NK cells have been the cells most extensively studied, primarily because they constitute the predominant
leukocyte population present in the endometrium at the time of implantation and in early pregnancy
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shared by Nathan Goodyear on 07 Dec 12
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Estrogen receptor related beta is expressed in human endometrium throughout the normal ... - 0 views
humrep.oxfordjournals.org/...2782.full
ER-alpha ER-beta estrogen receptor estrogen receptors estrogen receptor alpha estrogen receptor beta estrogen receptor alpha beta endometrium menstrual cycle human
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ER-beta found throughout both the proliferative and secretory phases of the menstrual cycle. ER-beta expression was higher in the proliferative versus the secretory phases, though not statistically significant. This makes since as estrogen stimulation dominates the proliferative phase. Additionally, ER-beta expression was found throughout all levels of the endometrium and the myometrium.
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shared by Nathan Goodyear on 07 Dec 12
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Oestrogen receptor α and β mRNA expression in human endometrium throughout th... - 0 views
molehr.oxfordjournals.org/...559.full
endometrium ER-alpha ER-beta estrogen receptor alpha estrogen receptor beta estrogen receptor estrogen receptors estrogen receptor receptors alpha beta menstrual cycle human
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Estrogen receptors alpha and beta show dominance in the proliferative phases, with alpha isoform predominating. In the secretory phase, less expression of ER was present. ER alpha was predominantly expressed in the epithelial and stromal cells in the proliferative phase. ER beta was predominantly expressed in glandular cells in the same proliferative phase. in the luteal phase, ER alpha expression declined in the funtionalis layers. ER alpha in the basalis remained unchanged. ER beta in the functionalis layers also declined in the luteal phase. No relative change was found in the weak expression of ER alpha/beta in the myometrium.
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shared by Nathan Goodyear on 15 Apr 12
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Natural Killer Cells in Pregnancy and Recurrent Pregnancy Loss: Endocrine and Immunolog... - 0 views
edrv.endojournals.org/...44.full
natural killer cells pregnancy loss recurrent immune system miscarriage NK
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parental chromosomal abnormalities, uterine anatomic anomalies, endometrial infections, endocrine etiologies (luteal phase defect, thyroid dysfunction, uncontrolled diabetes mellitus), antiphospholipid syndrome, inherited thrombophilias, and alloimmune causes
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In summary, in vivo animal experiments have shown an inhibitory role of estrogen on peripheral NK cell lytic activity, which is partly due to suppression of NK cell output by the bone marrow and partly due to suppression of individual NK cell cytotoxicity. However, in vitro studies so far have failed to show conclusively a direct effect of estrogen on NK cells.
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At the progesterone concentrations believed to be present in the uterus [up to 10−5 m at the maternal-fetal interface (35)], studies consistently show inhibition of lymphocyte proliferation (33) and inhibition of NK cytolytic activity in vitro
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The overall effects of estrogen on NK cells are likely multifactorial, therefore, and depend on the type of cell affected as well as the kind of ER expressed by that cell.
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It is known that progesterone can directly affect T cell differentiation in vitro, suppressing development of the Th1 pathway and enhancing differentiation along the Th2 pathway (44)
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Th1 cells predominantly produce interferon-γ (IFN-γ), IL-2, and TNF-β and are involved in cell-mediated immunity. Th2 cells produce IL-4, IL-5, IL-6, IL-10, and IL-13 and stimulate humoral immunity
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Furthermore, in response to progesterone, γδ T cells produce progesterone-induced blocking factor (PIBF) (54
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A defining characteristic of NK cells is their ability to lyse target cells without prior sensitization and without restriction by HLA antigens.
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IL-2 causes both NK cell proliferation and enhanced cytotoxicity. IFN-γ augments NK cytolytic activity, but does not cause NK proliferation. The two cytokines act synergistically to augment NK cytotoxicity (6).
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The largest leukocyte population in the endometrium consists of NK cells named large granulated lymphocytes
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there is a significant increase in the number of uNK cells throughout the secretory phase, which peaks in early pregnancy when uNK cells comprise about 75% of uterine leukocytes (62)
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general proinflammatory effect of estrogen, causing an influx of macrophages and neutrophils, which is antagonized by progesterone through its receptor (70, 71).
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Through promotion of a uterine Th2 environment, progesterone could indirectly affect uNK cell function
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The mechanism of this increase in uNK cell numbers has been addressed in both human and mouse models, and is likely the result of: 1) recruitment of peripheral NK cells to the uterus, and 2) proliferation of existing uNK cells
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uNK cells express a different cytokine profile, compared with resting peripheral NK cells. mRNAs for granulocyte CSF, M-CSF, GM-CSF, TNF-α, IFN-γ, TGF-β, and leukemia inhibitory factor (LIF) have been found in decidual CD56+ cells
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Their increased numbers in early pregnancy, their hormonal dependence, and their close proximity to the infiltrating trophoblast all suggest that they play an important role in the regulation of the maternal immune response to the fetal allograft and the control of trophoblast growth and invasion during human pregnancy
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Th1 immunity to trophoblast is associated with RPL, whereas Th2 immunity is associated with a successful pregnancy
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Transdermal progesterone cream as an alternative p... [Altern Ther Health Med. 2005 Nov... - 0 views
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The river blindness drug Ivermectin and related macrocyclic lactones inhibit WNT-TCF pa... - 0 views
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early colon cancers commonly display loss of function of the tumor suppressor Adenomatous polyposis coli (APC), a key component of the β-CATENIN destruction complex
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Other cancers also show an active canonical WNT pathway; these include carcinomas of the lung, stomach, cervix, endometrium, and lung as well as melanomas and gliomas
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In normal embryogenesis and homeostasis, the canonical WNT pathway is activated by secreted WNT ligands produced in highly controlled context-dependent manners and in precise amounts. WNT activity is transduced in the cytoplasm, inactivates the APC destruction complex, and results in the translocation of activate β-CATENIN to the nucleus, where it cooperates with DNA-binding TCF/LEF factors to regulate WNT-TCF targets and the ensuing genomic response
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beyond the loss of activity of the APC destruction complex, for instance throughAPC mutation, phosphorylation of β-CATENIN at C-terminal sites is required for the full activation of WNT-TCF signaling and the ensuing WNT-TCF responses in cancer.
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The WNT-TCF response blockade that we describe for low doses of Ivermectin suggests an action independent to the deregulation of chloride channels
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involve the repression of the levels of C-terminally phosphorylated β-CATENIN forms and of CYCLIN D1, a critical target that is an oncogene and positive cell cycle regulator.
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the Avermectin single-molecule derivative Selamectin, a drug widely used in veterinarian medicine (Nolan & Lok, 2012), is ten times more potent acting in the nanomolar range
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Ivermectin also diminished the protein levels of CYCLIN D1, a direct TCF target and oncogene, in both HT29 and H358 tumor cells
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Activated Caspase3 was used as a marker of apoptosis by immunohistochemistry 48 h after drug treatment. Selamectin and Ivermectin induced up to a sevenfold increase in the number of activated Caspase3+ cells in two primary (CC14 and CC36) and two cell line (DLD1 and Ls174T) colon cancer cell types (Fig(Fig2C).2C). All changes were significative
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The strong downregulation of the expression of the intestinal stem cell genesASCL2 andLGR5 (van der Flieret al, 2009; Scheperset al, 2012; Zhuet al, 2012b) by Ivermectin and Selamectin (Fig(Fig2D)2D) raised the possibility that these drugs could affect WNT-TCF-dependent colon cancer stem cell behavior
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Ivermectin hasin vivo efficacy against human colon cancer xenografts sensitive to TCF inhibition with no discernable side effects
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Ivermectin (Campbellet al, 1983), an off-patent drug approved for human use, and related macrocyclic lactones, have WNT-TCF pathway response blocking and anti-cancer activities
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these drugs block WNT-TCF pathway responses, likely acting at the level of β-CATENIN/TCF function, affecting β-CATENIN phosphorylation status.
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Ivermectin has a well-known anti-parasitic activity mediated via the deregulation of chloride channels, leading to paralysis and death (Hibbs & Gouaux, 2011; Lynagh & Lynch, 2012). The same mode of action has been suggested to underlie the toxicity of Ivermectin for liquid tumor cells and the potentiation or sensitization effect of Avermectin B1 on classical chemotherapeutics
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the specificity of the blockade of WNT-TCF responses we document, at low micromolar doses for Ivermectin and low nanomolar doses for Selamectin, indicate that the blockade of WNT-TCF responses and chloride channel deregulation are distinct modes of action
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What is key then is to find a dose and a context where the use of Ivermectin has beneficial effects in patients, paralleling our results with xenografts in mice.
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Cell toxicity appears at doses greater (> 10 μM for 12 h or longer or > 5 μM for 48 h or longer for Ivermectin) than those required to block TCF responses and induce apoptosis.
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Our data point to a repression of WNT-β-CATENIN/TCF transcriptional responses by Ivermectin, Selamectin and related macrocylic lactones.
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(i) The ability of Avermectin B1 to inhibit the activation of WNT-TCF reporter activity by N-terminal mutant (APC-insensitive) β-CATENIN as detected in our screen
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(ii) The ability of Avermectin B1, Ivermectin, Doramectin, Moxidectin and Selamectin to parallel the modulation of WNT-TCF targets by dnTCF
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(iii) The finding that the specific WNT-TCF response blockade by low doses of Ivermectin and Selamectin is reversed by constitutively active TCF
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(iv) The repression of key C-terminal phospho-isoforms of β-CATENIN resulting in the repression of the TCF target and positive cell cycle regulator CYCLIN D1 by Ivermectin and Selamectin
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(v) The specific inhibition ofin-vivo-TCF-dependent, but notin-vivo-TCF-independent cancer cells by Ivermectin in xenografts.
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These results together with the reduction of the expression of the colon cancer stem cell markersASCL2 andLGR5 (e.g., Hirschet al, 2013; Ziskinet al, 2013) raise the possibility of an inhibitory effect of Ivermectin, Selamectin and related macrocyclic lactones on TCF-dependent cancer stem cells.
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the capacity of cancer cells to form 3D spheroids in culture, as well as the growth of these, is also WNT-TCF-dependent (Kanwaret al, 2010) and they were also affected by Ivermectin treatment
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If Ivermectin is specific, it should only block TCF-dependent tumor growth. Indeed, the sensitivity and insensitivity of DLD1 and CC14 xenografts to Ivermectin treatment, respectively, together with the desensitization to Ivermectin actionin vivo by constitutively active TCF provide evidence of the specificity of this drug to block an activated WNT-TCF pathway in human cancer.
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Ivermectin has a good safety profile since onlyin-vivo-dnTCF-sensitive cancer xenografts are responsive to Ivermectin treatment, and we have not detected side effects in Ivermectin-treated mice at the doses used
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previous work has shown that side effects from systemic treatments with clinically relevant doses in humans are rare (Yang, 2012), that birth defects were not observed after exposure of pregnant mothers (Pacquéet al, 1990) and that this drug does not cross the blood–brain barrier (Kokozet al, 1999). Similarly, only dogs with mutantABCB1 (MDR1) alleles leading to a broken blood–brain barrier show Ivermectin neurotoxicity (Mealeyet al, 2001; Orzechowskiet al, 2012)
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Indications may include treatment for incurable β-CATENIN/TCF-dependent advanced and metastatic human tumors of the lung, colon, endometrium, and other organs.
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Ivermectin, Selamectin, or related macrocyclic lactones could also serve as topical agents for WNT-TCF-dependent skin lesions and tumors such as basal cell carcinomas
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they might also be useful as routine prophylactic agents, for instance against nascent TCF-dependent intestinal tumors in patients with familial polyposis and against nascent sporadic colon tumors in the general aging population
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shared by Nathan Goodyear on 24 Nov 12
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Colocalization of progesterone receptors A and B by dual immunofluourescent histochemis... - 0 views
jcem.endojournals.org/...2963.full.pdf
progesterone receptor progesterone receptors PR-A PR-B progesterone receptor receptors
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shared by Nathan Goodyear on 26 Nov 12
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Relative Expression of Progesterone Receptors A and B in Endometrioid Cancers of the En... - 0 views
cancerres.aacrjournals.org/...4576.long
progesterone receptor progesterone receptors A B PR-A PR-B endometrial cancer uterine progesterone receptor receptors
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Estrogen receptor related beta is expressed in human endometrium throughout the normal ... - 0 views
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shared by Nathan Goodyear on 18 Mar 12
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ScienceDirect.com - Prostaglandins, Leukotrienes and Medicine - Progesterone and antipr... - 0 views
www.sciencedirect.com/...0262174687900072
progesterone prostaglandin inflammation menstrual cramps dysmenorrhea
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Metformin in cancer prevention and therapy - 0 views
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relative risks imparted by diabetes are greatest (about two fold or higher) for cancers of the liver, pancreas, and endometrium, and lesser (about 1.2-1.5 fold) for cancers of the colon and rectum, breast, and bladder