Role of inflammation and aromatase expression in the eutopic endometrium and its relationship with the development of endometriosis.

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Role of inflammation and aromatase expression in the eutopic endometrium and its relationship with the development of endometriosis.

Womens Health (Lond Engl). 2012 Nov;8(6):647-58

Authors: Maia H, Haddad C, Coelho G, Casoy J

Abstract
Epigenetic changes favoring the transcription of the aromatase gene in the endometrium allow endometrial cells to survive in ectopic locations by producing estrogens that spare them from destruction through activated macrophages. Local estrogen production hastens prostaglandin synthesis by stimulating COX-2 activity, thus creating a self-perpetuating sequence of augmented estrogen formation and enhanced inflammation. Repetitive retrograde menstruation reintroduces aromatase-positive endometrial cells endowed with the capacity to implant and invade the peritoneum. In order to control endometriosis, an effective medication must inhibit aromatase, block COX-2, decrease fibrosis and induce amenorrhea. Within this framework, progestins, either alone or in the form of oral contraceptives, appear as first-line treatment for endometriosis owing to their capacity to block enzymes such as aromatase and COX-2.

PMID: 23181530 [PubMed - indexed for MEDLINE]

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Role of inflammation and aromatase expression in the eutopic endometrium and its relationship with the development of endometriosis.

Related Articles

Role of inflammation and aromatase expression in the eutopic endometrium and its relationship with the development of endometriosis.

Womens Health (Lond Engl). 2012 Nov;8(6):647-58

Authors: Maia H, Haddad C, Coelho G, Casoy J

Abstract
Epigenetic changes favoring the transcription of the aromatase gene in the endometrium allow endometrial cells to survive in ectopic locations by producing estrogens that spare them from destruction through activated macrophages. Local estrogen production hastens prostaglandin synthesis by stimulating COX-2 activity, thus creating a self-perpetuating sequence of augmented estrogen formation and enhanced inflammation. Repetitive retrograde menstruation reintroduces aromatase-positive endometrial cells endowed with the capacity to implant and invade the peritoneum. In order to control endometriosis, an effective medication must inhibit aromatase, block COX-2, decrease fibrosis and induce amenorrhea. Within this framework, progestins, either alone or in the form of oral contraceptives, appear as first-line treatment for endometriosis owing to their capacity to block enzymes such as aromatase and COX-2.

PMID: 23181530 [PubMed - indexed for MEDLINE]

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PKC-mediated USP phosphorylation at Ser35 modulates 20-hydroxyecdysone signaling in Drosophila.

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PKC-mediated USP phosphorylation at Ser35 modulates 20-hydroxyecdysone signaling in Drosophila.

J Proteome Res. 2012 Dec 7;11(12):6187-96

Authors: Wang S, Wang J, Sun Y, Song Q, Li S

Abstract
The nuclear receptor complex of the steroid hormone, 20-hydroxyecdysone (20E), is a heterodimer composed of EcR and USP. Our previous studies in Drosophila suggest that PKC modulates 20E signaling by phosphorylating EcR-USP. However, the exact phosphorylation sites in EcR and USP have not been identified. Using LC-MS/MS analysis, we first identified Ser35 of USP as a PKC phosphorylation site. Mutation of USP Ser35 to Ala35 in S2 cells not only eliminated USP phosphorylation, but also attenuated the 20E-induced luciferase activity, mimicking the treatment with a PKC-specific inhibitor chelerythrine chloride in Kc cells. In the larval salivary glands (SG), inhibition of PKC activity with the binary GAL4/UAS system reduced USP phosphorylation and down-regulated the 20E primary-response genes, E75B and Br-C, and RNAi knockdown of Rack1 had stronger inhibitory effects than overexpression of PKCi. Moreover, RNAi knockdown of four PKC isozyme genes expressed in the SG exhibited a variety of inhibitory effects on USP phosphorylation and expression of E75B and Br-C, with the strongest inhibitory effects occurring when aPKC was knocked down by RNAi. Taken together, we conclude that PKC-mediated USP phosphorylation at Ser35 modulates 20E signaling in Drosophila.

PMID: 23136906 [PubMed - indexed for MEDLINE]

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Optimizing megakaryocyte polyploidization by targeting multiple pathways of cytokinesis.

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Optimizing megakaryocyte polyploidization by targeting multiple pathways of cytokinesis.

Transfusion. 2012 Nov;52(11):2406-13

Authors: Avanzi MP, Chen A, He W, Mitchell WB

Abstract
BACKGROUND: Large-scale in vitro production of platelets (PLTs) from cord blood stem cells is one goal of stem cell research. One step toward this goal will be to produce polyploid megakaryocytes capable of releasing high numbers of PLTs. Megakaryocyte polyploidization requires distinct cytoskeletal and cellular mechanisms, including actin polymerization, myosin activation, microtubule formation, and increased DNA production. In this study we variably combined inhibition of these principal mechanisms of cytokinesis with the goal of driving polyploidization in megakaryocytes.
STUDY DESIGN AND METHODS: Megakaryocytes were derived from umbilical cord blood and cultured with reagents that inhibit distinct mechanisms of cytokinesis: Rho-Rock inhibitor (RRI), Src inhibitor (SI), nicotinamide (NIC), aurora B inhibitor (ABI), and myosin light chain kinase inhibitor (MLCKI). Combinations of reagents were used to determine their interactions and to maximize megakaryocyte ploidy.
RESULTS: Treatment with RRI, NIC, SI, and ABI, but not with MLCKI, increased the final ploidy and RRI was the most effective single reagent. RRI and MLCKI, both inhibitors of MLC activation, resulted in opposite ploidy outcomes. Combinations of reagents also increased ploidy and the use of NIC, SI, and ABI was as effective as RRI alone. Addition of MLCKI to NIC, SI, and ABI reached the highest level of polyploidization.
CONCLUSION: Megakaryocyte polyploidization results from modulation of a combination of distinct cytokinesis pathways. Reagents targeting distinct cytoskeletal pathways produced additive effects in final megakaryocyte ploidy. The RRI, however, showed no additive effect but produced a high final ploidy due to overlapping inhibition of multiple cytokinesis pathways.

PMID: 22612069 [PubMed - indexed for MEDLINE]

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Memantine is Associated with Longer Survival than Donepezil in a Veterans Affairs Prescription Database, 1997 to 2008.

Memantine is Associated with Longer Survival than Donepezil in a Veterans Affairs Prescription Database, 1997 to 2008.

J Alzheimers Dis. 2013 May 23;

Authors: Lazzeroni LC, Halbauer JD, Ashford JW, Noda A, Hernandez B, Azor V, Hozack N, Hasson N, Henderson VW, Yesavage JA, Tinklenberg JR

Abstract
Alzheimer's disease (AD) shortens life-expectancy, but the effects of pharmacological treatments for this disorder on mortality have not been studied. We compared two commonly prescribed medications, donepezil and memantine, with respect to the length of survival of veterans presumed to have AD. The Computerized Medical Records System at the Veterans Affairs Palo Alto Health Care System (VAPAHCS) was used to identify all patients prescribed these medications between 1997 and 2008. The VAPAHCS approved donepezil in 1997 and memantine in 2004. Kaplan-Meier and Cox regression analyses were used to test for chronological and drug-related associations with survival in 2,083 male veterans aged 55 years and older receiving prescriptions for donepezil, memantine, or both. Overall patient mortality decreased in the 2004 to 2008 era, compared with the 1997 to 2003 era, pre-memantine (HR: 0.75; 95% CI: 0.63, 0.89; p = 0.001). In analyses confined to the 2004 to 2008 era, patients prescribed memantine alone survived significantly longer (median survival 8.9 years) than those prescribed donepezil alone (HR: 2.24; 95% CI: 1.53, 3.28; p < 0.001) or both donepezil and memantine (HR: 1.83; 95% CI: 1.14, 2.94; p = 0.012). While this study has several limitations, these findings suggest that memantine treatment is associated with an increased life-expectancy relative to donepezil treatment. Additional research is needed to replicate these unexpected findings and identify potential mechanisms to explain this apparent association, to establish if the relationship applies to other cholinesterase inhibitors, and to discover whether the findings generalize to women and patient populations with characteristics different from those of the veterans in this study.

PMID: 23703151 [PubMed - as supplied by publisher]

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PKC-mediated USP phosphorylation at Ser35 modulates 20-hydroxyecdysone signaling in Drosophila.

Related Articles

PKC-mediated USP phosphorylation at Ser35 modulates 20-hydroxyecdysone signaling in Drosophila.

J Proteome Res. 2012 Dec 7;11(12):6187-96

Authors: Wang S, Wang J, Sun Y, Song Q, Li S

Abstract
The nuclear receptor complex of the steroid hormone, 20-hydroxyecdysone (20E), is a heterodimer composed of EcR and USP. Our previous studies in Drosophila suggest that PKC modulates 20E signaling by phosphorylating EcR-USP. However, the exact phosphorylation sites in EcR and USP have not been identified. Using LC-MS/MS analysis, we first identified Ser35 of USP as a PKC phosphorylation site. Mutation of USP Ser35 to Ala35 in S2 cells not only eliminated USP phosphorylation, but also attenuated the 20E-induced luciferase activity, mimicking the treatment with a PKC-specific inhibitor chelerythrine chloride in Kc cells. In the larval salivary glands (SG), inhibition of PKC activity with the binary GAL4/UAS system reduced USP phosphorylation and down-regulated the 20E primary-response genes, E75B and Br-C, and RNAi knockdown of Rack1 had stronger inhibitory effects than overexpression of PKCi. Moreover, RNAi knockdown of four PKC isozyme genes expressed in the SG exhibited a variety of inhibitory effects on USP phosphorylation and expression of E75B and Br-C, with the strongest inhibitory effects occurring when aPKC was knocked down by RNAi. Taken together, we conclude that PKC-mediated USP phosphorylation at Ser35 modulates 20E signaling in Drosophila.

PMID: 23136906 [PubMed - indexed for MEDLINE]

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FGF Receptors: Cancer Biology and Therapeutics.

FGF Receptors: Cancer Biology and Therapeutics.

Med Res Rev. 2013 May 21;

Authors: Katoh M, Nakagama H

Abstract
Fibroblast growth factors (FGFs) are involved in a variety of cellular processes, such as stemness, proliferation, anti-apoptosis, drug resistance, and angiogenesis. Here, FGF signaling network, cancer genetics/genomics of FGF receptors (FGFRs), and FGFR-targeted therapeutics will be reviewed. FGF signaling to RAS-MAPK branch and canonical WNT signaling cascade mutually regulate transcription programming. FGF signaling to PI3K-AKT branch and Hedgehog, Notch, TGF?, and noncanonical WNT signaling cascades regulate epithelial-to-mesenchymal transition (EMT) and invasion. Gene amplification of FGFR1 occurs in lung cancer and estrogen receptor (ER)-positive breast cancer, and that of FGFR2 in diffuse-type gastric cancer and triple-negative breast cancer. Chromosomal translocation of FGFR1 occurs in the 8p11 myeloproliferative syndrome and alveolar rhabdomyosarcoma, as with FGFR3 in multiple myeloma and peripheral T-cell lymphoma. FGFR1 and FGFR3 genes are fused to neighboring TACC1 and TACC3 genes, respectively, due to interstitial deletions in glioblastoma multiforme. Missense mutations of FGFR2 are found in endometrial uterine cancer and melanoma, and similar FGFR3 mutations in invasive bladder tumors, and FGFR4 mutations in rhabdomyosarcoma. Dovitinib, Ki23057, ponatinib, and AZD4547 are orally bioavailable FGFR inhibitors, which have demonstrated striking effects in preclinical model experiments. Dovitinib, ponatinib, and AZD4547 are currently in clinical trial as anticancer drugs. Because there are multiple mechanisms of actions for FGFR inhibitors to overcome drug resistance, FGFR-targeted therapy is a promising strategy for the treatment of refractory cancer. Whole exome/transcriptome sequencing will be introduced to the clinical laboratory as the companion diagnostic platform facilitating patient selection for FGFR-targeted therapeutics in the era of personalized medicine.

PMID: 23696246 [PubMed - as supplied by publisher]

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