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  • 1
    Publication Date: 2018-09-15
    Description: Purpose: Cancer stem-like cells (CSC) contribute to the progression and androgen deprivation therapy (ADT) resistance of prostate cancer. As CSCs depend on their specific niche, including tumor-associated macrophages (TAM), elucidating the network between CSCs and TAMs may help to effectively inhibit the progression and ADT resistance of prostate cancer. Experimental Design: The underlying intracellular mechanism that sustains the stem-like characteristics of CSCs in prostate cancer was assessed via RNA sequencing, co-immunoprecipitation, chromatin immunoprecipitation, and other assays. A coculture system and cytokine antibody arrays were used to examine the interaction network between CSCs and TAMs. In addition, an orthotopic prostate cancer model was established to evaluate the in vivo effects of the combined targeting of CSCs and their interaction with TAMs on ADT resistance. Results: Autophagy-related gene 7 (ATG7) facilitated the transcription of OCT4 via β-catenin, which binds to the OCT4 promoter, promoting CSC characteristics in prostate cancer, including self-renewal, tumor initiation, and drug resistance. In addition, CSCs remodeled their specific niche by educating monocytes/macrophages toward TAMs, and the CSC-educated TAMs reciprocally promoted the stem-like properties of CSCs, progression and ADT resistance of prostate cancer via IL6/STAT3. Furthermore, the combined targeting of CSCs and their interaction with TAMs by inhibiting ATG7/OCT4 and IL6 receptor effectively ameliorated ADT resistance in an orthotopic prostate cancer model. Conclusions: Targeting CSCs and their niche may prove to be a more powerful strategy than targeting CSCs alone, providing a rational approach to ameliorating ADT resistance in prostate cancer. Clin Cancer Res; 24(18); 4612–26. ©2018 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 2
    Publication Date: 2018-02-10
    Description: The Hippo pathway plays a vital role in tissue homeostasis and tumorigenesis. The transcription factor IRF3 is essential for innate antiviral immunity. In this study, we discovered IRF3 as an agonist of Yes-associated protein (YAP). The expression of IRF3 is positively correlated with that of YAP and its target genes in gastric cancer; the expression of both IRF3 and YAP is up-regulated and prognosticates patient survival. IRF3 interacts with both YAP and TEAD4 in the nucleus to enhance their interaction, promoting nuclear translocation and activation of YAP. IRF3 and YAP–TEAD4 are associated genome-wide to cobind and coregulate many target genes of the Hippo pathway. Overexpression of active IRF3 increased, but depletion of IRF3 reduced, the occupancy of YAP on the target genes. Knockdown or pharmacological targeting of IRF3 by Amlexanox, a drug used clinically for antiinflammatory treatment, inhibits gastric tumor growth in a YAP-dependent manner. Collectively, our study identifies IRF3 as a positive regulator for YAP, highlighting a new therapeutic target against YAP-driven cancers.
    Keywords: Solid Tumors
    Print ISSN: 0022-1007
    Electronic ISSN: 1540-9538
    Topics: Medicine
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  • 3
    ISSN: 1432-0851
    Keywords: Key words Levamisole ; Natural cytotoxicity ; NC-1.1+ cells ; Tumor surveillance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Murine natural cytotoxicity, which is a major component of the innate immune response in cancer, is mediated by leukocytes that express the NC-1.1 receptor. Mice depleted of natural cytotoxicity by treatment with an anti-NC-l.1 mAb show enhanced growth of certain transplantable tumors, so agents that enhance natural cytotoxicity by NC-1.1+ cells have the potential to be effective anticancer therapeutic agents. We have examined the immunomodulatory effect of levamisole on natural cytotoxicity mediated by NC-1.1+ cells against the BALB/c WEHI-164 murine fibrosarcoma. Administration of levamisole to BALB/c mice significantly enhanced in vitro splenic natural cytotoxicity against 51Cr-labeled WEHI-164 tumor cells. The effect was most marked 48 h after levamisole treatment, at a dose of 10 mg/kg body weight. This enhancement of natural cytotoxicity by levamisole could be completely abrogated by pretreatment of mice with an anti-NC-1.1 mAb. Treatment of BALB/c mice with 10 mg/kg levamisole significantly reduced the growth of WEHI-164 and this effect was abrogated by pretreatment of mice with anti-NC-1.1, indicating that the antitumor effect of levamisole was mediated, at least in part, via NC-1.1+ cells.
    Type of Medium: Electronic Resource
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  • 4
    Publication Date: 2018-04-13
    Description: Background Acute bronchitis (AB) is one of the principal causes of childhood morbidity. Increasing number of studies has shown that air pollution is an important environmental contributor of respiratory disease. However, evidence so far is scarce regarding the effects of air pollution on childhood AB, and it also remains unclear how the risk of AB will change by season and age. Methods Data on hospital visits for AB in children, air pollution and meteorological factors from 1 January 2015 to 31 December 2016 were collected in Hefei, China. Time-series analysis was applied to assess the short-term effects of traffic-related air pollution on childhood AB outpatient visits. A Poisson generalised linear regression model combined with a distributed lag non-linear model was used to estimate the relationships, controlling for long-term trends, seasonal patterns, meteorological factors and other possible confounders. Results We found that an IQR increase in concentrations of nitrogen dioxide, particulate matter 〈2.5 µm and carbon monoxide significantly increased the daily hospital visits for childhood AB with 4-day cumulative effect estimates (relative risks: 1.03, 95% CI 1.01 to 1.05; 1.09, 95% CI 1.07 to 1.11; 1.07, 95% CI 1.05 to 1.09). Notably, the risk estimates during the cold season are pronounced; however, no significant association was observed during the warm season. Interestingly, children aged 6–14 years were more vulnerable to air pollutants than children aged less than 1 year and within 1–5 years. However, no gender difference was observed. Conclusion A significant association of traffic-related air pollution and increased department visits for childhood AB was observed, notably in school-age children and during the cold season.
    Keywords: Public health
    Print ISSN: 0143-005X
    Electronic ISSN: 1470-2738
    Topics: Medicine
    Published by BMJ Publishing Group
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  • 5
    Publication Date: 2018-04-17
    Description: SPAG5 promotes proliferation and suppresses apoptosis in bladder urothelial carcinoma by upregulating Wnt3 via activating the AKT/mTOR pathway and predicts poorer survival SPAG5 promotes proliferation and suppresses apoptosis in bladder urothelial carcinoma by upregulating Wnt3 via activating the AKT/mTOR pathway and predicts poorer survival, Published online: 17 April 2018; doi:10.1038/s41388-018-0223-2 SPAG5 promotes proliferation and suppresses apoptosis in bladder urothelial carcinoma by upregulating Wnt3 via activating the AKT/mTOR pathway and predicts poorer survival
    Print ISSN: 0950-9232
    Topics: Medicine
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  • 6
    Publication Date: 2018-05-02
    Description: Frequent relapse and drug resistance in patients with hepatocellular carcinoma (HCC) can be attributed to the existence of tumor-initiating cells (TIC) within the tumor bulk. Therefore, targeting liver TICs may improve the prognosis of these patients. From transcriptome sequencing of 16 pairs of clinical HCC samples, we report that interleukin-1 receptor-associated kinase 1 (IRAK1) in the TLR/IRAK pathway is significantly upregulated in HCC. IRAK1 overexpression in HCC was further confirmed at the mRNA and protein levels and correlated with advanced tumor stages and poor patient survival. Interestingly, IRAK4, an upstream regulator of IRAK1, was also consistently upregulated. IRAK1 regulated liver TIC properties, including self-renewal, tumorigenicity, and liver TIC marker expression. IRAK1 inhibition sensitized HCC cells to doxorubicin and sorafenib treatment in vitro via suppression of the apoptotic cascade. Pharmacological inhibition of IRAK1 with a specific IRAK1/4 kinase inhibitor consistently suppressed liver TIC populations. We identified aldo-keto reductase family 1 member 10 (AKR1B10) as a novel downstream target of IRAK1, which was found to be overexpressed in HCC and significantly correlated with IRAK1 expression. Knockdown of AKR1B10 negated IRAK1-induced TIC functions via modulation of the AP-1 complex. Inhibition of IRAK1/4 inhibitor in combination with sorafenib synergistically suppressed tumor growth in an HCC xenograft model. In conclusion, targeting the IRAK4/IRAK1/AP-1/AKR1B10 signaling pathway may be a potential therapeutic strategy against HCC.Significance: IRAK4/IRAK1/AP-1/AKR1B10 signaling pathway regulates cancer stemness and drug resistance and may be a novel therapeutic target in HCC. Cancer Res; 78(9); 2332–42. ©2018 AACR.
    Print ISSN: 0008-5472
    Electronic ISSN: 1538-7445
    Topics: Medicine
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  • 7
    Publication Date: 2018-05-24
    Description: A low-cost and eco-friendly superabsorbent composite is prepared through the free-radical graft co-polymerization of wheat bran (WB), acrylic acid (AA) and laterite (LA) in an aqueous solution. Elemental map, scanning electron microscopy and Fourier transform infrared spectra revealed that the LA evenly distributed in the superabsorbent composite and wheat bran-g-poly(acrylic acid)/laterite (WB-g-PAA/LA) formed successfully. Thermogravimetric analysis confirmed that the WB-g-PAA/LA had high thermal stability. Furthermore, the properties of the WB-g-PAA/LA, such as swelling in saline solutions and degradation, are also assessed. The final WB-g-PAA/LA (5 wt%) superabsorbent composite attained an optimum water absorbency of 1425 g g –1 in distilled water and 72 g g –1 in 0.9 wt% NaCl solution. The water absorbency of WB-g-PAA/LA (10 wt%) is even greater than that of the WB-g-PAA. Moreover, the water-retention capacity of WB-g-PAA/LA (5 wt%) is high, and the water-retention process followed a zero-order reaction. The reaction rate constant is 8.2428 x 10 5 exp(– E a /RT ) and the apparent activation energy ( E a ) is 35.11 kJ mol –1 . Furthermore, WB-g-PAA/LA (5 wt%) may regulate the release of urea, indicating that the superabsorbent composite could provide a promising application as a urea fertilizer carrier. Additionally, it increased the germination and growth rates of Glycyrrhiza uralensis Fisch, suggesting it could influence the growth of Chinese herbal medicine.
    Keywords: chemical ecology, environmental chemistry
    Electronic ISSN: 2054-5703
    Topics: Natural Sciences in General
    Published by Royal Society
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  • 8
    Publication Date: 2018-06-02
    Description: Introduction High blood pressure (BP) affects over 40% of adults over the age of 25 worldwide and is the leading global risk factor for death or disability. Hypertension is also the most important risk factor for endovascular atherosclerosis, which, when combined with other cardiovascular risk factors, leads to atherosclerotic cardiovascular disease (ASCVD). Statins are one of the most widely used drugs for the prevention of ASCVD. The recently announced study of Heart Outcomes Prevention Evaluation-3 suggests that cholesterol-lowering agents combined with antihypertensive therapy can prevent cardiovascular events and reduce the combined endpoint. We plan to conduct a systematic review and meta-analysis to evaluate whether combined antihypertensive and statin therapy is more beneficial than antihypertensive therapy alone in patients with hypertension without complications. Methods and analysis We will perform a comprehensive search for randomised controlled trials evaluating combined antihypertensive and statin therapy for the treatment of patients with hypertension. The following English electronic databases will be searched: The Cochrane Library, EMBASE and PubMed. Outcomes will be categorised as short-term (≤6 months) or long-term (〉6 months). When evaluating the effects of combined antihypertensive and statin therapy, a short-term outcome is usually defined as a change in BP or lipid levels, while a long-term outcome is usually defined as cardiovascular benefits or risks. The data screening and extraction will be conducted by two different reviewers. The quality of the RCTs will be assessed according to the Cochrane handbook risk of bias tool. Ethics and dissemination This review does not require ethics approval and the results of the meta-analysis will be submitted to a peer-review journal. PROSPERO registration number CRD 42017071935 .
    Keywords: Open access, Cardiovascular medicine
    Electronic ISSN: 2044-6055
    Topics: Medicine
    Published by BMJ Publishing
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  • 9
    Publication Date: 2018-06-08
    Description: Objective Lipid homoeostasis is disturbed in patients with HCV infection. Direct-acting antiviral agent (DAA) treatment eradicates chronic HCV viraemia, but the dynamics of lipid components remain elusive. This study investigates the clinical manifestation and mechanistic relevance of plasma triglyceride (TG), cholesterol (Chol), lipoproteins and apolipoproteins (apos) after DAA treatment. Design Twenty-four patients with chronic genotype 1 (GT1) HCV treated with elbasvir/grazoprevir or ledipasvir/sofosbuvir for 12 weeks, and followed-up thereafter, were recruited. Their TG, Chol, apoAI and apoB levels were quantified in plasma samples and individually fractionated lipoprotein of various classes. Liver fibrosis was evaluated using the FIB-4 Score. The TG and Chol loading capacities were calculated with normalisation to apoB, which represents per very low density lipoprotein (VLDL) and LDL particle unit Results DAA treatment achieved a sustained virological response rate of 91.7% and reduced the FIB-4 Score. Relative to the baseline, the plasma TG level was reduced but the Chol level increased gradually. Plasma apoB levels and apoB/apoAI ratio were transiently downregulated as early as the first 4 weeks of treatment. The TG and Chol loading capacities in VLDL were elevated by ~20% during the period of DAA treatment and had steadily increased by 100% at follow-up. Furthermore, the TG-to-Chol ratio in VLDL was increased, while the ratio in LDL was reduced, indicating an efficient catabolism. Conclusion The DAA treatment of patients with chronic hepatitis C might lead to efficient HCV eradication and hepatic improvement concomitantly evolving with favouring lipoprotein/apo metabolisms.
    Keywords: Gut
    Print ISSN: 0017-5749
    Electronic ISSN: 1468-3288
    Topics: Medicine
    Published by BMJ Publishing Group
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  • 10
    Publication Date: 2018-07-05
    Description: Correction: eEF-2 kinase is a critical regulator of Warbrug effect through controlling PP2A-A synthesis Correction: eEF-2 kinase is a critical regulator of Warbrug effect through controlling PP2A-A synthesis, Published online: 04 July 2018; doi:10.1038/s41388-018-0322-0 Correction: eEF-2 kinase is a critical regulator of Warbrug effect through controlling PP2A-A synthesis
    Print ISSN: 0950-9232
    Topics: Medicine
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