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Search Results: 1 - 10 of 332789 matches for " Michael J. Birrer "
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RASSF1A and the Taxol Response in Ovarian Cancer
Susannah Kassler,Howard Donninger,Michael J. Birrer,Geoffrey J. Clark
Molecular Biology International , 2012, DOI: 10.1155/2012/263267
Abstract: The RASSF1A tumor suppressor gene is frequently inactivated by promoter methylation in human tumors. The RASSF1A protein forms an endogenous complex with tubulin and promotes the stabilization of microtubules. Loss of RASSF1A expression sensitizes cells to microtubule destabilizing stimuli. We have observed a strong correlation between the loss of RASSF1A expression and the development of Taxol resistance in primary ovarian cancer samples. Thus, we sought to determine if RASSF1A levels could dictate the response to Taxol and whether an epigenetic therapy approach might be able to reverse the Taxol resistant phenotype of RASSF1A negative ovarian tumor cells. We found that knocking down RASSF1A expression in an ovarian cancer cell line inhibited Taxol-mediated apoptosis and promoted cell survival during Taxol treatment. Moreover, using a combination of small molecule inhibitors of DNA Methyl Transferase enzymes, we were able restore RASSF1A expression and Taxol sensitivity. This identifies a role for RASSF1A in modulating the tumor response to Taxol and provides proof of principal for the use of epigenetic therapy to overcome Taxol resistance. 1. Introduction RASSF1A is a poorly understood tumor suppressor that can modulate the cell cycle, tubulin dynamics and apoptosis [1–3]. It is subjected to epigenetic inactivation at high frequency in a broad range of human tumors, including approximately 50% of ovarian tumors [1, 4, 5]. Overexpression of RASSF1A promotes hyperstabilization of microtubules reminiscent of Taxol [6, 7], and previous investigations have shown that loss of RASSF1A sensitizes cells to microtubule destabilizing drugs such as nocodazole [7]. Thus, RASSF1A appears to play an important role in modulating microtubule stabilization. This implies that the RASSF1A levels in a tumor cell may impact how the cell responds to Taxol treatment. The development of resistance to Taxol remains a serious problem in the treatment of ovarian cancer. The most frequent mechanism by which RASSF1A is inactivated in tumors is by hypermethylation promoter leading to transcriptional silencing [1, 4, 5]. Thus, the gene remains intact, just dormant. Over recent years, a series of small molecules have been identified that can inhibit the DNA methylation system and restore expression of genes that have suffered aberrant promoter methylation [8]. This has given rise to the concept of epigenetic therapy, whereby a tumor would be treated with drugs to restore the expression and function of RASSF1A or some other epigenetically inactivated target. If RASSF1A plays a key
Identification of a Potential Ovarian Cancer Stem Cell Gene Expression Profile from Advanced Stage Papillary Serous Ovarian Cancer
Vinod Vathipadiekal, Deepa Saxena, Samuel C. Mok, Peter V. Hauschka, Laurent Ozbun, Michael J. Birrer
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0029079
Abstract: Identification of gene expression profiles of cancer stem cells may have significant implications in the understanding of tumor biology and for the design of novel treatments targeted toward these cells. Here we report a potential ovarian cancer stem cell gene expression profile from isolated side population of fresh ascites obtained from women with high-grade advanced stage papillary serous ovarian adenocarcinoma. Affymetrix U133 Plus 2.0 microarrays were used to interrogate the differentially expressed genes between side population (SP) and main population (MP), and the results were analyzed by paired T-test using BRB-ArrayTools. We identified 138 up-regulated and 302 down-regulated genes that were differentially expressed between all 10 SP/MP pairs. Microarray data was validated using qRT-PCR and17/19 (89.5%) genes showed robust correlations between microarray and qRT-PCR expression data. The Pathway Studio analysis identified several genes involved in cell survival, differentiation, proliferation, and apoptosis which are unique to SP cells and a mechanism for the activation of Notch signaling is identified. To validate these findings, we have identified and isolated SP cells enriched for cancer stem cells from human ovarian cancer cell lines. The SP populations were having a higher colony forming efficiency in comparison to its MP counterpart and also capable of sustained expansion and differentiation in to SP and MP phenotypes. 50,000 SP cells produced tumor in nude mice whereas the same number of MP cells failed to give any tumor at 8 weeks after injection. The SP cells demonstrated a dose dependent sensitivity to specific γ-secretase inhibitors implicating the role of Notch signaling pathway in SP cell survival. Further the generated SP gene list was found to be enriched in recurrent ovarian cancer tumors.
p21-Activated Kinase 3 (PAK3) Is an AP-1 Regulated Gene Contributing to Actin Organisation and Migration of Transformed Fibroblasts
Nina Holderness Parker, Howard Donninger, Michael J. Birrer, Virna D. Leaner
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0066892
Abstract: Activating Protein 1 (AP-1) plays a vital role in cell proliferation, differentiation and apoptosis. While de-regulation of AP-1 has been linked to many cancers, little is known regarding its downstream transcriptional targets that associate with cellular transformation. Previous studies identified PAK3, a serine/threonine kinase, as a potential AP-1 target gene. PAK3 has been implicated in a variety of pathological disorders and over-expression of other PAK-family members has been linked to cancer. In this study, we investigate AP-1 regulation of PAK3 expression and the role of PAK3 in cJun/AP-1-associated cellular transformation. Our results showed elevated PAK3 expression at both the mRNA and protein level in cJun-over-expressing Rat1a fibroblasts, as well as in transformed human fibroblasts. Elevated PAK3 expression in cJun/AP-1 over-expressing cells associated with a significant increase in PAK3 promoter activation. This increased promoter activity was lost when a single putative Jun binding site, which can bind AP-1 directly both in vitro and in vivo, was mutated. Further, inhibition of PAK3 using siRNA showed a regression in the cell morphology, migratory potential and actin organisation associated with AP-1 transformed cells. Our study is a first to describe a role for AP-1 in regulating PAK3 expression and suggest that PAK3 is an AP-1 target required for actin organization and migration observed in transformed cells.
Multi-Gene Expression Predictors of Single Drug Responses to Adjuvant Chemotherapy in Ovarian Carcinoma: Predicting Platinum Resistance
J. Stuart Ferriss, Youngchul Kim, Linda Duska, Michael Birrer, Douglas A. Levine, Christopher Moskaluk, Dan Theodorescu, Jae K. Lee
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0030550
Abstract: Despite advances in radical surgery and chemotherapy delivery, ovarian cancer is the most lethal gynecologic malignancy. Standard therapy includes treatment with platinum-based combination chemotherapies yet there is no biomarker model to predict their responses to these agents. We here have developed and independently tested our multi-gene molecular predictors for forecasting patients' responses to individual drugs on a cohort of 55 ovarian cancer patients. To independently validate these molecular predictors, we performed microarray profiling on FFPE tumor samples of 55 ovarian cancer patients (UVA-55) treated with platinum-based adjuvant chemotherapy. Genome-wide chemosensitivity biomarkers were initially discovered from the in vitro drug activities and genomic expression data for carboplatin and paclitaxel, respectively. Multivariate predictors were trained with the cell line data and then evaluated with a historical patient cohort. For the UVA-55 cohort, the carboplatin, taxol, and combination predictors significantly stratified responder patients and non-responder patients (p = 0.019, 0.04, 0.014) with sensitivity = 91%, 96%, 93 and NPV = 57%, 67%, 67% in pathologic clinical response. The combination predictor also demonstrated a significant survival difference between predicted responders and non-responders with a median survival of 55.4 months vs. 32.1 months. Thus, COXEN single- and combination-drug predictors successfully stratified platinum resistance and taxane response in an independent cohort of ovarian cancer patients based on their FFPE tumor samples.
An RNA Interference Lethality Screen of the Human Druggable Genome to Identify Molecular Vulnerabilities in Epithelial Ovarian Cancer
Geetika Sethi, Harsh B. Pathak, Hong Zhang, Yan Zhou, Margret B. Einarson, Vinod Vathipadiekal, Sumedha Gunewardena, Michael J. Birrer, Andrew K. Godwin
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0047086
Abstract: Targeted therapies have been used to combat many tumor types; however, few have effectively improved the overall survival in women with epithelial ovarian cancer, begging for a better understanding of this deadly disease and identification of essential drivers of tumorigenesis that can be targeted effectively. Therefore, we used a loss-of-function screening approach to help identify molecular vulnerabilities that may represent key points of therapeutic intervention. We employed an unbiased high-throughput lethality screen using a 24,088 siRNA library targeting over 6,000 druggable genes and studied their effects on growth and/or survival of epithelial ovarian cancer (EOC) cell lines. The top 300 “hits” affecting the viability of A1847 cells were rescreened across additional EOC cell lines and non-tumorigenic, human immortalized ovarian epithelial cell lines. Fifty-three gene candidates were found to exhibit effects in all tumorigenic cell lines tested. Extensive validation of these hits refined the list to four high quality candidates (HSPA5, NDC80, NUF2, and PTN). Mechanistic studies show that silencing of three genes leads to increased apoptosis, while HSPA5 silencing appears to alter cell growth through G1 cell cycle arrest. Furthermore, two independent gene expression studies show that NDC80, NUF2 and PTN were significantly aberrantly overexpressed in serous adenocarcinomas. Overall, our functional genomics results integrated with the genomics data provide an important unbiased avenue towards the identification of prospective therapeutic targets for drug discovery, which is an urgent and unmet clinical need for ovarian cancer.
The Role of Expectations in System Innovation: The Electronic Health Record, Immoderate Goal or Achievable Necessity?
Wouter Mensink,Frans A. J. Birrer
Central European Journal of Public Policy , 2010,
Abstract: We critically assess expectations in radical system innovation from the point of view of their "moderateness", i.e. whether alternative scenarios have been properly considered, and whether counterarguments have been addressed. We use the case of the planning of the Dutch Electronic Health Record (EHR) to illustrate the role of immoderate expectations and their underlying assumptions. By discussing these assumptions in the light of contested issues in international literature, we uncover the uncritical reception of innovations like the EHR, and their potential consequences. We show that certain relevant aspects of academic critique are barely voiced in the political debate. Our analysis can be connected to expectations in innovation in general, in particular those involving ICT, such as expecting to deal with "ideal users", to be able to take information out of its original context, to achieve cost-efficiency by automation, and to overcome human errors by technology. Based on our observations, we plead for a more realistic view of innovation, in which immoderate expectations can to a certain extent be "unpacked" without falling back to essentialist claims.
Comparison of Expression Profiles in Ovarian Epithelium In Vivo and Ovarian Cancer Identifies Novel Candidate Genes Involved in Disease Pathogenesis
Catherine Emmanuel,Natalie Gava,Catherine Kennedy,Rosemary L. Balleine,Raghwa Sharma,Gerard Wain,Alison Brand,Russell Hogg,Dariush Etemadmoghadam,Joshy George,Michael J. Birrer,Christine L. Clarke,Georgia Chenevix-Trench,David D. L. Bowtell,Paul R. Harnett,Anna deFazio
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0017617
Abstract: Molecular events leading to epithelial ovarian cancer are poorly understood but ovulatory hormones and a high number of life-time ovulations with concomitant proliferation, apoptosis, and inflammation, increases risk. We identified genes that are regulated during the estrous cycle in murine ovarian surface epithelium and analysed these profiles to identify genes dysregulated in human ovarian cancer, using publically available datasets. We identified 338 genes that are regulated in murine ovarian surface epithelium during the estrous cycle and dysregulated in ovarian cancer. Six of seven candidates selected for immunohistochemical validation were expressed in serous ovarian cancer, inclusion cysts, ovarian surface epithelium and in fallopian tube epithelium. Most were overexpressed in ovarian cancer compared with ovarian surface epithelium and/or inclusion cysts (EpCAM, EZH2, BIRC5) although BIRC5 and EZH2 were expressed as highly in fallopian tube epithelium as in ovarian cancer. We prioritised the 338 genes for those likely to be important for ovarian cancer development by in silico analyses of copy number aberration and mutation using publically available datasets and identified genes with established roles in ovarian cancer as well as novel genes for which we have evidence for involvement in ovarian cancer. Chromosome segregation emerged as an important process in which genes from our list of 338 were over-represented including two (BUB1, NCAPD2) for which there is evidence of amplification and mutation. NUAK2, upregulated in ovarian surface epithelium in proestrus and predicted to have a driver mutation in ovarian cancer, was examined in a larger cohort of serous ovarian cancer where patients with lower NUAK2 expression had shorter overall survival. In conclusion, defining genes that are activated in normal epithelium in the course of ovulation that are also dysregulated in cancer has identified a number of pathways and novel candidate genes that may contribute to the development of ovarian cancer.
Deregulation of MYCN, LIN28B and LET7 in a Molecular Subtype of Aggressive High-Grade Serous Ovarian Cancers
?slaug Helland,Michael S. Anglesio,Joshy George,Prue A. Cowin,Cameron N. Johnstone,Colin M. House,Karen E. Sheppard,Dariush Etemadmoghadam,Nataliya Melnyk,Anil K. Rustgi,Wayne A. Phillips,Hilde Johnsen,Ruth Holm,Gunnar B. Kristensen,Michael J. Birrer,Richard B. Pearson,Anne-Lise B?rresen-Dale,David G. Huntsman,Anna deFazio,Chad J. Creighton,Gordon K. Smyth,David D. L. Bowtell
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0018064
Abstract: Molecular subtypes of serous ovarian cancer have been recently described. Using data from independent datasets including over 900 primary tumour samples, we show that deregulation of the Let-7 pathway is specifically associated with the C5 molecular subtype of serous ovarian cancer. DNA copy number and gene expression of HMGA2, alleles of Let-7, LIN28, LIN28B, MYC, MYCN, DICER1, and RNASEN were measured using microarray and quantitative reverse transcriptase PCR. Immunohistochemistry was performed on 127 samples using tissue microarrays and anti-HMGA2 antibodies. Fluorescence in situ hybridisation of bacterial artificial chromosomes hybridized to 239 ovarian tumours was used to measure translocation at the LIN28B locus. Short interfering RNA knockdown in ovarian cell lines was used to test the functionality of associations observed. Four molecular subtypes (C1, C2, C4, C5) of high-grade serous ovarian cancers were robustly represented in each dataset and showed similar pattern of patient survival. We found highly specific activation of a pathway involving MYCN, LIN28B, Let-7 and HMGA2 in the C5 molecular subtype defined by MYCN amplification and over-expression, over-expression of MYCN targets including the Let-7 repressor LIN28B, loss of Let-7 expression and HMGA2 amplification and over-expression. DICER1, a known Let-7 target, and RNASEN were over-expressed in C5 tumours. We saw no evidence of translocation at the LIN28B locus in C5 tumours. The reported interaction between LIN28B and Let-7 was recapitulated by siRNA knockdown in ovarian cancer cell lines. Our results associate deregulation of MYCN and downstream targets, including Let-7 and oncofetal genes, with serous ovarian cancer. We define for the first time how elements of an oncogenic pathway, involving multiple genes that contribute to stem cell renewal, is specifically altered in a molecular subtype of serous ovarian cancer. By defining the drivers of a molecular subtype of serous ovarian cancers we provide a novel strategy for targeted therapeutic intervention.
Unpacking European Living Labs: Analysing Innovation’s Social Dimensions
Beno?t Dutilleul,Frans A. J. Birrer,Wouter Mensink
Central European Journal of Public Policy , 2010,
Abstract: Since their official launch in 2006, over one hundred Living Labs have been established and networked to tackle Europe’s declining economic competitiveness and societal challenges. The innovative potential of Living Labs is based on new social configurations for organising innovation. Applying a framework that supports the description of such social configurations and that focuses on barriers manifested by motivational and cognitive asymmetries between actors, we analyse the contributions and impediments to innovation and identify the problems that characterise innovation in Living Labs. We demonstrate the framework’s analytical power to uncover and articulate contributions and challenges inherent to the ‘social dimension’ of innovation. At the same time, we pinpoint and examine some contributions of and challenges for Living Labs. On the basis of a literature review, we untangle and describe the three main facets of the Living Lab concept: as a setting for in vivo experimentation on social systems, for innovation and product development approaches involving users, and for innovation systems. We conclude by gathering some crucial questions facing contemporary Living Labs.
Inhibition of Hedgehog Signaling Antagonizes Serous Ovarian Cancer Growth in a Primary Xenograft Model
Christopher K. McCann, Whitfield B. Growdon, Kashmira Kulkarni-Datar, Michael D. Curley, Anne M. Friel, Jennifer L. Proctor, Hana Sheikh, Igor Deyneko, Jeanne A. Ferguson, Vinod Vathipadiekal, Michael J. Birrer, Darrell R. Borger, Gayatry Mohapatra, Lawrence R. Zukerberg, Rosemary Foster, John R. MacDougall, Bo R. Rueda
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0028077
Abstract: Background Recent evidence links aberrant activation of Hedgehog (Hh) signaling with the pathogenesis of several cancers including medulloblastoma, basal cell, small cell lung, pancreatic, prostate and ovarian. This investigation was designed to determine if inhibition of this pathway could inhibit serous ovarian cancer growth. Methodology We utilized an in vivo pre-clinical model of serous ovarian cancer to characterize the anti-tumor activity of Hh pathway inhibitors cyclopamine and a clinically applicable derivative, IPI-926. Primary human serous ovarian tumor tissue was used to generate tumor xenografts in mice that were subsequently treated with cyclopamine or IPI-926. Principal Findings Both compounds demonstrated significant anti-tumor activity as single agents. When IPI-926 was used in combination with paclitaxel and carboplatinum (T/C), no synergistic effect was observed, though sustained treatment with IPI-926 after cessation of T/C continued to suppress tumor growth. Hh pathway activity was analyzed by RT-PCR to assess changes in Gli1 transcript levels. A single dose of IPI-926 inhibited mouse stromal Gli1 transcript levels at 24 hours with unchanged human intra-tumor Gli1 levels. Chronic IPI-926 therapy for 21 days, however, inhibited Hh signaling in both mouse stromal and human tumor cells. Expression data from the micro-dissected stroma in human serous ovarian tumors confirmed the presence of Gli1 transcript and a significant association between elevated Gli1 transcript levels and worsened survival. Conclusions/Significance IPI-926 treatment inhibits serous tumor growth suggesting the Hh signaling pathway contributes to the pathogenesis of ovarian cancer and may hold promise as a novel therapeutic target, especially in the maintenance setting.
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