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Author Hasan, N.; Ohman, A.W.; Dinulescu, D.M. url  openurl
  Title The promise and challenge of ovarian cancer models Type Journal Article
  Year 2015 Publication Abbreviated Journal Transl Cancer Res  
  Volume 4 Issue 1 Pages 14-28  
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  Abstract The complexity and heterogeneity of ovarian cancer cases are difficult to reproduce in in vitro studies, which cannot adequately elucidate the molecular events involved in tumor initiation and disease metastasis. It has now become clear that, although the multiple histological subtypes of ovarian cancer are being treated with similar surgical and therapeutic approaches, they are in fact characterized by distinct phenotypes, cell of origin, and underlying key genetic and genomic alterations. Consequently, the development of more personalized treatment methodologies, which are aimed at improving patient care and prognosis, will greatly benefit from a better understanding of the key differences between various subtypes. To accomplish this, animal models of all histotypes need to be generated in order to provide accurate in vivo platforms for research and the testing of targeted treatments and immune therapies. Both genetically engineered mouse models (GEMMs) and xenograft models have the ability to further our understanding of key mechanisms facilitating tumorigenesis, and at the same time offer insight into enhanced imaging and treatment modalities. While genetic models may be better suited to examine oncogenic functions and interactions during tumorigenesis, patient-derived xenografts (PDXs) are likely a superior model to assess drug efficacy, especially in concurrent clinical trials, due to their similarity to the tumors from which they are derived. Genetic and avatar models possess great clinical utility and have both benefits and limitations. Additionally, the laying hen model, which spontaneously develops ovarian tumors, has inherent advantages for the study of epithelial ovarian cancer (EOC) and recent work champions this model especially when assessing chemoprevention strategies. While high-grade ovarian serous tumors are the most prevalent form of EOC, rarer ovarian cancer variants, such as small cell ovarian carcinoma of the hypercalcemic type and transitional cell carcinoma, or non-epithelial tumors, including germ cell tumors, will also benefit from the generation of improved models to advance our understanding of tumorigenic mechanisms and the development of selective therapeutic options.  
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  Call Number UofT @ ankit.sinha @ Serial 45119  
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Author Bobbs, A.S.; Cole, J.M.; Cowden Dahl, K.D. url  openurl
  Title Emerging and Evolving Ovarian Cancer Animal Models Type Journal Article
  Year 2015 Publication Abbreviated Journal Cancer Growth Metastasis  
  Volume 8 Issue Suppl 1 Pages 29-36  
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  Abstract Ovarian cancer (OC) is the leading cause of death from a gynecological malignancy in the United States. By the time a woman is diagnosed with OC, the tumor has usually metastasized. Mouse models that are used to recapitulate different aspects of human OC have been evolving for nearly 40 years. Xenograft studies in immunocompromised and immunocompetent mice have enhanced our knowledge of metastasis and immune cell involvement in cancer. Patient-derived xenografts (PDXs) can accurately reflect metastasis, response to therapy, and diverse genetics found in patients. Additionally, multiple genetically engineered mouse models have increased our understanding of possible tissues of origin for OC and what role individual mutations play in establishing ovarian tumors. Many of these models are used to test novel therapeutics. As no single model perfectly copies the human disease, we can use a variety of OC animal models in hypothesis testing that will lead to novel treatment options. The goal of this review is to provide an overview of the utility of different mouse models in the study of OC and their suitability for cancer research.  
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  Call Number UofT @ ankit.sinha @ Serial 45127  
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Author Kadiyska, T.; Nossikoff, A. url  openurl
  Title Stool DNA methylation assays in colorectal cancer screening Type Journal Article
  Year 2015 Publication Abbreviated Journal World J Gastroenterol  
  Volume 21 Issue 35 Pages 10057-10061  
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  Abstract Colorectal cancer (CRC) is fourth most common cancer in men and third in women worldwide. Developing a diagnostic panel of sensitive and specific biomarkers for the early detection of CRC is recognised as to be crucial for early initial diagnosis, which in turn leads to better long term survival. Most of the research on novel potential CRC biomarkers in the last 2 decades has been focussed on stool DNA analysis. In this paper, we describe the recent advances in non-invasive CRC screening and more specifically in molecular assays for aberrantly methylated BMP3 and NDRG4 promoter regions. In several research papers these markers showed superior rates for sensitivity and specificity in comparison to previously described assays. These tests detected the majority of adenomas ≥ 1 cm in size and the detection rates progressively increased with larger adenomas. The methylation status of the BMP3 and NDRG4 promoters demonstrated effective detection of neoplasms at all sites throughout the colon and was not affected by common clinical variables. Recently, a multitarget stool DNA test consisting of molecular assays for aberrantly methylated BMP3 and NDRG4 promoter regions, mutant KRAS and immunochemical assay for human haemoglobin has been made commercially available and is currently reimbursed in the United States. Although this is the most sensitive non-invasive CRC screening test, there is the need for further research in several areas – establishment of the best timeframe for repeated DNA stool testing; validation of the results in populations outside of North America; usefulness for surveillance and prognosis of patients; cost-effectiveness of DNA stool testing in real-life populations.  
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  Call Number UofT @ ankit.sinha @ Serial 45144  
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Author Das, S.; Batra, S.K. url  openurl
  Title Understanding the Unique Attributes of MUC16 (CA125): Potential Implications in Targeted Therapy Type Journal Article
  Year 2015 Publication Abbreviated Journal Cancer Res  
  Volume 75 Issue 22 Pages 4669-4674  
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  Abstract CA125, the most widely used ovarian cancer biomarker, was first identified approximately 35 years ago in an antibody screen against ovarian cancer antigen. Two decades later, it was cloned and characterized to be a transmembrane mucin, MUC16. Since then, several studies have investigated its expression, functional, and mechanistic involvement in multiple cancer types. Antibody-based therapeutic approaches primarily using antibodies against the tandem repeat domains of MUC16 (e.g., oregovomab and abagovomab) have been the modus operandi for MUC16-targeted therapy, but have met with very limited success. In addition, efforts have been also made to disrupt the functional cooperation of MUC16 and its interacting partners; for example, use of a novel immunoadhesin HN125 to interfere MUC16 binding to mesothelin. Since the identification of CA125 to be MUC16, it is hypothesized to undergo proteolytic cleavage, a process that is considered to be critical in determining the kinetics of MUC16 shedding as well as generation of a cell-associated carboxyl-terminal fragment with potential oncogenic functions. In addition to our experimental demonstration of MUC16 cleavage, recent studies have demonstrated the functional importance of carboxyl terminal fragments of MUC16 in multiple tumor types. Here, we provide how our understanding of the basic biologic processes involving MUC16 influences our approach toward MUC16-targeted therapy.  
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  Call Number UofT @ ankit.sinha @ Serial 45164  
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Author Lannoo, N.; Van Damme, E.J. url  openurl
  Title Review/N-glycans: The making of a varied toolbox Type Journal Article
  Year 2015 Publication Abbreviated Journal Plant Sci  
  Volume 239 Issue Pages 67-83  
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  Abstract Asparagine (N)-linked protein glycosylation is one of the most crucial, prevalent, and complex co- and post-translational protein modifications. It plays a pivotal role in protein folding, quality control, and endoplasmic reticulum (ER)-associated degradation (ERAD) as well as in protein sorting, protein function, and in signal transduction. Furthermore, glycosylation modulates many important biological processes including growth, development, morphogenesis, and stress signaling processes. As a consequence, aberrant or altered N-glycosylation is often associated with reduced fitness, diseases, and disorders. The initial steps of N-glycan synthesis at the cytosolic side of the ER membrane and in the lumen of the ER are highly conserved. In contrast, the final N-glycan processing in the Golgi apparatus is organism-specific giving rise to a wide variety of carbohydrate structures. Despite our vast knowledge on N-glycans in yeast and mammals, the modus operandi of N-glycan signaling in plants is still largely unknown. This review will elaborate on the N-glycosylation biosynthesis pathway in plants but will also critically assess how N-glycans are involved in different signaling cascades, either active during normal development or upon abiotic and biotic stresses.  
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  Call Number UofT @ ankit.sinha @ Serial 45205  
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Author Rush, J.S. url  openurl
  Title Role of Flippases in Protein Glycosylation in the Endoplasmic Reticulum Type Journal Article
  Year 2015 Publication Abbreviated Journal Lipid Insights  
  Volume 8 Issue Suppl 1 Pages 45-53  
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  Abstract Glycosylation is essential to the synthesis, folding, and function of glycoproteins in eukaryotes. Proteins are co- and posttranslationally modified by a variety of glycans in the endoplasmic reticulum (ER); modifications include C- and O-mannosylation, N-glycosylation, and the addition of glycosylphosphatidylinositol membrane anchors. Protein glycosylation in the ER of eukaryotes involves enzymatic steps on both the cytosolic and lumenal surfaces of the ER membrane. The glycans are first assembled as precursor glycolipids, on the cytosolic surface of the ER, which are tethered to the membrane by attachment to a long-chain polyisoprenyl phosphate (dolichol) containing a reduced α-isoprene. The lipid-anchored building blocks then migrate transversely (flip) across the ER membrane to the lumenal surface, where final assembly of the glycan is completed. This strategy allows the cell to export high-energy biosynthetic intermediates as lipid-bound glycans, while constraining the glycosyl donors to the site of assembly on the membrane surface. This review focuses on the flippases that participate in protein glycosylation in the ER.  
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  Call Number UofT @ ankit.sinha @ Serial 45207  
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Author Stowell, S.R.; Ju, T.; Cummings, R.D. url  openurl
  Title Protein glycosylation in cancer Type Journal Article
  Year 2015 Publication Abbreviated Journal Annu Rev Pathol  
  Volume 10 Issue Pages 473-510  
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  Abstract Neoplastic transformation results in a wide variety of cellular alterations that impact the growth, survival, and general behavior of affected tissue. Although genetic alterations underpin the development of neoplastic disease, epigenetic changes can exert an equally significant effect on neoplastic transformation. Among neoplasia-associated epigenetic alterations, changes in cellular glycosylation have recently received attention as a key component of neoplastic progression. Alterations in glycosylation appear to not only directly impact cell growth and survival but also facilitate tumor-induced immunomodulation and eventual metastasis. Many of these changes may support neoplastic progression, and unique alterations in tumor-associated glycosylation may also serve as a distinct feature of cancer cells and therefore provide novel diagnostic and even therapeutic targets.  
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  Call Number UofT @ ankit.sinha @ Serial 45212  
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Author Sowers, J.L.; Mirfattah, B.; Xu, P.; Tang, H.; Park, I.Y.; Walker, C.; Wu, P.; Laezza, F.; Sowers, L.C.; Zhang, K. url  openurl
  Title Quantification of histone modifications by parallel-reaction monitoring: a method validation Type Journal Article
  Year 2015 Publication Abbreviated Journal Anal Chem  
  Volume 87 Issue 19 Pages 10006-10014  
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  Abstract Abnormal epigenetic reprogramming is one of the major causes leading to irregular gene expression and regulatory pathway perturbations, in the cells, resulting in unhealthy cell development or diseases. Accurate measurements of these changes of epigenetic modifications, especially the complex histone modifications, are very important, and the methods for these measurements are not trivial. By following our previous introduction of PRM to targeting histone modifications (Tang, H.; Fang, H.; Yin, E.; Brasier, A. R.; Sowers, L. C.; Zhang, K. Multiplexed parallel reaction monitoring targeting histone modifications on the QExactive mass spectrometer. Anal. Chem. 2014, 86 (11), 5526-34), herein we validated this method by varying the protein/trypsin ratios via serial dilutions. Our data demonstrated that PRM with SILAC histones as the internal standards allowed reproducible measurements of histone H3/H4 acetylation and methylation in the samples whose histone contents differ at least one-order of magnitude. The method was further validated by histones isolated from histone H3 K36 trimethyltransferase SETD2 knockout mouse embryonic fibroblasts (MEF) cells. Furthermore, histone acetylation and methylation in human neural stem cells (hNSC) treated with ascorbic acid phosphate (AAP) were measured by this method, revealing that H3 K36 trimethylation was significantly down-regulated by 6 days of treatment with vitamin C.  
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  Call Number UofT @ ankit.sinha @ Serial 45227  
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Author Robertson, I.B.; Horiguchi, M.; Zilberberg, L.; Dabovic, B.; Hadjiolova, K.; Rifkin, D.B. url  openurl
  Title Latent TGF-β-binding proteins Type Journal Article
  Year 2015 Publication Abbreviated Journal Matrix Biol  
  Volume 47 Issue Pages 44-53  
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  Abstract The LTBPs (or latent transforming growth factor β binding proteins) are important components of the extracellular matrix (ECM) that interact with fibrillin microfibrils and have a number of different roles in microfibril biology. There are four LTBPs isoforms in the human genome (LTBP-1, -2, -3, and -4), all of which appear to associate with fibrillin and the biology of each isoform is reviewed here. The LTBPs were first identified as forming latent complexes with TGFβ by covalently binding the TGFβ propeptide (LAP) via disulfide bonds in the endoplasmic reticulum. LAP in turn is cleaved from the mature TGFβ precursor in the trans-golgi network but LAP and TGFβ remain strongly bound through non-covalent interactions. LAP, TGFβ, and LTBP together form the large latent complex (LLC). LTBPs were originally thought to primarily play a role in maintaining TGFβ latency and targeting the latent growth factor to the extracellular matrix (ECM), but it has also been shown that LTBP-1 participates in TGFβ activation by integrins and may also regulate activation by proteases and other factors. LTBP-3 appears to have a role in skeletal formation including tooth development. As well as having important functions in TGFβ regulation, TGFβ-independent activities have recently been identified for LTBP-2 and LTBP-4 in stabilizing microfibril bundles and regulating elastic fiber assembly.  
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  Call Number UofT @ ankit.sinha @ Serial 45253  
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Author Blume-Jensen, P.; Berman, D.M.; Rimm, D.L.; Shipitsin, M.; Putzi, M.; Nifong, T.P.; Small, C.; Choudhury, S.; Capela, T.; Coupal, L.; Ernst, C.; Hurley, A.; Kaprelyants, A.; Chang, H.; Giladi, E.; Nardone, J.; Dunyak, J.; Loda, M.; Klein, E.A.; Magi-Galluzzi, C.; Latour, M.; Epstein, J.I.; Kantoff, P.; Saad, F. url  openurl
  Title Development and clinical validation of an in situ biopsy-based multimarker assay for risk stratification in prostate cancer Type Journal Article
  Year 2015 Publication Abbreviated Journal Clin Cancer Res  
  Volume 21 Issue 11 Pages 2591-2600  
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  Abstract PURPOSE: Prostate cancer aggressiveness and appropriate therapy are routinely determined following biopsy sampling. Current clinical and pathologic parameters are insufficient for accurate risk prediction leading primarily to overtreatment and also missed opportunities for curative therapy. EXPERIMENTAL DESIGN: An 8-biomarker proteomic assay for intact tissue biopsies predictive of prostate pathology was defined in a study of 381 patient biopsies with matched prostatectomy specimens. A second blinded study of 276 cases validated this assay’s ability to distinguish “favorable” versus “nonfavorable” pathology independently and relative to current risk classification systems National Comprehensive Cancer Network (NCCN and D’Amico). RESULTS: A favorable biomarker risk score of ≤0.33, and a nonfavorable risk score of >0.80 (possible range between 0 and 1) were defined on “false-negative” and “false-positive” rates of 10% and 5%, respectively. At a risk score ≤0.33, predictive values for favorable pathology in very low-risk and low-risk NCCN and low-risk D’Amico groups were 95%, 81.5%, and 87.2%, respectively, higher than for these current risk classification groups themselves (80.3%, 63.8%, and 70.6%, respectively). The predictive value for nonfavorable pathology was 76.9% at biomarker risk scores >0.8 across all risk groups. Increased biomarker risk scores correlated with decreased frequency of favorable cases across all risk groups. The validation study met its two coprimary endpoints, separating favorable from nonfavorable pathology (AUC, 0.68; P < 0.0001; OR, 20.9) and GS-6 versus non-GS-6 pathology (AUC, 0.65; P < 0.0001; OR, 12.95). CONCLUSIONS: The 8-biomarker assay provided individualized, independent prognostic information relative to current risk stratification systems, and may improve the precision of clinical decision making following prostate biopsy.  
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  Call Number UofT @ ankit.sinha @ Serial 45258  
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