Altered glycosylation of glycodelin in endometrial carcinoma

Glycodelin is a major glycoprotein expressed in reproductive tissues, like secretory and decidualized endometrium. It has several reproduction related functions that are dependent on specific glycosylation, but it has also been found to drive differentiation of endometrial carcinoma cells toward a less malignant phenotype. Here we aimed to elucidate whether the glycosylation and function of glycodelin is altered in endometrial carcinoma as compared with a normal endometrium. We carried out glycan structure analysis of glycodelin expressed in HEC-1B human endometrial carcinoma cells (HEC-1B Gd) by mass spectrometry glycomics strategies. Glycans of HEC-1B Gd were found to comprise a typical mixture of high-mannose, hybrid, and complex-type N-glycans, often containing undecorated LacNAc (Gal beta 1-4GlcNAc) antennae. However, several differences, as compared with previously reported glycan structures of normal human decidualized endometrium-derived glycodelin isoform, glycodelin-A (GdA), were also found. These included a lower level of sialylation and more abundant poly-LacNAc antennae, some of which are fucosylated. This allowed us to select lectins that showed different binding to these classes of glycodelin. Despite the differences in glycosylation between HEC-1B Gd and GdA, both showed similar inhibitory activity on trophoblast cell invasion and peripheral blood mononuclear cell proliferation. For the detection of cancer associated glycodelin, we established a novel in situ proximity-ligation based histochemical staining method using a specific glycodelin antibody and UEAI lectin. We found that the UEAI reactive glycodelin was abundant in endometrial carcinoma, but virtually absent in normal endometrial tissue even when glycodelin was strongly expressed. In conclusion, we established a histochemical staining method for the detection of endometrial carcinoma-associated glycodelin and showed that this specific glycodelin is exclusively expressed in cancer, not in normal endometrium. Similar methods can be used for studies of other glycoproteins. Glycodelin is a major endometrial glycoprotein. The authors analyzed glycan structures of endometrial carcinoma associated glycodelin and established a novel glycodelin-glycoform specific histochemical staining method. With this, they showed that glycodelin is differentially glycosylated in endometrial carcinoma tissue, as compared to normal endometrium, representing a neoantigen with potential clinical applications.Peer reviewe

Low Expression of Stanniocalcin 1 (STC-1) Protein Is Associated With Poor Clinicopathologic Features of Endometrial Cancer

Stanniocalcin-1 (STC-1) is a glycoprotein hormone involved in diverse biological processes, including regulation of calcium phosphate homeostasis, cell proliferation, apoptosis, inflammation, oxidative stress responses, and cancer development. The role of STC-1 in endometrial cancer (EC) is yet to be elucidated. In this study, we investigated the protein expression pattern of STC-1 in a tissue microarray (TMA) cohort of hysterectomy specimens from 832 patients with EC. We then evaluated the prognostic value of STC-1 expression regarding the clinicopathologic features and patients survival over a period of 140 months. Our results revealed that in EC tissue samples, STC-1 is mainly localized in the endometrial epithelium, although some expression was also observed in the stroma. Decreased STC-1 expression was associated with factors relating to a worse prognosis, such as grade 3 endometrioid tumors (p = 0.030), deep myometrial invasion (p = 0.003), lymphovascular space invasion (p = 0.050), and large tumor size (p = 0.001). Moreover, STC-1 expression was decreased in tumors obtained from obese women (p = 0.014) and in women with diabetes mellitus type 2 (DMT2; p = 0.001). Interestingly, the data also showed an association between DNA mismatch repair (MMR) deficiency and weak STC-1 expression, specifically in the endometrial epithelium (p = 0.048). No association was observed between STC-1 expression and disease-specific survival. As STC-1 expression was particularly low in cases with obesity and DMT2 in the TMA cohort, we also evaluated the correlation between metformin use and STC-1 expression in an additional EC cohort that only included women with DMT2 (n = 111). The analysis showed no difference in STC-1 expression in either the epithelium or the stroma in women undergoing metformin therapy compared to metformin non-users. Overall, our data may suggest a favorable role for STC-1 in EC behavior; however, further studies are required to elucidate the detailed mechanism and possible applications to cancer treatment.</p

Diabetic retinopathy: loss of neuroretinal adaptation to the diabetic metabolic environment

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106882/1/nyas12412.pd

Growth factor concentrations and their placental mRNA expression are modulated in gestational diabetes mellitus: possible interactions with macrosomia

<p>Abstract</p> <p>Background</p> <p>Gestational diabetes mellitus (GDM) is a form of diabetes that occurs during pregnancy. GDM is a well known risk factor for foetal overgrowth, termed macrosomia which is influenced by maternal hypergycemia and endocrine status through placental circulation. The study was undertaken to investigate the implication of growth factors and their receptors in GDM and macrosomia, and to discuss the role of the materno-foeto-placental axis in the <it>in-utero </it>regulation of foetal growth.</p> <p>Methods</p> <p>30 women with GDM and their 30 macrosomic babies (4.75 ± 0.15 kg), and 30 healthy age-matched pregnant women and their 30 newborns (3.50 ± 0.10 kg) were recruited in the present study. Serum concentrations of GH and growth factors, <it>i.e</it>., IGF-I, IGF-BP3, FGF-2, EGF and PDGF-B were determined by ELISA. The expression of mRNA encoding for GH, IGF-I, IGF-BP3, FGF-2, PDGF-B and EGF, and their receptors, <it>i.e</it>., GHR, IGF-IR, FGF-2R, EGFR and PDGFR-β were quantified by using RT-qPCR.</p> <p>Results</p> <p>The serum concentrations of IGF-I, IGF-BP3, EGF, FGF-2 and PDGF-B were higher in GDM women and their macrosomic babies as compared to their respective controls. The placental mRNA expression of the growth factors was either upregulated (FGF-2 or PDGF-B) or remained unaltered (IGF-I and EGF) in the placenta of GDM women. The mRNA expression of three growth factor receptors, <it>i.e</it>., IGF-IR, EGFR and PDGFR-β, was upregulated in the placenta of GDM women. Interestingly, serum concentrations of GH were downregulated in the GDM women and their macrosomic offspring. Besides, the expression of mRNAs encoding for GHR was higher, but that encoding for GH was lower, in the placenta of GDM women than control women.</p> <p>Conclusions</p> <p>Our results demonstrate that growth factors might be implicated in GDM and, in part, in the pathology of macrosomia via materno-foeto-placental axis.</p

The association of breast mitogens with mammographic densities

Radiologically dense breast tissue (mammographic density) is strongly associated with risk of breast cancer, but the biological basis for this association is unknown. In this study we have examined the association of circulating levels of hormones and growth factors with mammographic density. A total of 382 subjects, 193 premenopausal and 189 postmenopausal, without previous breast cancer or current hormone use, were selected in each of five categories of breast density from mammography units. Risk factor information, anthropometric measures, and blood samples were obtained, and oestradiol, progesterone, sex hormone binding globulin, growth hormone, insulin-like growth factor-I and its principal binding protein, and prolactin measured. Mammograms were digitised and measured using a computer-assisted method. After adjustment for other risk factors, we found in premenopausal women that serum insulin-like growth factor-I levels, and in postmenopausal women, serum levels of prolactin, were both significantly and positively associated with per cent density. Total oestradiol and progesterone levels were unrelated to per cent density in both groups. In postmenopausal women, free oestradiol (negatively), and sex hormone binding globulin (positively), were significantly related to per cent density. These data show an association between blood levels of breast mitogens and mammographic density, and suggest a biological basis for the associated risk of breast cancer

Statin medication in patients with epiretinal membrane is associated with low intravitreal EPO, TGF-beta-1, and VEGF levels

Raimo Tuuminen,1 Sirpa Loukovaara2 1Department of Ophthalmology, Kymenlaakso Central Hospital, Kotka, Finland; 2Unit of Vitreoretinal Surgery, Dept of Ophthalmology, Helsinki University Hospital, University of Helsinki, Helsinki, FinlandBackground: In eyes with idiopathic epiretinal membrane (iERM), the intravitreal growth factor and cytokine levels may associate with postvitrectomy outcomes. Here, we have analyzed the perioperative intravitreal protein levels of potent vasoactive, proinflammatory, and extracellular matrix-remodeling factors in iERM eyes and evaluated the postvitrectomy outcomes.Methods: This was an institutional, observational study. Eyes operated on for iERM (n=26) were analyzed according to the use of statin medication. Vitreous samples were subjected to protein measurements of angiopoietin-1 and -2, erythropoietin, transforming growth factor-&beta;1, and vascular endothelial growth factor by enzyme-linked immunosorbent assay, and of matrix metalloproteinase-2 and -9 by gelatin zymography. One-month visual outcomes and 1-year revitrectomy rates were recorded.Results: In iERM eyes of patients taking statins, intravitreal levels of erythropoietin (mean&nbsp;&plusmn;&nbsp;standard deviation, 10.8&plusmn;4.9 vs 82.9&plusmn;119.5 mIU/mg, P=0.003), transforming growth factor-&beta;1 (2.3&plusmn;4.7 vs 15.8&plusmn;16.3 pg/mg, P=0.035), and vascular endothelial growth factor (5.5&plusmn;9.9 vs 236.6&plusmn;491.6 pg/mg, P=0.006) were lower than in nonstatin-treated patients. At 1-month, visual gain did not significantly differ between iERM eyes of patients with statins and those without (improvement 0.27&plusmn;0.20 vs 0.16&plusmn;0.38 logarithm of the minimum angle of resolution units, P=0.118).Conclusion: Systemic statin therapy might have a favorable effect on intravitreal factors involved in vascular permeability, inflammation, and fibroproliferation in aging human iERM&nbsp;eyes.Keywords: epiretinal membrane, erythropoietin, HMG-CoA reductase inhibitors, transforming growth factor-beta, vascular endothelial growth factor, vitrectom

A retrospective study comparing outcomes of primary rhegmatogenous retinal detachment repair by scleral buckling and pars plana vitrectomy in Finland

Sari Sahanne,1 Raimo Tuuminen,2 Jari Haukka,3 Sirpa Loukovaara4 1Department of Anesthesiology, Helsinki University Central Hospital, Helsinki, 2Department of Ophthalmology, Kymenlaakso Central Hospital, Kotka, 3Hjelt Institute, Faculty of Medicine, University of Helsinki, 4Unit of Vitreoretinal Surgery, Department of Ophthalmology, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland Background: Rhegmatogenous retinal detachment (RRD) is the most common form of retinal detachment and an ophthalmic emergency. Here, we compared outcomes of primary RRD eyes operated with conventional scleral buckling (SB) with cryoretinopexy to those operated with standard pars plana vitrectomy (PPV). Methods: This is an institutional, retrospective, register-based, observational, comparative study. Based on the surgical procedure, 319 eyes of 319 patients were divided into two groups: SB plus cryotherapy (n=50) and PPV (n=269). Changes in intraocular pressure (IOP) and best-corrected visual acuity (BCVA) were recorded at 30 days and reoperation rates within 180 days postoperatively. Results: Eyes operated with PPV had less reoperations within the first 180 days as compared with SB eyes (P=0.001, log-rank test); however, changes in IOP were more prominent (mean &plusmn; standard deviation: +8.1&plusmn;8.8 vs. +4.4&plusmn;7.0&nbsp;mmHg, respectively; P=0.006). Changes in BCVA did not differ between the surgical procedures. Conclusion: PPV was associated with higher primary anatomic success rates and lower risk of reoperation but significant IOP elevation when compared to SB. These factors should be case-specifically considered when choosing treatment modality for primary RRD. Keywords: rhegmatogenous retinal detachment, vitrectomy, scleral bucklin

Lysosomal destabilization activates the NLRP3 inflammasome in human umbilical vein endothelial cells (HUVECs)

Inflammation is a crucial component in the pathogenesis of many vascular diseases, such as atherosclerosis and diabetes. Inflammasomes are intracellular signalling complexes whose activation promotes inflammation. Nucleotide-binding domain and Leucine-rich repeat Receptor containing a Pyrin domain 3 (NLRP3) is a pattern recognition receptor (PRR) forming the best-known inflammasome. Disturbances in NLRP3 have been associated with multiple diseases. The purpose of this study was to explore the lysosomal destabilizationrelated NLRP3 inflammasome signaling pathway in human endothelial cells. In order to prime and activate NLRP3, human umbilical vein cells (HUVECs) were exposed to TNF-alpha and the lysosomal destructive agent Leusine-Leusine-OMethylesther (Leu-Leu-OMe), respectively. A caspase-1 inhibitor was used to block caspase-1' s enzymatic function and an interleukin 1 receptor antagonist (IL-1RA) to prevent any possible secondary effects of IL-1 beta. Leu-Leu-OMe increased the expression of NLRP3, IL-1 beta, and IL-18 in HUVECs. Exposure to Leu-Leu-OMe significantly promoted the production of IL-6 and IL-8 in primed HUVECs; this effect was prevented by the pre-treatment of cells with an IL-1RA. Our results suggest that lysosomal destabilization activates the NLRP3 inflammasome pathway that promotes the production of IL-6 and IL-8 in an autocrine manner in HUVEC cells.Peer reviewe

Association Between NSAID and Statin Therapy and the Incidence of Intravitreal Anti-vascular Endothelial Growth Factor Injections and Nd:YAG Laser Treatment After Cataract Surgery in Finland

Purpose: To examine the association between the use of topical non-steroidal antiinflammatory (NSAID) medication, systemic statin therapy, and the incidence rate of two of the most common postsurgical procedures in adult patients undergoing Cataract surgery in Finland between January 1, 2010 and December 31, 2016. Methods: This retrospective, nationwide cohort study considered 176,052 Cataract operations coded with the International Classification of Disease coding: early adult (H25.0), normal (H25.1), other senile (H25.8), pre-senile (H26.02), or other (related to trauma, other eye disease, or medication). Operations were linked to purchased and reimbursed medications using Anatomical Therapeutic Chemical codes. The incidence rate of intravitreal anti-vascular endothelial growth factor (VEGF) injections, and neodymium-doped yttrium aluminum (Nd:YAG) laser treatments of posterior capsular opacification were evaluated using the Poisson regression model. Results: In our registry cohort, patients with a prescription of topical NSAID (ketorolac) at the time of Cataract surgery were less likely treated with intravitreal anti-VEGF injections after surgery (adjusted Poisson regression model IRR 0.3; 95% CI: 0.15–0.60, P = 0.0007), and also had reduced incidence of Nd:YAG laser (0.59, CI: 0.43–0.81, P = 0.0011) treatments. Unlike topical NSAID, the use of systemic statin therapy was not associated with these two most common surgical procedures (RR 1.04, 95% CI: 0.96–1.12, P = 0.33). Conclusion: The use of topical NSAIDs is associated with reduced rates of intravitreal anti-VEGF injections and Nd:YAG laser treatments after Cataract surgery. More observational and experimental studies are warranted to confirm possible benefits of topical NSAID administration after Cataract surgery