The Experts below are selected from a list of 1068 Experts worldwide ranked by ideXlab platform
Sydney Chang - One of the best experts on this subject based on the ideXlab platform.
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a kinase anchoring protein 13 akap13 augments progesterone signaling in uterine fibroid cells
The Journal of Clinical Endocrinology and Metabolism, 2019Co-Authors: Sinnie Sin Man Ng, Soledad Jorge, Szu Chi Su, Charles R Armstrong, Joshua T Brennan, Sydney Chang, M Malik, Joy BrittenAbstract:Context: Uterine leiomyomata (fibroids) are prevalent sex hormone‒dependent tumors with an altered response to mechanical stress. Ulipristal acetate, a selective progesterone receptor (PR) modulator, significantly reduces fibroid size in patients. However, PR signaling in fibroids and its relationship to mechanical signaling are incompletely understood. Objective: Our prior studies revealed that A-kinase anchoring protein 13 (AKAP13) was overexpressed in fibroids and contributed to altered mechanotransduction in fibroids. Because AKAP13 augmented nuclear receptor signaling in other tissues, we sought to determine whether AKAP13 might influence PR signaling in fibroids. Methods and Results: Fibroid samples from patients treated with Ulipristal acetate or placebo were examined for AKAP13 expression by using immunohistochemistry. In immortalized uterine fibroid cell lines and COS-7 cells, we observed that AKAP13 increased ligand-dependent PR activation of luciferase reporters and endogenous progesterone-responsive genes for PR-B but not PR-A. Inhibition of ERK reduced activation of PR-dependent signaling by AKAP13, but inhibition of p38 MAPK had no effect. In addition, glutathione S-transferase‒binding assays revealed that AKAP13 was bound to PR-B through its carboxyl terminus. Conclusion: These data suggest an intersection of mechanical signaling and PR signaling involving AKAP13 through ERK. Further elucidation of the integration of mechanical and hormonal signaling pathways in fibroids may provide insight into fibroid development and suggest new therapeutic strategies for treatment.
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a kinase anchoring protein 13 akap13 augments progesterone signaling in uterine fibroid cells
The Journal of Clinical Endocrinology and Metabolism, 2019Co-Authors: Sinnie Sin Man Ng, Soledad Jorge, Szu Chi Su, Charles R Armstrong, Joshua T Brennan, Sydney Chang, M Malik, Joy BrittenAbstract:Context: Uterine leiomyomata (fibroids) are prevalent sex hormone‒dependent tumors with an altered response to mechanical stress. Ulipristal acetate, a selective progesterone receptor (PR) modulator, significantly reduces fibroid size in patients. However, PR signaling in fibroids and its relationship to mechanical signaling are incompletely understood. Objective: Our prior studies revealed that A-kinase anchoring protein 13 (AKAP13) was overexpressed in fibroids and contributed to altered mechanotransduction in fibroids. Because AKAP13 augmented nuclear receptor signaling in other tissues, we sought to determine whether AKAP13 might influence PR signaling in fibroids. Methods and Results: Fibroid samples from patients treated with Ulipristal acetate or placebo were examined for AKAP13 expression by using immunohistochemistry. In immortalized uterine fibroid cell lines and COS-7 cells, we observed that AKAP13 increased ligand-dependent PR activation of luciferase reporters and endogenous progesterone-responsive genes for PR-B but not PR-A. Inhibition of ERK reduced activation of PR-dependent signaling by AKAP13, but inhibition of p38 MAPK had no effect. In addition, glutathione S-transferase‒binding assays revealed that AKAP13 was bound to PR-B through its carboxyl terminus. Conclusion: These data suggest an intersection of mechanical signaling and PR signaling involving AKAP13 through ERK. Further elucidation of the integration of mechanical and hormonal signaling pathways in fibroids may provide insight into fibroid development and suggest new therapeutic strategies for treatment.
Jacques Donnez - One of the best experts on this subject based on the ideXlab platform.
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gonadotropin releasing hormone antagonist linzagolix a new therapy for uterine adenomyosis
Fertility and Sterility, 2020Co-Authors: Olivier Donnez, Jacques DonnezAbstract:Objective To compare the efficacy of a selective progesterone receptor modulator, Ulipristal acetate, and a gonadotropin-releasing hormone antagonist, linzagolix, in a case of severe uterine adenomyosis. Design Case report. Setting Private clinic and infertility research unit. Patient One patient born in 1981 who presented because of heavy menstrual bleeding, pelvic pain, and dysmenorrhea due to diffuse and disseminated uterine adenomyosis confirmed by magnetic resonance imaging (MRI). Intervention The patient received a first treatment of 5 mg UPA daily for one course of 3 months. This therapy was discontinued because MRI revealed a worsened aspect. One year later, a once-daily dose of 200 mg linzagolix administered orally was initiated for 3 months, followed by another 3-month course of 100 mg once daily. Main Outcome Measures Clinical symptoms and MRI aspect. Results During treatment with UPA, the symptoms (pelvic pain, dysmenorrhea, bulk symptoms) worsened and MRI revealed aggravation of the adenomyotic lesions. During the 12-week course of once-daily 200 mg linzagolix, the patient remained in amenorrhea and noted a very significant improvement in symptoms. On MRI, the uterine volume had fallen from 875 cm3 to 290 cm3, and the adenomyotic lesions had significantly regressed. During the 100-mg linzagolix course (weeks 13–24), the patient reported continued alleviation of her symptoms. Conclusion To our knowledge, this is the first reported use of linzagolix, a new oral gonadotropin-releasing hormone antagonist that significantly reduced lesion size and improved quality of life in a patient with severe adenomyosis, who was previously nonresponsive to treatment with a selective progesterone receptor modulator, Ulipristal acetate.
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liver safety parameters of Ulipristal acetate for the treatment of uterine fibroids a comprehensive review of the clinical development program
Expert Opinion on Drug Safety, 2018Co-Authors: Jacques Donnez, Pablo Arriagada, Marcin Marciniak, Dominique LarreyAbstract:ABSTRACTIntroduction: Uterine fibroids are benign tumors within the uterine wall affecting women. Ulipristal acetate 5 mg was first authorized in the European Union on 23 February 2012, with a post...
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Emerging treatment options for uterine fibroids.
Expert Opinion on Emerging Drugs, 2018Co-Authors: Jacques Donnez, Olivier Donnez, Pablo Arriagada, Marie-madeleine DolmansAbstract:ABSTRACTIntroduction: Uterine fibroids (also known as leiomyomas or myomas) are the most common form of benign uterine tumors. Current management strategies involve mainly surgical interventions, but the choice of treatment is guided by patient age and desire to preserve fertility or avoid ‘radical’ surgery such as hysterectomy.Areas covered: There is growing evidence of the crucial role of progesterone pathways in the pathophysiology of uterine fibroids, leading to increasing use of selective progesterone receptor modulators (SPRMs) such as Ulipristal acetate. We searched all published studies on medical management of fibroids with SPRMs.Expert opinion: The need for alternatives to surgical intervention is very real, especially for women seeking to preserve their fertility. These options now exist, with SPRMs proven to treat fibroid symptoms effectively. Gynecologists now have new tools in their armamentarium, opening up novel strategies for the management of uterine fibroids.
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the current place of medical therapy in uterine fibroid management
Best Practice & Research in Clinical Obstetrics & Gynaecology, 2017Co-Authors: Jacques Donnez, Olivier Donnez, Marie-madeleine DolmansAbstract:Abstract Uterine fibroids (also known as leiomyomas or myomas) are the most common form of benign uterine tumors. Current management strategies mainly involve surgical interventions, but the choice of treatment is guided by patient's age and desire to preserve fertility or avoid “radical” surgery. Surgical and non-surgical approaches include hysterectomy myomectomy by hysteroscopy, myomectomy by laparotomy or laparoscopy, uterine artery embolization, and magnetic resonance-guided focused ultrasound surgery. The need for alternatives to surgical intervention is very real, especially for women seeking to preserve their fertility. There is growing evidence of the crucial role of progesterone pathways in the pathophysiology of uterine fibroids, and the efficacy of long-term intermittent use of selective progesterone receptor modulators such as Ulipristal acetate was recently demonstrated by randomized controlled studies.
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long term medical management of uterine fibroids with Ulipristal acetate
Fertility and Sterility, 2016Co-Authors: Jacques Donnez, Robert Hudecek, Olivier Donnez, Dace Matule, Hans Joachim Ahrendt, Janos Zatik, Zaneta Kasilovskiene, Mihai Cristian Dumitrascu, H Fernandez, David H BarlowAbstract:Objective To investigate the efficacy and safety of repeated 12-week courses of 5 or 10 mg daily Ulipristal acetate for intermittent treatment of symptomatic uterine fibroids. Design Double-blind, randomized administration of four 12-week courses of Ulipristal acetate. Setting Gynecology centers. Patient(s) Four hundred fifty-one subjects with symptomatic uterine fibroid(s) and heavy menstrual bleeding. Intervention(s) Four repeated 12-week treatment courses of daily 5 or 10 mg Ulipristal acetate. Main Outcome Measure(s) Endometrial safety and general safety, laboratory parameters, amenorrhea, controlled bleeding, fibroid volume, quality of life (QoL), and pain. Result(s) Efficacy results, such as bleeding control and fibroid volume reduction, were in line with previously published data. Pain and QoL showed marked improvements from screening, even during the off-treatment intervals. The safety profile of Ulipristal acetate was confirmed, and repeated treatment courses did not increase the occurrence of adverse reactions. There were no significant changes in laboratory parameters during the study. The percentage of subjects with endometrial thickness ≥16 mm was 7.4% (all subjects) after the first treatment course and returned to below screening levels (4.9%) in subsequent treatment courses. As in previous studies, Ulipristal acetate did not increase the occurrence of endometrial features of concern. The frequency of nonphysiological changes did not increase with repeated treatment. They were observed in 17.8% and 13.3% of biopsies after treatment courses 2 and 4, respectively, and were reversible after treatment cessation. Conclusion(s) The results of this study demonstrate the efficacy and further support the safety profile of repeated intermittent treatment of symptomatic fibroids with Ulipristal acetate. Clinical Trial Registration Number NCT01629563.
Soledad Jorge - One of the best experts on this subject based on the ideXlab platform.
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a kinase anchoring protein 13 akap13 augments progesterone signaling in uterine fibroid cells
The Journal of Clinical Endocrinology and Metabolism, 2019Co-Authors: Sinnie Sin Man Ng, Soledad Jorge, Szu Chi Su, Charles R Armstrong, Joshua T Brennan, Sydney Chang, M Malik, Joy BrittenAbstract:Context: Uterine leiomyomata (fibroids) are prevalent sex hormone‒dependent tumors with an altered response to mechanical stress. Ulipristal acetate, a selective progesterone receptor (PR) modulator, significantly reduces fibroid size in patients. However, PR signaling in fibroids and its relationship to mechanical signaling are incompletely understood. Objective: Our prior studies revealed that A-kinase anchoring protein 13 (AKAP13) was overexpressed in fibroids and contributed to altered mechanotransduction in fibroids. Because AKAP13 augmented nuclear receptor signaling in other tissues, we sought to determine whether AKAP13 might influence PR signaling in fibroids. Methods and Results: Fibroid samples from patients treated with Ulipristal acetate or placebo were examined for AKAP13 expression by using immunohistochemistry. In immortalized uterine fibroid cell lines and COS-7 cells, we observed that AKAP13 increased ligand-dependent PR activation of luciferase reporters and endogenous progesterone-responsive genes for PR-B but not PR-A. Inhibition of ERK reduced activation of PR-dependent signaling by AKAP13, but inhibition of p38 MAPK had no effect. In addition, glutathione S-transferase‒binding assays revealed that AKAP13 was bound to PR-B through its carboxyl terminus. Conclusion: These data suggest an intersection of mechanical signaling and PR signaling involving AKAP13 through ERK. Further elucidation of the integration of mechanical and hormonal signaling pathways in fibroids may provide insight into fibroid development and suggest new therapeutic strategies for treatment.
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a kinase anchoring protein 13 akap13 augments progesterone signaling in uterine fibroid cells
The Journal of Clinical Endocrinology and Metabolism, 2019Co-Authors: Sinnie Sin Man Ng, Soledad Jorge, Szu Chi Su, Charles R Armstrong, Joshua T Brennan, Sydney Chang, M Malik, Joy BrittenAbstract:Context: Uterine leiomyomata (fibroids) are prevalent sex hormone‒dependent tumors with an altered response to mechanical stress. Ulipristal acetate, a selective progesterone receptor (PR) modulator, significantly reduces fibroid size in patients. However, PR signaling in fibroids and its relationship to mechanical signaling are incompletely understood. Objective: Our prior studies revealed that A-kinase anchoring protein 13 (AKAP13) was overexpressed in fibroids and contributed to altered mechanotransduction in fibroids. Because AKAP13 augmented nuclear receptor signaling in other tissues, we sought to determine whether AKAP13 might influence PR signaling in fibroids. Methods and Results: Fibroid samples from patients treated with Ulipristal acetate or placebo were examined for AKAP13 expression by using immunohistochemistry. In immortalized uterine fibroid cell lines and COS-7 cells, we observed that AKAP13 increased ligand-dependent PR activation of luciferase reporters and endogenous progesterone-responsive genes for PR-B but not PR-A. Inhibition of ERK reduced activation of PR-dependent signaling by AKAP13, but inhibition of p38 MAPK had no effect. In addition, glutathione S-transferase‒binding assays revealed that AKAP13 was bound to PR-B through its carboxyl terminus. Conclusion: These data suggest an intersection of mechanical signaling and PR signaling involving AKAP13 through ERK. Further elucidation of the integration of mechanical and hormonal signaling pathways in fibroids may provide insight into fibroid development and suggest new therapeutic strategies for treatment.
Joy Britten - One of the best experts on this subject based on the ideXlab platform.
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a kinase anchoring protein 13 akap13 augments progesterone signaling in uterine fibroid cells
The Journal of Clinical Endocrinology and Metabolism, 2019Co-Authors: Sinnie Sin Man Ng, Soledad Jorge, Szu Chi Su, Charles R Armstrong, Joshua T Brennan, Sydney Chang, M Malik, Joy BrittenAbstract:Context: Uterine leiomyomata (fibroids) are prevalent sex hormone‒dependent tumors with an altered response to mechanical stress. Ulipristal acetate, a selective progesterone receptor (PR) modulator, significantly reduces fibroid size in patients. However, PR signaling in fibroids and its relationship to mechanical signaling are incompletely understood. Objective: Our prior studies revealed that A-kinase anchoring protein 13 (AKAP13) was overexpressed in fibroids and contributed to altered mechanotransduction in fibroids. Because AKAP13 augmented nuclear receptor signaling in other tissues, we sought to determine whether AKAP13 might influence PR signaling in fibroids. Methods and Results: Fibroid samples from patients treated with Ulipristal acetate or placebo were examined for AKAP13 expression by using immunohistochemistry. In immortalized uterine fibroid cell lines and COS-7 cells, we observed that AKAP13 increased ligand-dependent PR activation of luciferase reporters and endogenous progesterone-responsive genes for PR-B but not PR-A. Inhibition of ERK reduced activation of PR-dependent signaling by AKAP13, but inhibition of p38 MAPK had no effect. In addition, glutathione S-transferase‒binding assays revealed that AKAP13 was bound to PR-B through its carboxyl terminus. Conclusion: These data suggest an intersection of mechanical signaling and PR signaling involving AKAP13 through ERK. Further elucidation of the integration of mechanical and hormonal signaling pathways in fibroids may provide insight into fibroid development and suggest new therapeutic strategies for treatment.
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a kinase anchoring protein 13 akap13 augments progesterone signaling in uterine fibroid cells
The Journal of Clinical Endocrinology and Metabolism, 2019Co-Authors: Sinnie Sin Man Ng, Soledad Jorge, Szu Chi Su, Charles R Armstrong, Joshua T Brennan, Sydney Chang, M Malik, Joy BrittenAbstract:Context: Uterine leiomyomata (fibroids) are prevalent sex hormone‒dependent tumors with an altered response to mechanical stress. Ulipristal acetate, a selective progesterone receptor (PR) modulator, significantly reduces fibroid size in patients. However, PR signaling in fibroids and its relationship to mechanical signaling are incompletely understood. Objective: Our prior studies revealed that A-kinase anchoring protein 13 (AKAP13) was overexpressed in fibroids and contributed to altered mechanotransduction in fibroids. Because AKAP13 augmented nuclear receptor signaling in other tissues, we sought to determine whether AKAP13 might influence PR signaling in fibroids. Methods and Results: Fibroid samples from patients treated with Ulipristal acetate or placebo were examined for AKAP13 expression by using immunohistochemistry. In immortalized uterine fibroid cell lines and COS-7 cells, we observed that AKAP13 increased ligand-dependent PR activation of luciferase reporters and endogenous progesterone-responsive genes for PR-B but not PR-A. Inhibition of ERK reduced activation of PR-dependent signaling by AKAP13, but inhibition of p38 MAPK had no effect. In addition, glutathione S-transferase‒binding assays revealed that AKAP13 was bound to PR-B through its carboxyl terminus. Conclusion: These data suggest an intersection of mechanical signaling and PR signaling involving AKAP13 through ERK. Further elucidation of the integration of mechanical and hormonal signaling pathways in fibroids may provide insight into fibroid development and suggest new therapeutic strategies for treatment.
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Ulipristal Acetate and Extracellular Matrix Production in Human Leiomyomas In Vivo: A Laboratory Analysis of a Randomized Placebo Controlled Trial
Reproductive Sciences, 2018Co-Authors: Jeris Cox, Joy Britten, Minnie Malik, Terrence Lewis, William H. CatherinoAbstract:In a prior randomized controlled study, patients treated with Ulipristal acetate (UPA) or placebo for 3 months had a decrease in leiomyoma size. A total of 10 patients’ tissue samples (5 placebo and 5 treated with 10 mg/d UPA) that underwent hysterectomy and tissue preservation were identified from this study. Quantitative real-time reverse transcriptase polymerase chain reaction and Western blotting were used to assess fold gene and protein expression of extracellular membrane (ECM) proteins: collagen IA (COLI A), fibronectin (FNI), and versican (VCAN) of the samples. Confirmatory immunohistochemical analysis was performed. Changes in total matrix collagen were examined using Masson trichrome staining. Multiplex measurement of the matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases was performed. Compared to placebo-treated surgical specimens, 80% of the treated specimens showed decrease in VCAN protein, 60% showed decrease in FNI, but no consistent alteration in COLI A. This effect was also supported by immunohistochemistry where leiomyoma surgical specimens demonstrated decreased amount of FNI and VCAN on UPA treatment. Increased MMP2 and decreased MMP9 in treated patient leiomyomas indicate both degradation of the matrix and inhibition of the pathway involved in matrix production. Treatment with UPA decreased fibroid volume in placebo-controlled, randomized trials. Treatment with UPA decreased gene expression and protein production in leiomyoma tissue, suggesting both an impact on water content and ECM protein concentration as a mechanism of Ulipristal-mediated decrease in leiomyoma size.
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the synchronization of the leiomyoma extracellular matrix signaling pathways of surgical specimens in response to Ulipristal acetate
Fertility and Sterility, 2015Co-Authors: M Malik, Joy Britten, J Cox, A Patel, Lynnette K Nieman, William H. CatherinoAbstract:THE SYNCHRONIZATION OF THE LEIOMYOMA EXTRACELLULAR MATRIX SIGNALING PATHWAYS OF SURGICAL SPECIMENS IN RESPONSE TO Ulipristal ACETATE. M. Malik, J. Cox, J. Britten, A. Patel, L. K. Nieman, W. H. Catherino. Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, MD; Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD; Henry Jackson Foundation, Bethesda, MD; Reproductive Biology and Medicine Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD.
M Malik - One of the best experts on this subject based on the ideXlab platform.
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a kinase anchoring protein 13 akap13 augments progesterone signaling in uterine fibroid cells
The Journal of Clinical Endocrinology and Metabolism, 2019Co-Authors: Sinnie Sin Man Ng, Soledad Jorge, Szu Chi Su, Charles R Armstrong, Joshua T Brennan, Sydney Chang, M Malik, Joy BrittenAbstract:Context: Uterine leiomyomata (fibroids) are prevalent sex hormone‒dependent tumors with an altered response to mechanical stress. Ulipristal acetate, a selective progesterone receptor (PR) modulator, significantly reduces fibroid size in patients. However, PR signaling in fibroids and its relationship to mechanical signaling are incompletely understood. Objective: Our prior studies revealed that A-kinase anchoring protein 13 (AKAP13) was overexpressed in fibroids and contributed to altered mechanotransduction in fibroids. Because AKAP13 augmented nuclear receptor signaling in other tissues, we sought to determine whether AKAP13 might influence PR signaling in fibroids. Methods and Results: Fibroid samples from patients treated with Ulipristal acetate or placebo were examined for AKAP13 expression by using immunohistochemistry. In immortalized uterine fibroid cell lines and COS-7 cells, we observed that AKAP13 increased ligand-dependent PR activation of luciferase reporters and endogenous progesterone-responsive genes for PR-B but not PR-A. Inhibition of ERK reduced activation of PR-dependent signaling by AKAP13, but inhibition of p38 MAPK had no effect. In addition, glutathione S-transferase‒binding assays revealed that AKAP13 was bound to PR-B through its carboxyl terminus. Conclusion: These data suggest an intersection of mechanical signaling and PR signaling involving AKAP13 through ERK. Further elucidation of the integration of mechanical and hormonal signaling pathways in fibroids may provide insight into fibroid development and suggest new therapeutic strategies for treatment.
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a kinase anchoring protein 13 akap13 augments progesterone signaling in uterine fibroid cells
The Journal of Clinical Endocrinology and Metabolism, 2019Co-Authors: Sinnie Sin Man Ng, Soledad Jorge, Szu Chi Su, Charles R Armstrong, Joshua T Brennan, Sydney Chang, M Malik, Joy BrittenAbstract:Context: Uterine leiomyomata (fibroids) are prevalent sex hormone‒dependent tumors with an altered response to mechanical stress. Ulipristal acetate, a selective progesterone receptor (PR) modulator, significantly reduces fibroid size in patients. However, PR signaling in fibroids and its relationship to mechanical signaling are incompletely understood. Objective: Our prior studies revealed that A-kinase anchoring protein 13 (AKAP13) was overexpressed in fibroids and contributed to altered mechanotransduction in fibroids. Because AKAP13 augmented nuclear receptor signaling in other tissues, we sought to determine whether AKAP13 might influence PR signaling in fibroids. Methods and Results: Fibroid samples from patients treated with Ulipristal acetate or placebo were examined for AKAP13 expression by using immunohistochemistry. In immortalized uterine fibroid cell lines and COS-7 cells, we observed that AKAP13 increased ligand-dependent PR activation of luciferase reporters and endogenous progesterone-responsive genes for PR-B but not PR-A. Inhibition of ERK reduced activation of PR-dependent signaling by AKAP13, but inhibition of p38 MAPK had no effect. In addition, glutathione S-transferase‒binding assays revealed that AKAP13 was bound to PR-B through its carboxyl terminus. Conclusion: These data suggest an intersection of mechanical signaling and PR signaling involving AKAP13 through ERK. Further elucidation of the integration of mechanical and hormonal signaling pathways in fibroids may provide insight into fibroid development and suggest new therapeutic strategies for treatment.
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the synchronization of the leiomyoma extracellular matrix signaling pathways of surgical specimens in response to Ulipristal acetate
Fertility and Sterility, 2015Co-Authors: M Malik, Joy Britten, J Cox, A Patel, Lynnette K Nieman, William H. CatherinoAbstract:THE SYNCHRONIZATION OF THE LEIOMYOMA EXTRACELLULAR MATRIX SIGNALING PATHWAYS OF SURGICAL SPECIMENS IN RESPONSE TO Ulipristal ACETATE. M. Malik, J. Cox, J. Britten, A. Patel, L. K. Nieman, W. H. Catherino. Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, MD; Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD; Henry Jackson Foundation, Bethesda, MD; Reproductive Biology and Medicine Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD.