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4.  Overcoming platinum resistance in preclinical models of ovarian cancer using the neddylation inhibitor MLN4924 
Molecular cancer therapeutics  2013;12(10):1958-1967.
The nearly ubiquitous development of chemoresistant disease remains a major obstacle against improving outcomes for ovarian cancer patients. In this investigation we evaluated the preclinical activity of MLN4924, an investigational inhibitor of the NEDD8-activating enzyme, in ovarian cancer cells. Efficacy of MLN4924 both alone and in combination with platinum was assessed. Overall, single agent MLN4924 exhibited moderate activity in ovarian cancer cell lines. However, the combination of MLN4924 with cisplatin or carboplatin produced synergistic effects in SKOV3 and ES2 cells, as well as, in primary ovarian cancer cell lines established from high grade serous, clear cell, and serous borderline ovarian tumors. The efficacy of cisplatin plus MLN4924 was also evident in several in vitro models of platinum resistant ovarian cancer. Mechanistically, the combination of cisplatin and MLN4924 was not associated with DNA re-replication, altered platinum-DNA adduct formation, abrogation of FANCD2 monoubiquitination, or CHK1 phosphorylation. An siRNA screen was used to investigate the contribution of each member of the Cullin RING-Ligase (CRL) family of E3 ubiquitin ligases, the best characterized downstream mediators of MLN4924’s biological effects . Cisplatin-induced cytotoxicity was augmented by depletion of CUL3, and antagonized by siCUL1 in both ES2 and SKOV3 ovarian cancer cells. This investigation identifies inhibition of Neddylation as a novel mechanism for overcoming platinum resistance in vitro, and provides a strong rationale for clinical investigations of platinum and MLN4924 combinations in ovarian cancer.
doi:10.1158/1535-7163.MCT-12-1028
PMCID: PMC3795967  PMID: 23939375
MLN4924; cisplatin; ovarian cancer; neddylation; cullin ring ligase; platinum resistance
5.  The Influence of Declining Air Lead Levels on Blood Lead–Air Lead Slope Factors in Children 
Environmental Health Perspectives  2014;122(7):754-760.
Background: It is difficult to discern the proportion of blood lead (PbB) attributable to ambient air lead (PbA), given the multitude of lead (Pb) sources and pathways of exposure. The PbB–PbA relationship has previously been evaluated across populations. This relationship was a central consideration in the 2008 review of the Pb national ambient air quality standards.
Objectives: The objectives of this study were to evaluate the relationship between PbB and PbA concentrations among children nationwide for recent years and to compare the relationship with those obtained from other studies in the literature.
Methods: We merged participant-level data for PbB from the National Health and Nutrition Examination Survey (NHANES) III (1988–1994) and NHANES 9908 (1999–2008) with PbA data from the U.S. Environmental Protection Agency. We applied mixed-effects models, and we computed slope factor, d[PbB]/d[PbA] or the change in PbB per unit change in PbA, from the model results to assess the relationship between PbB and PbA.
Results: Comparing the NHANES regression results with those from the literature shows that slope factor increased with decreasing PbA among children 0–11 years of age.
Conclusion: These findings suggest that a larger relative public health benefit may be derived among children from decreases in PbA at low PbA exposures. Simultaneous declines in Pb from other sources, changes in PbA sampling uncertainties over time largely related to changes in the size distribution of Pb-bearing particulate matter, and limitations regarding sampling size and exposure error may contribute to the variability in slope factor observed across peer-reviewed studies.
Citation: Richmond-Bryant J, Meng Q, Davis A, Cohen J, Lu SE, Svendsgaard D, Brown JS, Tuttle L, Hubbard H, Rice J, Kirrane E, Vinikoor-Imler LC, Kotchmar D, Hines EP, Ross M. 2014. The Influence of declining air lead levels on blood lead–air lead slope factors in children. Environ Health Perspect 122:754–760; http://dx.doi.org/10.1289/ehp.1307072
doi:10.1289/ehp.1307072
PMCID: PMC4080523  PMID: 24667492
7.  Cardiovascular Outcomes and the Physical and Chemical Properties of Metal Ions Found in Particulate Matter Air Pollution: A QICAR Study 
Environmental Health Perspectives  2013;121(5):558-564.
Background: This paper presents an application of quantitative ion character–activity relationships (QICAR) to estimate associations of human cardiovascular (CV) diseases (CVDs) with a set of metal ion properties commonly observed in ambient air pollutants. QICAR has previously been used to predict ecotoxicity of inorganic metal ions based on ion properties.
Objectives: The objective of this work was to examine potential associations of biological end points with a set of physical and chemical properties describing inorganic metal ions present in exposures using QICAR.
Methods: Chemical and physical properties of 17 metal ions were obtained from peer-reviewed publications. Associations of cardiac arrhythmia, myocardial ischemia, myocardial infarction, stroke, and thrombosis with exposures to metal ions (measured as inference scores) were obtained from the Comparative Toxicogenomics Database (CTD). Robust regressions were applied to estimate the associations of CVDs with ion properties.
Results: CVD was statistically significantly associated (Bonferroni-adjusted significance level of 0.003) with many ion properties reflecting ion size, solubility, oxidation potential, and abilities to form covalent and ionic bonds. The properties are relevant for reactive oxygen species (ROS) generation, which has been identified as a possible mechanism leading to CVDs.
Conclusion: QICAR has the potential to complement existing epidemiologic methods for estimating associations between CVDs and air pollutant exposures by providing clues about the underlying mechanisms that may explain these associations.
doi:10.1289/ehp.1205793
PMCID: PMC3673192  PMID: 23462649
air pollution; cardiovascular disease; multipollutant; QICAR; QSAR
11.  Molecular Requirements for Transformation of Fallopian Tube Epithelial Cells into Serous Carcinoma12 
Neoplasia (New York, N.Y.)  2011;13(10):899-911.
Although controversial, recent studies suggest that serous ovarian carcinomas may arise from fallopian tube fimbria rather than ovarian surface epithelium. We developed an in vitro model for serous carcinogenesis in which primary human fallopian tube epithelial cells (FTECs) were exposed to potentially oncogenic molecular alterations delivered by retroviral vectors. To more closely mirror in vivo conditions, transformation of FTECs was driven by the positive selection of growth-promoting alterations rather antibiotic selection. Injection of the transformed FTEC lines in SCID mice resulted in xenografts with histologic and immunohistochemical features indistinguishable from poorly differentiated serous carcinomas. Transcriptional profiling revealed high similarity among the transformed and control FTEC lines and patient-derived serous ovarian carcinoma cells and was used to define a malignancy-related transcriptional signature. Oncogene-treated FTEC lines were serially analyzed using quantitative reverse transcription-polymerase chain reaction and immunoblot analysis to identify oncogenes whose expression was subject to positive selection. The combination of p53 and Rb inactivation (mediated by SV40 T antigen), hTERT expression, and oncogenic C-MYC and HRAS accumulation showed positive selection during transformation. Knockdown of each of these selected components resulted in significant growth inhibition of the transformed cell lines that correlated with p27 accumulation. The combination of SV40 T antigen and hTERT expression resulted in immortalized cells that were nontumorigenic in mice, whereas forced expression of a dominant-negative p53 isoform (p53DD) and hTERT resulted in senescence. Thus, our investigation supports the tubal origin of serous carcinoma and provides a dynamic model for studying early molecular alterations in serous carcinogenesis.
PMCID: PMC3201567  PMID: 22028616

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