121 results on '"Monsivais D"'
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2. Endometrial receptivity and implantation require uterine BMP signaling through an ACVR2A-SMAD1/SMAD5 axis
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Monsivais, D. (Diana), Nagashima, T. (Takashi), Prunskaite-Hyyryläinen, R. (Renata), Nozawa, K. (Kaori), Shimada, K. (Keisuke), Tang, S. (Suni), Hamor, C. (Clark), Agno, J. E. (Julio E.), Chen, F. (Fengju), Masand, R. P. (Ramya P.), Young, S. L. (Steven L.), Creighton, C. J. (Chad J.), DeMayo, F. J. (Francesco J.), Ikawa, M. (Masahito), Lee, S.-J. (Se-Jin), and Matzuk, M. M. (Martin M)
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animal structures ,embryonic structures - Abstract
During early pregnancy in the mouse, nidatory estrogen (E2) stimulates endometrial receptivity by activating a network of signaling pathways that is not yet fully characterized. Here, we report that bone morphogenetic proteins (BMPs) control endometrial receptivity via a conserved activin receptor type 2 A (ACVR2A) and SMAD1/5 signaling pathway. Mice were generated to contain single or double conditional deletion of SMAD1/5 and ACVR2A/ACVR2B receptors using progesterone receptor (PR)-cre. Female mice with SMAD1/5 deletion display endometrial defects that result in the development of cystic endometrial glands, a hyperproliferative endometrial epithelium during the window of implantation, and impaired apicobasal transformation that prevents embryo implantation and leads to infertility. Analysis of Acvr2a-PRcre and Acvr2b-PRcre pregnant mice determined that BMP signaling occurs via ACVR2A and that ACVR2B is dispensable during embryo implantation. Therefore, BMPs signal through a conserved endometrial ACVR2A/SMAD1/5 pathway that promotes endometrial receptivity during embryo implantation.
- Published
- 2021
3. ERβ- and Prostaglandin E2-Regulated Pathways Integrate Cell Proliferation via Ras-like and Estrogen-Regulated Growth Inhibitor in Endometriosis
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Monsivais, D., Dyson, M. T., Yin, P., Coon, J. S., Navarro, A., Feng, G., Malpani, S. S., Ono, M., Ercan, C. M., Wei, J. J., Pavone, M. E., Su, E., and Bulun, S. E.
- Published
- 2014
4. Quantifying gender preferences in human social interactions using a large cellphone dataset
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Ghosh, A, Monsivais, D, Bhattacharya, K, Dunbar, R, Kaski, K, Department of Computer Science, Kaski Kimmo group, University of Oxford, Aalto-yliopisto, and Aalto University
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GROUP-SIZE ,Sex differences ,Egocentric networks ,lcsh:R858-859.7 ,Gender differences ,Mobile phones ,lcsh:Computer applications to medicine. Medical informatics ,Life history ,Social networks - Abstract
openaire: EC/H2020/662725/EU//IBSEN In human relations individuals’ gender and age play a key role in the structures and dynamics of their social arrangements. In order to analyze the gender preferences of individuals in interaction with others at different stages of their lives we study a large mobile phone dataset. To do this we consider four fundamental gender-related caller and callee combinations of human interactions, namely male to male, male to female, female to male, and female to female, which together with age, kinship, and different levels of friendship give rise to a wide scope of human sociality. Here we analyse the relative strength of these four types of interaction using call detail records. Our analysis suggests strong age dependence for an individual of one gender choosing to call an individual of either gender. We observe a strong bonding with the opposite gender across most of their reproductive age. However, older women show a strong tendency to connect to another female that is one generation younger in a way that is suggestive of the grandmothering effect. We also find that the relative strength among the four possible interactions depends on phone call duration. For calls of medium and long duration, opposite gender interactions are significantly more probable than same gender interactions during the reproductive years, suggesting potential emotional exchange between spouses. By measuring the fraction of calls to other generations we find that mothers tend to make calls more to their daughters than to their sons, whereas fathers make calls more to their sons than to their daughters. For younger callers, most of their calls go to the same generation contacts, while older people call the younger people more frequently, which supports the suggestion that affection flows downward. Our study primarily rests on resolving the nature of interactions by examining the durations of calls. In addition, we analyse the intensity of the observed effects using a score based on a null model.
- Published
- 2019
5. Differences in retinoid uptake and metabolism alters paracrine signaling in endometriosis
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Pavone, M., primary, Malpani, S., additional, Dyson, M., additional, Monsivais, D., additional, Mittal, N., additional, and Bulun, S.E., additional
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- 2013
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6. Reliability and validity of 2012 Spanish translation of Barriers Questionnaire II (BQ-II)
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Robinson, K., primary and Monsivais, D., additional
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- 2013
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7. Pain research team training using significant learning experiences
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Monsivais, D., primary and Robinson, K., additional
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- 2013
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8. Fenretinide as a novel treatment for endometriosis
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Pavone, M.E., primary, Malpani, S., additional, Dyson, M., additional, Monsivais, D., additional, and Bulun, S.E., additional
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- 2012
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9. Differences in retinoid uptake and metabolism causes altered paracrine signaling in endometriosis
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Pavone, M.E., primary, Malpani, S., additional, Dyson, M., additional, Monsivais, D., additional, Kakinuma, T., additional, and Bulun, S.E., additional
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- 2012
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10. Aberrant regulation of DNA methyltransferase 3B observed in women with endometriosis
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Kakinuma, T., primary, Dyson, M., additional, Pavone, M.E., additional, Monsivais, D., additional, and Bulun, S., additional
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- 2011
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11. Return to work prescription increases return to work rate in a primarily Hispanic population with chronic pain
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Monsivais, J., primary, Monsivais, D., additional, and Robinson, K., additional
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- 2010
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12. Acculturation, somatization of depression, and function in Mexican Americans with chronic pain
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Robinson, K., primary, Monsivais, J., additional, and Monsivais, D., additional
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- 2010
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13. Profile of litigators with chronic limb pain in a predominantly Hispanic workers'-compensation population
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Monsivais, J., primary, Robinson, K., additional, and Monsivais, D., additional
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- 2010
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14. “I'm just not that sick.” Cultural constructions of pain medication use among Mexican American women
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Monsivais, D., primary and Engebretson, J., additional
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- 2010
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15. “I was ashamed…like it was psychological.” Dangerous silence: cultural constructions of expressing and communicating pain symptoms among Mexican American women
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Monsivais, D., primary and Engebretson, J., additional
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- 2010
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16. The Association of Peripheral Nerve Compression and Reflex Sympathetic Dystrophy
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MONSIVAIS, J. J., primary, BAKER, J., additional, and MONSIVAIS, D., additional
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- 1993
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17. Activated glucocorticoid and eicosanoid pathways in endometriosis.
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Monsivais D, Bray JD, Su E, Pavone ME, Dyson MT, Navarro A, Kakinuma T, Bulun SE, Monsivais, Diana, Bray, Jeffrey D, Su, Emily, Pavone, Mary Ellen, Dyson, Matthew T, Navarro, Antonia, Kakinuma, Toshiyuki, and Bulun, Serdar E
- Abstract
Objective: To define altered gene expression networks in endometriosis.Design: Experiments using endometriotic tissues and primary cells.Setting: Division of Reproductive Biology Research, Northwestern University.Patient(s): Premenopausal women.Intervention(s): Matched samples of eutopic endometrium and ovarian endometriosis (n = 8 patients) were analyzed by microarray and verified in a separate set of tissues (n = 6 patients). Experiments to define signaling pathways were performed in primary endometriotic stromal cells (n = 12 patients).Main Outcomes Measure(s): Using a genome-wide in vivo approach, we identified 1,366 differentially expressed genes and a new gene network favoring increased glucocorticoid levels and action in endometriosis.Result(s): Transcript and protein levels of 11β-hydroxysteroid dehydrogenase (HSD11B1), which produces cortisol, the biologically active glucocorticoid, were strikingly higher, whereas messenger RNA (mRNA) levels of the cortisol-degrading HSD11B2 enzyme were significantly lower in endometriotic tissue. Glucocorticoid receptor mRNA and protein levels were significantly higher in endometriosis. The inflammatory cytokine tumor necrosis factor robustly induced mRNA and protein levels of HSD11B1 and glucocorticoid receptor but suppressed HSD11B2 mRNA in primary endometriotic stromal cells, suggesting that tumor necrosis factor stimulates cortisol production and action. We also uncovered a subset of genes critical for prostaglandin synthesis and degradation, which favor high eicosanoid levels and activity in endometriosis.Conclusion(s): The proinflammatory milieu of the endometriotic lesion stimulates cortisol synthesis and action in endometriotic lesions. [ABSTRACT FROM AUTHOR]- Published
- 2012
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18. (950): Pain medication attitudes and beliefs in patients with non-malignant chronic pain syndromes
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Monsivais, D. and McNeill, J.
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- 2006
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19. American Medical Writers Association website review.
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Monsivais D
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- 2008
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20. Daring to write a book review.
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Monsivais D
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- 2008
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21. 3DMOUSEneST: a volumetric label-free imaging method evaluating embryo-uterine interaction and decidualization efficacy.
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Savolainen A, Kapiainen E, Ronkainen VP, Izzi V, Matzuk MM, Monsivais D, and Prunskaite-Hyyryläinen R
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- Animals, Female, Pregnancy, Mice, Uterus physiology, Embryo, Mammalian, Mice, Knockout, Imaging, Three-Dimensional methods, Mice, Inbred C57BL, Embryo Implantation physiology, Decidua
- Abstract
Effective interplay between the uterus and the embryo is essential for pregnancy establishment; however, convenient methods to screen embryo implantation success and maternal uterine response in experimental mouse models are currently lacking. Here, we report 3DMOUSEneST, a groundbreaking method for analyzing mouse implantation sites based on label-free higher harmonic generation microscopy, providing unprecedented insights into the embryo-uterine dynamics during early pregnancy. The 3DMOUSEneST method incorporates second-harmonic generation microscopy to image the three-dimensional structure formed by decidual fibrillar collagen, named 'decidual nest', and third-harmonic generation microscopy to evaluate early conceptus (defined as the embryo and extra-embryonic tissues) growth. We demonstrate that decidual nest volume is a measurable indicator of decidualization efficacy and correlates with the probability of early pregnancy progression based on a logistic regression analysis using Smad1/5 and Smad2/3 conditional knockout mice with known implantation defects. 3DMOUSEneST has great potential to become a principal method for studying decidual fibrillar collagen and characterizing mouse models associated with early embryonic lethality and fertility issues., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)
- Published
- 2024
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22. Identification of potent pan-ephrin receptor kinase inhibitors using DNA-encoded chemistry technology.
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Madasu C, Liao Z, Parks SE, Sharma KL, Bohren KM, Ye Q, Li F, Palaniappan M, Tan Z, Yuan F, Creighton CJ, Tang S, Masand RP, Guan X, Young DW, Monsivais D, and Matzuk MM
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- Humans, Female, Endometriosis drug therapy, Endometriosis metabolism, Endometriosis pathology, DNA metabolism, Receptors, Eph Family metabolism, Receptors, Eph Family antagonists & inhibitors, Receptor, EphA2 metabolism, Receptor, EphA2 antagonists & inhibitors, Small Molecule Libraries pharmacology, Small Molecule Libraries chemistry, Cell Movement drug effects, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors chemistry
- Abstract
EPH receptors (EPHs), the largest family of tyrosine kinases, phosphorylate downstream substrates upon binding of ephrin cell surface-associated ligands. In a large cohort of endometriotic lesions from individuals with endometriosis, we found that EPHA2 and EPHA4 expressions are increased in endometriotic lesions relative to normal eutopic endometrium. Because signaling through EPHs is associated with increased cell migration and invasion, we hypothesized that chemical inhibition of EPHA2/4 could have therapeutic value. We screened DNA-encoded chemical libraries (DECL) to rapidly identify EPHA2/4 kinase inhibitors. Hit compound, CDD-2693, exhibited picomolar/nanomolar kinase activity against EPHA2 (K
i : 4.0 nM) and EPHA4 (Ki : 0.81 nM). Kinome profiling revealed that CDD-2693 bound to most EPH family and SRC family kinases. Using NanoBRET target engagement assays, CDD-2693 had nanomolar activity versus EPHA2 (IC50 : 461 nM) and EPHA4 (IC50 : 40 nM) but was a micromolar inhibitor of SRC, YES, and FGR. Chemical optimization produced CDD-3167, having picomolar biochemical activity toward EPHA2 (Ki : 0.13 nM) and EPHA4 (Ki : 0.38 nM) with excellent cell-based potency EPHA2 (IC50 : 8.0 nM) and EPHA4 (IC50 : 2.3 nM). Moreover, CDD-3167 maintained superior off-target cellular selectivity. In 12Z endometriotic epithelial cells, CDD-2693 and CDD-3167 significantly decreased EFNA5 (ligand) induced phosphorylation of EPHA2/4, decreased 12Z cell viability, and decreased IL-1β-mediated expression of prostaglandin synthase 2 ( PTGS2 ). CDD-2693 and CDD-3167 decreased expansion of primary endometrial epithelial organoids from patients with endometriosis and decreased Ewing's sarcoma viability. Thus, using DECL, we identified potent pan-EPH inhibitors that show specificity and activity in cellular models of endometriosis and cancer., Competing Interests: Competing interests statement:The authors declare no competing interest.- Published
- 2024
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23. Affinity-tagged SMAD1 and SMAD5 mouse lines reveal transcriptional reprogramming mechanisms during early pregnancy.
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Liao Z, Tang S, Nozawa K, Shimada K, Ikawa M, Monsivais D, and Matzuk M
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- Pregnancy, Female, Humans, Mice, Animals, Signal Transduction physiology, Embryo Implantation, Smad5 Protein genetics, Smad5 Protein metabolism, Uterus metabolism, Endometrium metabolism
- Abstract
Endometrial decidualization, a prerequisite for successful pregnancies, relies on transcriptional reprogramming driven by progesterone receptor (PR) and bone morphogenetic protein (BMP)-SMAD1/SMAD5 signaling pathways. Despite their critical roles in early pregnancy, how these pathways intersect in reprogramming the endometrium into a receptive state remains unclear. To define how SMAD1 and/or SMAD5 integrate BMP signaling in the uterus during early pregnancy, we generated two novel transgenic mouse lines with affinity tags inserted into the endogenous SMAD1 and SMAD5 loci ( Smad1
HA/HA and Smad5PA/PA ). By profiling the genome-wide distribution of SMAD1, SMAD5, and PR in the mouse uterus, we demonstrated the unique and shared roles of SMAD1 and SMAD5 during the window of implantation. We also showed the presence of a conserved SMAD1, SMAD5, and PR genomic binding signature in the uterus during early pregnancy. To functionally characterize the translational aspects of our findings, we demonstrated that SMAD1/5 knockdown in human endometrial stromal cells suppressed expressions of canonical decidual markers ( IGFBP1, PRL, FOXO1 ) and PR-responsive genes ( RORB , KLF15 ). Here, our studies provide novel tools to study BMP signaling pathways and highlight the fundamental roles of SMAD1/5 in mediating both BMP signaling pathways and the transcriptional response to progesterone (P4) during early pregnancy., Competing Interests: ZL, ST, KN, KS, MI, DM, MM No competing interests declared, (© 2023, Liao et al.)- Published
- 2024
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24. A GREB1-steroid receptor feedforward mechanism governs differential GREB1 action in endometrial function and endometriosis.
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Chadchan SB, Popli P, Liao Z, Andreas E, Dias M, Wang T, Gunderson SJ, Jimenez PT, Lanza DG, Lanz RB, Foulds CE, Monsivais D, DeMayo FJ, Yalamanchili HK, Jungheim ES, Heaney JD, Lydon JP, Moley KH, O'Malley BW, and Kommagani R
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- Animals, Female, Humans, Mice, Endometrium metabolism, Estrogens metabolism, Progesterone metabolism, Receptors, Progesterone genetics, Receptors, Progesterone metabolism, Steroids metabolism, Endometriosis genetics, Endometriosis metabolism, Neoplasm Proteins metabolism, Receptors, Steroid genetics, Receptors, Steroid metabolism
- Abstract
Cellular responses to the steroid hormones, estrogen (E2), and progesterone (P4) are governed by their cognate receptor's transcriptional output. However, the feed-forward mechanisms that shape cell-type-specific transcriptional fulcrums for steroid receptors are unidentified. Herein, we found that a common feed-forward mechanism between GREB1 and steroid receptors regulates the differential effect of GREB1 on steroid hormones in a physiological or pathological context. In physiological (receptive) endometrium, GREB1 controls P4-responses in uterine stroma, affecting endometrial receptivity and decidualization, while not affecting E2-mediated epithelial proliferation. Of mechanism, progesterone-induced GREB1 physically interacts with the progesterone receptor, acting as a cofactor in a positive feedback mechanism to regulate P4-responsive genes. Conversely, in endometrial pathology (endometriosis), E2-induced GREB1 modulates E2-dependent gene expression to promote the growth of endometriotic lesions in mice. This differential action of GREB1 exerted by a common feed-forward mechanism with steroid receptors advances our understanding of mechanisms that underlie cell- and tissue-specific steroid hormone actions., (© 2024. The Author(s).)
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- 2024
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25. Impaired bone morphogenetic protein (BMP) signaling pathways disrupt decidualization in endometriosis.
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Liao Z, Tang S, Jiang P, Geng T, Cope DI, Dunn TN, Guner J, Radilla LA, Guan X, and Monsivais D
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- Pregnancy, Female, Humans, Decidua metabolism, Bone Morphogenetic Proteins genetics, Bone Morphogenetic Proteins metabolism, Transforming Growth Factor beta metabolism, Signal Transduction, Endometriosis genetics, Endometriosis metabolism, Infertility metabolism, Pregnancy Complications metabolism
- Abstract
Endometriosis is linked to increased infertility and pregnancy complications due to defective endometrial decidualization. We hypothesized that identification of altered signaling pathways during decidualization could identify the underlying cause of infertility and pregnancy complications. Our study reveals that transforming growth factor β (TGFβ) pathways are impaired in the endometrium of individuals with endometriosis, leading to defective decidualization. Through detailed transcriptomic analyses, we discovered abnormalities in TGFβ signaling pathways and key regulators, such as SMAD4, in the endometrium of affected individuals. We also observed compromised activity of bone morphogenetic proteins (BMP), a subset of the TGFβ family, that control endometrial receptivity. Using 3-dimensional models of endometrial stromal and epithelial assembloids, we showed that exogenous BMP2 improved decidual marker expression in individuals with endometriosis. Our findings reveal dysfunction of BMP/SMAD signaling in the endometrium of individuals with endometriosis, explaining decidualization defects and subsequent pregnancy complications in these individuals., (© 2024. The Author(s).)
- Published
- 2024
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26. Inhibition of CSF1R and KIT With Pexidartinib Reduces Inflammatory Signaling and Cell Viability in Endometriosis.
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Dunn TN, Cope DI, Tang S, Sirupangi T, Parks SE, Liao Z, Yuan F, Creighton CJ, Masand RP, Alpuing Radilla L, Guan X, Detti L, Monsivais D, and Matzuk MM
- Subjects
- Humans, Female, Cell Survival, Signal Transduction, Receptor Protein-Tyrosine Kinases metabolism, Endometriosis metabolism, Aminopyridines, Pyrroles
- Abstract
Endometriosis is a common and debilitating disease, affecting ∼170 million women worldwide. Affected patients have limited therapeutic options such as hormonal suppression or surgical excision of the lesions, though therapies are often not completely curative. Targeting receptor tyrosine kinases (RTKs) could provide a nonhormonal treatment option for endometriosis. We determined that 2 RTKs, macrophage-colony stimulating factor 1 receptor (CSF1R) and mast/stem cell growth factor receptor KIT (KIT), are overexpressed in endometriotic lesions and could be novel nonhormonal therapeutic targets for endometriosis. The kinase activity of CSF1R and KIT is suppressed by pexidartinib, a small molecule inhibitor that was recently approved by the US Food and Drug Administration. Using immunohistochemistry, we detected CSF1R and KIT in endometriotic tissues obtained from peritoneal lesions, colorectal lesions, and endometriomas. Specifically, we show that KIT is localized to the epithelium of the lesions, while CSF1R is expressed in the stroma and macrophages of the endometriotic lesions. Given the high epithelial expression of CSF1R and KIT, 12Z endometriotic epithelial cells were used to evaluate the efficacy of dual CSF1R and KIT inhibition with pexidartinib. We found that pexidartinib suppressed activation in 12Z cells of JNK, STAT3, and AKT signaling pathways, which control key proinflammatory and survival networks within the cell. Using quantitative real-time polymerase chain reaction, we determined that pexidartinib suppressed interleukin 8 (IL8) and cyclin D1 (CCND1) expression. Lastly, we demonstrated that pexidartinib decreased cell growth and viability. Overall, these results indicate that pexidartinib-mediated CSF1R and KIT inhibition reduces proinflammatory signaling and cell viability in endometriosis., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
- Published
- 2024
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27. Chemical Catalysis Guides Structural Identification for the Major In Vivo Metabolite of the BET Inhibitor JQ1.
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Holmes S, Jain P, Rodriguez KG, Williams J, Yu Z, Cerda-Smith C, Samuel ELG, Campbell J, Hakenjos JM, Monsivais D, Li F, Chamakuri S, Matzuk MM, Santini C, MacKenzie KR, and Young DW
- Abstract
The bromodomain inhibitor (+)-JQ1 is a highly validated chemical probe; however, it exhibits poor in vivo pharmacokinetics. To guide efforts toward improving its pharmacological properties, we identified the (+)-JQ1 primary metabolite using chemical catalysis methods. Treatment of (+)-JQ1 with tetrabutylammonium decatungstate under photochemical conditions resulted in selective formation of an aldehyde at the 2-position of the thiophene ring [(+)-JQ1-CHO], which was further reduced to the 2-hydroxymethyl analog [(+)-JQ1-OH]. Comparative LC/MS analysis of (+)-JQ1-OH to the product obtained from liver microsomes suggested (+)-JQ1-OH as the major metabolite of (+)-JQ1. The 2-thienyl position was then substituted to generate a trideuterated (-CD
3 , (+)-JQ1-D) analog having half-lives that were 1.8- and 2.8-fold longer in mouse and human liver microsomes, respectively. This result unambiguously confirmed (+)-JQ1-OH as the major metabolite of (+)-JQ1. These studies demonstrate an efficient process for studying drug metabolism and identifying the metabolic soft spots of bioactive compounds., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)- Published
- 2024
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28. Endometrial TGFβ signaling fosters early pregnancy development by remodeling the fetomaternal interface.
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Parks SE, Geng T, and Monsivais D
- Subjects
- Pregnancy, Female, Humans, Endometrium metabolism, Uterus metabolism, Embryo Implantation physiology, Signal Transduction, Decidua metabolism, Transforming Growth Factor beta metabolism
- Abstract
The endometrium is a unique and highly regenerative tissue with crucial roles during the reproductive lifespan of a woman. As the first site of contact between mother and embryo, the endometrium, and its critical processes of decidualization and immune cell recruitment, play a leading role in the establishment of pregnancy, embryonic development, and reproductive capacity. These integral processes are achieved by the concerted actions of steroid hormones and a myriad of growth factor signaling pathways. This review focuses on the roles of the transforming growth factor β (TGFβ) pathway in the endometrium during the earliest stages of pregnancy through the lens of immune cell regulation and function. We discuss how key ligands in the TGFβ family signal through downstream SMAD transcription factors and ultimately remodel the endometrium into a state suitable for embryo implantation and development. We also focus on the key roles of the TGFβ signaling pathway in recruiting uterine natural killer cells and their collective remodeling of the decidua and spiral arteries. By providing key details about immune cell populations and TGFβ signaling within the endometrium, it is our goal to shed light on the intricate remodeling that is required to achieve a successful pregnancy., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2023
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29. Impaired bone morphogenetic protein (BMP) signaling pathways disrupt decidualization in endometriosis.
- Author
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Monsivais D, Liao Z, Tang S, Jiang P, Geng T, Cope D, Dunn T, Guner J, Radilla LA, and Guan X
- Abstract
Endometriosis is linked to increased infertility and pregnancy complications due to defective endometrial decidualization. We hypothesized that identification of altered signaling pathways during decidualization could identify the underlying cause of infertility and pregnancy complications. Our study reveals that transforming growth factor β (TGFβ) pathways are impaired in the endometrium of individuals with endometriosis, leading to defective decidualization. Through detailed transcriptomic analyses, we discovered abnormalities in TGFβ signaling pathways and key regulators, such as SMAD4, in the endometrium of affected individuals. We also observed compromised activity of bone morphogenetic proteins (BMP), a subset of the TGFβ family, that control endometrial receptivity. Using 3-dimensional models of endometrial stromal and epithelial assembloids, we showed that exogenous BMP2 improved decidual marker expression in individuals with endometriosis. Our findings unveil a previously unidentified dysfunction in BMP/SMAD signaling in the endometrium of individuals with endometriosis, explaining decidualization defects and subsequent pregnancy complications in these individuals., Competing Interests: COMPETING INTERESTS. There are no competing interests to declare.
- Published
- 2023
- Full Text
- View/download PDF
30. Oral follicle-stimulating hormone receptor agonist affects granulosa cells differently than recombinant human FSH.
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Guner JZ, Monsivais D, Yu H, Stossi F, Johnson HL, Gibbons WE, Matzuk MM, and Palmer S
- Subjects
- Female, Humans, Follicle Stimulating Hormone, Human pharmacology, Aromatase genetics, Follicle Stimulating Hormone pharmacology, Granulosa Cells metabolism, Gonadal Steroid Hormones metabolism, Receptors, FSH genetics, Receptors, FSH metabolism, Polycystic Ovary Syndrome drug therapy, Polycystic Ovary Syndrome metabolism
- Abstract
Objective: To determine whether TOP5300, a novel oral follicle-stimulating hormone (FSH) receptor (FSHR) allosteric agonist, elicits a different cellular response than recombinant human FSH (rh-FSH) in human granulosa cells from patients undergoing in vitro fertilization., Design: Basic science research with a preclinical allosteric FSHR agonist., Setting: University hospital., Patient(s): Patients with infertility at a single academic fertility clinic were recruited under an Institutional Review Board-approved protocol. Primary granulosa cell cultures were established for 41 patients, of whom 8 had normal ovarian reserve (NOR), 17 were of advanced reproductive age (ARA), 12 had a diagnosis of polycystic ovary syndrome (PCOS), and 4 had a combination of diagnoses, such as ARA and PCOS., Intervention(s): Primary granulosa-lutein (GL) cell cultures were treated with rh-FSH, TOP5300, or vehicle., Main Outcome Measure(s): Estradiol (E
2 ) production using enzyme-linked immunosorbent assay, steroid pathway gene expression of StAR and aromatase using quantitative polymerase chain reaction, and FSHR membrane localization using immunofluorescence were measured in human GL cells., Result(s): TOP5300 consistently stimulated E2 production among patients with NOR, ARA, and PCOS. Recombinant FSH was the more potent ligand in GL cells from patients with NOR but was ineffective in cells from patients with ARA or PCOS. The lowest level of FSHR plasma membrane localization was seen in patients with ARA, although FSHR localization was more abundant in cells from patients with PCOS; the highest levels were present in cells from patients with NOR. The localization of FSHR was not affected by TOP5300 relative to rh-FSH in any patient group. TOP5300 stimulated greater expression of StAR and CYP19A1 across cells from all patients with NOR, ARA, and PCOS combined, although rh-FSH was unable to stimulate StAR and aromatase (CYP19A1) expression in cells from patients with PCOS. TOP5300-induced expression of StAR and CYP19A1 mRNA among patients with ARA and NOR was consistently lower than that observed in cells from patients with PCOS., Conclusion(s): TOP5300 appears to stimulate E2 production and steroidogenic gene expression from GL cells more than rh-FSH in PCOS, relative to patients with ARA and NOR. It does not appear that localization of FSHR at cell membranes is a limiting step for TOP5300 or rh-FSH stimulation of steroidogenic gene expression and E2 production., Competing Interests: Declaration of interests J.Z.G. reports funding from NIH R01 HD032067 and Baylor College of Medicine Department of Obstetrics and Gynecology for the submitted work. D.M. has nothing to disclose. H.Y. is the Chief executive officer and reports stock options from CanWell Pharma. F.S.S. has nothing to disclose. H.L.J. has nothing to disclose. W.E.G. has nothing to disclose. M.M.M. has nothing to disclose. S.P. has nothing to disclose., (Copyright © 2023 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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31. Impaired bone morphogenetic protein signaling pathways disrupt decidualization in endometriosis.
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Liao Z, Tang S, Jiang P, Geng T, Cope DI, Dunn TN, Guner J, Radilla LA, Guan X, and Monsivais D
- Abstract
It is hypothesized that impaired endometrial decidualization contributes to decreased fertility in individuals with endometriosis. To identify the molecular defects that underpin defective decidualization in endometriosis, we subjected endometrial stromal cells from individuals with or without endometriosis to time course in vitro decidualization with estradiol, progesterone, and 8-bromo-cyclic-AMP (EPC) for 2, 4, 6, or 8 days. Transcriptomic profiling identified differences in key pathways between the two groups, including defective bone morphogenetic protein (BMP)/SMAD4 signaling ( ID2, ID3, FST ), oxidate stress response ( NFE2L2, ALOX15, SLC40A1 ), and retinoic acid signaling pathways ( RARRES, RARB, ALDH1B1 ). Genome-wide binding analyses identified an altered genomic distribution of SMAD4 and H3K27Ac in the decidualized stromal cells from individuals without endometriosis relative to those with endometriosis, with target genes enriched in pathways related to signaling by transforming growth factor β (TGFβ), neurotrophic tyrosine kinase receptors (NTRK), and nerve growth factor (NGF)-stimulated transcription. We found that direct SMAD1/5/4 target genes control FOXO, PI3K/AKT, and progesterone-mediated signaling in decidualizing cells and that BMP2 supplementation in endometriosis patient-derived assembloids elevated the expression of decidualization markers. In summary, transcriptomic and genome-wide binding analyses of patient-derived endometrial cells and assembloids identified that a functional BMP/SMAD1/5/4 signaling program is crucial for engaging decidualization., Competing Interests: COMPETING INTERESTS. There are no competing interests to declare.
- Published
- 2023
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32. Oocyte-specific Wee1-like protein kinase 2 is dispensable for fertility in mice.
- Author
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Nozawa K, Liao Z, Satouh Y, Geng T, Ikawa M, Monsivais D, and Matzuk MM
- Subjects
- Humans, Female, Animals, Mice, Oocytes metabolism, Fertility genetics, Protein-Tyrosine Kinases genetics, Protein-Tyrosine Kinases metabolism, Protein Kinases metabolism, Cell Cycle Proteins genetics, Cell Cycle Proteins metabolism
- Abstract
Wee1-like protein kinase 2 (WEE2) is an oocyte-specific protein tyrosine kinase involved in the regulation of oocyte meiotic arrest in humans. As such, it has been proposed as a candidate for non-hormonal female contraception although pre-clinical models have not been reported. Therefore, we developed two novel knockout mouse models using CRISPR/Cas9 to test loss-of-function of Wee2 on female fertility. A frameshift mutation at the Wee2 translation start codon in exon 2 had no effect on litter size, litter production, or the ability of oocytes to maintain prophase I arrest. Because of the lack of a reproductive phenotype, we additionally generated a Wee2 allele with a large deletion by removing all coding exons. While there was no difference in the total number of litters produced, homozygous Wee2 female knockout mice with the larger deletion produced fewer pups than heterozygous littermates. Furthermore, there was no difference for key reproductive parameters measured in the mouse models, including ovarian weight, number of ovulated oocytes, or oocytes that underwent in vitro maturation. Therefore, as loss of Wee2 in mice shows only minor effects on overall fecundity, contraceptive development with WEE2 should consider exploiting alternative properties such as gain-of-function or protein-protein interactions, as Wee2 loss-of-function is likely complicated by biological redundancies with other proteins co-expressed in oocytes., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Nozawa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
- Published
- 2023
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33. Beclin-1-dependent autophagy, but not apoptosis, is critical for stem-cell-mediated endometrial programming and the establishment of pregnancy.
- Author
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Popli P, Tang S, Chadchan SB, Talwar C, Rucker EB 3rd, Guan X, Monsivais D, Lydon JP, Stallings CL, Moley KH, and Kommagani R
- Subjects
- Animals, Female, Humans, Mice, Pregnancy, Autophagy, Beclin-1, Stem Cells, Endometrium, Uterus
- Abstract
The human endometrium shows a remarkable regenerative capacity that enables cyclical regeneration and remodeling throughout a woman's reproductive life. Although early postnatal uterine developmental cues direct this regeneration, the vital factors that govern early endometrial programming are largely unknown. We report that Beclin-1, an essential autophagy-associated protein, plays an integral role in uterine morphogenesis during the early postnatal period. We show that conditional depletion of Beclin-1 in the uterus triggers apoptosis and causes progressive loss of Lgr5
+ /Aldh1a1+ endometrial progenitor stem cells, with concomitant loss of Wnt signaling, which is crucial for stem cell renewal and epithelial gland development. Beclin-1 knockin (Becn1 KI) mice with disabled apoptosis exhibit normal uterine development. Importantly, the restoration of Beclin-1-driven autophagy, but not apoptosis, promotes normal uterine adenogenesis and morphogenesis. Together, the data suggest that Beclin-1-mediated autophagy acts as a molecular switch that governs the early uterine morphogenetic program by maintaining the endometrial progenitor stem cells., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)- Published
- 2023
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- View/download PDF
34. Using cancer proteomics data to identify gene candidates for therapeutic targeting.
- Author
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Monsivais D, Parks SE, Chandrashekar DS, Varambally S, and Creighton CJ
- Subjects
- Humans, Genomics, Protein Kinases, Proteomics, Neoplasms drug therapy, Neoplasms genetics, Neoplasms metabolism
- Abstract
Gene-level associations obtained from mass-spectrometry-based cancer proteomics datasets represent a resource for identifying gene candidates for functional studies. When recently surveying proteomic correlates of tumor grade across multiple cancer types, we identified specific protein kinases having a functional impact on uterine endometrial cancer cells. This previously published study provides just one template for utilizing public molecular datasets to discover potential novel therapeutic targets and approaches for cancer patients. Proteomic profiling data combined with corresponding multi-omics data on human tumors and cell lines can be analyzed in various ways to prioritize genes of interest for interrogating biology. Across hundreds of cancer cell lines, CRISPR loss of function and drug sensitivity scoring can be readily integrated with protein data to predict any gene's functional impact before bench experiments are carried out. Public data portals make cancer proteomics data more accessible to the research community. Drug discovery platforms can screen hundreds of millions of small molecule inhibitors for those that target a gene or pathway of interest. Here, we discuss some of the available public genomic and proteomic resources while considering approaches to how these could be leveraged for molecular biology insights or drug discovery. We also demonstrate the inhibitory effect of BAY1217389, a TTK inhibitor recently tested in a Phase I clinical trial for the treatment of solid tumors, on uterine cancer cell line viability.
- Published
- 2023
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35. SMAD2/3 signaling in the uterine epithelium controls endometrial cell homeostasis and regeneration.
- Author
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Kriseman ML, Tang S, Liao Z, Jiang P, Parks SE, Cope DI, Yuan F, Chen F, Masand RP, Castro PD, Ittmann MM, Creighton CJ, Tan Z, and Monsivais D
- Subjects
- Animals, Female, Mice, Cell Differentiation, Epithelium, Homeostasis, Endometrium metabolism, Uterus, Smad Proteins metabolism
- Abstract
The regenerative potential of the endometrium is attributed to endometrial stem cells; however, the signaling pathways controlling its regenerative potential remain obscure. In this study, genetic mouse models and endometrial organoids are used to demonstrate that SMAD2/3 signaling controls endometrial regeneration and differentiation. Mice with conditional deletion of SMAD2/3 in the uterine epithelium using Lactoferrin-iCre develop endometrial hyperplasia at 12-weeks and metastatic uterine tumors by 9-months of age. Mechanistic studies in endometrial organoids determine that genetic or pharmacological inhibition of SMAD2/3 signaling disrupts organoid morphology, increases the glandular and secretory cell markers, FOXA2 and MUC1, and alters the genome-wide distribution of SMAD4. Transcriptomic profiling of the organoids reveals elevated pathways involved in stem cell regeneration and differentiation such as the bone morphogenetic protein (BMP) and retinoic acid signaling (RA) pathways. Therefore, TGFβ family signaling via SMAD2/3 controls signaling networks which are integral for endometrial cell regeneration and differentiation., (© 2023. The Author(s).)
- Published
- 2023
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36. Discovery of Highly Potent and BMPR2-Selective Kinase Inhibitors Using DNA-Encoded Chemical Library Screening.
- Author
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Modukuri RK, Monsivais D, Li F, Palaniappan M, Bohren KM, Tan Z, Ku AF, Wang Y, Madasu C, Li JY, Tang S, Miklossy G, Palmer SS, Young DW, and Matzuk MM
- Subjects
- Humans, Gene Library, Bone Morphogenetic Protein Receptors, Type II chemistry, Bone Morphogenetic Protein Receptors, Type II genetics, Bone Morphogenetic Protein Receptors, Type II metabolism, Signal Transduction, DNA
- Abstract
The discovery of monokinase-selective inhibitors for patients is challenging because the 500+ kinases encoded by the human genome share highly conserved catalytic domains. Until now, no selective inhibitors unique for a single transforming growth factor β (TGFβ) family transmembrane receptor kinase, including bone morphogenetic protein receptor type 2 (BMPR2), have been reported. This dearth of receptor-specific kinase inhibitors hinders therapeutic options for skeletal defects and cancer as a result of an overactivated BMP signaling pathway. By screening 4.17 billion "unbiased" and "kinase-biased" DNA-encoded chemical library molecules, we identified hits CDD-1115 and CDD-1431, respectively, that were low-nanomolar selective kinase inhibitors of BMPR2. Structure-activity relationship studies addressed metabolic lability and high-molecular-weight issues, resulting in potent and BMPR2-selective inhibitor analogs CDD-1281 (IC
50 = 1.2 nM) and CDD-1653 (IC50 = 2.8 nM), respectively. Our work demonstrates that DNA-encoded chemistry technology (DEC-Tec) is reliable for identifying novel first-in-class, highly potent, and selective kinase inhibitors.- Published
- 2023
- Full Text
- View/download PDF
37. Establishing 3D Endometrial Organoids from the Mouse Uterus.
- Author
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Tang S, Parks SE, Liao Z, Cope DI, Blutt SE, and Monsivais D
- Subjects
- Pregnancy, Female, Mice, Animals, Epithelium metabolism, Estrogens, Organoids metabolism, Endometrium metabolism, Uterus
- Abstract
Endometrial tissue lines the inner cavity of the uterus and is under the cyclical control of estrogen and progesterone. It is a tissue that is composed of luminal and glandular epithelium, a stromal compartment, a vascular network, and a complex immune cell population. Mouse models have been a powerful tool to study the endometrium, revealing critical mechanisms that control implantation, placentation, and cancer. The recent development of 3D endometrial organoid cultures presents a state-of-the-art model to dissect the signaling pathways that underlie endometrial biology. Establishing endometrial organoids from genetically engineered mouse models, analyzing their transcriptomes, and visualizing their morphology at a single-cell resolution are crucial tools for the study of endometrial diseases. This paper outlines methods to establish 3D cultures of endometrial epithelium from mice and describes techniques to quantify gene expression and analyze the histology of the organoids. The goal is to provide a resource that can be used to establish, culture, and study the gene expression and morphological characteristics of endometrial epithelial organoids.
- Published
- 2023
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- View/download PDF
38. BMP/SMAD1/5 Signaling in the Endometrial Epithelium Is Essential for Receptivity and Early Pregnancy.
- Author
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Tang S, Cope DI, Vasquez YM, and Monsivais D
- Subjects
- Animals, Embryo Implantation, Endometrium metabolism, Epithelium metabolism, Female, Mice, Pregnancy, Signal Transduction, Smad1 Protein genetics, Smad1 Protein metabolism, Smad5 Protein, Uterus metabolism, Lactoferrin metabolism
- Abstract
The biological processes that control endometrial receptivity and embryo implantation are critical for the successful outcome of pregnancy. The endometrium is the complex inner lining of the uterine wall that is under the cyclical control of estrogen and progesterone and is a site of intimate contact between mother and blastocyst. The bone morphogenetic signaling (BMP) pathway is a highly conserved signaling pathway that controls key cellular processes throughout pregnancy and exerts intracellular effects via the SMAD1/5 transcription factors. To delineate the endometrial compartment-specific roles of BMP signaling, we generated mice with epithelial-specific conditional deletion of SMAD1/5 using Lactoferrin-icre (Smad1flox/flox;Smad5flox/flox;Lactoferrin-cre, "Smad1/5 cKO"). Histological analysis of the reproductive tracts showed that Smad1/5 cKO mice were developmentally normal and displayed no defects in glandular morphology. In fertility analyses, single SMAD1 or SMAD5 deletion had no effect on fertility; however, double-conditional deletion of SMAD1 and SMAD5 resulted in severe subfertility. Timed mating analyses revealed endometrial receptivity defects in the Smad1/5 cKO mice beginning at 3.5 days post coitum (dpc) that perturbed embryo implantation at 4.5 dpc, as demonstrated by the detection of unattached blastocysts in the uterus, decreased COX2 expression, and FOXO1 cytoplasmic mislocalization. We also found that defects that arose during peri-implantation adversely affected embryonic and decidual development at 5.5 and 6.5 dpc. Thus, uterine epithelial BMP/SMAD1/5 signaling is essential during early pregnancy and SMAD1/5 epithelial-specific deletion has detrimental effects on stromal cell decidualization and pregnancy development., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2022
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- View/download PDF
39. Progesterone Receptor Signaling in the Uterus Is Essential for Pregnancy Success.
- Author
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Cope DI and Monsivais D
- Subjects
- Animals, Female, Humans, Infant, Newborn, Mammals, Parturition physiology, Placenta, Pregnancy, Progesterone, Uterus, Premature Birth, Receptors, Progesterone
- Abstract
The uterus plays an essential role in the reproductive health of women and controls critical processes such as embryo implantation, placental development, parturition, and menstruation. Progesterone receptor (PR) regulates key aspects of the reproductive function of several mammalian species by directing the transcriptional program in response to progesterone (P4). P4/PR signaling controls endometrial receptivity and decidualization during early pregnancy and is critical for the establishment and outcome of a successful pregnancy. PR is also essential throughout gestation and during labor, and it exerts critical roles in the myometrium, mainly by the specialized function of its two isoforms, progesterone receptor A (PR-A) and progesterone receptor B (PR-B), which display distinct and separate roles as regulators of transcription. This review summarizes recent studies related to the roles of PR function in the decidua and myometrial tissues. We discuss how PR acquired key features in placental mammals that resulted in a highly specialized and dynamic role in the decidua. We also summarize recent literature that evaluates the myometrial PR-A/PR-B ratio at parturition and discuss the efficacy of current treatment options for preterm birth.
- Published
- 2022
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- View/download PDF
40. Using Simulation to Facilitate Transition to the Nurse Educator Role: An Integrative Review.
- Author
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Fitzwater J, McNeill J, Monsivais D, and Nunez F
- Subjects
- Humans, Learning, Nurse's Role, Nursing Education Research, Faculty, Nursing, Nurse Clinicians
- Abstract
Background: Nurse clinicians transitioning to the educator role require competency development. Simulation methods may increase knowledge and skill development in nurse educators., Purpose: The purpose of this review was to examine what is known about using simulation to facilitate transition to the nurse educator role., Methods: A literature search was completed including simulation methods at any level of fidelity with nurse educators as learners., Results: Using Meleis' Transitions Theory, the outcomes of reviewed reports demonstrated properties of transitions, facilitators of transitions, and indicators of successful transitions to the nurse educator role. Transition outcomes related to mastery of the role were not evident in the reports., Conclusions: Simulation learning has the potential to support the nurse educator in role transition and development., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2021
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41. Morningness-eveningness assessment from mobile phone communication analysis.
- Author
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Roy C, Monsivais D, Bhattacharya K, Dunbar RIM, and Kaski K
- Abstract
Human behaviour follows a 24-h rhythm and is known to be governed by the individual chronotypes. Due to the widespread use of technology in our daily lives, it is possible to record the activities of individuals through their different digital traces. In the present study we utilise a large mobile phone communication dataset containing time stamps of calls and text messages to study the circadian rhythms of anonymous users in a European country. After removing the effect of the synchronization of East-West sun progression with the calling activity, we used two closely related approaches to heuristically compute the chronotypes of the individuals in the dataset, to identify them as morning persons or "larks" and evening persons or "owls". Using the computed chronotypes we showed how the chronotype is largely dependent on age with younger cohorts being more likely to be owls than older cohorts. Moreover, our analysis showed how on average females have distinctly different chronotypes from males. Younger females are more larkish than males while older females are more owlish. Finally, we also studied the period of low calling activity for each of the users which is considered as a marker of their sleep period during the night. We found that while "extreme larks" tend to sleep more than "extreme owls" on the weekends, we do not observe much variation between them on weekdays. In addition, we have observed that women tend to sleep even less than males on weekdays while there is not much difference between them on the weekends., (© 2021. The Author(s).)
- Published
- 2021
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42. Endometrial receptivity and implantation require uterine BMP signaling through an ACVR2A-SMAD1/SMAD5 axis.
- Author
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Monsivais D, Nagashima T, Prunskaite-Hyyryläinen R, Nozawa K, Shimada K, Tang S, Hamor C, Agno JE, Chen F, Masand RP, Young SL, Creighton CJ, DeMayo FJ, Ikawa M, Lee SJ, and Matzuk MM
- Subjects
- Activin Receptors, Type II genetics, Activin Receptors, Type II metabolism, Animals, Biopsy, Disease Models, Animal, Endometrium metabolism, Endometrium pathology, Estrogens metabolism, Female, Humans, Mice, Mice, Knockout, Pregnancy, Signal Transduction physiology, Smad1 Protein analysis, Smad1 Protein genetics, Smad1 Protein metabolism, Smad5 Protein analysis, Smad5 Protein genetics, Smad5 Protein metabolism, Bone Morphogenetic Proteins metabolism, Embryo Implantation, Infertility, Female genetics
- Abstract
During early pregnancy in the mouse, nidatory estrogen (E2) stimulates endometrial receptivity by activating a network of signaling pathways that is not yet fully characterized. Here, we report that bone morphogenetic proteins (BMPs) control endometrial receptivity via a conserved activin receptor type 2 A (ACVR2A) and SMAD1/5 signaling pathway. Mice were generated to contain single or double conditional deletion of SMAD1/5 and ACVR2A/ACVR2B receptors using progesterone receptor (PR)-cre. Female mice with SMAD1/5 deletion display endometrial defects that result in the development of cystic endometrial glands, a hyperproliferative endometrial epithelium during the window of implantation, and impaired apicobasal transformation that prevents embryo implantation and leads to infertility. Analysis of Acvr2a-PRcre and Acvr2b-PRcre pregnant mice determined that BMP signaling occurs via ACVR2A and that ACVR2B is dispensable during embryo implantation. Therefore, BMPs signal through a conserved endometrial ACVR2A/SMAD1/5 pathway that promotes endometrial receptivity during embryo implantation.
- Published
- 2021
- Full Text
- View/download PDF
43. Human-agent coordination in a group formation game.
- Author
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Takko T, Bhattacharya K, Monsivais D, and Kaski K
- Abstract
Coordination and cooperation between humans and autonomous agents in cooperative games raise interesting questions on human decision making and behaviour changes. Here we report our findings from a group formation game in a small-world network of different mixes of human and agent players, aiming to achieve connected clusters of the same colour by swapping places with neighbouring players using non-overlapping information. In the experiments the human players are incentivized by rewarding to prioritize their own cluster while the model of agents' decision making is derived from our previous experiment of purely cooperative game between human players. The experiments were performed by grouping the players in three different setups to investigate the overall effect of having cooperative autonomous agents within teams. We observe that the human subjects adjust to autonomous agents by being less risk averse, while keeping the overall performance efficient by splitting the behaviour into selfish and cooperative actions performed during the rounds of the game. Moreover, results from two hybrid human-agent setups suggest that the group composition affects the evolution of clusters. Our findings indicate that in purely or lesser cooperative settings, providing more control to humans could help in maximizing the overall performance of hybrid systems.
- Published
- 2021
- Full Text
- View/download PDF
44. Cell-type specific analysis of physiological action of estrogen in mouse oviducts.
- Author
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McGlade EA, Herrera GG, Stephens KK, Olsen SLW, Winuthayanon S, Guner J, Hewitt SC, Korach KS, DeMayo FJ, Lydon JP, Monsivais D, and Winuthayanon W
- Subjects
- Animals, Estrogens pharmacology, Fallopian Tubes cytology, Fallopian Tubes drug effects, Female, Gene Expression Profiling, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Oviducts cytology, Oviducts drug effects, Receptors, Progesterone physiology, Biomarkers metabolism, Estradiol pharmacology, Fallopian Tubes physiology, Gene Expression Regulation, Developmental drug effects, Insulin-Like Growth Factor I physiology, Oviducts physiology, Single-Cell Analysis methods
- Abstract
One of the endogenous estrogens, 17β-estradiol (E
2 ) is a female steroid hormone secreted from the ovary. It is well established that E2 causes biochemical and histological changes in the uterus. However, it is not completely understood how E2 regulates the oviductal environment in vivo. In this study, we assessed the effect of E2 on each oviductal cell type, using an ovariectomized-hormone-replacement mouse model, single-cell RNA-sequencing (scRNA-seq), in situ hybridization, and cell-type-specific deletion in mice. We found that each cell type in the oviduct responded to E2 distinctively, especially ciliated and secretory epithelial cells. The treatment of exogenous E2 did not drastically alter the transcriptomic profile from that of endogenous E2 produced during estrus. Moreover, we have identified and validated genes of interest in our datasets that may be used as cell- and region-specific markers in the oviduct. Insulin-like growth factor 1 (Igf1) was characterized as an E2 -target gene in the mouse oviduct and was also expressed in human fallopian tubes. Deletion of Igf1 in progesterone receptor (Pgr)-expressing cells resulted in female subfertility, partially due to an embryo developmental defect and embryo retention within the oviduct. In summary, we have shown that oviductal cell types, including epithelial, stromal, and muscle cells, are differentially regulated by E2 and support gene expression changes, such as growth factors that are required for normal embryo development and transport in mouse models. Furthermore, we have identified cell-specific and region-specific gene markers for targeted studies and functional analysis in vivo., (© 2021 Federation of American Societies for Experimental Biology.)- Published
- 2021
- Full Text
- View/download PDF
45. Mass-spectrometry-based proteomic correlates of grade and stage reveal pathways and kinases associated with aggressive human cancers.
- Author
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Monsivais D, Vasquez YM, Chen F, Zhang Y, Chandrashekar DS, Faver JC, Masand RP, Scheurer ME, Varambally S, Matzuk MM, and Creighton CJ
- Subjects
- Female, Gene Expression Regulation, Neoplastic genetics, Humans, Male, Neoplasm Grading classification, Neoplasm Staging classification, Neoplasms classification, Neoplasms pathology, Phosphoproteins genetics, Phosphotransferases classification, Phosphotransferases genetics, Transcriptome genetics, Cell Cycle Proteins genetics, MAP Kinase Kinase Kinase 2 genetics, Microtubule-Associated Proteins genetics, Neoplasms genetics, Protein Serine-Threonine Kinases genetics, Protein-Tyrosine Kinases genetics, Proteomics
- Abstract
Proteomic signatures associated with clinical measures of more aggressive cancers could yield molecular clues as to disease drivers. Here, utilizing the Clinical Proteomic Tumor Analysis Consortium (CPTAC) mass-spectrometry-based proteomics datasets, we defined differentially expressed proteins and mRNAs associated with higher grade or higher stage, for each of seven cancer types (breast, colon, lung adenocarcinoma, clear cell renal, ovarian, uterine, and pediatric glioma), representing 794 patients. Widespread differential patterns of total proteins and phosphoproteins involved some common patterns shared between different cancer types. More proteins were associated with higher grade than higher stage. Most proteomic signatures predicted patient survival in independent transcriptomic datasets. The proteomic grade signatures, in particular, involved DNA copy number alterations. Pathways of interest were enriched within the grade-associated proteins across multiple cancer types, including pathways of altered metabolism, Warburg-like effects, and translation factors. Proteomic grade correlations identified protein kinases having functional impact in vitro in uterine endometrial cancer cells, including MAP3K2, MASTL, and TTK. The protein-level grade and stage associations for all proteins profiled-along with corresponding information on phosphorylation, pathways, mRNA expression, and copy alterations-represent a resource for identifying new potential targets. Proteomic analyses are often concordant with corresponding transcriptomic analyses, but with notable exceptions.
- Published
- 2021
- Full Text
- View/download PDF
46. Link-centric analysis of variation by demographics in mobile phone communication patterns.
- Author
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Fudolig MID, Bhattacharya K, Monsivais D, Jo HH, and Kaski K
- Subjects
- Adolescent, Adult, Age Factors, Aged, Demography, Humans, Middle Aged, Records, Sex Factors, Text Messaging, Young Adult, Cell Phone trends, Communication
- Abstract
We present a link-centric approach to study variation in the mobile phone communication patterns of individuals. Unlike most previous research on call detail records that focused on the variation of phone usage across individual users, we examine how the calling and texting patterns obtained from call detail records vary among pairs of users and how these patterns are affected by the nature of relationships between users. To demonstrate this link-centric perspective, we extract factors that contribute to the variation in the mobile phone communication patterns and predict demographics-related quantities for pairs of users. The time of day and the channel of communication (calls or texts) are found to explain most of the variance among pairs that frequently call each other. Furthermore, we find that this variation can be used to predict the relationship between the pairs of users, as inferred from their age and gender, as well as the age of the younger user in a pair. From the classifier performance across different age and gender groups as well as the inherent class overlap suggested by the estimate of the bounds of the Bayes error, we gain insights into the similarity and differences of communication patterns across different relationships., Competing Interests: We have read the journal’s policy and the authors of this manuscript have the following competing interests: Hang-Hyun Jo is currently serving on the editorial board of PLOS ONE. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
- Published
- 2020
- Full Text
- View/download PDF
47. Group formation on a small-world: experiment and modelling.
- Author
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Bhattacharya K, Takko T, Monsivais D, and Kaski K
- Subjects
- Female, Humans, Male, Cooperative Behavior, Decision Making physiology, Games, Experimental
- Abstract
As a step towards studying human-agent collectives, we conduct an online game with human participants cooperating on a network. The game is presented in the context of achieving group formation through local coordination. The players set initially to a small-world network with limited information on the location of other players, coordinate their movements to arrange themselves into groups. To understand the decision-making process, we construct a data-driven model of agents based on probability matching. The model allows us to gather insight into the nature and degree of rationality employed by the human players. By varying the parameters in agent-based simulations, we are able to benchmark the human behaviour. We observe that while the players use the neighbourhood information in limited capacity, the perception of risk is optimal. We also find that for certain parameter ranges, the agents are able to act more efficiently when compared to the human players. This approach would allow us to simulate the collective dynamics in games with agents having varying strategies playing alongside human proxies.
- Published
- 2019
- Full Text
- View/download PDF
48. Reply to Liu et al.: ALK5-mediated tumor suppressor signaling through SMAD2 and SMAD3 in the uterus.
- Author
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Monsivais D, Kriseman M, Creighton CJ, and Matzuk MM
- Subjects
- Female, Humans, Smad2 Protein, Smad3 Protein, Transforming Growth Factor beta, Endometrial Neoplasms, Signal Transduction
- Abstract
Competing Interests: The authors declare no conflict of interest.
- Published
- 2019
- Full Text
- View/download PDF
49. Activin-like kinase 5 (ALK5) inactivation in the mouse uterus results in metastatic endometrial carcinoma.
- Author
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Monsivais D, Peng J, Kang Y, and Matzuk MM
- Subjects
- Adenocarcinoma pathology, Animals, Disease Models, Animal, Endometrial Neoplasms pathology, Endometrium metabolism, Endometrium pathology, Female, Humans, Lung Neoplasms genetics, Lung Neoplasms pathology, Lung Neoplasms secondary, Mice, Neoplasm Metastasis, Receptor, Transforming Growth Factor-beta Type I antagonists & inhibitors, Receptor, Transforming Growth Factor-beta Type II genetics, Signal Transduction, Transforming Growth Factor beta genetics, Uterus pathology, Adenocarcinoma genetics, Carcinogenesis genetics, Endometrial Neoplasms genetics, Receptor, Transforming Growth Factor-beta Type I genetics, Uterus metabolism
- Abstract
The endometrial lining of the uterine cavity is a highly dynamic tissue that is under the continuous control of the ovarian steroid hormones, estrogen and progesterone. Endometrial adenocarcinoma arises from the uncontrolled growth of the endometrial glands, which is typically associated with unopposed estrogen action and frequently occurs in older postmenopausal women. The incidence of endometrial cancer among younger women has been rising due to increasing rates of obesity, a major risk factor for the disease. The transforming growth factor β (TGFβ) family is a highly conserved group of proteins with roles in cellular differentiation, proliferation, and cancer. Inactivating mutations in the genes encoding the TGFβ cell surface receptors ( TGFBR1/ALK5 and TGFBR2 ) have been detected in various human cancers, indicating that a functional TGFβ signaling pathway is required for evading tumorigenesis. In this study, we present a mouse model with conditional inactivation of activin receptor-like kinase 5 (ALK5) in the mouse uterus using progesterone receptor cre (" Alk5 cKO") that develops endometrial adenocarcinoma with metastasis to the lungs. The cancer and metastatic lung nodules are estrogen dependent and retain estrogen receptor α (ERα) reactivity, but have decreased levels of progesterone receptor (PR) protein. The endometrial tumors develop only in Alk5 cKO mice that are mated to fertile males, indicating that TGFβ-mediated postpartum endometrial repair is critical for endometrial function. Overall, these studies indicate that TGFβ signaling through TGFBR1/ALK5 in the endometrium is required for endometrial homeostasis, tumor suppression, and postpartum endometrial regeneration., Competing Interests: Conflict of interest statement: D.M. and T.E.S. are coauthors on a 2015 Commentary article., (Copyright © 2019 the Author(s). Published by PNAS.)
- Published
- 2019
- Full Text
- View/download PDF
50. Uterine double-conditional inactivation of Smad2 and Smad3 in mice causes endometrial dysregulation, infertility, and uterine cancer.
- Author
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Kriseman M, Monsivais D, Agno J, Masand RP, Creighton CJ, and Matzuk MM
- Subjects
- Animals, Carcinogenesis genetics, Cell Proliferation genetics, Endometrium metabolism, Endometrium pathology, Female, Gene Expression Regulation genetics, Humans, Infertility pathology, Mice, Mice, Knockout, Pregnancy, Receptors, Progesterone genetics, Uterine Neoplasms pathology, Uterus metabolism, Uterus pathology, Infertility genetics, Smad2 Protein genetics, Smad3 Protein genetics, Uterine Neoplasms genetics
- Abstract
SMAD2 and SMAD3 are downstream proteins in the transforming growth factor-β (TGF β) signaling pathway that translocate signals from the cell membrane to the nucleus, bind DNA, and control the expression of target genes. While SMAD2/3 have important roles in the ovary, we do not fully understand the roles of SMAD2/3 in the uterus and their implications in the reproductive system. To avoid deleterious effects of global deletion, and given previous data showing redundant function of Smad2 and Smad3 , a double-conditional knockout was generated using progesterone receptor-cre ( Smad2/3 cKO ) mice. Smad2/3 cKO mice were infertile due to endometrial hyperproliferation observed as early as 6 weeks of postnatal life. Endometrial hyperplasia worsened with age, and all Smad2/3 cKO mice ultimately developed bulky endometrioid-type uterine cancers with 100% mortality by 8 months of age. The phenotype was hormone-dependent and could be prevented with removal of the ovaries at 6 weeks of age but not at 12 weeks. Uterine tumor epithelium was associated with decreased expression of steroid biosynthesis genes, increased expression of inflammatory response genes, and abnormal expression of cell cycle checkpoint genes. Our results indicate the crucial role of SMAD2/3 in maintaining normal endometrial function and confirm the hormone-dependent nature of SMAD2/3 in the uterus. The hyperproliferation of the endometrium affected both implantation and maintenance of pregnancy. Our findings generate a mouse model to study the roles of SMAD2/3 in the uterus and serve to provide insight into the mechanism by which the endometrium can escape the plethora of growth regulatory proteins., Competing Interests: Conflict of interest statement: D.M. and T.E.S. are coauthors on a 2015 Commentary article., (Copyright © 2019 the Author(s). Published by PNAS.)
- Published
- 2019
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