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PIK3R1 targeting by miR-21 suppresses tumor cell migration and invasion by reducing PI3K/AKT signaling and reversing EMT, and predicts clinical outcome of breast cancer
Li-Xu Yan et al. Int J Oncol. 2016 Feb.
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We have previously shown that dysregulation of miR-21 functioned as an oncomiR in breast cancer. The aim of the present study was to elucidate the mechanisms by which miR-21 regulate breast tumor migration and invasion. We applied pathway analysis on genome microarray data and target-predicting algorithms for miR-21 target screening, and used luciferase reporting assay to confirm the direct target. Thereafter, we investigated the function of the target gene phosphoinositide-3-kinase, regulatory subunit 1 (α) (PIK3R1), and detected PIK3R1 coding protein (p85α) by immunohistochemistry and miR-21 by RT-qPCR on 320 archival paraffin-embedded tissues of breast cancer to evaluate the correlation of their expression with prognosis. First, we found that PIK3R1 suppressed growth, invasiveness, and metastatic properties of breast cancer cells. Next, we identified the PIK3R1 as a direct target of miR-21 and showed that it was negatively regulated by miR-21. Furthermore, we demonstrated that p85α overexpression phenocopied the suppression effects of antimiR-21 on breast cancer cell growth, migration and invasion, indicating its tumor suppressor role in breast cancer. On the contrary, PIK3R1 knockdown abrogated antimiR‑21-induced effect on breast cancer cells. Notably, antimiR-21 induction increased p85α, accompanied by decreased p-AKT level. Besides, antimiR-21/PIK3R1-induced suppression of invasiveness in breast cancer cells was mediated by reversing epithelial-mesenchymal transition (EMT). p85α downregulation was found in 25 (7.8%) of the 320 breast cancer patients, and was associated with inferior 5-year disease-free survival (DFS) and overall survival (OS). Taken together, we provide novel evidence that miR-21 knockdown suppresses cell growth, migration and invasion partly by inhibiting PI3K/AKT activation via direct targeting PIK3R1 and reversing EMT in breast cancer. p85α downregulation defined a specific subgroup of breast cancer with shorter 5-year DFS and OS, which may require more aggressive treatment.
Figures

Figure 1
PIK3R1 overexpression reduces breast cancer…

Figure 2
miR-21 targets the 3′-UTR of…

Figure 3
The miR-21-dependent proto-oncogene PI3K/AKT pathway…

Figure 4
AntimiR-21-induced suppression of proliferation, clonogenicity,…

Figure 5
Tissue microarray based immunohistochemical analysis…

Figure 6
Prognostic impact of p85α protein…
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Show all 47 references
Publication types
Research Support, Non-U.S. Gov't
MeSH terms
Breast Neoplasms / genetics*
Cell Line, Tumor
Cell Movement / genetics*
Cell Proliferation / genetics
Class Ia Phosphatidylinositol 3-Kinase
Disease-Free Survival
Down-Regulation / genetics
Epithelial-Mesenchymal Transition / genetics*
Female
Gene Expression Regulation, Neoplastic / genetics
Humans
MCF-7 Cells
MicroRNAs / genetics*
Neoplasm Invasiveness / genetics*
Phosphatidylinositol 3-Kinases / genetics*
Prognosis
Proto-Oncogene Proteins c-akt / genetics*
Signal Transduction / genetics
Substances
MIRN21 microRNA, human
MicroRNAs
PIK3R1 protein, human
Class Ia Phosphatidylinositol 3-Kinase
Proto-Oncogene Proteins c-akt
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An miR-502-binding site single-nucleotide polymorphism in the 3'-untranslated region of the SET8 gene is associated with early age of breast cancer onset
Fengju Song et al. Clin Cancer Res. 2009.
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Purpose: MicroRNAs regulate gene expression by binding to the 3'-untranslated region (UTR) of target genes. Single-nucleotide polymorphisms of critical genes may affect their regulation by microRNAs. We have identified a single-nucleotide polymorphism within the miR-502 seed binding region in the 3'-UTR of the SET8 gene. SET8 methylates TP53 and regulates genome stability. We investigated the role of this SET8 single-nucleotide polymorphism and in concert with the TP53 codon 72 single-nucleotide polymorphism in the propensity for onset of breast cancer.
Experimental design: We measured the SET8 single-nucleotide polymorphisms in a case-control study on 1,110 breast cancer cases and 1,097 controls.
Results: The SET8 CC and TP53 GG genotypes were independently associated with an earlier age of breast cancer onset in an allele-dose-dependent manner (for SET8, 52.2 years for TT, 51.4 for TC, and 49.5 for CC; and for TP53, 53.1 years for CC, 51.5 for GC, 50.7 for GG). Individuals with combined SET8 CC and TP53 GG genotypes developed cancer at a median age of 47.7 years as compared with 54.6 years for individuals with combined SET8 TT and TP53 CC genotypes. In the 51 breast cancer tissue samples tested, the SET8 CC genotype was associated with reduced SET8, but not miR-502, transcript levels.
Conclusions: These data suggest that the miR-502-binding site single-nucleotide polymorphism in the 3'-UTR of SET8 modulates SET8 expression and contributes to the early development of breast cancer, either independently or together with the TP53 codon 72 single-nucleotide polymorphism. Larger studies with multiethnic groups are warranted to validate our findings.
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[SNP rs16917496 within SET8 3'UTR is associated with the age of onset of breast cancer].
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MeSH terms
3' Untranslated Regions / genetics*
Adult
Age of Onset
Aged
Aged, 80 and over
Base Sequence
Binding Sites / genetics
Breast Neoplasms / epidemiology
Breast Neoplasms / genetics*
Case-Control Studies
DNA Mutational Analysis
Female
Gene Frequency
Genetic Predisposition to Disease
Genotype
Histone-Lysine N-Methyltransferase / genetics*
Histone-Lysine N-Methyltransferase / metabolism
Humans
MicroRNAs / metabolism*
Middle Aged
Polymorphism, Single Nucleotide*
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MIRN502 microRNA, human
MicroRNAs
Histone-Lysine N-Methyltransferase
KMT5A protein, human
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miR-181b-3p promotes epithelial-mesenchymal transition in breast cancer cells through Snail stabilization by directly targeting YWHAG
Je-Ok Yoo et al. Biochim Biophys Acta. 2016 Jul.
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Epithelial-mesenchymal transition (EMT) is essential for increased invasion and metastasis during cancer progression. Among the candidate EMT-regulating microRNAs that we previously identified, miR-181b-3p was found to induce EMT in MCF7 breast cancer cells, as indicated by an EMT-characteristic morphological change, increased invasiveness, and altered expression of an EMT marker. Transfection with a miR-181b-3p inhibitor reduced the expression of mesenchymal markers and the migration and invasion of highly invasive breast cancer cells. miR-181b-3p induced the upregulation of Snail, a master EMT inducer and transcriptional repressor of E-cadherin, through protein stabilization. YWHAG was identified as a direct target of miR-181b-3p, downregulation of which induced Snail stabilization and EMT phenotypes. Ectopic expression of YWHAG abrogated the effect of miR-181b-3p, including Snail stabilization and the promotion of invasion. In situ hybridization and immunohistochemical analyses indicated that YWHAG expression was inversely correlated with the expression of miR-181b-3p and Snail in human breast cancer tissues. Furthermore, transfection with miR-181b-3p increased the frequency of metastatic nodule formation in the lungs of mice in experimental metastasis assays using MDA-MB-231 cells. Taken together, our data suggest that miR-181b-3p functions as a metastasis activator by promoting Snail-induced EMT, and may therefore be a therapeutic target in metastatic cancers.
Keywords: EMT; Metastasis; Snail; YWHAG; miR-181b-3p.
Copyright © 2016 Elsevier B.V. All rights reserved.
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Publication types
Research Support, Non-U.S. Gov't
MeSH terms
14-3-3 Proteins / genetics
14-3-3 Proteins / metabolism*
3' Untranslated Regions
Animals
Binding Sites
Breast Neoplasms / enzymology*
Breast Neoplasms / genetics
Breast Neoplasms / pathology
Cell Movement
Epithelial-Mesenchymal Transition*
Female
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Neoplastic
Humans
Lung Neoplasms / enzymology
Lung Neoplasms / genetics
Lung Neoplasms / secondary
MCF-7 Cells
Mice, Inbred BALB C
Mice, Nude
MicroRNAs / genetics
MicroRNAs / metabolism*
Neoplasm Invasiveness
Phenotype
Protein Stability
Signal Transduction
Snail Family Transcription Factors
Time Factors
Transcription Factors / genetics
Transcription Factors / metabolism*
Transfection
Substances
14-3-3 Proteins
3' Untranslated Regions
MIrn181 microRNA, human
MicroRNAs
Snail Family Transcription Factors
Transcription Factors
YWHAG protein, human
Related information
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Efficacy of NND-502, a novel imidazole antimycotic agent, in experimental models of Candida albicans and Aspergillus fumigatus infections
Y Niwano et al. Int J Antimicrob Agents. 1999 Aug.
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In vitro and in vivo anti-Candida albicans and anti-Aspergillus fumigatus activities of NND-502, a new imidazole-antimycotic, were compared with those of fluconazole (FCZ), itraconazole (ITZ) and/or amphotericin B (AmB). NND-502 exhibited strong in vitro antifungal activity against both fungal species; its MIC against C. albicans was 1-4 times lower than that of FCZ, and its MIC against A. fumigatus was at least 60-2000 times lower than that of ITZ and AmB. In vivo antifungal treatments with each drug were initiated 1 h after inoculation in the experimental models, so that antifungal potential reflected prophylactic activity rather than therapeutic activity. The oral regimen of NND-502 in a murine model of systemic C. albicans infection was much less effective than that of FCZ. In vivo anti-A. fumigatus activity of oral NND-502 in a murine model of systemic infection was apparently superior to that of FCZ and ITZ in terms of prolonging survival. In addition to the murine model of systemic aspergillosis, intravenous NND-502 was shown to be highly effective in a rat model of pulmonary aspergillosis compared with intravenous AmB; 90% of animals survived at a dose of 2.5 mg/kg per day of NND-502 while only 30% of animals escaped death when 5 mg/kg per day of AmB was used. This potent efficacy of NND-502 was also confirmed in a sublethal challenge study in which the administration of the agent at a dose as low as 1.25 mg/kg per day resulted in the significant reduction of organisms in the lung; no comparable effect of AmB was found.
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MeSH terms
Amphotericin B / therapeutic use
Animals
Antifungal Agents / pharmacology
Antifungal Agents / therapeutic use*
Aspergillosis / drug therapy*
Aspergillosis / microbiology
Aspergillus fumigatus / drug effects*
Candida albicans / drug effects*
Candidiasis / drug therapy*
Candidiasis / microbiology
Imidazoles / pharmacology
Imidazoles / therapeutic use*
Lung Diseases / drug therapy
Lung Diseases / microbiology
Male
Microbial Sensitivity Tests
Rats
Rats, Sprague-Dawley
Substances
Antifungal Agents
Imidazoles
Amphotericin B
luliconazole
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Clinical Trial
Long-term treatment with a new non-ergot long-acting dopamine agonist, CV 205-502, in women with hyperprolactinaemia
C Rasmussen et al. Clin Endocrinol (Oxf). 1988 Sep.
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Abstract
Twenty-four hyperprolactinaemic women were treated for 6 months with the new, non-ergot, long-acting dopamine agonist, CV 205-502. The treatment resulted in normalization of PRL secretion in 17 of the 24 women at once-daily doses of 0.05 to 0.15 mg of the drug. Sixteen of these women as well as 4 of those who remained hyperprolactinaemic had regular menstrual bleeding. Five of the patients had previously discontinued bromocriptine therapy because of adverse effects but had no problems tolerating CV 205-502. Of three bromocriptine-resistant women, two responded partially while one also remained unresponsive to CV 205-502 treatment. Mild to moderate galactorrhoea was recorded at baseline in 19 of the 24 women. After 6 months' treatment mild galactorrhoea was still present in six patients, four of whom had attained normal PRL levels. Side-effects were mild and transient. CV 205-502 seems to be a valuable compound in the management of patients with hyperprolactinaemia.
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A double-blind study comparing a new non-ergot, long-acting dopamine agonist, CV 205-502, with bromocriptine in women with hyperprolactinaemia.
Homburg R, et al. Clin Endocrinol (Oxf). 1990. PMID: 1973085 Clinical Trial.
Clinical response and prolactin concentration in hyperprolactinemic women during and after treatment for 24 months with the new dopamine agonist, CV 205-502.
Rasmussen C, et al. Acta Endocrinol (Copenh). 1991. PMID: 1680264
CV 205-502, a new dopamine agonist, versus bromocriptine in the treatment of hyperprolactinaemia.
van der Heijden PF, et al. Eur J Obstet Gynecol Reprod Biol. 1991. PMID: 1676973 Clinical Trial.
A comparative review of the tolerability profiles of dopamine agonists in the treatment of hyperprolactinaemia and inhibition of lactation.
Webster J. Drug Saf. 1996. PMID: 8713691 Review.
Novel approaches to the management of hyperprolactinemia.
Philosophe R, et al. Curr Opin Obstet Gynecol. 1991. PMID: 1687504 Review.
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Treatment of hyperprolactinemia: a systematic review and meta-analysis.
Wang AT, et al. Syst Rev. 2012. PMID: 22828169 Free PMC article. Review.
A practical guide to the diagnosis and management of amenorrhoea.
Crosignani PG, et al. Drugs. 1996. PMID: 9118817 Review.
Diagnosis and drug therapy of prolactinoma.
Ciccarelli E, et al. Drugs. 1996. PMID: 8736617 Review.
A cross-over study with the two novel dopaminergic drugs cabergoline and quinagolide in hyperprolactinemic patients.
Giusti M, et al. J Endocrinol Invest. 1994. PMID: 7911813 Clinical Trial.
Control of prolactin secretion.
Benker G, et al. Klin Wochenschr. 1990. PMID: 2126309 Review.
See all "Cited by" articles
Publication types
Clinical Trial
Randomized Controlled Trial
MeSH terms
Adult
Aminoquinolines / therapeutic use*
Clinical Trials as Topic
Dopamine Agents / therapeutic use*
Double-Blind Method
Female
Galactorrhea / drug therapy
Humans
Hyperprolactinemia / drug therapy*
Middle Aged
Time Factors
Substances
Aminoquinolines
Dopamine Agents
quinagolide
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Clinical Trial
A double-blind study comparing a new non-ergot, long-acting dopamine agonist, CV 205-502, with bromocriptine in women with hyperprolactinaemia
R Homburg et al. Clin Endocrinol (Oxf). 1990 May.
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Abstract
Twenty-two hyperprolactinaemic women were randomly allocated to two groups and treated with bromocriptine or the new, non-ergot, long-acting dopamine agonist, CV 205-502. The study was double-blind for 6 months. Four patients in the bromocriptine group, but none in the CV 205-502 group, discontinued the study because of adverse reactions. Adverse reactions in those receiving the new drug were milder and more transient than with bromocriptine. With once-daily doses of 0.075 mg CV 205-502, eight of 11 women achieved normal PRL concentrations after 8 weeks treatment (median (95% confidence limits), 352 (70-987) mU/l) compared with two of nine receiving a divided daily dose of 5 mg bromocriptine (1802 (1205-4438) mU/l) (P less than 0.002). With doses of 0.075-0.15 mg of CV 205-502, 10 of 11 women achieved normal PRL concentrations at 24 weeks compared with three of the remaining seven women on doses of 5-10 mg of bromocriptine. Regular menstrual bleeding was restored and galactorrhoea relieved in the majority of patients, with marginally greater efficacy with CV 205-502. CV 205-502 is highly effective for the long-term treatment of hyperprolactinaemia. It is better tolerated than bromocriptine, is effective in a once-daily dose, appears to be safe, and provides a valuable alternative to the dopamine agonist drugs in use today.
Similar articles
Long-term treatment with a new non-ergot long-acting dopamine agonist, CV 205-502, in women with hyperprolactinaemia.
Rasmussen C, et al. Clin Endocrinol (Oxf). 1988. PMID: 2908030 Clinical Trial.
CV 205-502, a new dopamine agonist, versus bromocriptine in the treatment of hyperprolactinaemia.
van der Heijden PF, et al. Eur J Obstet Gynecol Reprod Biol. 1991. PMID: 1676973 Clinical Trial.
Acute and long-term effects of once-daily oral bromocriptine and a new long-acting non-ergot dopamine agonist, quinagolide, in the treatment of hyperprolactinemia: a double-blind study.
Verhelst JA, et al. Acta Endocrinol (Copenh). 1991. PMID: 1683503 Clinical Trial.
A comparative review of the tolerability profiles of dopamine agonists in the treatment of hyperprolactinaemia and inhibition of lactation.
Webster J. Drug Saf. 1996. PMID: 8713691 Review.
Novel approaches to the management of hyperprolactinemia.
Philosophe R, et al. Curr Opin Obstet Gynecol. 1991. PMID: 1687504 Review.
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Cited by 8 articles
Pharmacokinetics and pharmacodynamics of ropinirole in patients with prolactinomas.
Liu S, et al. Br J Clin Pharmacol. 2019. PMID: 30362146 Free PMC article. Clinical Trial.
Dopamine agonists for preventing future miscarriage in women with idiopathic hyperprolactinemia and recurrent miscarriage history.
Chen H, et al. Cochrane Database Syst Rev. 2016. PMID: 27455388 Free PMC article. Review.
Treatment of hyperprolactinemia: a systematic review and meta-analysis.
Wang AT, et al. Syst Rev. 2012. PMID: 22828169 Free PMC article. Review.
Medical treatment of prolactinomas.
Colao A, et al. Nat Rev Endocrinol. 2011. PMID: 21423245 Review.
Quinagolide in the management of prolactinoma.
Schultz PN, et al. Pituitary. 2000. PMID: 11788012 Clinical Trial.
See all "Cited by" articles
Publication types
Clinical Trial
Comparative Study
Randomized Controlled Trial
MeSH terms
Adult
Aminoquinolines / adverse effects
Aminoquinolines / therapeutic use*
Bromocriptine / adverse effects
Bromocriptine / therapeutic use*
Dopamine Agents / adverse effects
Dopamine Agents / therapeutic use*
Double-Blind Method
Female
Humans
Hyperprolactinemia / drug therapy*
Iodine Radioisotopes
Menstruation
Middle Aged
Prolactin / blood
Prolactin / immunology
Radioimmunoassay
Randomized Controlled Trials as Topic
Substances
Aminoquinolines
Dopamine Agents
Iodine Radioisotopes
Bromocriptine
quinagolide
Prolactin
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miR-502 medaited histone methyltransferase SET8 expression is associated with outcome of esophageal squamous cell carcinoma
Cuiju Wang et al. Sci Rep. 2016.
Free PMC article
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Abstract
The histone methyltransferase SET8, whose expression is regulated by miR-502 though the binding site in the 3' UTR of SET8, implicated in cancer development. Single nucleotide polymorphism (SNP) of rs16917496 located in the miR-502 and SET8 binding site was analyzed in esophageal squamous cell carcinoma (ESCC) patients, the SET8 C/C genotype was independently associated with longer post-operative survival by multivariate analysis (relative risk, 2.250; 95% CI, 1.041-4.857; p = 0.039). Moreover, the reduced SET8 expression mediated by SET8 C/C genotype was associated with longer ESCC survival. Functional assay indicated that the SET8 knock down could inhibit proliferation and promote apoptosis of ESCC cells. The subsequent assay also showed the markedly inhibition of ESCC cell migration and invasion by SET8 knock down. Our data suggested that the altering SET8 expression, which is mediated at least partly by miR-502 through changing the binding affinity between miR-502 and SET8 3' UTR, could modify the ESCC outcome by inhibiting the proliferation and invasion as well as promoting the apoptosis of ECSS cell. Our data indicated that SET8 was a new target for ESCC therapy.
Figures

Figure 1. The rs16917496 SNP was associated…

Figure 2. SET8 knockdown inhibits proliferation, induces…

Figure 3. SET8 knockdown inhibited the growth…
Similar articles
A polymorphism at the miR-502 binding site in the 3'-untranslated region of the histone methyltransferase SET8 is associated with hepatocellular carcinoma outcome.
Guo Z, et al. Int J Cancer. 2012. PMID: 22095217
Down-regulated miR-26a promotes proliferation, migration, and invasion via negative regulation of MTDH in esophageal squamous cell carcinoma.
Yang C, et al. FASEB J. 2017. PMID: 28174206
SMYD3 stimulates EZR and LOXL2 transcription to enhance proliferation, migration, and invasion in esophageal squamous cell carcinoma.
Zhu Y, et al. Hum Pathol. 2016. PMID: 26980013
Plasma miR-185 is decreased in patients with esophageal squamous cell carcinoma and might suppress tumor migration and invasion by targeting RAGE.
Jing R, et al. Am J Physiol Gastrointest Liver Physiol. 2015. PMID: 26316588
MiR-214 promotes cell meastasis and inhibites apoptosis of esophageal squamous cell carcinoma via PI3K/AKT/mTOR signaling pathway.
Guanen Q, et al. Biomed Pharmacother. 2018. PMID: 29864623
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Epigenetic Modifier SETD8 as a Therapeutic Target for High-Grade Serous Ovarian Cancer.
Wada M, et al. Biomolecules. 2020. PMID: 33339442 Free PMC article.
Histone methyltransferase SET8 is regulated by miR-192/215 and induces oncogene-induced senescence via p53-dependent DNA damage in human gastric carcinoma cells.
Zhang X, et al. Cell Death Dis. 2020. PMID: 33127874 Free PMC article.
Epigenetic Alterations in Oesophageal Cancer: Expression and Role of the Involved Enzymes.
Lopes N, et al. Int J Mol Sci. 2020. PMID: 32429269 Free PMC article. Review.
Downregulation of histone methyltransferase SET8 inhibits progression of hepatocellular carcinoma.
Wu J, et al. Sci Rep. 2020. PMID: 32161353 Free PMC article.
MiR-502 is the first reported miRNA simultaneously targeting two components of the classical non-homologous end joining (C-NHEJ) in pancreatic cell lines.
Smolinska A, et al. Heliyon. 2020. PMID: 32042960 Free PMC article.
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References
Jemal A. et al.. Global cancer statistics. CA Cancer J. Clin. 61, 69–90 (2011). - PubMed
Blot W. J. & Li J. Y. Some considerations in the design of a nutrition intervention trial in Linxian. Natl Cancer Inst. Monogr. 69, 29–34 (1985). - PubMed
Blanchard P., Quero L. & Hennequin C. Prognostic and predictive factor of oesophageal carcinoma. Bull Cancer. 96, 379–389 (2009). - PubMed
Zhang R. et al.. Single nucleotide polymorphisms in the mitochondrial displacement loop and outcome of esophageal squamous cell carcinoma. J. Exp. Clin Cancer Res. 29, 155 (2010). - PMC - PubMed
Bartel D. P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 116, 281–297 (2004). - PubMed
Show all 35 references
Publication types
Research Support, Non-U.S. Gov't
MeSH terms
Animals
Apoptosis
Carcinoma, Squamous Cell / genetics*
Cell Line, Tumor
Cell Movement
Cell Proliferation
Esophageal Neoplasms / genetics*
Esophageal Squamous Cell Carcinoma
Female
Genotype
Histone-Lysine N-Methyltransferase / genetics*
Humans
Kaplan-Meier Estimate
Male
Mice, Inbred BALB C
Mice, Nude
MicroRNAs / genetics*
Middle Aged
Polymorphism, Single Nucleotide
Wound Healing
Substances
MIRN502 microRNA, human
MicroRNAs
Histone-Lysine N-Methyltransferase
KMT5A protein, human
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Clinical Trial
CV 205-502: a new long-acting drug for inhibition of prolactin hypersecretion
C Rasmussen et al. Clin Endocrinol (Oxf). 1987 Mar.
Show details
Abstract PubMed PMID
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Abstract
CV 205-502, an octahydrobenzo(g)quinoline, is a new non-ergot long-acting prolactin inhibitor. The substance was given to 24 hyperprolactinaemic women for 7 d. The women were randomized to one of three dose regimens, 0.01 mg, 0.03 mg or 0.06 mg daily. Two patients in each group were given placebo. Frequent blood samples were obtained during days 1, 7 and 8. The prolactin levels in serum were depressed dose-dependently in all patients given active substance. In group 1 (0.01 mg) the dose was insufficient to induce normal serum prolactin levels except in one woman, while two women in group 2 (0.03 mg) and four in group 3 (0.06 mg) became normoprolactinaemic. The depressant effect on prolactin secretion lasted for 24 h in group 2 and 3. Side-effects were mild and transient. No change in blood pressure was observed. CV 205-502 was an effective and long-acting drug for treatment of patients with hyperprolactinaemia in this short-term study and this new drug deserves investigation of its usefulness in long-term treatment.
Similar articles
A comparative review of the tolerability profiles of dopamine agonists in the treatment of hyperprolactinaemia and inhibition of lactation.
Webster J. Drug Saf. 1996. PMID: 8713691 Review.
Long-term treatment with a new non-ergot long-acting dopamine agonist, CV 205-502, in women with hyperprolactinaemia.
Rasmussen C, et al. Clin Endocrinol (Oxf). 1988. PMID: 2908030 Clinical Trial.
Effect of CV 205-502 in hyperprolactinaemic patients intolerant of bromocriptine.
Newman CB, et al. Clin Endocrinol (Oxf). 1989. PMID: 2576397 Clinical Trial.
A double-blind study comparing a new non-ergot, long-acting dopamine agonist, CV 205-502, with bromocriptine in women with hyperprolactinaemia.
Homburg R, et al. Clin Endocrinol (Oxf). 1990. PMID: 1973085 Clinical Trial.
Cabergoline. A review of its pharmacological properties and therapeutic potential in the treatment of hyperprolactinaemia and inhibition of lactation.
Rains CP, et al. Drugs. 1995. PMID: 7729332 Review.
See all similar articles
Cited by 8 articles
Current management of prolactinomas.
Nomikos P, et al. J Neurooncol. 2001. PMID: 11761431 Review.
New medical treatment for acromegaly.
van der Lely AJ, et al. Pituitary. 1999. PMID: 11081177 Review.
Cabergoline: a first-choice treatment in patients with previously untreated prolactin-secreting pituitary adenoma.
Cannavò S, et al. J Endocrinol Invest. 1999. PMID: 10401709 Clinical Trial.
Feasibility, endocrine and anti-tumour effects of a triple endocrine therapy with tamoxifen, a somatostatin analogue and an antiprolactin in post-menopausal metastatic breast cancer: a randomized study with long-term follow-up.
Bontenbal M, et al. Br J Cancer. 1998. PMID: 9459155 Free PMC article. Clinical Trial.
A comparative review of the tolerability profiles of dopamine agonists in the treatment of hyperprolactinaemia and inhibition of lactation.
Webster J. Drug Saf. 1996. PMID: 8713691 Review.
See all "Cited by" articles
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MeSH terms
Adolescent
Adult
Aminoquinolines / therapeutic use*
Clinical Trials as Topic
Dose-Response Relationship, Drug
Female
Humans
Hyperprolactinemia / drug therapy*
Middle Aged
Prolactin / antagonists & inhibitors*
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NGINX 502 Bad Gateway: PHP-FPM

Evan Mouzakitis
@vagelim

David Lentz
Last updated: March 9, 2020

tip / nginx / 502 bad gateway / php
Editor's note: php-fpm uses the term "master" to describe its primary process. Datadog does not use this term. Within this blog post, we will refer to this as "primary," except for the sake of clarity in instances where we must reference a specific process name.
This post is part of a series on troubleshooting NGINX 502 Bad Gateway errors. If you're not using PHP-FPM, check out our other article on troubleshooting NGINX 502s with Gunicorn as a backend.
PHP-FastCGI Process Manager (PHP-FPM) is a daemon for handling web server requests for PHP applications. In production, PHP-FPM is often deployed behind an NGINX web server. NGINX proxies web requests and passes them on to PHP-FPM worker processes that execute the PHP application.

NGINX will return a 502 Bad Gateway error if it can't successfully proxy a request to PHP-FPM, or if PHP-FPM fails to respond. In this post, we'll examine some common causes of 502 errors in the NGINX/PHP-FPM stack, and we'll provide guidance on where you can find information that can help you resolve these errors.
Explore the metrics, logs, and traces behind NGINX 502 Bad Gateway errors using Datadog.
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Some possible causes of 502s
In this section, we'll describe how the following conditions can cause NGINX to return a 502 error:
PHP-FPM is not running
NGINX can't communicate with PHP-FPM
PHP-FPM is timing out
If NGINX is unable to communicate with PHP-FPM for any of these reasons, it will respond with a 502 error, noting this in its access log (/var/log/nginx/access.log) as shown in this example:
access.log
COPY
127.0.0.1 - - [31/Jan/2020:18:30:55 +0000] "GET / HTTP/1.1" 502 182 "-" "curl/7.58.0"
NGINX's access log doesn't explain the cause of a 502 error, but you can consult its error log (/var/log/nginx/error.log) to learn more. For example, here is a corresponding entry in the NGINX error log that shows that the cause of the 502 error is that the socket doesn't exist, possibly because PHP-FPM isn't running. (In the next section, we'll look at how to detect and correct this problem.)
error.log
COPY
2020/01/31 18:30:55 [crit] 13617#13617: *557 connect() to unix:/run/php/php7.2-fpm.sock failed (2: No such file or directory) while connecting to upstream, client: 127.0.0.1, server: localhost, request: "GET / HTTP/1.1", upstream: "fastcgi://unix:/run/php/php7.2-fpm.sock:", host: "localhost"
PHP-FPM isn't running
Note: This section includes a process name that uses the term "master." Except when referring to specific processes, this article uses the term "primary" instead.
If PHP-FPM isn't running, NGINX will return a 502 error for any request meant to reach the PHP application. If you're seeing 502s, first check to confirm that PHP-FPM is running. For example, on a Linux host, you can use a ps command like this one to look for running PHP-FPM processes:
COPY
sudo ps aux | grep 'php'
PHP-FPM organizes its worker processes in groups called pools. The sample output below shows that the PHP-FPM primary process is running, as are two worker processes in the default pool (named www):
COPY
root 29852 0.0 2.2 435484 22396 ? Ssl 16:27 0:00 php-fpm: master process (/etc/php/7.2/fpm/php-fpm.conf) www-data 29873 0.0 1.5 438112 15220 ? Sl 16:27 0:00 php-fpm: pool www www-data 29874 0.0 1.6 438112 16976 ? Sl 16:27 0:00 php-fpm: pool www
If the output of the ps command doesn't show any PHP-FPM primary or pool processes, you'll need to get PHP-FPM running to resolve the 502 errors.
In a production environment, you should consider using systemd to run PHP-FPM as a service. This can make your PHP application more reliable and scalable, since the PHP-FPM daemon will automatically start serving your PHP app when your server starts or when a new instance launches. PHP-FPM is included in the PHP source code, so you can add PHP-FPM as a systemd service when you configure PHP.
Once your PHP-FPM project is configured as a service, you can use the following command to ensure that it starts automatically when your server starts up:
COPY
sudo systemctl enable php7.2-fpm.service
Then you can use the list-unit-files command to see information about your service:
COPY
sudo systemctl list-unit-files | grep -E 'php[^fpm]*fpm'
On a PHP 7.2 server that has PHP-FPM installed (even if it is not running), the output of this command will be:
COPY
php7.2-fpm.service enabled
To see information about your PHP-FPM service, use this command:
COPY
sudo systemctl is-active php7.2-fpm.service
This command should return an output of active. If it doesn't, you can start the service with:
COPY
sudo service php7.2-fpm start
NGINX can't access the socket
When PHP-FPM starts, it creates one or more TCP or Unix sockets to communicate with the NGINX web server. PHP-FPM's worker processes use these sockets to listen for requests from NGINX.
To determine whether a 502 error was caused by a socket misconfiguration, confirm that PHP-FPM and NGINX are configured to use the same socket. PHP-FPM uses a separate configuration file for each worker process pool; these files are located at /etc/php/7.2/fpm/pool.d/. Each pool's socket is defined in a listen directive in the pool's configuration file. For example, the listen directive below configures a pool named mypool to use a Unix socket located at /run/php/mypool.sock:
mypool.conf
COPY
listen = /run/php/mypool.sock
If NGINX can't access the socket for a particular pool, you can determine which worker pool is involved in the issue by checking which socket is named in the NGINX error log entry. For example, if PHP-FPM had failed to start the mypool worker pool, NGINX would return a 502 and its error log entry would include:
error.log
COPY
connect() to unix:/run/php/mypool.sock failed (2: No such file or directory)
Check your nginx.conf file to ensure that the relevant location block specifies the same socket. The example below contains an include directive that loads some general configuration information for PHP-FPM, and a fastcgi_pass directive that specifies the same Unix socket named in the mypool.conf file, above.
nginx.conf
COPY
location / { include snippets/fastcgi-php.conf; fastcgi_pass unix:/run/php/mypool.sock; }
Unix sockets are subject to Unix file system permissions. The PHP-FPM pool's configuration file specifies the mode and ownership of the socket, as shown here:
www.conf
COPY
listen.owner = www-data listen.group = www-data listen.mode = 0660
Make sure these permissions allow the user and group running NGINX to access the socket. If the permissions on the socket are incorrect, NGINX will log a 502 error in its access log, and a message like the one shown below in its error log:
error.log
COPY
2020/02/20 17:12:03 [crit] 3059#3059: *4 connect() to unix:/run/php/mypool.sock failed (13: Permission denied) while connecting to upstream, client: 127.0.0.1, server: localhost, request: "GET / HTTP/1.1", upstream: "fastcgi://unix:/run/php/mypool.sock:", host: "localhost"
Note that the default values of listen.owner and listen.group match the default owner and group running NGINX, and listen.mode defaults to 0660. Using these defaults, NGINX should be able to access the socket.
If PHP-FPM is listening on a TCP socket, the pool conifguration's listen directive will have a value in the form of address:port, as shown below:
www.conf
COPY
listen = 127.0.0.1:9000
Just as with a Unix socket, you can prevent 502 errors by confirming that the location of this socket matches the one specified in the NGINX configuration.
PHP-FPM is timing out
If your application is taking too long to respond, your users will experience a timeout error. If PHP-FPM's timeout—which is set in the pool configuration's request_terminate_timeout directive (and defaults to 20 seconds)—is less than NGINX's timeout (which defaults to 60 seconds), NGINX will respond with a 502 error. The NGINX error log shown below indicates that its upstream process—which is PHP-FPM—closed the connection before sending a valid response. In other words, this is the error log we see when PHP-FPM times out:
error.log
COPY
2020/02/20 17:17:12 [error] 3059#3059: *29 recv() failed (104: Connection reset by peer) while reading response header from upstream, client: 127.0.0.1, server: localhost, request: "GET / HTTP/1.1", upstream: "fastcgi://unix:/run/php/mypool.sock:", host: "localhost"
In this case, the PHP-FPM log (which by default is located at /var/log/php7.2-fpm.log) shows a correlated message which provides further information:
php7.2-fpm.log
COPY
[20-Feb-2020 17:17:12] WARNING: [pool mypool] child 2120, script '/var/www/html/index.php' (request: "GET /index.php") execution timed out (25.755070 sec), terminating
You can raise PHP-FPM's timeout setting by editing the pool's configuration file, but this could cause another issue: NGINX may time out before receiving a response from PHP-FPM. The default NGINX timeout is 60 seconds; if you've raised your PHP-FPM timeout above 60 seconds, NGINX will return a 504 Gateway Timeout error if your PHP application hasn't responded in time. You can prevent this by also raising your NGINX timeout. In the example below, we've raised the timeout value to 90 seconds by adding the fastcgi_read_timeout item to the http block of /etc/nginx/nginx.conf:
nginx.conf
COPY
http { ... fastcgi_buffers 8 16k; fastcgi_buffer_size 32k; fastcgi_connect_timeout 90; fastcgi_send_timeout 90; fastcgi_read_timeout 90; }
Reload your NGINX configuration to apply this change:
COPY
nginx -s reload
Next, to determine why PHP-FPM timed out, you can collect logs and application performance monitoring (APM) data that can reveal causes of latency within and outside your application.
Collect and analyze your logs
To troubleshoot application errors, you can collect your logs and send them to a log management service. In addition to the NGINX logs we examined above, PHP can log errors and other events that might be valuable to you. See our PHP logging guide for more information.
When you bring your PHP and NGINX logs into a log management service, combined with logs from relevant technologies like caching servers and databases, you can analyze logs from throughout your web stack in a single platform.
Datadog's Log Analytics shows logs from multiple services, grouped by status.
Collect APM data from your web stack
APM can help you identify bottlenecks and resolve issues, like 502 errors, which affect the performance of your app. The screenshot below shows NGINX's APM data visualized in Datadog. This view summarizes request volume, error rates, and latency for an NGINX-based service and helps you investigate performance problems like 502 errors.

200 OK
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HTTP Error 502 Bad gateway
The 502 Bad Gateway error usually happens when there are some network errors between computer and internet severs . This means that a server (not necessarily a web server) acting as a gateway or proxy and received an invalid response from an upstream (or origin) server. In most cases the problem is not with you computer or your internet connection , it's far more likely that it's the website's server instead.

HTTP status code
In essence, if you see a 502 Bad Gateway error, this is an HTTP status code . HTTP status codes are three-digit codes, and are grouped into five different classes. The class of a status code can be quickly identified by its first digit:
1xx: Informational
2xx: Success
3xx: Redirection
4xx: Client Error
5xx: Server Error
The 502 'Bad Gateway' error is coming from the server , and usually has nothing to do with your PC. It usually happens when you visit a website that uses a relay point, called a proxy server, that keeps data separate from the server hosting the site's main page. If the main server and proxy server don't properly connect due to incorrect Transmission Control Protocol data, your browser determines the proxy, or gateway, to be bad.
Error Messages
Different sites and services will often customize their error messages , both for the sake of them appearing unique, and also help tech-savvy users to better understand the cause of the error.
502 Bad Gateway
502 Proxy Error
502. That's an error
HTTP Error 502 - Bad Gateway
502 Service Temporarily Overloaded
Bad Gateway: The proxy server received an invalid response from an upstream server
502 Server Error: The server encountered a temporary error and could not complete your request
Cause of 502 Bad Gateway Errors
The 502 Bad Gateway Error is an indication that something has gone wrong within the server of your application, as opposed to the client side request. At its heart, the cause is simple, two online servers are having trouble communicating. Often, simply refreshing or reloading the page (Ctrl-F5) will work, but sometimes the problem can persist for days. There are 5 main problems that cause 502 Bad Gateway responses. These include:
Server failure: The gateway receives a negative result if the target server has failed completely. This can occur due to a system crash .
Domain name not resolvable: The domain name is not resolving to the correct IP or it does not resolve to any IP. It is important to note that DNS changes could take same time until they are global fully propagated and active. This is dependant on the TTL, or time to live, defined per record.
Webserver overload: If a webserver reaches its limit, it can't answer any more requests , the gateway then delivers the status code 502 Bad Gateway.
Firewall blocks request: Firewalls can cause errors on both sides of the communication (server and client) with the forwarding of requests.
Browser error: Browser extensions can also sometimes cause errors with the display of a website and generate a 502 error .
How to Fix a 502 Error
Perform a hard-refresh in your browser. On Macs, this is done by pressing Cmd + Shift + R.
This problem is due to poor IP communication between back-end computers, possibly including the Web server at the site you are trying to visit. Before analysing this problem, you should clear your browser cache completely.
If you get this problem for only some of the Web sites you try to visit then it is likely to be a problem at those sites i.e. one of their pieces of equipment is failing/overloaded. Contact the people at those sites.
If you are surfing the Web and see this problem for all Web sites you try to visit, then either 1) your ISP has a major equipment failure/overload or 2) there is something wrong with your internal Internet connection e.g. your firewall is not functioning correctly. In the first case, only your ISP can help you. In the second case, you need to fix whatever it is that is preventing you reaching the Internet.
In some cases, this error caused by low computer hard disk space, you can go check the free space of your computer hard disk. If there is really not enough free space left, clean your computer hard disk well.
Start your browser in Safe Mode. Running a browser in Safe Mode means to run it with default settings and without add-ons or extensions, including toolbars.
If your web application is configured to listen on a socket, ensure that the socket exists in the correct location and that it has the proper permissions
Finally, restart your computer/networking equipment. Some temporary issues with your computer and how it's connecting to your network could be causing 502 errors, especially if you're seeing the error on more than one website. In these cases, a restart would help.
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In Vitro and In Vivo Characterization of NOSO-502, a Novel Inhibitor of Bacterial Translation
Emilie Racine et al. Antimicrob Agents Chemother. 2018.
Free PMC article
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Abstract
Antibacterial activity screening of a collection of Xenorhabdus strains led to the discovery of the odilorhabdins, a new antibiotic class with broad-spectrum activity against Gram-positive and Gram-negative pathogens. Odilorhabdins inhibit bacterial translation by a new mechanism of action on ribosomes. A lead optimization program identified NOSO-502 as a promising candidate. NOSO-502 has MIC values ranging from 0.5 to 4 μg/ml against standard Enterobacteriaceae strains and carbapenem-resistant Enterobacteriaceae (CRE) isolates that produce KPC, AmpC, or OXA enzymes and metallo-β-lactamases. In addition, this compound overcomes multiple chromosome-encoded or plasmid-mediated resistance mechanisms of acquired resistance to colistin. It is effective in mouse systemic infection models against Escherichia coli EN122 (extended-spectrum β-lactamase [ESBL]) or E. coli ATCC BAA-2469 (NDM-1), achieving a 50% effective dose (ED50) of 3.5 mg/kg of body weight and 1-, 2-, and 3-log reductions in blood burden at 2.6, 3.8, and 5.9 mg/kg, respectively, in the first model and 100% survival in the second, starting with a dose as low as 4 mg/kg. In a urinary tract infection (UTI) model with E. coli UTI89, urine, bladder, and kidney burdens were reduced by 2.39, 1.96, and 1.36 log10 CFU/ml, respectively, after injection of 24 mg/kg. There was no cytotoxicity against HepG2, HK-2, or human renal proximal tubular epithelial cells (HRPTEpiC), no inhibition of hERG-CHO or Nav 1.5-HEK current, and no increase of micronuclei at 512 μM. NOSO-502, a compound with a new mechanism of action, is active against Enterobacteriaceae, including all classes of CRE, has a low potential for resistance development, shows efficacy in several mouse models, and has a favorable in vitro safety profile.
Keywords: bacterial translation; carbapenem-resistant Enterobacteriaceae; inhibitor; preclinical candidate.
Copyright © 2018 Racine et al.
Figures

FIG 1
Chemical structure of NOSO-502.

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Pharmacokinetic studies with CD-1 mice…

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Efficacy of NOSO-502 and ciprofloxacin…

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All figures (7)
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Asempa TE, et al. Antimicrob Agents Chemother. 2019. PMID: 30670411 Free PMC article.
Rapid Increase in Prevalence of Carbapenem-Resistant Enterobacteriaceae (CRE) and Emergence of Colistin Resistance Gene mcr-1 in CRE in a Hospital in Henan, China.
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From Worms to Drug Candidate: The Story of Odilorhabdins, a New Class of Antimicrobial Agents.
Racine E, et al. Front Microbiol. 2019. PMID: 31921069 Free PMC article. Review.
A new antibiotic selectively kills Gram-negative pathogens.
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Wu W, et al. Clin Microbiol Rev. 2019. PMID: 30700432 Free PMC article. Review.
References
Centers for Disease Control and Prevention. 2013. Antibiotic resistance threats in the United States, 2013. Centers for Disease Control and Prevention, Atlanta, GA. http://www.cdc.gov/drugresistance/threat-report-2013/pdf/ar-threats-2013-508.pdf Accessed 26 November 2014.
Zhang Y, Wang Q, Yin Y, Chen H, Jin L, Gu B, Xie L, Yang C, Ma X, Li H, Li W, Zhang X, Liao K, Man S, Wang S, Wen H, Li B, Guo Z, Tian J, Pei F, Liu L, Zhang L, Zou C, Hu T, Cai J, Yang H, Huang J, Jia X, Huang W, Cao B, Wang H. 2018. Epidemiology of carbapenem-resistant Enterobacteriaceae infections: report from the China CRE Network. Antimicrob Agents Chemother 62:e01882-. doi:10.1128/AAC.00529-18. - DOI - PMC - PubMed
Pantel L, Florin T, Dobosz-Bartoszek M, Racine E, Sarciaux M, Serri M, Houard J, Campagne JM, Marcia de Figueiredo R, Gaudriault S, Givaudan A, Forst S, Aumelas A, Cotteaux-Lautard C, Bolla JM, Vingsbo Lundberg C, Huseby D, Hughes D, Vázquez-Laslop N, Mankin AS, Polikanov YS, Gualtieri M. 2018. Odilorhabdins, a class of potent antibacterial agents, cause miscoding by binding at a new ribosomal site. Mol Cell 70:83–94. doi:10.1016/j.molcel.2018.03.001. - DOI - PubMed
Cheng YH, Lin TL, Lin YT, Wang JT. 2018. A putative RND-type efflux pump, H239_3064, contributes to colistin resistance through CrrB in Klebsiella pneumoniae. J Antimicrob Chemother 73:1509–1516. doi:10.1093/jac/dky054. - DOI - PMC - PubMed
Wright MS, Suzuki Y, Jones MB, Marshall SH, Rudin SD, van Duin D, Kaye K, Jacobs MR, Bonomo RA, Adams MD. 2015. Genomic and transcriptomic analyses of colistin-resistant clinical isolates of Klebsiella pneumoniae reveal multiple pathways of resistance. Antimicrob Agents Chemother 59:536–543. doi:10.1128/AAC.04037-14. - DOI - PMC - PubMed
Show all 46 references
Publication types
Research Support, Non-U.S. Gov't
MeSH terms
Animals
Anti-Bacterial Agents / pharmacology*
Bacterial Proteins / metabolism
CHO Cells
Carbapenem-Resistant Enterobacteriaceae / drug effects*
Carbapenem-Resistant Enterobacteriaceae / metabolism
Cell Line
Cell Line, Tumor
Colistin / pharmacology
Cricetulus
Dogs
Enterobacteriaceae Infections / drug therapy
Escherichia coli / drug effects*
Escherichia coli / metabolism
Haplorhini
Hep G2 Cells
Humans
Mice
Microbial Sensitivity Tests / methods
Plasmids / metabolism
Rats
beta-Lactamases / metabolism
Substances
Anti-Bacterial Agents
Bacterial Proteins
beta-Lactamases
Colistin
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Gene (nucleotide/PMC)
PubChem Compound (MeSH Keyword)
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The role of local ancestry adjustment in association studies using admixed populations
Jianqi Zhang et al. Genet Epidemiol. 2014 Sep.
Free PMC article
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Abstract
Association analysis using admixed populations imposes challenges and opportunities for disease mapping. By developing some explicit results for the variance of an allele of interest conditional on either local or global ancestry and by simulation of recently admixed genomes we evaluate power and false-positive rates under a variety of scenarios concerning linkage disequilibrium (LD) and the presence of unmeasured variants. Pairwise LD patterns were compared between admixed and nonadmixed populations using the HapMap phase 3 data. Based on the above, we showed that as follows: For causal variants with similar effect size in all populations, power is generally higher in a study using admixed population than using nonadmixed population, especially for highly differentiated SNPs. This gain of power is achieved with adjustment of global ancestry, which completely removes any cross-chromosome inflation of type I error rates, and addresses much of the intrachromosome inflation. If reliably estimated, adjusting for local ancestry precisely recovers the localization that could have been achieved in a stratified analysis of source populations. Improved localization is most evident for highly differentiated SNPs; however, the advantage of higher power is lost on exactly the same differentiated SNPs. In the real admixed populations such as African Americans and Latinos, the expansion of LD is not as dramatic as in our simulation. While adjustment for global ancestry is required prior to announcing a novel association seen in an admixed population, local ancestry adjustment may best be regarded as a localization tool not strictly required for discovery purposes.
Keywords: admixture; genetic association studies; global ancestry; local ancestry; power and type I error.
© 2014 WILEY PERIODICALS, INC.
Figures

Figure 1
Power comparison with adjustment of…

Figure 2
Manhattan plot of simulated association…

Figure 3
Cumulative density of the number…

Figure 4
Distribution of distance from the…
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References
Adeyemo A, Gerry N, Chen GJ, Herbert A, Doumatey A, Huang HX, Zhou J, Lashley K, Chen YX, Christman M. A genome-wide association study of hypertension and blood pressure in African Americans. Plos Genet. 2009;5(7):11. others. - PMC - PubMed
Armitage P. Tests for linear trends in proportions and frequencies. Biometrics. 1955;11(3):375–386.
Balding D, Nichols R. A method for quantifying differentiation between populations at multi-allelic. Genetica. 1995;96(0016-6707 (Print)):3–12. - PubMed
Beleza S, Johnson NA, Candille SI, Absher DM, Coram MA, Lopes J, Campos J, Araujo II, Anderson TM, Vilhjalmsson BJ. Genetic architecture of skin and eye color in an African-European admixed population. PLoS Genet. 2013;9(3):e1003372. others. - PMC - PubMed
Chakraborty R, Weiss KM. Admixture as a tool for finding linked genes and detecting that difference from allelic association between loci. Proc Natl Acad Sci USA. 1988;85(23):9119–9123. - PMC - PubMed
Show all 48 references
Publication types
Research Support, N.I.H., Extramural
MeSH terms
African Americans / genetics
Alleles
Genetics, Population*
Genome-Wide Association Study*
Genotype
HapMap Project
Hispanic Americans / genetics
Humans
Linkage Disequilibrium
Models, Genetic
Polymorphism, Single Nucleotide
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MedGen
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P01CA138338/CA/NCI NIH HHS/United States
R01 CA165862/CA/NCI NIH HHS/United States
U01 HG004802/HG/NHGRI NIH HHS/United States
5R01CA165862-02/CA/NCI NIH HHS/United States
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Heterogeneity of tensile strength and matrix metalloproteinase activity in the wall of abdominal aortic aneurysms
Srinivasa R Vallabhaneni et al. J Endovasc Ther. 2004 Aug.
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Purpose: To measure the tensile strength of the aneurysm wall and the matrix metalloproteinase (MMP) activity in similar samples of aortic tissue.
Methods: Detailed mechanical testing was conducted on 124 standardized specimens of aneurysm wall harvested from 24 patients undergoing elective aneurysm repair. The intrasac pressure required to cause aneurysm rupture was calculated based upon the Law of Laplace. In addition, MMP-2 and 9 were assayed from these specimens. Sixty specimens of nonaneurysmal aorta from 6 cadaveric organ donors served as controls. Intrasubject and intersubject variations were analyzed.
Results: In the aneurysm specimens, the Young's modulus was 1.80x10(6) N/m(2), the load at break was 6.36 N, the strain at break was 0.30, the ultimate strength was 0.53x10(6) N/ m(2), and the MMP activity was 312 for MMP-2 and 460 for MMP-9. In the controls, the circumferential measurements were a Young's modulus of 1.82x10(6) N/m(2), a load at break of 5.43 N, strain at break of 0.29, ultimate strength of 0.61x10(6) N/m(2), and MMP activity of 395 for MMP-2 and 2019 for MMP-9. Longitudinal measurements in controls were a Young's modulus of 1.38x10(6) N/m(2), a load at break of 11.39 N, a strain at break of 0.33, and ultimate strength of 1.30x10(6) N/m(2). Intra and intersubject variation of all parameters was very high. Based upon the lowest measured tensile strength for each aneurysm, the intrasac pressure required to cause rupture varied from 142 to 982 mmHg.
Conclusions: Localized "hot spots" of MMP hyperactivity could lead to focal weakening of the aneurysm wall and rupture at relatively low levels of intraluminal pressure. These data suggest that tensile strength of the sac is just as important as intrasac tension in determining the risk of rupture. Moreover, these observations may explain why some small aneurysms rupture and larger aneurysms do not. Assessment of rupture risk based on computation or measurement of wall stress may be subject to error and inaccuracy due to variations in wall tensile strength.
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Activity of matrix metalloproteinase-2 and -9 in abdominal aortic aneurysms. Relation to size and rupture.
Petersen E, et al. Eur J Vasc Endovasc Surg. 2000. PMID: 11112465
Immunohistochemical expression of metalloproteinases MMP-2 and MMP-9 in abdominal aortic aneurysms: correlation with symptoms and aortic diameter.
Papalambros E, et al. Int J Mol Med. 2003. PMID: 14612975
Factors promoting rupture of abdominal aortic aneurysms.
Van Damme H, et al. Acta Chir Belg. 2005. PMID: 15790196 Review.
Localization of matrix metalloproteinase 2 within the aneurysmal and normal aortic wall.
Crowther M, et al. Br J Surg. 2000. PMID: 11044166
Advancements in identifying biomechanical determinants for abdominal aortic aneurysm rupture.
Kontopodis N, et al. Vascular. 2015. PMID: 24757027 Review.
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The influence of sample geometry and size on porcine aortic material properties from uniaxial tensile tests using custom-designed tissue cutters, clamps and molds.
Pei M, et al. PLoS One. 2021. PMID: 33556052 Free PMC article.
Comparison of Correction Techniques for the Spill in Effect in Emission Tomography.
Akerele MI, et al. IEEE Trans Radiat Plasma Med Sci. 2020. PMID: 33542967 Free PMC article.
Targeted Gold Nanoparticles as an Indicator of Mechanical Damage in an Elastase Model of Aortic Aneurysm.
Lane BA, et al. Ann Biomed Eng. 2020. PMID: 32240423
Biomechanics of aortic wall failure with a focus on dissection and aneurysm: A review.
Sherifova S, et al. Acta Biomater. 2019. PMID: 31419563 Free PMC article. Review.
Effects of Collagen Heterogeneity on Myocardial Infarct Mechanics in a Multiscale Fiber Network Model.
Korenczuk CE, et al. J Biomech Eng. 2019. PMID: 31141605 Free PMC article.
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Publication types
Research Support, Non-U.S. Gov't
MeSH terms
Aorta, Abdominal / enzymology
Aorta, Abdominal / physiopathology*
Aortic Aneurysm, Abdominal / enzymology*
Aortic Aneurysm, Abdominal / physiopathology*
Aortic Rupture / etiology
Case-Control Studies
Humans
Matrix Metalloproteinase 2 / metabolism*
Matrix Metalloproteinase 9 / metabolism*
Risk Factors
Stress, Mechanical
Tensile Strength*
Substances
Matrix Metalloproteinase 2
Matrix Metalloproteinase 9
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