Glycolysis is critical for cancer stem cell reprogramming; however, the underlying regulatory mechanisms remain elusive. Here, we show that pyruvate dehydrogenase kinase 1 (PDK1) is enriched in ...breast cancer stem cells (BCSCs), whereas depletion of PDK1 remarkably diminishes ALDH
subpopulations, decreases stemness-related transcriptional factor expression, and inhibits sphere-formation ability and tumor growth. Conversely, high levels of PDK1 enhance BCSC properties and are correlated with poor overall survival. In mouse xenograft tumor, PDK1 is accumulated in hypoxic regions and activates glycolysis to promote stem-like traits. Moreover, through screening hypoxia-related long non-coding RNAs (lncRNAs) in PDK1-positive tissue, we find that lncRNA H19 is responsible for glycolysis and BCSC maintenance. Furthermore, H19 knockdown decreases PDK1 expression in hypoxia, and ablation of PDK1 counteracts H19-mediated glycolysis and self-renewal ability in vitro and in vivo. Accordingly, H19 and PDK1 expression exhibits strong correlations in primary breast carcinomas. H19 acting as a competitive endogenous RNA sequesters miRNA let-7 to release Hypoxia-inducible factor 1α, leading to an increase in PDK1 expression. Lastly, aspirin markedly attenuates glycolysis and cancer stem-like characteristics by suppressing both H19 and PDK1. Thus, these novel findings demonstrate that the glycolysis gatekeeper PDK1 has a critical role in BCSC reprogramming and provides a potential therapeutic strategy for breast malignancy.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract
STUDY QUESTION
Is there a temporal relationship between endometriosis and infertility?
SUMMARY ANSWER
Endometriosis is associated with a higher risk of subsequent infertility, but only among ...women age <35 years.
WHAT IS KNOWN ALREADY
Endometriosis is the most commonly observed gynecologic pathology among infertile women undergoing laparoscopic examination. Whether endometriosis is a cause of infertility or an incidental discovery during the infertility examination is unknown.
STUDY DESIGN, SIZE, DURATION
This study included data collected from 58 427 married premenopausal female nurses <40 years of age from 1989 to 2005, who are participants of the Nurses' Health Study II prospective cohort.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Our exposure was laparoscopically confirmed endometriosis. Multivariate Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for infertility risk (defined as attempting to conceive for >12 months) among women with and without endometriosis.
MAIN RESULTS AND THE ROLE OF CHANCE
We identified 4612 incident cases of infertility due to any cause over 362 219 person-years of follow-up. Compared with women without a history of endometriosis, women with endometriosis had an age-adjusted 2-fold increased risk of incident infertility (HR = 2.12, 95% CI = 1.76–2.56) that attenuated slightly after accounting for parity. The relationship with endometriosis was only observed among women <35 years of age (multivariate HR <35 years = 1.77, 95% CI = 1.46–2.14; multivariate HR 35–39 years = 1.20, 95% CI = 0.94–1.53; P-interaction = 0.008). Risk of primary versus secondary infertility was similar subsequent to endometriosis diagnosis. Among women with primary infertility, 50% became parous after the endometriosis diagnosis, and among all women with endometriosis, 83% were parous by age 40 years.
LIMITATIONS, REASONS FOR CAUTION
We did not have information on participants' intentions to conceive, but by restricting the analytic population to married women we increased the likelihood that pregnancies were planned (and therefore infertility would be recognized). Women in our cohort with undiagnosed asymptomatic endometriosis will be misclassified as unexposed. However, the small proportion of these women are diluted among the >50 000 women accurately classified as endometriosis-free, minimizing the impact of exposure misclassification on the effect estimates.
WIDER IMPLICATIONS OF THE FINDINGS
This study supports a temporal association between endometriosis and infertility risk. Our prospective analysis indicates a possible detection bias in previous studies, with our findings suggesting that the infertility risk posed by endometriosis is about half the estimates observed in cross-sectional analyses.
STUDY FUNDING/COMPETING INTERESTS
This work was supported by the National Institutes of Health (grant numbers: UM1 CA176726, HD52473, HD57210, T32DK007703, T32HD060454, K01DK103720). We have no competing interests to declare.
The ability of the ivy sign on contrast-enhanced T1-weighted MR imaging (CEMR) to reflect cerebral perfusion and postoperative revascularization in Moyamoya disease remains largely unknown. We aimed ...to compare the capabilities of CEMR and FLAIR.
CEMR, FLAIR, arterial spin-labeling, and DSA were performed in 44 patients with Moyamoya disease. The ivy sign was scored separately on CEMR and FLAIR using the Alberta Stroke Program Early CT Score. The status of leptomeningeal collaterals was scored on DSA. The postoperative Matsushima grade was evaluated at least 3 months after surgical revascularization.
Scoring of the ivy sign on CEMR showed excellent interrater reliability, and FLAIR vascular hyperintensity showed moderate interrater reliability. Correlation analyses revealed that DSA scores were more consistent with the CEMR-based ivy sign score (
=
0.25,
= .03) than with FLAIR vascular hyperintensity (
= 0.05,
= .65). The CEMR-based ivy sign score was significantly correlated with CBF in late-Suzuki stage Moyamoya disease (
= -2.64,
= .02). The CEMR-based ivy sign score at baseline was significantly correlated with the postoperative Matsushima grade (
=
0.48,
= .03).
In this study, CEMR outperformed FLAIR in capturing the ivy sign in Moyamoya disease. In addition, the CEMR-based ivy sign score provided adequate information on hemodynamic status and postoperative neovascularization. The current study suggested that CEMR could be considered as an alternative to FLAIR in future studies investigating leptomeningeal collaterals in Moyamoya disease.
► Alginate biopolymer is used as controlled environment for preparation of ZnO nanoparticles. ► A novel synthetic procedure is introduced for preparation of ZnO–alginate nanocomposites. ► The ...obtained ZnO–alginate nanocomposites exhibit strong antimicrobial activity. ► The antimicrobial activity was found to depend slightly on the preparation conditions. ► XPS spectroscopy was used to study the defects on the surface of ZnO nanoparticles.
Alginate was used as a controlled environment for the growth of ZnO nanoparticles. The formation of nanostructured particles was confirmed by a blue shift in the onset of the optical absorption with respect to bulk ZnO. From the XRD measurements it was found that the obtained ZnO nanoparticles have a hexagonal crystal structure. The emission spectrum of the nanocomposite is dominated by a strong band-to-band recombination, while the emission from the ZnO defect states depended on the preparation conditions. Besides showing the presence of Zn 2p, O 1s, Na 1s and C 1s core levels, the XPS analysis also showed that the O 1s spectra can be resolved into two lines that are attributed to the presence of OH groups on the surface of the particles and ZnO, respectively. Antimicrobial tests revealed that the ZnO–alginate nanocomposite exhibits a strong activity against the common pathogens
Staphylococcus aureus and
Escherichia coli.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Integration of host resistance and prothioconazole + tebuconazole fungicide application at anthesis to manage Fusarium head blight (FHB) and deoxynivalenol (DON) in wheat was evaluated using data ...from over 40 trials in 12 U.S. states. Means of FHB index (index) and DON from up to six resistance class-fungicide management combinations per trial (susceptible treated S_TR and untreated S_UT; moderately susceptible treated MS_TR and untreated MS_UT; moderately resistant treated MR_TR and untreated MR_UT) were used in multivariate meta-analyses, and mean log response ratios across trials were estimated and transformed to estimate mean percent control ( ) due to the management combinations relative to S_UT. All combinations led to a significant reduction in index and DON (P < 0.001). MR_TR was the most effective combination, with a of 76% for index and 71% for DON, followed by MS_TR (71 and 58%, respectively), MR_UT (54 and 51%, respectively), S_TR (53 and 39%, respectively), and MS_UT (43 and 30%, respectively). Calculations based on the principle of treatment independence showed that the combination of fungicide application and resistance was additive in terms of percent control for index and DON. Management combinations were ranked based on percent control relative to S_UT within each trial, and nonparametric analyses were performed to determine management combination stability across environments (trials) using the Kendall coefficient of concordance (W). There was a significant concordance of management combinations for both index and DON (P < 0.001), indicating a nonrandom ranking across environments and relatively low variability in the within-environment ranking of management combinations. MR_TR had the highest mean rank (best control relative to S_UT) and was one of the most stable management combinations across environments, with low rank stability variance (0.99 for index and 0.67 for DON). MS_UT had the lowest mean rank (poorest control) but was also one of the most stable management combinations. Based on Piepho's nonparametric rank-based variance homogeneity U test, there was an interaction of management combination and environment for index (P = 0.011) but not for DON (P = 0.147), indicating that the rank ordering for index depended somewhat on environment. In conclusion, although the magnitude of percent control will likely vary among environments, integrating a single tebuconazole + prothioconazole application at anthesis with cultivar resistance will be a more effective and stable management practice for both index and DON than either approach used alone.
The present study was designed to study the process of stress adaptation in roots and shoot of
Zea mays seedlings grown under hydroponic conditions during exposure to lead (Pb) (0–200
μM) for 1–7
d. ...The alterations in growth and in the level of various biochemical parameters were accessed vis-à-vis Pb accumulation. The accumulation of Pb increased in a concentration-duration-dependent manner, however its translocation from root to shoot was low. At the same time, the level of malondialdehyde (MDA) increased with increasing Pb concentration. However, growth parameters, such as dry weight and root length did not show a significant decline to any of the Pb concentrations. In addition, the level of photosynthetic pigments decreased only upon exposure to high Pb concentrations. These results suggested an alleviation of the stress that was presumably being achieved by antioxidants viz., superoxide dismutase (SOD) and catalase (CAT) as well as ascorbic acid (AsA), which increased linearly with increasing Pb levels and exposure time. However, the level of non-protein thiols (NP-SH) in roots, in general, showed a decline beyond 4
d that could be attributed to their consumption for the purpose of Pb detoxification. In conclusion,
Zea mays can be used as an indicator species for Pb, and the various antioxidants might play a key role in the detoxification of Pb induced toxic effects.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Intervertebral disc degeneration is associated with back pain and radiculopathy which, being a leading cause of disability, seriously affects the quality of life and presents a hefty burden to ...society. There is no effective intervention for the disease and the etiology remains unclear. Here, we show that disc degeneration exhibits features of fibrosis in humans and confirmed this in a puncture‐induced disc degeneration (PDD) model in rabbit. Implantation of bone marrow‐derived mesenchymal stem cells (MSCs) to PDD discs can inhibit fibrosis in the nucleus pulposus with effective preservation of mechanical properties and overall spinal function. We showed that the presence of MSCs can suppress abnormal deposition of collagen I in the nucleus pulposus, modulating profibrotic mediators MMP12 and HSP47, thus reducing collagen aggregation and maintaining proper fibrillar properties and function. As collagen fibrils can regulate progenitor cell activities, our finding provides new insight to the limited self‐repair capability of the intervertebral disc and importantly the mechanism by which MSCs may potentiate tissue regeneration through regulating collagen fibrillogenesis in the context of fibrotic diseases. Stem Cells 2014;32:2164–2177
Correction to: Oncogene (2018) 37, 1062-1074; doi: 10.1038/onc.2017.368; published online 6 November 2017 This article was originally published under NPG's License to Publish, but has now been made ...available under a CC BY license. The PDF and HTML versions of the paper have been modified accordingly.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
To evaluate the relationship between blood glucose fluctuation and macrovascular dysfunction.
Eighty-eight type 2 diabetes mellitus (T2DM) patients with or without coronary heart disease (CHD) and 30 ...healthy control subjects were recruited. Glycosylated hemoglobin A1c (HbA1c), fasting insulin (FIns), and C-reaction protein (CRP) and some other general clinical variables were measured. A 72-hour continuous glucose monitoring (CGM) and brachial artery endothelium-dependent flow-mediated dilation (FMD) assessment were performed. The glucose excursion, MAGE (mean amplitude of glycemic excursions), LAGE (largest amplitude of glycemic excursions), MPPGE (mean postprandial glycemic excursions), MODD (absolute means of daily differences), and IAUC70 (incremental area under the curve below 70 mg/dl) during the CGM were analyzed. Correlations between the various variables were analyzed.
Enhanced blood glucose fluctuation was observed in T2DM patients with CHD as compared to other participants. And blood glucose fluctuation was correlated with FMD, CRP and HOMA-IR.
Blood glucose fluctuation is an important factor that affects inflammatory response and possibly induces CHD in T2DM patients.
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