The Experts below are selected from a list of 10452 Experts worldwide ranked by ideXlab platform
William H. Catherino - One of the best experts on this subject based on the ideXlab platform.
-
nav3 a tumor suppressor gene is decreased in uterine Leiomyoma tissue and cells
Reproductive Sciences, 2020Co-Authors: J M Aly, William H. Catherino, M Malik, Joy Britten, T D Lewis, Toral ParikhAbstract:NAV 3 is a tumor suppressor of unknown function in Leiomyomas. The objective of this study is to assess NAV3 expression and its potential role in human uterine Leiomyomas. NAV3 protein expression was examined in patient Leiomyoma and patient-matched myometrial tissue samples by Western blot and immunohistochemistry. NAV3 mRNA and protein expression was assessed in leuprolide acetate– and cetrorelix-treated cell line Leiomyoma samples. RNAseq analysis of placebo-treated Leiomyoma compared with myometrium demonstrated the presence of transcripts encoding for several neuronal proteins. For NAV3, RNA sequence analysis demonstrated decreased expression in Leiomyoma as compared with myometrium (0.86 ± 0.03 fold). Presence of NAV3 mRNA was also decreased in Leiomyoma surgical samples (0.43 fold ± 0.05, p = 0.026) compared with patient-matched myometrium. Confirmatory qRT-PCR results on immortalized Leiomyoma and myometrial cell lines similarly demonstrated a decrease in expression of NAV3 in Leiomyomas (0.28 ± 0.02, p = 0.00075). Immunohistochemical analysis demonstrated a significant decrease in NAV 3 protein in Leiomyomas (H-score 154.7 ± 6.2) as compared with myometrium (H-score; 312.5 ± 14.7, p < 0.0001). Leuprolide acetate–treated Leiomyoma cells demonstrated an increase in NAV 3 mRNA expression (1.53 ± 0.13, p < 0.0001). Similarly, Western blot analysis on leuprolide-treated Leiomyoma cells showed a non-significant increase in NAV 3 protein expression (1.26 ± 0.09, p = 0.063). NAV 3, a tumor suppressor in numerous cancers, is decreased in Leiomyoma cells and tissue compared with myometrium, and increased by GnRH analog treatment, suggesting that NAV3 may mediate steroid hormone–independent Leiomyoma regulation by GnRH analogs.
-
ulipristal acetate decreases active tgf β3 and its canonical signaling in uterine Leiomyoma via two novel mechanisms
Fertility and Sterility, 2019Co-Authors: T D Lewis, William H. Catherino, M Malik, Joy Britten, Toral Parikh, Jeris CoxAbstract:Objective To characterize the effect of ulipristal acetate (UPA) treatment on transforming growth factor (TGF) canonical and noncanonical signaling pathways in uterine Leiomyoma tissue and cells. UPA decreased extracellular matrix in surgical specimens; we characterize the mechanism in this study. Design Laboratory study. Setting University. Intervention(s) Exposure of Leiomyoma cell lines to UPA. Main Outcome Measure(s) RNAseq was performed on matched myometrium and Leiomyoma surgical specimens of placebo- and UPA-treated patients. Changes in gene expression and protein were measured using quantitative polymerase chain reaction and western immunoblot analysis, respectively. Result(s) In surgical specimen, mRNA for TGF-β3 was elevated 3.75-fold and TGFR2 was decreased 0.50-fold in placebo Leiomyomas compared with myometrium. Analysis of Leiomyomas from UPA-treated women by western blot revealed significant reductions of active TGF-β3 (0.64 ± 0.12-fold), p-TGFR2 (0.56 ± 0.23-fold), pSmad 2 (0.54 ± 0.04-fold), and pSmad 3 (0.65 ± 0.09-fold) compared with untreated Leiomyomas. UPA treatment demonstrated statistically significant reduction in collagen 1, fibronectin, and versican proteins. Notably, there was a statistically significant increase of the extracellular matrix protein fibrillin in Leiomyoma treated with UPA (1.48 ± 0.41-fold). Data from in vitro assays with physiologic concentrations of UPA supported the in vivo findings. Conclusion(s) TGF-β pathway is highly up-regulated in Leiomyoma and is directly responsible for development of the fibrotic phenotype. UPA attenuates this pathway by reducing TGF-β3 message and protein expression, resulting in a reduction in TGF-β canonical signaling. In addition, UPA significantly increased fibrillin protein expression, which can serve to bind inactive TGF-β complexes. Therefore, UPA inhibits Leiomyoma fibrosis by decreasing active TGF-β3 and diminishing signaling through the canonical pathway. Clinical Trial Registration Number NCT00290251.
-
Ulipristal Acetate Mediates Decreased Proteoglycan Expression Through Regulation of Nuclear Factor of Activated T-Cells (NFAT5)
Reproductive Sciences, 2019Co-Authors: Joy L. Britten, Minnie Malik, Terrence D. Lewis, William H. CatherinoAbstract:Nuclear factor of activated T-cells (NFAT5) is a tissue specific, osmoadaptive transcription factor essential for the control of hydration homeostasis in mammalian cells. Nuclear factor of activated T-cells regulates osmolyte transporters aldo-keto reductase family 1 member B1 (AKR1B1) and solute carrier family 5 member 3 (SLC5A3) to maintain fluid equilibrium in cells. The osmotic potential of the extracellular matrix of Leiomyomas is attributed to the role of proteoglycans. In Leiomyoma cells, NFAT5 is overexpressed compared to myometrial cells. The selective progesterone receptor modulator, ulipristal acetate, has been reported to decrease the size of Leiomyomas in clinical trials. When treated with ulipristal acetate, both patient Leiomyoma tissue and Leiomyoma cells grown in 3-dimensional cultures show a decrease in the expression of NFAT5 protein, solute transporters AKR1B1 and SLC5A3, and results in an associated decline in the expression of proteoglycans, versican, aggrecan, and brevican. In summary, ulipristal acetate induces changes in Leiomyoma cell osmoregulation which result in a decrease in proteoglycan expression.
-
simvastatin at clinically relevant concentrations affects human uterine Leiomyoma growth and extracellular matrix production
Fertility and Sterility, 2018Co-Authors: M Malik, Joy Britten, Mostafa A Borahay, James H Segars, William H. CatherinoAbstract:Objective To observe the antifibroid effects of therapeutic concentrations of simvastatin, which interferes with cholesterol biosynthesis, a known precursor of five major classes of steroid hormones, including progesterone and estrogen, which play a major role in the development and growth of uterine Leiomyomas. Design Two-dimensional and three-dimensional cell culture study of immortalized human Leiomyoma and patient-matched myometrium cells treated with simvastatin. Setting University laboratory. Patient(s) None. Interventions(s) None. Main Outcome Measure(s) Cell proliferation, alteration in apoptotic signaling pathways, and extracellular matrix (ECM) protein production. Result(s) Simvastatin demonstrated a concentration-dependent antiproliferative effect on both the Leiomyoma cells and the patient-matched myometrium cells, but a higher inhibitory effect at lower concentrations of simvastatin was observed in Leiomyoma cells. Simvastatin also regulated Leiomyoma cell apoptosis through a concentration-dependent increase in activity of caspase-3. Simvastatin significantly inhibited expression of major ECM proteins collagen I, collagen III, fibronectin, versican, and brevican in Leiomyoma cells at concentrations as low as 10−9 mol/L within 48 hours of exposure. Conclusion(s) Simvastatin induces apoptosis in uterine Leiomyoma cells at low concentrations, as evidenced by increased active caspase levels. Furthermore, inhibited production of the ECM proteins may lead to reduction in tumor size. Simvastatin may represent a novel therapeutic treatment strategy for uterine Leiomyomas.
-
Leiomyoma fibrosis inhibited by liarozole a retinoic acid metabolic blocking agent
Fertility and Sterility, 2010Co-Authors: M Gilden, William H. Catherino, M Malik, Joy Britten, Tania Delgado, Gary A LevyAbstract:Objective To study the influence of liarozole on Leiomyoma cell proliferation and extracellular matrix (ECM) gene expression in immortalized Leiomyoma cells. Design Laboratory study. Setting University hospital. Patient(s) None. Intervention(s) Tissue culture, real-time reverse transcription-polymerase chain reaction, Western blot. Main Outcome Measure(s) Proliferation, messenger RNA (mRNA), and ECM protein expression. Result(s) Proliferation of Leiomyoma cells was inhibited by treatment with liarozole at suprapharmacologic concentrations. The mRNA and protein expression of COL1A1, COL4A2, versican, fibromodulin, and fibronectin was increased in untreated Leiomyoma cells compared with untreated patient-matched myometrial cells. Extracellular matrix mRNA expression was decreased in a dose-dependent manner in Leiomyoma cells treated with pharmacologic concentrations of liarozole. In addition, myometrial cells treated with liarozole demonstrated no statistically significant alteration in ECM regulation. Conclusion(s) Liarozole inhibited ECM protein production at pharmacologic concentrations in immortalized human Leiomyoma cells. Retinoic acid metabolic blocking agents represent a potential therapeutic drug family for human Leiomyomas.
Anu Suomalainen - One of the best experts on this subject based on the ideXlab platform.
-
downregulation of srf fos junb pathway in fumarate hydratase deficiency and in uterine Leiomyomas
Oncogene, 2009Co-Authors: Nuno Raimundo, Lauri A. Aaltonen, Sakari Vanharanta, Iiris Hovatta, Anu SuomalainenAbstract:Defects of metabolic enzymes result in a variety of manifestations not logically explained by the primary metabolic function. Dominant defects of fumarate hydratase (FH) result in predisposition to cutaneous and uterine Leiomyomas, and renal cell cancer. FH is a metabolic enzyme of the tricarboxylic acid cycle, and its tumor-suppressor mechanism is not fully understood. We compared the consequences of FH deficiency and respiratory chain (RC) deficiency using global expression pattern of diploid primary fibroblasts. This approach utilized the information that RC defects do not seem to predispose to tumorigenesis, and the aim was to identify FH-specific signaling effects that might have relevance to tumor formation. These results were then compared to global expression patterns of FH-deficient and sporadic uterine Leiomyoma data sets. We show here that FH-deficient fibroblasts share a common transcriptional fingerprint with FH-deficient and sporadic Leiomyomas, highlighting the downregulation of serum response factor (SRF)-regulated transcripts, particularly the FOS-JUNB pathway. We confirmed the downregulation of this pathway at transcriptional and protein level. SRF has a fundamental function in the differentiation of smooth muscle progenitor cells, and its downregulation both in diploid FH-deficient primary fibroblasts and in Leiomyomas suggests an early function in the mechanism of uterine Leiomyoma formation in FH deficiency. Concordantly, the phosphorylated form of SRF, known to activate transcription, is undetectable in Leiomyomas whereas clearly detected in several nuclei in the differentiated myometrium. A similar transcriptional SRF-pathway fingerprint in FH-deficient and sporadic Leiomyomas emphasizes the potential importance of this pathway in primary events leading to Leiomyomatosis.
M Malik - One of the best experts on this subject based on the ideXlab platform.
-
nav3 a tumor suppressor gene is decreased in uterine Leiomyoma tissue and cells
Reproductive Sciences, 2020Co-Authors: J M Aly, William H. Catherino, M Malik, Joy Britten, T D Lewis, Toral ParikhAbstract:NAV 3 is a tumor suppressor of unknown function in Leiomyomas. The objective of this study is to assess NAV3 expression and its potential role in human uterine Leiomyomas. NAV3 protein expression was examined in patient Leiomyoma and patient-matched myometrial tissue samples by Western blot and immunohistochemistry. NAV3 mRNA and protein expression was assessed in leuprolide acetate– and cetrorelix-treated cell line Leiomyoma samples. RNAseq analysis of placebo-treated Leiomyoma compared with myometrium demonstrated the presence of transcripts encoding for several neuronal proteins. For NAV3, RNA sequence analysis demonstrated decreased expression in Leiomyoma as compared with myometrium (0.86 ± 0.03 fold). Presence of NAV3 mRNA was also decreased in Leiomyoma surgical samples (0.43 fold ± 0.05, p = 0.026) compared with patient-matched myometrium. Confirmatory qRT-PCR results on immortalized Leiomyoma and myometrial cell lines similarly demonstrated a decrease in expression of NAV3 in Leiomyomas (0.28 ± 0.02, p = 0.00075). Immunohistochemical analysis demonstrated a significant decrease in NAV 3 protein in Leiomyomas (H-score 154.7 ± 6.2) as compared with myometrium (H-score; 312.5 ± 14.7, p < 0.0001). Leuprolide acetate–treated Leiomyoma cells demonstrated an increase in NAV 3 mRNA expression (1.53 ± 0.13, p < 0.0001). Similarly, Western blot analysis on leuprolide-treated Leiomyoma cells showed a non-significant increase in NAV 3 protein expression (1.26 ± 0.09, p = 0.063). NAV 3, a tumor suppressor in numerous cancers, is decreased in Leiomyoma cells and tissue compared with myometrium, and increased by GnRH analog treatment, suggesting that NAV3 may mediate steroid hormone–independent Leiomyoma regulation by GnRH analogs.
-
ulipristal acetate decreases active tgf β3 and its canonical signaling in uterine Leiomyoma via two novel mechanisms
Fertility and Sterility, 2019Co-Authors: T D Lewis, William H. Catherino, M Malik, Joy Britten, Toral Parikh, Jeris CoxAbstract:Objective To characterize the effect of ulipristal acetate (UPA) treatment on transforming growth factor (TGF) canonical and noncanonical signaling pathways in uterine Leiomyoma tissue and cells. UPA decreased extracellular matrix in surgical specimens; we characterize the mechanism in this study. Design Laboratory study. Setting University. Intervention(s) Exposure of Leiomyoma cell lines to UPA. Main Outcome Measure(s) RNAseq was performed on matched myometrium and Leiomyoma surgical specimens of placebo- and UPA-treated patients. Changes in gene expression and protein were measured using quantitative polymerase chain reaction and western immunoblot analysis, respectively. Result(s) In surgical specimen, mRNA for TGF-β3 was elevated 3.75-fold and TGFR2 was decreased 0.50-fold in placebo Leiomyomas compared with myometrium. Analysis of Leiomyomas from UPA-treated women by western blot revealed significant reductions of active TGF-β3 (0.64 ± 0.12-fold), p-TGFR2 (0.56 ± 0.23-fold), pSmad 2 (0.54 ± 0.04-fold), and pSmad 3 (0.65 ± 0.09-fold) compared with untreated Leiomyomas. UPA treatment demonstrated statistically significant reduction in collagen 1, fibronectin, and versican proteins. Notably, there was a statistically significant increase of the extracellular matrix protein fibrillin in Leiomyoma treated with UPA (1.48 ± 0.41-fold). Data from in vitro assays with physiologic concentrations of UPA supported the in vivo findings. Conclusion(s) TGF-β pathway is highly up-regulated in Leiomyoma and is directly responsible for development of the fibrotic phenotype. UPA attenuates this pathway by reducing TGF-β3 message and protein expression, resulting in a reduction in TGF-β canonical signaling. In addition, UPA significantly increased fibrillin protein expression, which can serve to bind inactive TGF-β complexes. Therefore, UPA inhibits Leiomyoma fibrosis by decreasing active TGF-β3 and diminishing signaling through the canonical pathway. Clinical Trial Registration Number NCT00290251.
-
simvastatin at clinically relevant concentrations affects human uterine Leiomyoma growth and extracellular matrix production
Fertility and Sterility, 2018Co-Authors: M Malik, Joy Britten, Mostafa A Borahay, James H Segars, William H. CatherinoAbstract:Objective To observe the antifibroid effects of therapeutic concentrations of simvastatin, which interferes with cholesterol biosynthesis, a known precursor of five major classes of steroid hormones, including progesterone and estrogen, which play a major role in the development and growth of uterine Leiomyomas. Design Two-dimensional and three-dimensional cell culture study of immortalized human Leiomyoma and patient-matched myometrium cells treated with simvastatin. Setting University laboratory. Patient(s) None. Interventions(s) None. Main Outcome Measure(s) Cell proliferation, alteration in apoptotic signaling pathways, and extracellular matrix (ECM) protein production. Result(s) Simvastatin demonstrated a concentration-dependent antiproliferative effect on both the Leiomyoma cells and the patient-matched myometrium cells, but a higher inhibitory effect at lower concentrations of simvastatin was observed in Leiomyoma cells. Simvastatin also regulated Leiomyoma cell apoptosis through a concentration-dependent increase in activity of caspase-3. Simvastatin significantly inhibited expression of major ECM proteins collagen I, collagen III, fibronectin, versican, and brevican in Leiomyoma cells at concentrations as low as 10−9 mol/L within 48 hours of exposure. Conclusion(s) Simvastatin induces apoptosis in uterine Leiomyoma cells at low concentrations, as evidenced by increased active caspase levels. Furthermore, inhibited production of the ECM proteins may lead to reduction in tumor size. Simvastatin may represent a novel therapeutic treatment strategy for uterine Leiomyomas.
-
Leiomyoma fibrosis inhibited by liarozole a retinoic acid metabolic blocking agent
Fertility and Sterility, 2010Co-Authors: M Gilden, William H. Catherino, M Malik, Joy Britten, Tania Delgado, Gary A LevyAbstract:Objective To study the influence of liarozole on Leiomyoma cell proliferation and extracellular matrix (ECM) gene expression in immortalized Leiomyoma cells. Design Laboratory study. Setting University hospital. Patient(s) None. Intervention(s) Tissue culture, real-time reverse transcription-polymerase chain reaction, Western blot. Main Outcome Measure(s) Proliferation, messenger RNA (mRNA), and ECM protein expression. Result(s) Proliferation of Leiomyoma cells was inhibited by treatment with liarozole at suprapharmacologic concentrations. The mRNA and protein expression of COL1A1, COL4A2, versican, fibromodulin, and fibronectin was increased in untreated Leiomyoma cells compared with untreated patient-matched myometrial cells. Extracellular matrix mRNA expression was decreased in a dose-dependent manner in Leiomyoma cells treated with pharmacologic concentrations of liarozole. In addition, myometrial cells treated with liarozole demonstrated no statistically significant alteration in ECM regulation. Conclusion(s) Liarozole inhibited ECM protein production at pharmacologic concentrations in immortalized human Leiomyoma cells. Retinoic acid metabolic blocking agents represent a potential therapeutic drug family for human Leiomyomas.
Sharon W Weiss - One of the best experts on this subject based on the ideXlab platform.
-
do Leiomyomas of deep soft tissue exist an analysis of highly differentiated smooth muscle tumors of deep soft tissue supporting two distinct subtypes
The American Journal of Surgical Pathology, 2001Co-Authors: Steven D Billings, Andrew L Folpe, Sharon W WeissAbstract:There is a prevailing view that Leiomyomas of deep soft tissue are rare or nonexistent, but there are limited data on this subject in the form of large clinical studies with long follow-up information. We reviewed 36 consultation cases that had been diagnosed as Leiomyoma or probable Leiomyoma based
Jinsun Park - One of the best experts on this subject based on the ideXlab platform.
-
a rare case of primary ovarian Leiomyoma with atypical meigs syndrome
Korean Journal of Obstetrics & Gynecology, 2012Co-Authors: Seungyeon Choi, Jinsun ParkAbstract:Primary ovarian Leiomyoma is a rare benign ovarian tumor. Ovarian Leiomyoma accompanied with atypical Meigs’ syndrome is extremely rare. A 13-year-old woman had underlying primary lymphedema and visited our clinic due to associated vulvar edema. During a gynecologic examination, we detected a right ovarian tumor with large amounts of ascites on transrectal ultrasonography. The tumor size increased from 4 to 7 cm during 6 months follow-up. After laparoscopic right ovarian tumorectomy, the final pathology of the tumor was primary ovarian Leiomyoma. Ovarian Leiomyomas are not typically suspected before surgery due to their extreme rarity and because they are easily misdiagnosed as fi broma during frozen biopsy due to similarities between both diseases. Here we introduce the case of a primary ovarian Leiomyoma accompanied with atypical Meigs’ syndrome.