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Sofia D Merajver - One of the best experts on this subject based on the ideXlab platform.

  • synergistic inhibition of aggressive breast cancer cell migration and invasion by cytoplasmic delivery of anti RhoC silencing rna and presentation of eppt1 peptide on smart particles
    Journal of Controlled Release, 2018
    Co-Authors: Neha Kaushal, Sofia D Merajver, Yasemin Yuksel Durmaz, Li Wei Bao, Gopinath Tiruchinapally, Rabia A Gilani, Mohamed E H Elsayed
    Abstract:

    Abstract Overexpression of RhoC protein in breast cancer patients has been linked to increased cancer cell invasion, migration, and metastases. Suppressing RhoC expression in aggressive breast cancer cells using silencing RNA (siRNA) molecules is a viable strategy to inhibit the metastatic spread of breast cancer. In this report, we describe the synthesis of a series of asymmetric pH-sensitive, membrane-destabilizing polymers engineered to complex anti-RhoC siRNA molecules forming “smart” nanoparticles. Using β-CD as the particle core, polyethylene glycol (PEG) chains were conjugated to the primary face via non-cleavable bonds and amphiphilic polymers incorporating hydrophobic and cationic monomers were grafted to the secondary face via acid-labile linkages. We investigated the effect of PEG molecular weight (2 & 5 kDa) on transfection capacity and serum stability of the formed particles. We evaluated the efficacy of EPPT1 peptides presented on the free tips of the PEG brush to function as a targeting ligand against underglycosylated MUC1 (uMUC1) receptors overexpressed on the surface of metastatic breast cancer cells. Results show that “smart” nanoparticles successfully delivered anti-RhoC siRNA into the cytoplasm of aggressive SUM149 and MDA-MB-231 breast cancer cells, which resulted in a dose-dependent inhibition of cell migration and invasion. Further, EPPT1-targeted nanoparticles demonstrate a synergistic inhibition of cell migration and invasion imparted via RhoC knockdown and EPPT1-mediated signaling via the uMUC1 receptor.

  • abstract 5156 RhoC decreases tight junction stabilization in breast cancer cells revealing a potential therapeutic target
    Cancer Research, 2018
    Co-Authors: Hannah Cheriyan, Joel A Yates, Sofia D Merajver
    Abstract:

    RhoC, a member of the Rho GTPase family, has been shown to have a role specifically in facilitating metastasis of breast cancer cells1, however no conclusive mechanism for how RhoC promotes metastasis currently exists. We demonstrate that CRISPR-Cas9 knockout of RhoC in SUM149 and MDA-MB231 cells results in increased epithelial morphology, cell-cell connections, and tight junction marker (ZO-1, occludin, PATJ/PALS1/CRB3) colocalization compared to wild type cells, as studied via immunofluorescent staining. These results suggest that high expression of RhoC in cancer cells destabilizes tight junctions, which could allow for the increased metastatic potential observed with RhoC-overexpressing cells in prior studies2-4. Ongoing work investigates whether these morphological and molecular changes are observed in other breast cancer cell lines, such as SUM190 and VARI-068, a low-passage PDX-derived triple negative breast cancer cell line. Furthermore, we will determine whether RhoC knockout in these cells lines actively modulates tight junction stability as measured via transepithelial electrical resistance (TEER). Taken together, these data support an important role for RhoC in tight junction modulation, thereby revealing a potential highly specific new therapeutic target in RhoC-driven metastases control. References 1. Hakem, A. et al. RhoC is dispensable for embryogenesis and tumor initiation but essential for metastasis. Genes Dev. 19, 1974-1979 (2005). 2. van Golen, K. L., Wu, Z. F., Qiao, X. T., Bao, L. W. & Merajver, S. D. RhoC GTPase, a novel transforming oncogene for human mammary epithelial cells that partially recapitulates the inflammatory breast cancer phenotype. Cancer Res. 60, 5832-8 (2000). 3. van Golen, K. L., Wu, Z. F., Qiao, X. T., Bao, L. & Merajver, S. D. RhoC GTPase overexpression modulates induction of angiogenic factors in breast cells. Neoplasia 2, 418-25 (2000). 4. Wu, M., Wu, Z. F., Rosenthal, D. T., Rhee, E. M. & Merajver, S. D. Characterization of the roles of RhoC and RHOA GTPases in invasion, motility, and matrix adhesion in inflammatory and aggressive breast cancers. Cancer 116, 2768-2782 (2010). Citation Format: Hannah Cheriyan, Zhi-Fen Wu, Joel Yates, Sofia D. Merajver. RhoC decreases tight junction stabilization in breast cancer cells, revealing a potential therapeutic target [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5156.

  • abstract 3236 macrophages increase the expression of RhoC in inflammatory breast cancer leading to increased migration
    Cancer Research, 2016
    Co-Authors: Julie Madden, Li Wei Bao, Chelsea Fournier, Steve Allen, Yuchi Shen, Sofia D Merajver
    Abstract:

    Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA Inflammatory breast cancer (IBC) is considered the most lethal form of breast cancer due to its ability to progress quickly and the frequent presence of metastasis at diagnosis. African Americas are disproportionally diagnosed with IBC and often have worse outcomes than Caucasians. By investigating IBC in both African American and Caucasian cell lines we seek to understand the differences in IBC progression and help address disparities by providing new anti-IBC strategies. RhoC GTPase is overexpressed in 90% of IBC tumors and is known to increase cell motility. Sites of inflammation, as seen in IBC, attract tumor associated macrophages (TAMs), which have been found to facilitate the movement and invasion of many breast cancers. We hypothesize that TAMs play a role in increasing RhoC expression in IBC cell lines, consequently leading to IBC's severe migratory and metastatic potential. A novel microfluidic device created by our team was used to measure the migratory phenotype of IBC cell lines in response to macrophage conditioned media (CM) and cytokine stimulation. IBC cell lines were treated with CM, cytokines, or pathway inhibitors then Western blotting was used to determine protein expression and phosphorylation to identify important signaling pathways. We found the expression of RhoC significantly increased in two different IBC cell lines, SUM149 (African American) and SUM190 (Caucasian), after culturing with conditioned media from the macrophage-differentiated U937 monocytic cell line. This increase was not detected in either the normal-like MCF-10A breast epithelial cell line or the non-IBC MDA-MB-231 triple negative breast cancer cell line. CM caused a significant increase in the migration distance and frequency of both SUM149 and SUM190 cell lines. Analysis of the CM determined CCL2, CCL5, and IL-8 to be the key mediators in the macrophage CM. Western blotting proposes that CCL2, CCL5, and IL-8 stimulation causes twice as much RhoC expression compared to the control. Further analysis suggests a role for the MAPK pathway in controlling RhoC expression and migration. Macrophage conditioned media causes an increase in RhoC expression in IBC cell lines and stimulates migration. Individual cytokines can lead to an increase in RhoC possibly through the MAPK pathway. Studies involving RhoC inhibitors are ongoing and could yield promising therapies for the prevention of metastasis in IBC. By understanding the specific mechanism of TAMs’ effects on IBC, we hope to learn how to control the lethal metastatic nature of IBC and improve outcomes for patients of all ethnicities. Citation Format: Julie Madden, Steve Allen, Yu-Chi Shen, Chelsea Fournier, ZhiFen Wu, Liwei Bao, Sofia Merajver. Macrophages increase the expression of RhoC in inflammatory breast cancer leading to increased migration. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3236.

  • abstract 1203 metastasis associated oncogene RhoC as a regulator of glutamine metabolism in the inflammatory breast cancer cell line sum149
    Cancer Research, 2015
    Co-Authors: Joel A Yates, Michelle L Wynn, Zhifen Wu, Charles R Evans, Charles F Burant, Santiago Schnell, Sofia D Merajver
    Abstract:

    Metabolic reprogramming is increasingly recognized as a fundamental hallmark of cancer. While the Warburg effect and normal proliferative metabolism are similar, they are not equivalent. We hypothesize that there are key drivers of malignant metabolism that can be modulated to impede cancer proliferation without substantial effects on normal tissue growth. Using 13C-labeled glucose and glutamine tracers in combination with mass spectrometry and measurements of extracellular glucose, lactate, and glutamine flux, we have characterized system level differences in a series of breast cancer cell lines as well as normal-like breast epithelial cells. We observed an increase in the reductive carboxylation of glutamine-derived citrate and alpha-ketoglutarate in the triple-negative inflammatory breast cancer cell line SUM149. We also observed that the SUM149 exhibit high levels of HIF-1α and low levels of oxygen consumption under normoxia, suggesting that the cell line is highly adapted to hypoxia. Surprisingly, the stable depletion of HIF-1α via shRNA had no significant effect on the metabolic profile of these cells. Previous work by our lab and others has demonstrated that the GTPase RhoC is a driver of the metastatic phenotype exhibited by inflammatory breast cancer. Activation of RhoC is known to induce cytoskeletal rearrangements and increase invasive potential. The Rho GTPase family of proteins has also recently been linked to metabolism, specifically regulation of glutaminase activity. Here we show that stable knockdown of RhoC in SUM149 cells results in a marked decrease in the rate of both glutamine uptake and intracellular reductive carboxylation. This work reinforces the role of RhoC as an important driver of inflammatory breast cancer metastatic potential. We conclude that RhoC remains an important clinical target with the potential to alter patient outcomes. Citation Format: Joel A. Yates, Michelle L. Wynn, ZhiFen Wu, Charles R. Evans, Charles Burant, Santiago D. Schnell, Sofia D. Merajver. Metastasis-associated oncogene RhoC as a regulator of glutamine metabolism in the inflammatory breast cancer cell line SUM149. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1203. doi:10.1158/1538-7445.AM2015-1203

  • smart nanoparticles enhance the cytoplasmic delivery of anti RhoC silencing rna and inhibit the migration and invasion of aggressive breast cancer cells
    Molecular Pharmaceutics, 2015
    Co-Authors: Neha Kaushal, Sofia D Merajver, Yasemin Yuksel Durmaz, Lewei Bao, Mohamed E H Elsayed
    Abstract:

    Rho-GTPases are small GTP-binding proteins that contribute to the epithelial-to-mesenchymal transition by regulating several cellular processes including organization of the actin cytoskeleton, cell motility, transcription, and cell proliferation. Overexpression of RhoC-GTPases (RhoC) in breast cancer has been implicated in poor disease prognosis due to increased cancer cells invasion, migration, and motility, which warranted its consideration as a therapeutic target for inhibiting breast cancer metastasis. Using silencing RNA (siRNA) molecules to knockdown RhoC expression is a promising approach to inhibit breast cancer metastases. However, transforming anti-RhoC siRNA molecules into a viable therapy remains a challenge due to the lack of a biocompatible carrier that can selectively deliver the RNA cargo into breast cancer cells. We report the use of a degradable, pH-sensitive, β-cyclodextrin (βCD)-based polymeric carrier that condenses anti-RhoC siRNA forming "smart" particles. These smart anti-RhoC particles were efficiently internalized, successfully escaped the endosome, and delivered the RNA cargo into the cytoplasm of SUM149 and MDA-MB-231 breast cancer cells. Our results show that anti-RhoC particles used at a low N/P ratio of 2.5/1 suppressed RhoC protein levels by 100% and 90% in SUM149 and MDA-MB-231 cells, respectively. Further, anti-RhoC particles inhibited the invasion, motility, and migration of SUM149 and MDA-MB-231 cells by 40-47%, 57-60%, and 61.5-73%, respectively. Smart particles encapsulating the scrambled siRNA sequence did not affect RhoC protein expression or the invasion, motility, and migration of SUM149 and MDA-MB-231 cells, which indicate the biocompatibility of the polymeric carrier and selectivity of the observed RhoC knockdown. These results collectively indicate the therapeutic potential of smart anti-RhoC particles in arresting the metastatic spread of breast cancer cells.

Kenneth L Van Golen - One of the best experts on this subject based on the ideXlab platform.

  • caveolin 1 mediates inflammatory breast cancer cell invasion via the akt1 pathway and RhoC gtpase
    Journal of Cellular Biochemistry, 2017
    Co-Authors: Madhura Joglekar, Weam O Elbazanti, Matthew Weitzman, Heather L Lehman, Kenneth L Van Golen
    Abstract:

    With a propensity to invade the dermal lymphatic vessels of the skin overlying the breast and readily metastasize, inflammatory breast cancer (IBC) is arguably the deadliest form of breast cancer. We previously reported that caveolin-1 is overexpressed in IBC and that RhoC GTPase is a metastatic switch responsible for the invasive phenotype. RhoC-driven invasion requires phosphorylation by Akt1. Using a reliable IBC cell line we set out to determine if caveolin-1 expression affects RhoC-mediated IBC invasion. Caveolin-1 was down regulated by introduction of siRNA or a caveolin scaffolding domain. The ability of the cells to invade was tested and the status of Akt1 and RhoC GTPase examined. IBC cell invasion is significantly decreased when caveolin-1 is down regulated. Activation of Akt1 is decreased when caveolin-1 is down regulated, leading to decreased phosphorylation of RhoC GTPase. Thus, we report here that caveolin-1 overexpression mediates IBC cell invasion through activation Akt1, which phosphorylates RhoC GTPase.

  • utility of RhoC and zag protein expression as biomarkers for prediction of psa failure following radical prostatectomy for high grade prostate cancer
    Pathology, 2012
    Co-Authors: John Mills, Alice Oliver, Justin C Sherwin, Mark Frydenberg, J Peters, Anthony J Costello, Laurence Harewood, Christopher G Love, Nicholas Redgrave, Kenneth L Van Golen
    Abstract:

    Summary Aims To assess the prognostic utility of semi-quantiative expression of RhoC protein in whole prostates from patients who had radical prostatectomies for high grade prostate cancer (PCa). Methods Subjects who had surgery >55 months previously with primary Gleason pattern 4 PCa were identified from practice records, archival tissues were retrieved for review and RhoC immunohistochemistry, and ZAG expression was also assessed as a control. Results Eighty-nine subjects were included in the study; 57 had a rising prostate specific antigen (PSA) post-operatively (‘cases’) and 32 did not (‘controls’). By univariate analysis, expression of both RhoC and ZAG proteins was greater in controls than cases, but this was significant only for ZAG. By multivariate analysis, Gleason variables (patterns and score), extraprostatic extension and decreased RhoC staining all contributed to predicting PSA failure ( p Conclusions Increased RhoC expression predicted a good outcome after radical prostatectomy. ZAG staining also correlated with a favourable outcome but was not independently predictive due to its relationship with Gleason pattern.

  • farnesyl transferase inhibitor treatment of breast cancer cells leads to altered rhoa and RhoC gtpase activity and induces a dormant phenotype
    International Journal of Cancer, 2011
    Co-Authors: Moumita Chatterjee, Kenneth L Van Golen
    Abstract:

    Farnesyl transferase inhibitors (FTIs) were shown to be effective in modulating tumor growth in Ras-transformed tumor cells. Recent studies have focused on Rho GTPases as putative targets of FTI action. Previously, we demonstrated that FTIs were effective in inhibiting the growth and invasiveness of RhoC GTPase-overexpressing inflammatory breast cancer (IBC) cells however, RhoC activity was increased. In this study, we examine the mechanisms of FTI action on breast cancer cells in culture through modulation of RhoC and RhoA GTPases. We found that FTI inhibition of breast cancer cell growth was reversible and resembled what has been described for an in vitro model of tumor cell dormancy. On FTI treatment, levels of active RhoA decreased significantly, whereas levels of active RhoC increased 3.8-fold. We studied the role of these two GTPases in a fibronectin and basic FGF-induced model of breast cancer cell dormancy. Hypoactivation of RhoA and hyperactivation of RhoC were seen to induce morphology and growth changes consistent with tumor cell dormancy in culture. In addition, the JNK/SAPK pathway was induced on FTI treatment. A pharmacologic inhibitor of the JNK/SAPK pathway significantly reduced the number of dormant cells. This study has implications for the use of FTIs as therapeutic agents as well as potential mechanisms for breast cancer cell dormancy.

  • type i collagen receptor α2β1 signaling promotes prostate cancer invasion through RhoC gtpase
    Neoplasia, 2008
    Co-Authors: Christopher L Hall, Cara W Dubyk, Tracy A Riesenberger, Evan T Keller, Daniel Shein, Kenneth L Van Golen
    Abstract:

    The most frequent site of metastasis in human prostate cancer (PCa) is the bone. Preferential adhesion of PCa cells to bone-specific factors may facilitate the selective metastasis of the skeleton. The most abundant protein within the skeleton is type I collagen. We previously demonstrated that PCa cells selected in vitro for collagen I binding (LNCaPcol) are highly motile and acquired the capacity to grow within the bone compared to nontumorigenic LNCaP parental cells. Treatment with α2β1-neutralizing antibodies selectively blocked collagen-stimulated migration, suggesting that integrin signaling mediates PCa migration. To elucidate the mechanism of collagen-stimulated migration, we evaluated integrin-associated signaling pathways in non-collagen-binding LNCaP parental cells and in collagen-binding isogenic C4-2B and LNCaPcol PCa cells. The expression and activity of RhoC guanosine triphosphatase was increased five- to eightfold in collagen-binding LNCaPcol and C4-2B cells, respectively, compared to parental LNCaP cells. RhoC activation was selectively blocked with antibodies to α2β1 where treatment with a small hairpin RNA specific for RhoC suppressed collagen-mediated invasion without altering the PCa cells' affinity for collagen I. We conclude that the ligation of α2β1 by collagen I activates RhoC guanosine triphosphatase, which mediates PCa invasion, and suggests a mechanism for the preferential metastasis of PCa cells within the bone.

  • RhoC gtpase is a novel tissue biomarker associated with biologically aggressive carcinomas of the breast
    Breast Cancer Research and Treatment, 2005
    Co-Authors: Celina G Kleer, Kent A Griffith, Michael S Sabel, Gary Gallagher, Kenneth L Van Golen, Sofia D Merajver
    Abstract:

    Summary Background. There is a need for reliable predictors of breast cancer aggressiveness that will further refine the staging classification and help guide the implementation of novel therapies. We have identified RhoC as being nearly always overexpressed in the most aggressive form of breast cancer, inflammatory breast cancer (IBC); in subsequent work we identified RhoC to be a promising marker of aggressive behavior in breast cancers less than 1 cm in diameter. We hypothesized that RhoC expression would identify aggressive, non-IBC tumors breast cancer patients at any stage with worse outcomes defined as recurrence and/or metastasis. Methods. We constructed four high-density tissue microarrays (TMAs) using 801 tissue cores from 280 patients. These tissues represent a wide range of normal breast and breast disease, including intraductal hyperplasia, ductal carcinoma in situ (DCIS), invasive carcinomas, and distant metastases. The TMAs were immunostained using a polyclonal anti-RhoC antibody developed in our laboratory. Cytoplasmic RhoC expression was scored as negative, weak, moderate, or strong by a previously validated scoring schema. Results. RhoC expression increases with breast cancer progression. All samples of normal breast epithelium had negative to weak staining, whereas staining intensity increased in hyperplasia, DCIS, invasive carcinoma, and metastases (Kruskal–Wallis p < 0.001). In patients with invasive carcinoma, high RhoC expression was associated with features of aggressive behavior including high histologic grade, positive lymph nodes, and negative hormonal receptor status. High RhoC expression was a predictor of overall survival in patients with breast cancer (log rank test, p= 0.002) and was associated with 100% increase in the risk of death as compared to patients with low RhoC expression. Importantly, high RhoC was an independent predictor of poor response to doxorubicin-based chemotherapy with a hazard ratio of 3.1 and a 95% CI of 1.2–7.7 ( p= 0.02). Conclusion. RhoC expression increases with breast cancer progression and RhoC protein level in tumor tissue is strongly associated with biologically aggressive invasive carcinomas of the breast. RhoC expression, if validated, may identify patients who are less likely benefit from doxorubicin therapy and suggests RhoC overexpression as a new target for intervention.

Yang Zhao - One of the best experts on this subject based on the ideXlab platform.

  • the role of RhoC in malignant tumor invasion metastasis and targeted therapy
    Histology and Histopathology, 2018
    Co-Authors: Xue Guan, Shuo Chen, Yang Zhao
    Abstract:

    As an important member of the RhoGTPase family, RhoC has various biological functions, such as regulating cytoskeleton reorganization, influencing cell adhesion, and migration. During recent decades, RhoC has been proven to be involved in the invasion and metastasis of malignant tumor and is thus a promising target of tumor therapy. This review focuses on the molecular mechanism of RhoC in invasion and metastasis of malignant tumors, as well as its research prospects as a potential target for tumor therapy.

  • effects and mechanism of RhoC downregulation in suppressing ovarian cancer stem cell proliferation drug resistance invasion and metastasis
    Oncology Reports, 2016
    Co-Authors: Xiubo Sang, Shuo Chen, Zhihong Zong, Kaixuan Sun, Lili Wang, Yang Zhao
    Abstract:

    Cancer stem cells are considered to be the root cause of tumor initiation, metastasis, recurrence and therapeutic resistance. Recent studies have reported that RhoC plays a critical role in regulating cancer stem cells; however, its function in ovarian cancer stem cells (OCSCs) remains unknown. The ovarian cancer cell line A2780, and the paclitaxel-resistant A2780 cell line (A2780-PTX) were obtained. A2780 cells were used to isolate and identify the highly invasive A2780-PM cells, and A2780-PTX cells were used to isolate and identify the highly drug-resistant and highly invasive A2780-PTX-PM cells by Transwell assay. MTT, Transwell and wound healing assays were used to compare the differences in cell proliferation, invasion and migration ability among the four cell lines. Immunofluorescence was used to detect the expression of stem cell markers CD117 and CD133. OCSCs were sorted by flow cytometry. Following si-RhoC transfection of the OCSCs, cell proliferation, drug resistance, invasion and migration ability and RhoC, CD117 and CD133 expression levels were assayed. RT-PCR was used to assess RhoC, CD117, CD133 and matrix metalloproteinase 9 (MMP9) mRNA expression levels. A2780-PM and A2780‑PTX-PM cells exhibited higher cell proliferation, drug resistance, and invasion and migration ability than the A2780 and A2780-PTX cell lines. Furthermore, CD133 and CD117 expression levels were higher in the A2780-PM and A2780‑PTX-PM cells than levels in the A2780 and A2780-PTX cells. Transfection of si-RhoC in OCSCs suppressed the proliferation, drug resistance, invasion, migration and CD117 and CD133 expression levels. Furthermore, the expression levels of RhoC, CD117, CD133, MDR1, and MMP9 mRNA were downregulated in the transfected population. Taken together, our results demonstrated that RhoC downregulation may inhibit the proliferation, drug resistance, invasion and migration of OCSCs, and RhoC may play an important role in the formation of OCSCs.

  • RhoC is a major target of microrna 93 5p in epithelial ovarian carcinoma tumorigenesis and progression
    Molecular Cancer, 2015
    Co-Authors: Xi Chen, Yinling Xiu, Shuo Chen, Zhihong Zong, Kaixuan Sun, Yang Zhao
    Abstract:

    An increasing amount of evidence has revealed that microRNAs regulate various biological processes, including cell differentiation, cell proliferation, apoptosis, drug resistance, and fat metabolism. Studies have shown that miR-93’s targetome in cancer has not been fully defined. Moreover, the role of miR-93 in epithelial ovarian carcinoma (EOC) remains largely unknown. MIR-93 mRNA expression in normal ovarian tissue, benign tumors, borderline tumors, primary ovarian carcinomas, and metastatic omentum was quantified. The ovarian carcinoma cell lines OVCAR3, SKOV3/DDP, and HO8910-PM were transfected with miR-93-5P, after which cell phenotype and expression of relevant molecules were assayed. Dual-luciferase reporter assay and a xenograft mouse model were used to examine miR-93 and its target gene RhoC (Ras homolog gene family member C). MIR-93 mRNA expression was significantly lower in ovarian carcinomas and borderline tumors than in normal ovarian tissues (p < 0.05), and was lower in metastatic omentum than in relative primary ovarian carcinomas (p < 0.05). MIR-93 mRNA expression was also negatively associated with differentiation (well vs. poor and moderate) and International Federation of Gynecology and Obstetrics staging (FIGO stage I/II vs. stage III/IV) in ovarian carcinoma (p < 0.05), besides, miR-93 was higher expressed in mucinous adenocarcinoma than the other types (p < 0.05). MiR-93-5P overexpression reduced proliferation (p < 0.05); promoted G1 or S arrest and apoptosis (p < 0.05); suppressed migration and invasion (p < 0.05); and reduced RhoC, P70S6 kinase, Bcl-xL, matrix metalloproteinase 9 (MMP9) mRNA or protein expression; conversely, it induced P53 and cleaved PARP expression (p < 0.05). Dual-luciferase reporter assay indicated that miR-93 directly targeted RhoC by binding its 3′ untranslated region. MiR-93-5P transfection also suppressed tumor development and RhoC expression (determined by immunohistochemistry) in vivo in the xenograft mouse model (p < 0.05). This is the first demonstration that miR-93-5P may inhibit EOC tumorigenesis and progression by targeting RhoC. These findings indicate that miR-93-5P is a potential suppressor of ovarian cellular proliferation. The involvement of miR-93-5P–mediated RhoC downregulation in inhibiting EOC aggressiveness may provide extended insight into the molecular mechanisms underlying cancer aggressiveness.

  • the role of RhoC in epithelial to mesenchymal transition of ovarian carcinoma cells
    BMC Cancer, 2014
    Co-Authors: Wenfeng Gou, Yang Zhao, Xuefeng Yang, Yinling Xiu, Shuang Zhao, Jianmin Liu, Zhitu Zhu, Hongzhi Sun, Yunpeng Liu, Yasuo Takano
    Abstract:

    RhoC is a small G protein/GTPase and involved in tumor mobility, invasion and metastasis. Previously, up-regulated RhoC expression is found to play an important role in ovarian carcinogenesis and subsequent progression by modulating proliferation, apoptosis, migration and invasion. We transfected RhoC-expressing plasmid and RhoC siRNA into CAOV3 and OVCAR3 cells respectively. These cells and transfectants were exposed to vascular epithelial growth factor (VEGF), transforming growth factor (TGF)-β1 or their receptor inhibitors with the phenotypes and their related-molecules examined. TGF-β1R or VEGFR inhibitor suppressed the proliferation, migration, invasion and lamellipodia formation, the expression of N-cadherin, α-SMA, snail and Notch1 mRNA or protein, and enhanced E-cadherin mRNA and protein expression in CAOV3 and its RhoC-overexpressing transfectants, whereas both growth factors had the opposite effects in OVCAR3 cells and their RhoC-hypoexpressing transfectants. Ectopic RhoC expression enhanced migration, invasion, lamellipodia formation and the alteration in epithelial to mesenchymal transition (EMT) markers of CAOV3 cells regardless of the treatment of VEGFR or TGF-β1R inhibitor, whereas RhoC knockdown resulted in the converse in OVCAR3 cells even with the exposure to VEGF or TGF-β1. RhoC expression might be involved in EMT of ovarian epithelial carcinoma cells, stimulated by TGF-β1 and VEGF.

  • the role of RhoC in ovarian epithelial carcinoma a marker for carcinogenesis progression prognosis and target therapy
    Gynecologic Oncology, 2013
    Co-Authors: Yang Zhao, Wenfeng Gou, Huachuan Zheng, Shuo Chen, Lijun Xiao, Zhefeng Niu
    Abstract:

    Abstract Background Ras homolog gene family member C (RhoC) is a small G protein/guanosine triphosphatase involved in tumor mobility, invasion, and metastasis. Methods After RhoC siRNA transfection, we measured the changes in phenotypes and some relevant molecules in ovarian carcinoma cell, OVCAR3. The mRNA and protein expression of RhoC was detected in ovarian tumors. Results RhoC siRNA transfection resulted in low growth, G 1 arrest, and apoptotic induction in the OVCAR3 in comparison with the control and mock. Following RhoC knockdown, there was reduced mRNA or protein expression of protein kinase B (Akt), signal transducer and activator of transcription 3 (stat3), bcl-xL, surviving and phosphorylated p70S6 kinase (p-p70s6k), while the converse was true for Bax and caspase-3. Lovastatin induced apoptosis, suppressed proliferation, migration and invasion, and disrupted lamellipodia formation in OVCAR3. Lovastatin exposure induced lower RhoC, bcl-2, matrix metalloproteinase-9 (MMP-9), survivin, Akt, bcl-xL, vascular endothelial growth factor (VEGF), and p-p70s6k expression in OVCAR3 compared to the control, but higher caspase-3 and Bax expression. RhoC mRNA and protein expression was significantly higher in ovarian carcinoma than in benign tumors and normal ovary tissue (p Conclusions The up-regulated RhoC expression may affect ovarian carcinogenesis and should be considered a good biomarker for the differentiation and progression of ovarian carcinoma. RhoC plays an important role in apoptosis by modulating the relevant genes and the phosphorylation of downstream p70s6k.

Theodoros N Teknos - One of the best experts on this subject based on the ideXlab platform.

  • down regulation of RhoC by microrna 138 results in de activation of fak src and erk1 2 signaling pathway in head and neck squamous cell carcinoma
    Oral Oncology, 2014
    Co-Authors: Mozaffarul Islam, Jharna Datta, James C Lang, Theodoros N Teknos
    Abstract:

    Summary Objective RhoC a pro-metastatic oncogene is constitutively active in many head and neck squamous cell carcinomas. MicroRNA-138 which possesses a documented tumor suppressor function can bind to the 3′UTR of RhoC mRNA and inhibit its activity. We hypothesize that miR-138 can inhibit the function of RhoC and consequently the activation of downstream target molecules involve in the signaling cascade. For this reason we investigated the role of miR-138 in HNSCC. Methods In vitro studies were carried out to evaluate the role of miR-138 in HNSCC cell lines and in primary tumors obtained from HNSCC patients. Real time RT-PCR, Western blot, cell motility, invasion and colony formation assays were performed according to standard procedures. Results Data obtained by G-LISA and real time PCR shows an inverse correlation between RhoC expression and miR-138 in HNSCC cell lines. Additionally, we obtained a similar pattern of RhoC and miR-138 expression in primary tumors from HNSCC patients. Over expression of miR-138 in HNSCC lines showed down regulation of RhoC, as well as a decrease in cell motility, invasion colony and stress fiber formation. Furthermore, a significant down regulation was observed for FAK, Src and Erk1/2 upon miR-138 overexpression. Conclusion These findings strongly suggest that the inhibition of RhoC can be achieved by over expressing miR-138, which further attenuates the downstream signaling cascade leading to cancer progression and survival. Moreover, this study for the first time shows that down regulation of FAK, Src and Erk1/2 by miR-138 overexpression is due to inhibition of RhoC in HNSCC.

  • RhoC regulates cancer stem cells in head and neck squamous cell carcinoma by overexpressing il 6 and phosphorylation of stat3
    PLOS ONE, 2014
    Co-Authors: Mozaffarul Islam, Smita Sharma, Theodoros N Teknos
    Abstract:

    In this study we investigated the correlation between RhoC expression and cancer stem cells (CSCs) formation in head and neck squamous cell carcinoma (HNSCC). The inhibition of RhoC function was achieved using shRNA. The expression of stem cell surface markers, ALDH and CD44 were significantly low in two RhoC depleted HNSCC cell carcinoma cell lines. Furthermore, a striking reduction in tumorsphere formation was achieved in RhoC knockdown lines. The mRNA expression of RhoC in RhoC knockdown adherent and tumorspheres are dramatically down regulated as compared with the scrambled control. The mRNA expression of stem cell transcription factors; nanog, oct3/4 (Pouf1), and sox2 were significantly depleted in RhoC knockdown clones. Further, the phosphorylation of STAT3ser727, and STAT3tyr705 were significantly down regulated in RhoC knockdown clones. The overexpression of STAT3 in RhoC knockdown did not show any change in expression patterns of either-STAT3tyr705 or stem cell transcription factors, signifying the role of RhoC in STAT3 activation and thus the expression of nanog, oct3/4 and sox2 in HNSCC. The expression of Inter leukin-6 (IL-6) in RhoC knockdown HNSCC cell lines was dramatically low as compared to the scrambled control. Further, we have shown a rescue in STAT3 phosphorylation by IL-6 stimulation in RhoC knockdown lines. This study is the first of its kind to establish the involvement of RhoC in STAT3 phosphorylation and hence in promoting the activation of core cancer stem cells (CSCs) transcription factors. These findings suggest that RhoC may be a novel target for HNSCC therapy.

  • atorvastatin inhibits RhoC function and limits head and neck cancer metastasis
    Oral Oncology, 2013
    Co-Authors: Mozaffarul Islam, Smita Sharma, Bhavna Kumar, Theodoros N Teknos
    Abstract:

    Summary Objective RhoC oncogene is a well characterized marker of metastasis in a majority of invasive cancers, including HNSCC. Elevated RhoC expression has been found to be associated with distant metastasis. Statins are a class of drugs that are used to reduce cholesterol levels by inhibiting HMG-CoA reductase activity which in turns prevents mevalonate synthesis, which is a precursor for synthesis of cholesterol and prenylation. Interestingly, the proper function of Rho proteins depends on prenylation. Significantly, it has been reported that metastasis in human melanoma can be reduced by atorvastatin which inhibits RhoC activity by preventing its geranylgeranylation. Given that RhoC is a key oncogene involved in metastasis, we hypothesized Atorvastatin can reduce head and neck metastasis by inhibiting RhoC activity. Methods In vitro and in vivo studies were carried out to evaluate the ability of Atorvastatin to inhibit RhoC function and HNSCC metastasis. Cell motility, proliferation, cell invasion, and colony formation assays were performed according to the standard protocols. Results Atorvastatin treatment significantly reduced the active form of RhoC in vitro and diminished cell motility, invasion, proliferation and colony formation. Importantly, we observed a significant decrease in p-ERK1/2 and p-STAT3 in Atorvastatin treated cell lines. In vivo experiments revealed inhibition of angiogenesis and lung metastases with Atorvastatin therapy. Conclusions This study is the first of its kind to establish a potential role of Atorvastatin in head and neck cancer therapy. These findings suggest that Atorvastatin can be a potential low risk adjuvant therapy to minimize metastases in aggressive forms of HNSCC.

  • RhoC expression and head and neck cancer metastasis
    Molecular Cancer Research, 2009
    Co-Authors: Mozaffarul Islam, Sofia D Merajver, Giant C Lin, John C Brenner, Quintin Pan, Yanjun Hou, Pawan Kumar, Theodoros N Teknos
    Abstract:

    RhoC protein, a known marker of metastases in aggressive breast cancers and melanoma, has also been found to be overexpressed in certain head and neck cancers, thus we investigated the correlation between RhoC expression and the metastatic behavior of head and neck squamous cell carcinoma. Selective inhibition of RhoC expression was achieved using lentiviral small hairpin RNA (shRNA) transduced and tracked with green fluorescent protein to achieve 70% to 80% RhoC inhibition. Fluorescence microscopy of the RhoC knockdown stable clones showed strong green fluorescence in the majority of cells, signifying a high efficiency of transduction. Importantly, quantitative real-time PCR showed no significant decrease in the mRNA expression levels of other members of the Ras superfamily. Cell motility and invasion were markedly diminished in RhoC-depleted cell lines as compared with control transduced lines. H&E staining of lung tissue obtained from severe combined immunodeficiency mice, which had been implanted with RhoC knockdown cells, showed a marked decrease in lung metastasis and inflammation of the blood vessels. The cultured lung tissue showed a significant decrease in cell growth in mice implanted with RhoC-depleted cell lines as compared with shRNA-scrambled sequence control lines. Microscopic studies of CD31 expression revealed substantial quantitative and qualitative differences in the primary tumor microvessel density as compared with parental and shRNA-scrambled controls. This study is the first of its kind to establish the involvement of RhoC specifically in head and neck metastasis. These findings suggest that RhoC warrants further investigation to delineate its robustness as a novel potentially therapeutic target.

  • RhoC gtpase expression as a potential marker of lymph node metastasis in squamous cell carcinomas of the head and neck
    Clinical Cancer Research, 2006
    Co-Authors: Celina G Kleer, Theodoros N Teknos, Mozaffarul Islam, Benjamin Marcus, Sofia D Merajver
    Abstract:

    Purpose: Survival rates for squamous cell carcinoma of the head and neck (SCCHN) have remained unchanged for several decades due to local tumor recurrences as well as regional and distant metastases. Recent evidence has shown that RhoC GTPase is overexpressed in stages III and IV regionally metastatic SCCHN compared with stages I and II localized disease. This study evaluated the expression of RhoC in head and neck carcinoma and investigated the prognostic use of this marker on a large cohort of previously untreated patients with SCCHN. Experimental Design: Standard Western blot techniques were used to evaluate RhoC protein expression in nine established head and neck cancer cell lines and in normal oral epithelium. In vivo expression of RhoC in metastatic and nonmetastatic SCCHN was investigated using immunohistochemical analysis on a tissue microarray composed of 113 independent tumor samples. RhoC expression was analyzed as it related to clinical and pathologic variables of interest. Results: Levels of RhoC protein were increased in the SCCHN cell lines compared with normal oral epithelium. The in vivo expression of RhoC correlated with advanced clinical stage and lymph node metastases for the entire patient cohort as well as in small primary tumors (T 1 and T 2 ). Conclusions: This study is the first to examine the expression of RhoC GTPase protein in SCCHN and normal squamous epithelium. It is clear from the results that RhoC is a specific marker of lymph node metastases in patients with this challenging form of carcinoma. RhoC levels seem to identify a subset of patients with early tumor stage primary tumors and high metastatic potential that might benefit from more aggressive therapy. Through continued investigation, blockade of RhoC activity may be a potential target in the development of novel strategies for treating metastases of head and neck cancer.

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  • synergistic inhibition of aggressive breast cancer cell migration and invasion by cytoplasmic delivery of anti RhoC silencing rna and presentation of eppt1 peptide on smart particles
    Journal of Controlled Release, 2018
    Co-Authors: Neha Kaushal, Sofia D Merajver, Yasemin Yuksel Durmaz, Li Wei Bao, Gopinath Tiruchinapally, Rabia A Gilani, Mohamed E H Elsayed
    Abstract:

    Abstract Overexpression of RhoC protein in breast cancer patients has been linked to increased cancer cell invasion, migration, and metastases. Suppressing RhoC expression in aggressive breast cancer cells using silencing RNA (siRNA) molecules is a viable strategy to inhibit the metastatic spread of breast cancer. In this report, we describe the synthesis of a series of asymmetric pH-sensitive, membrane-destabilizing polymers engineered to complex anti-RhoC siRNA molecules forming “smart” nanoparticles. Using β-CD as the particle core, polyethylene glycol (PEG) chains were conjugated to the primary face via non-cleavable bonds and amphiphilic polymers incorporating hydrophobic and cationic monomers were grafted to the secondary face via acid-labile linkages. We investigated the effect of PEG molecular weight (2 & 5 kDa) on transfection capacity and serum stability of the formed particles. We evaluated the efficacy of EPPT1 peptides presented on the free tips of the PEG brush to function as a targeting ligand against underglycosylated MUC1 (uMUC1) receptors overexpressed on the surface of metastatic breast cancer cells. Results show that “smart” nanoparticles successfully delivered anti-RhoC siRNA into the cytoplasm of aggressive SUM149 and MDA-MB-231 breast cancer cells, which resulted in a dose-dependent inhibition of cell migration and invasion. Further, EPPT1-targeted nanoparticles demonstrate a synergistic inhibition of cell migration and invasion imparted via RhoC knockdown and EPPT1-mediated signaling via the uMUC1 receptor.

  • abstract 3236 macrophages increase the expression of RhoC in inflammatory breast cancer leading to increased migration
    Cancer Research, 2016
    Co-Authors: Julie Madden, Li Wei Bao, Chelsea Fournier, Steve Allen, Yuchi Shen, Sofia D Merajver
    Abstract:

    Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA Inflammatory breast cancer (IBC) is considered the most lethal form of breast cancer due to its ability to progress quickly and the frequent presence of metastasis at diagnosis. African Americas are disproportionally diagnosed with IBC and often have worse outcomes than Caucasians. By investigating IBC in both African American and Caucasian cell lines we seek to understand the differences in IBC progression and help address disparities by providing new anti-IBC strategies. RhoC GTPase is overexpressed in 90% of IBC tumors and is known to increase cell motility. Sites of inflammation, as seen in IBC, attract tumor associated macrophages (TAMs), which have been found to facilitate the movement and invasion of many breast cancers. We hypothesize that TAMs play a role in increasing RhoC expression in IBC cell lines, consequently leading to IBC's severe migratory and metastatic potential. A novel microfluidic device created by our team was used to measure the migratory phenotype of IBC cell lines in response to macrophage conditioned media (CM) and cytokine stimulation. IBC cell lines were treated with CM, cytokines, or pathway inhibitors then Western blotting was used to determine protein expression and phosphorylation to identify important signaling pathways. We found the expression of RhoC significantly increased in two different IBC cell lines, SUM149 (African American) and SUM190 (Caucasian), after culturing with conditioned media from the macrophage-differentiated U937 monocytic cell line. This increase was not detected in either the normal-like MCF-10A breast epithelial cell line or the non-IBC MDA-MB-231 triple negative breast cancer cell line. CM caused a significant increase in the migration distance and frequency of both SUM149 and SUM190 cell lines. Analysis of the CM determined CCL2, CCL5, and IL-8 to be the key mediators in the macrophage CM. Western blotting proposes that CCL2, CCL5, and IL-8 stimulation causes twice as much RhoC expression compared to the control. Further analysis suggests a role for the MAPK pathway in controlling RhoC expression and migration. Macrophage conditioned media causes an increase in RhoC expression in IBC cell lines and stimulates migration. Individual cytokines can lead to an increase in RhoC possibly through the MAPK pathway. Studies involving RhoC inhibitors are ongoing and could yield promising therapies for the prevention of metastasis in IBC. By understanding the specific mechanism of TAMs’ effects on IBC, we hope to learn how to control the lethal metastatic nature of IBC and improve outcomes for patients of all ethnicities. Citation Format: Julie Madden, Steve Allen, Yu-Chi Shen, Chelsea Fournier, ZhiFen Wu, Liwei Bao, Sofia Merajver. Macrophages increase the expression of RhoC in inflammatory breast cancer leading to increased migration. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3236.

  • RhoC impacts the metastatic potential and abundance of breast cancer stem cells
    PLOS ONE, 2012
    Co-Authors: Devin T Rosenthal, Celina G Kleer, Li Wei Bao, Lian Zhu, Jie Zhang, Kathy A Toy, Sofia D Merajver
    Abstract:

    Cancer stem cells (CSCs) have been shown to promote tumorigenesis of many tumor types, including breast, although their relevance to cancer metastasis remains unclear. While subpopulations of CSCs required for metastasis have been identified, to date there are no known molecular regulators of breast CSC (BCSC) metastasis. Here we identify RhoC GTPase as an important regulator of BCSC metastasis, and present evidence suggesting that RhoC also modulates the frequency of BCSCs within a population. Using an orthotopic xenograft model of spontaneous metastasis we discover that RhoC is both necessary and sufficient to promote SUM149 and MCF-10A BCSC metastasis–often independent from primary tumor formation–and can even induce metastasis of non-BCSCs within these cell lines. The relationship between RhoC and BCSCs persists in breast cancer patients, as expression of RhoC and the BCSC marker ALDH1 are highly correlated in clinical specimens. These results suggest new avenues to combating the deadliest cells driving the most lethal stage of breast cancer progression.

  • abstract 2139 RhoC is a determinant of metastatic potential and affects the abundance of breast cancer stem cells
    Cancer Research, 2012
    Co-Authors: Lian Zhu, Celina G Kleer, Li Wei Bao, Devin T Rosenthal, Jie Zhang, Kathy A Toy, Sofia D Merajver
    Abstract:

    Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Introduction: While the ALDH1 subpopulation of cancer stem cells have been identified as necessary for breast cancer metastasis, the molecular regulators of ALDH1 marked metastasis are less well known. We observed that expression of the metastatic oncogene RhoC GTPase is concurrently altered with ALDH1 activity. Based on this observation we asked whether expression of RhoC drives the aggressive metastatic nature of ALDH1 (+) breast cancer stem cells. Methods: The normal-like mammary epithelial cell line, MCF-10A, with endogenously low RhoC expression, was transfected with either a control plasmid (vec) or a constitutively active RhoC plasmid (G14V). The RhoC-overexpressing Inflammatory Breast Cancer (IBC) cell line SUM149 was transfected with either a scrambled control shRNA (scr) or a RhoC-targeting shRNA (shRhoC). The transfected cells were sorted for positive (+) and negative (-) ALDH1 activity via the ALDEFLOUR assay. The sorted cells were then orthotopically xenografted into the mammary fat pads of NOD/SCID mice, and the mice were monitored for tumor incidence and lung metastasis. The effect of RhoC expression on the cell phenotype in vitro was also studied by subjecting the same cell lines above to time lapse microscopy and 3D cell culture. Results: While we expectedly saw a lower overall number of lung metastases in the ALDH1(-) population when compared to the ALDH1(+), the number of lung metastases in the ALDH1(+) population varied depending on the level of RhoC expressed in the xenografted cells. Inhibiting RhoC in the SUM149 cells significantly decreased the number of mice presenting with lung metastases when compared with the SUM149 scr control group. Alternatively, overexpressing RhoC with the G14V vector in the 10A ALDH1(+) population significantly increased the number of metastases when compared with the 10A vec control ALDH1(+). Interestingly, 80% of the MCF-10A G14V ALDH1(+) lung metastases resulted without the formation of a primary tumor. Alternatively, the number of ALDH1(+) cells in each cell line was also counted via the ALDEFLOUR assay, and the number of ALDH1(+) cells in the high RhoC expressing cell lines (SUM149 scr, 10A G14V) was approximately twice the number in the corresponding low RhoC expressing cell lines (SUM149 shRhoC, 10A G14V). We also find that overexpressing RhoC in the slow moving 10A G14V line increases the ALDH1(+) population's cell speed significantly. We also find correspondingly that ALDH1(+) subpopulations that exhibit high RhoC expression forms invasive acinar-like structures in 3D cell culture. Conclusions: From these findings, we conclude that RhoC expression is an essential driver of the metastatic potential and abundance of the ALDH1(+) breast cancer stem cell phenotype. This data has important clinical implications for targeting metastatic cancer stem cells. Currently our lab is testing the therapeutic effects of a novel small molecule RhoC inhibitor. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2139. doi:1538-7445.AM2012-2139

  • abstract 5622 effect of novel RhoC inhibitor on breast cancer progression and metastasisin vivo
    Cancer Research, 2012
    Co-Authors: Connie R Shi, Li Wei Bao, Devin T Rosenthal, Judy C Pang, Steven G Allen, Sofia D Merajver
    Abstract:

    Introduction: The oncogene RhoC GTPase is overexpressed in highly aggressive inflammatory breast cancer (IBC) and increases cellular motility and invasiveness in mammary tissue by interacting with downstream effectors to reorganize cytoskeletal elements in the cell. A small molecule inhibitor of RhoC-effector interaction has been identified. This antagonist decreases proliferation and inhibits motility of IBC cells in vitro. Here we evaluate the in vivo effects of the novel RhoC antagonist in a transgenic mouse model of breast cancer. Methods: The PyMT-RhoC transgenic mouse model was used in this study. This double transgenic strain was created by crossing the polyoma middle T antigen (PyMT) breast cancer model to a RhoC-overexpressing strain driven by the mouse mammary tumor virus (MMTV) promoter. The RhoC inhibitor was administered by intraperitoneal injection beginning at 50 days of age. Tumor size was monitored throughout treatment. At the end of the treatment, mammary glands, tumors, and lungs were extracted, fixed, sectioned, and stained with HE 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5622. doi:1538-7445.AM2012-5622

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