfer, non-radiative recombination, and charge transport process in the PM6:N3 based device. At the same time, it has small effects on the exciton dissociation process and energetic disorder in the PM6:N3 based device. AFM, SEM, TEM, and GIXRD measurements gratifyingly found that the morphology of PM6:N3 active layer is relatively stable during the burn-in degradation. Therefore, those observed degradations are suspected results from the instability of interfaces and electrodes. The atoms in carrier transport layers and electrodes may diffuse to the active layer during the degradation, which changes the energy levels of each layer and causes traps at the interface and in the active layer. Conquering the instability of interfaces and electrodes is proposed as the prior task for PM6:N3 based OSCs to achieve long-term stability. Our study provides insights into the mechanism behind the burn-in degradation of the PM6:N3 based OSCs, which takes the first step to conquer this barrier.

6.
Medicine (Baltimore) ; 99(12): e18930, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32195925

RESUMO

BACKGROUND: Lumbar disc herniation (LDH) is a common disease that seriously affects patients' quality of life. Although several articles have reported that acupuncture can improve the symptoms of LDH, different guidelines do not evaluate the efficacy of acupuncture consistently, new randomized controlled trials have been published in recent years.The purpose of this study is to evaluate the efficacy and safety of acupuncture for LDH. METHOD: Electronic resource databases, trial registration platform, and different types of grey literature will be systematically searched for eligible studies by 2 authors independently. The type of trial will be limited to randomized controlled trials on acupuncture treatment for LDH. Search strategy will be a combination of terms associated with LDH (eg, low back pain or sciatica) and study of design (eg, randomized controlled trials or clinical trial). Data from homogeneous studies will be combined in a fixed-effects model, and the evidence level will be measured by grading of recommendations assessment, development, and evaluation. RESULTS: This study will provide high-quality evidence to evaluate the relief of pain intensity and improvement of dysfunction of acupuncture in patients with LDH, and to evaluate the safety of acupuncture. CONCLUSION: This study will provide strong evidence for evaluating whether acupuncture therapy is effective and safe for LDH patients. PROSPERO REGISTRATION NUMBER: CRD 42019137399.


Assuntos
Terapia por Acupuntura/métodos , Deslocamento do Disco Intervertebral/terapia , Vértebras Lombares , Terapia por Acupuntura/efeitos adversos , Humanos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa
7.
Mar Drugs ; 18(2)2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32028626

RESUMO

Three new compounds, monarubins A-C (1, 6 and 13), together with ten known compounds, including four alkaloids (2-5), two isocoumarins (7 and 8) and four polyketides (9-12), were isolated from marine shellfish-associated fungus Monascus ruber BB5. The structures were determined on the basis of the 1D and 2D NMR, MS, UV and IR data. The absolute configurations of compounds 3, 6 and 13 were determined by ECD calculations. The NMR data of compounds deoxyhydroxyaspergillic acid (3) and 2-hydroxy-6-(1-hydroxy-1-methylpropyl)-3-sec-buthylpyrazine (4) were first reported. All of the isolated compounds were evaluated for their cytotoxic activities against human nasopharyngeal carcinoma cell lines CNE1, CNE2, SUNE1 and HONE1 and hepatocellular carcinoma cell lines QGY7701 and HepG2. Monarubin B (6) displayed potent cytotoxicities against the cancer cell lines HepG2 and QGY7701 with IC50 values of 1.72 and 0.71 µΜ, respectively; lunatinin (7) showed moderate cytotoxic activities against the cancer cell lines HepG2, QGY7701 and SUNE1 with the IC50 values of 9.60, 7.12 and 28.12 µΜ, respectively.

9.
Chin Med J (Engl) ; 133(1): 33-40, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31923102

RESUMO

BACKGROUND: BK polyomavirus (BKPyV)-associated nephropathy (BKPyVAN) is an important cause of dysfunction and failure of renal transplants. This study aimed to assess the diagnostic performance of morning urine specific gravity (MUSG) in diagnosing BKPyVAN in kidney transplant recipients. METHODS: A total of 87 patients, including 27 with BKPyVAN, 22 with isolated BKPyV viruria, 18 with T cell-mediated rejection (TCMR), and 20 with stable graft function, were enrolled in the First Affiliated Hospital of Sun Yat-Sen University from March 2015 to February 2017. MUSG at biopsy and during a follow-up period of 24 months after biopsy was collected and analyzed. Receiver operating characteristic (ROC) curve analysis was used to determine the ability of MUSG to discriminate BKPyVAN. RESULTS: At biopsy, the MUSG of BKPyVAN group (1.008 ±â€Š0.003) was significantly lower than that of isolated BK viruria group (1.013 ±â€Š0.004, P < 0.001), TCMR group (1.011 ±â€Š0.003, P = 0.027), and control group (1.014 ±â€Š0.006, P < 0.001). There was no significant difference in MUSG among the isolated BK viruria group, TCMR group, and control group (P = 0.253). In BKPyVAN group, the timing and trend of MUSG elevate were consistent with the timing and trend of the decline of viral load in urine and plasma, reaching a statistical difference at 3 months after treatment (1.012 ±â€Š0.003, P < 0.001) compared with values at diagnosis. ROC analysis indicated that the optimal cut-off value of MUSG for diagnosis of BKPyVAN was 1.009, with an area under the ROC curve (AUC) of 0.803 (95% confidence interval [CI]: 0.721-0.937). For differentiating BKPyVAN and TCMR, the optimal MUSG cut-off value was 1.010, with an AUC of 0.811 (95% CI: 0.687-0.934). CONCLUSION: Combined detection of MUSG and BKPyV viruria is valuable for predicting BKPyVAN and distinguishing BKPyVAN from TCMR in renal transplant recipients.

10.
Leuk Lymphoma ; 61(1): 56-65, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31549889

RESUMO

Exposure-response relationships from a phase 1b (M13-365) and phase 3 (MURANO) study were investigated to assess benefit/risk of venetoclax 400 mg daily plus rituximab in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Dose intensities were summarized by tertiles of predicted venetoclax steady-state average concentrations based on nominal venetoclax dose (CmeanSS,nominal) for tolerability; exposure-safety analyses used logistic regression. Exposure-progression-free survival (PFS) relationships were assessed using MURANO data, with CmeanSS,nominal as a grouping factor. Covariates were demographics, geographic region, study, baseline disease characteristics, ECOG performance status, responsiveness to prior therapy, and chromosomal abnormalities. There was no significant effect of covariates on grade ≥3 neutropenia/infection or PFS, and no relationship between venetoclax exposure and these endpoints, or venetoclax or rituximab dose intensity. These results support the recommended venetoclax 400 mg daily dose in combination with rituximab in patients with R/R CLL or small lymphocytic leukemia.

11.
Hepatol Res ; 50(1): 110-120, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31661588

RESUMO

AIM: Our previous transcriptome sequencing analysis detected that retinol dehydrogenase 16 (RDH16) was dramatically downregulated in hepatocellular carcinoma (HCC). RDH16 belongs to the short-chain dehydrogenases/reductases super family, and its role in HCC remains unknown. This study aimed to investigate the expression and function of RDH16 in HCC. METHODS: The mRNA and protein level of RDH16 in HCC samples were detected by quantitative real-time polymerase chain reaction and immunohistochemistry analyses, respectively. The role of RDH16 in HCC was determined by in vitro and in vivo functional studies. RESULTS: Downregulation of RDH16 has been detected in approximately 90% of primary HCCs, which was significantly associated with high serum alpha-fetoprotein level, tumor size, microsatellite formation, thrombus, and poor overall survival of HCC patients. Compared with non-tumor tissues, higher density of methylation was identified in HCC samples. In addition, RDH16 increases the level of retinoic acid and blocks the de novo synthesis of fatty acid in HCC cells. Functional study shows that ectopic expression of RDH16 in HCC cells suppresses cell growth, clonogenicity, and cell motility. CONCLUSIONS: RDH16 might be a prognostic biomarker and intervention point for new therapeutic strategies in HCC.

12.
Gene ; 727: 144245, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31715302

RESUMO

DEK involves in the modulation of cell proliferation, differentiation, apoptosis, migration and cell senescence. However, direct genetic evidence proving the functions of DEK in disease resistance against pathogens is still deficient. In the present study, four DEKs were identified in tomato genome and their roles in disease resistance in tomato were analyzed. The expression levels of DEKs were differently induced by Botrytis cinerea, Pseudomonas syringae pv. tomato (Pst) DC3000 and defense-related signaling molecules (such as jasmonic acid, aethylene precursor and salicylic acid). The DEKs' silencing by virus induced gene silencing led to decreased resistance against B. cinerea or Pst DC3000. The underlying mechanisms may be through the upregulation of the accumulation of reactive oxygen species (ROS) and the changed expression levels of defense-related genes by pathogen inoculation. These results indicate that DEKs involve in disease resistance against different pathogens and thus broaden the knowledge of DEK genes' function in tomato.


Assuntos
Resistência à Doença/genética , Inativação Gênica/efeitos dos fármacos , Lycopersicon esculentum/genética , Botrytis/patogenicidade , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , Ciclopentanos/farmacologia , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Regulação da Expressão Gênica de Plantas/genética , Lycopersicon esculentum/metabolismo , Oxilipinas/farmacologia , Doenças das Plantas/genética , Reguladores de Crescimento de Planta/metabolismo , Proteínas de Plantas/genética , Plantas Geneticamente Modificadas/genética , Proteínas de Ligação a Poli-ADP-Ribose/genética , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Pseudomonas syringae/patogenicidade , Espécies Reativas de Oxigênio/metabolismo , Ácido Salicílico/farmacologia , Transdução de Sinais/genética , Fatores de Transcrição/genética
13.
J Phys Condens Matter ; 32(9): 095402, 2020 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-31689692

RESUMO

The changes of methane hydrate lattice with the decrease of cage occupancy were calculated by first-principles methods. The calculation results show that the decrease of the cages occupancy in sII and sH hydrate does not lead to large deformation in the lattice. Even if all the methane molecules are removed so that the hydrates have become new types of ice, the sII and sH lattices remain stable. The same conclusion is also true when the occupancy of the small cages in sI hydrate is reduced. However, the sI hydrate lattice will deform and almost collapse as the large cage occupancy decreases. These calculation results suggest that sI hydrate cannot exist with empty cages. Since the van der Waals-Platteeuw theory is based on the assumption that the stability of host lattice is independent of the occupancy of guest molecule, it would be applicable to sII and sH lattices, but not to sI hydrates. We propose a modification to the van der Waals-Platteeuw hypothesis so that the theory seems more reasonable.

14.
J Biochem Mol Toxicol ; 34(3): e22434, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31860763

RESUMO

The purpose of this paper is to observe the protective action and its effective mechanism of eriodictyol on lipopolysaccharide (LPS)-induced acute lung injury (ALI). In this study, our results indicated that eriodictyol could dramatically suppress the inflammatory mediators, including interleukin-6 (IL-6), IL-1ß, prostaglandin E2, and tumor necrosis factor-α in bronchoalveolar lavage fluid of LPS-challenged mice. Eriodictyol also alleviated the wet/dry ratio and improved pathological changes of the lung. In addition, eriodictyol significantly decreased myeloperoxidase activity and malondialdehyde content as well as increased superoxide dismutase activity. Moreover, eriodictyol inhibited the COX-2/NLRP3/NF-κB signaling pathway in the lung tissues of ALI mice. In conclusion, our observations validated that eriodictyol processed the protective effects on ALI mice, which was related to the regulation of the COX-2/NLRP3/NF-κB signaling pathway.

15.
Mol Cancer ; 18(1): 174, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31791342

RESUMO

BACKGROUND: Long noncoding RNAs (lncRNAs) play nonnegligible roles in the epigenetic regulation of cancer cells. This study aimed to identify a specific lncRNA that promotes the colorectal cancer (CRC) progression and could be a potential therapeutic target. METHODS: We screened highly expressed lncRNAs in human CRC samples compared with their matched adjacent normal tissues. The proteins that interact with LINRIS (Long Intergenic Noncoding RNA for IGF2BP2 Stability) were confirmed by RNA pull-down and RNA immunoprecipitation (RIP) assays. The proliferation and metabolic alteration of CRC cells with LINRIS inhibited were tested in vitro and in vivo. RESULTS: LINRIS was upregulated in CRC tissues from patients with poor overall survival (OS), and LINRIS inhibition led to the impaired CRC cell line growth. Moreover, knockdown of LINRIS resulted in a decreased level of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), a newly found N6-methyladenosine (m6A) 'reader'. LINRIS blocked K139 ubiquitination of IGF2BP2, maintaining its stability. This process prevented the degradation of IGF2BP2 through the autophagy-lysosome pathway (ALP). Therefore, knockdown of LINRIS attenuated the downstream effects of IGF2BP2, especially MYC-mediated glycolysis in CRC cells. In addition, the transcription of LINRIS could be inhibited by GATA3 in CRC cells. In vivo experiments showed that the inhibition of LINRIS suppressed the proliferation of tumors in orthotopic models and in patient-derived xenograft (PDX) models. CONCLUSION: LINRIS is an independent prognostic biomarker for CRC. The LINRIS-IGF2BP2-MYC axis promotes the progression of CRC and is a promising therapeutic target.

16.
Chin Med J (Engl) ; 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31855966

RESUMO

BACKGROUND: BK polyomavirus (BKPyV)-associated nephropathy (BKPyVAN) is an important cause of dysfunction and failure of renal transplants. This study aimed to assess the diagnostic performance of morning urine specific gravity (MUSG) in diagnosing BKPyVAN in kidney transplant recipients. METHODS: A total of 87 patients, including 27 with BKPyVAN, 22 with isolated BKPyV viruria, 18 with T cell-mediated rejection (TCMR), and 20 with stable graft function, were enrolled in the First Affiliated Hospital of Sun Yat-Sen University from March 2015 to February 2017. MUSG at biopsy and during a follow-up period of 24 months after biopsy was collected and analyzed. Receiver operating characteristic (ROC) curve analysis was used to determine the ability of MUSG to discriminate BKPyVAN. RESULTS: At biopsy, the MUSG of BKPyVAN group (1.008 ±â€Š0.003) was significantly lower than that of isolated BK viruria group (1.013 ±â€Š0.004, P < 0.001), TCMR group (1.011 ±â€Š0.003, P = 0.027), and control group (1.014 ±â€Š0.006, P < 0.001). There was no significant difference in MUSG among the isolated BK viruria group, TCMR group, and control group (P = 0.253). In BKPyVAN group, the timing and trend of MUSG elevate were consistent with the timing and trend of the decline of viral load in urine and plasma, reaching a statistical difference at 3 months after treatment (1.012 ±â€Š0.003, P < 0.001) compared with values at diagnosis. ROC analysis indicated that the optimal cut-off value of MUSG for diagnosis of BKPyVAN was 1.009, with an area under the ROC curve (AUC) of 0.803 (95% confidence interval [CI]: 0.721-0.937). For differentiating BKPyVAN and TCMR, the optimal MUSG cut-off value was 1.010, with an AUC of 0.811 (95% CI: 0.687-0.934). CONCLUSION: Combined detection of MUSG and BKPyV viruria is valuable for predicting BKPyVAN and distinguishing BKPyVAN from TCMR in renal transplant recipients.

17.
Nat Commun ; 10(1): 5114, 2019 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-31704972

RESUMO

Triple-negative breast cancer (TNBC), which lacks estrogen receptor α (ERα), progesterone receptor, and human epidermal growth factor receptor 2 (HER2) expression, is closely related to basal-like breast cancer. Previously, we and others report that cyclin E/cyclin-dependent kinase 2 (CDK2) phosphorylates enhancer of zeste homolog 2 (EZH2) at T416 (pT416-EZH2). Here, we show that transgenic expression of phospho-mimicking EZH2 mutant EZH2T416D in mammary glands leads to tumors with TNBC phenotype. Coexpression of EZH2T416D in mammary epithelia of HER2/Neu transgenic mice reprograms HER2-driven luminal tumors into basal-like tumors. Pharmacological inhibition of CDK2 or EZH2 allows re-expression of ERα and converts TNBC to luminal ERα-positive, rendering TNBC cells targetable by tamoxifen. Furthermore, the combination of either CDK2 or EZH2 inhibitor with tamoxifen effectively suppresses tumor growth and markedly improves the survival of the mice bearing TNBC tumors, suggesting that the mechanism-based combination therapy may be an alternative approach to treat TNBC.

18.
J Immunol ; 203(10): 2712-2723, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31597705

RESUMO

The inflammasomes play critical roles in numerous pathological conditions largely through IL-1ß and/or IL-18. However, additional effectors have been implied from multiple studies. In this study, through two independent mass spectrometry-based secretome screening approaches, we identified galectin-3 as an effector protein of the NLRP3 inflammasome. Although the activation of AIM2 or NLRC4 inflammasome also led to galectin-3 secretion, only the NLRP3 inflammasome controlled the serum galectin-3 level under physiological condition. Mechanistically, active gasdermin D drove the nonexosomal secretion of galectin-3 through the plasma membrane pores. In vivo, high-fat diet-fed Nlrp3-/- mice exhibited decreased circulating galectin-3 compared with wild-type animals. Of note, the improved insulin sensitivity in such Nlrp3-/- mice was aggravated by infusion of recombinant galectin-3. Moreover, galectin-3 was essential for insulin resistance induction in mice harboring the hyperactive Nlrp3A350V allele. Thus, the inflammasome-galectin-3 axis has been demonstrated as a promising target to intervene inflammasome and/or galectin-3 related diseases.

20.
Mini Rev Med Chem ; 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31660826

RESUMO

To explore the efficacy of pharmacokinetics-based 5-fluorouracil dose management by plasma concentration test in advanced colorectal cancer treatment. 153 samples of advanced colorectal cancer patients were enrolled and randomly assigned into control group and experimental group. All patients received double-week chemotherapy with 5-fluorouracil (four weeks were used as one period), and chemotherapy duration ranged from 2 to 6 periods. In the first period, all patients were administrated with classic strategy of body surface area (BSA). In the subsequent periods, the control group (77 samples) continued with BSA guided chemotherapy, while experimental group (76 samples) received pharmacokinetics AUC-based chemotherapy. Efficacy and toxic side effects were assessed during chemotherapy, and survival were recorded in follow-up. In the AUC experimental group, rate of diarrhea significantly decreased (37.50% vs 70.00%, P=0.010), and events of oral mucositis reduced (54.17% vs 82.50%, P=0.014). Compared with control group, Clinical benefit rate of experimental group was much higher (90.79% vs 79.22%, P=0.046). There was no significant difference in other 5-fluorouracil related toxic side effect events (nausea, vomiting, hand-foot syndrome) and progression free survival between two groups. Pharmacokinetics-based dose management of 5-Fluorouracil reduces toxicity of chemotherapy and improved long-term efficacy of chemotherapy for advanced colorectal cancer patients.

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