bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 540: A MALDI imaging mass spectrometry approach using tissue microarrays to identify an N-glycan biomarker panel for pancreatic cancers
Authors: Drake Richard R. , Powers Thomas W. , Neely Benjamin A. 
Published: August 2015

Abstract
We have recently developed a MALDI imaging mass spectrometry (MALDI-IMS) method to spatially profile N-linked glycans in frozen and formalin-fixed paraffin-embedded (FFPE) tissue sections and tissue microarrays (TMAs). Tissues are incubated with peptide N-glycosidase, and released N-glycans are detected directly using MALDI-FTICR, linked directly with tissue histopathology. Other methods to detect the localization of glycans in tissues rely on detection of broader glycan structural motifs (i.e., lectins or carbohydrate antigen antibodies), whereas our method is able to simultaneously identify and distinguish 40 or more components of the N-glycome on a single slide. To demonstrate the ability of MALDI-IMS to generate biomarker panels, pancreatic cancer tissue blocks and six TMAs containing matched tumor and non-tumor regions from over 70 patients were profiled. Aberrant glycosylation, such as elevated CA-19-9, is well documented in pancreatic cancer, making this an ideal sample set. To best analyze this complex data set, we developed an in-house analysis script that can extract spectra from tissue cores, and return non-biased statistics for observed glycan ions. Panels were generated using a training set of data and tested on external validation data set. The most accurate panel of 12 glycans achieved an overall sensitivity of 92.9% and specificity of 86.7%. Structural identification of N-glycans has been confirmed by techniques such as on-tissue CID, ethylation analysis, sequential glycosidase digestions, and comparison to glycan structural databases. Furthermore, imaging of entire FFPE sections matched with histological analysis revealed a vast diversity of N-glycan localizations, which could distinguish not only tumor from normal tissue, but also regions of pancreatitis and pancreatic intraepithelial neoplasia. The generated glycan tissue maps will also be used to determine specific glycoprotein carriers of biomarker candidate glycans in tissue and biofluid samples.
Citation Format: Richard R. Drake, Thomas W. Powers, Benjamin A. Neely. A MALDI imaging mass spectrometry approach using tissue microarrays to identify an N-glycan biomarker panel for pancreatic cancers. [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 540. doi:10.1158/1538-7445.AM2015-540
Abstract 5401: TGF-β signaling inhibition as a potential approach to target suboptimally debulked ovarian tumors
Authors: Wei Wei , Birrer Michael J. 
Published: August 2015

Abstract
The current standard of care for all patients with high-grade, advanced-stage serous ovarian cancer is surgery followed by adjuvant chemotherapy. Resection of all visible residual disease to less than 1 cm is associated with a favorable prognosis, but this optimal debulking can only be achieved in ∼70% of patients. Patients with suboptimal cytoreduction are presumed to have lower response rates to subsequent chemotherapy and are known to have a poor prognosis.
Recently, we performed a meta-analysis of 1,525 publicly available expression profiling assays and identified a 200-gene expression signature of primary ovarian tumors to predict the outcome of debulking surgery. The signature was validated using two independent sets of tumors. This debulking signature consists of transcripts positively regulated by TGF-β, indicating that hyperactivation of TGF-β signaling may be responsible of the aggressive biological and clinical behavior of suboptimally debulked tumors.
In this study, we evaluated the potential anti-tumor effect of TGF-β signaling blockade in ovarian cancer cells in vitro and in vivo. Integrated TGF-β signaling was observed in 8 of 10 ovarian cancer cell lines tested by a SMAD-binding element based luciferase assay. The potential anti-tumor effect of a small molecular TGFBR1 kinase inhibitor LY2157299 was further investigated in SKOV3 cell line, which presents both endogenous and inducible TGF-β signaling and is highly disseminative when inoculated into immunodeficient mice. Although imposing minimum effect on in vitro cellular proliferation, LY2157299 significantly inhibited tumor-dissemination related biological processes in SKOV3 cells including migration, invasion and mesothelial cell adhesion. In an interperitoneal SKOV3 xenograft model, administration of LY2157299 significantly increased cisplatin related cytotoxicity and tumor burden reduction. Taken together, our study has provided evidence for the potential clinical use of LY2157299 to improve the treatment and survival of women with suboptimal surgery.
Citation Format: Wei Wei, Michael J. Birrer. TGF-β signaling inhibition as a potential approach to target suboptimally debulked ovarian tumors. [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 5401. doi:10.1158/1538-7445.AM2015-5401
Abstract 5415: Therapeutic effects of TOPK inhibitor on triple-negative breast cancer
Authors: Park Jae-Hyun , Miyamoto Takashi , Matsuo Yo , Nakamura Yusuke 
Published: August 2015

Abstract
TOPK (T-LAK cell-originated protein kinase) is a novel mitotic kinase and frequently up-regulated in multiple types of cancer, including triple-negative breast cancer (TNBC), but not expressed in normal organs except testis. We previously showed that knockdown of TOPK using siRNAs induced cytokinesis defect in dividing cancer cells with elongated intercellular bridge. In addition, we recently reported that a potent TOPK inhibitor (OTS964) caused the cytokinesis defect and subsequently induced apoptosis of cancer cells in vitro as well as in in vivo xenograft models of human lung cancer. More importantly, liposomal formulation of OTS964 led to complete regression of transplanted tumors without any detectable adverse reactions in mice. Since the TOPK gene is up-regulated in the great majority of TNBCs, we examined therapeutic effect of OTS964 on TNBC cell lines. Western blot analysis revealed that TOPK was highly expressed in all of five TNBC cell lines examined. OTS964 was effective to MDA-MB-231 cells with the IC50 value of 73 nM, and caused cytokinesis defect and apoptosis. Moreover, in MDA-MB-231 xenograft model, oral administration of 75 mg/kg OTS964 for 2 weeks achieved 65% tumor growth inhibitory (TGI) effect at day 15, without any body weight loss. Collectively, our findings imply that targeting TOPK is a very promising therapeutic option for the treatment of TNBC patients who still have very limited treatment modalities.
Citation Format: Jae-Hyun Park, Takashi Miyamoto, Yo Matsuo, Yusuke Nakamura. Therapeutic effects of TOPK inhibitor on triple-negative breast cancer. [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 5415. doi:10.1158/1538-7445.AM2015-5415
Abstract 5417: The identification of BMS-595, an orally active imidazo[1,2-b]pyridazine CK2 inhibitor with in vivo anti-tumor activity
Authors: Tarby Christine M. , He Liqi , Fink Brian E. , Nation Andrew , Zhao Yufen , Kim Soong-Hoon , Chen Libing , Tokarski John S. , Yu Chiang , Pabalan Jonathan G. , Roongta Urvashi V. , Lippy Jonathan , Obermeier Mary , Elzinga Paul A. , Fura Aberra , Henley Benjamin , Fargnoli Joseph J. , Foster William R. , Gavai Ashvinikumar V. , Wong Tai W. , Hunt John T. , Vite Gregory D. , Purandare Ashok V. , Rupnow Brent A. 
Published: August 2015

Abstract
CK2 is a highly conserved, and constitutively active family of serine/threonine kinases abnormally elevated in a wide variety of cancers and linked to poor prognosis and disease progression. The enzymes form as hetero-tetrameric complexes comprised of two highly related catalytic subunits (α or α´) with two regulatory β subunits in various combinations and distributions, depending on cell type. While CK2 plays a role in normal growth and development, deregulation of the enzymes has been shown to promote and maintain a malignant phenotype through mechanisms in both the anti-apoptotic and the pro-proliferative signaling pathways. CK2 has been reported to modulate the activity of several oncogenic transcription factors including CREB, Myc, Jun and Fos. Studies with RNAi and small molecule compounds have demonstrated tumor cell dependence on CK2.
We sought to identify potent CK2 inhibitors to probe the function of CK2 in cancer-linked pathways and for evaluation in CK2 dependent tumor xenograft models. Herein we report SAR studies in the imidazo[1,2-b]pyridazine chemotype leading to the discovery of BMS-595, a highly potent and selective ATP-competitive CK2 inhibitor with a commensurate level of cellular potency. BMS-595 demonstrates strong PK/PD correlations and robust, oral anti-tumor efficacy in CK2-driven xenograft models at tolerated doses.
Citation Format: Christine M. Tarby, Liqi He, Brian E. Fink, Andrew Nation, Yufen Zhao, Soong-Hoon Kim, Libing Chen, John S. Tokarski, Chiang Yu, Jonathan G. Pabalan, Urvashi V. Roongta, Jonathan Lippy, Mary Obermeier, Paul A. Elzinga, Aberra Fura, Benjamin Henley, Joseph J. Fargnoli, William R. Foster, Ashvinikumar V. Gavai, Tai W. Wong, John T. Hunt, Gregory D. Vite, Ashok V. Purandare, Brent A. Rupnow. The identification of BMS-595, an orally active imidazo[1,2-b]pyridazine CK2 inhibitor with in vivo anti-tumor activity. [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 5417. doi:10.1158/1538-7445.AM2015-5417
Abstract 5424: Therapeutic targeting of KRAS mutation-driven tumor progression in colorectal cancer
Authors: Wu Christina , Lin Peng-Chan , Chu Po-Chen , Chuang Hsiao-Ching , Kulp Samuel , Bekaii-Saab Tanios , Chen Ching-Shih 
Published: August 2015

Abstract
KRAS is the most frequently altered gene in colorectal cancer (CRC), with mutations occurring in 30-40% of colorectal cancer. Although KRAS mutation is associated with poor prognosis and resistance to anti-epidermal growth factor receptor therapy, the mechanism by which it promotes tumor metastasis remains undefined. Our study explored a new hypothesis that targeting the Y-box binding protein-1 (YB-1)-insulin-like growth factor-I receptor (IGF-IR) signaling axis which is downstream of KRAS, with a novel integrin-linked kinase inhibitor, T315, represents a therapeutically relevant strategy to block KRAS mutation-driven tumor progression. In liver metastases from CRC patients, we observed that there was a preponderance (79/108) of over-expression in both YB-1 and IGF-1R by immunohistochemistry. In colon cancer cell lines HCT-116 and SW480, knockdown and over-expression of KRAS affected the protein and mRNA levels of IGF-1R in a dose-dependent manner. But KRAS only affected the protein level and not mRNA of YB-1, thus suggesting that KRAS regulated YB-1 expression at the post-transcriptional level. Manipulation of YB-1 via plasmid overexpression and siRNA affected IGF-1R protein and mRNA levels in a dose-dependent manner, and YB-1 and IGF-1R promoter binding was confirmed via ChIP assay. There was a dose-dependent decrease in YB-1 and IGF-1R protein levels with MEK162, a MEK inhibitor, but not with LY294002m a PI3K inhibitor. This demonstrated that the KRAS regulation of the YB-1- IGFR-1R signaling axis to be via the MEK signaling pathway and not PI3K/Akt. Our novel drug T315 targets YB-1, and was shown to inhibit cell viability and cell migration in a dose-dependent manner. T315 treatment of the colon cancer cells also decreased protein levels of YB-1 and IGF-1R and affected epidermal mesenchymal transition markers such as E-cadherin, vimentin, and snail. These results suggest that a combination of a MEK inhibitor and T315 may be an effective therapeutic strategy to target KRAS mutation driven CRC.
Citation Format: Christina Wu, Peng-Chan Lin, Po-Chen Chu, Hsiao-Ching Chuang, Samuel Kulp, Tanios Bekaii-Saab, Ching-Shih Chen. Therapeutic targeting of KRAS mutation-driven tumor progression in colorectal cancer. [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 5424. doi:10.1158/1538-7445.AM2015-5424
Abstract 5432: Discovery and characterization of USP22 inhibitors as novel anti-cancer agents
Authors: Wang Feng , Stanek Timothy R. , Biswas Leelabati , Kodrasov Matthew , LaRocque James , Wu Jian , Sterner David , Weinstock Joseph , Mattern Michael , McMahon Steven B. , Kumar Suresh 
Published: August 2015

Abstract
The degradation of most cellular proteins is regulated by coordinated addition and removal of ubiquitin by families of ubiquitin E3 ligases and deubiquitylating enzymes (DUBs) respectively. DUBs proteolytically cleave ubiquitin molecules from proteins resulting in modifications of protein activity, localization and function. Several DUBs are aberrantly regulated in cancer, including the best studied, USP7, selective inhibitors of which are active in cancer models. USP22, is another validated anticancer target, being one of 11 genes in the death-from-cancer gene signature, a component of the human SAGA transcriptional cofactor complex regulating myc transcription, and a regulator of the expression of p21, the histone deacetylase Sirt 1, and p53 activity. USP22 is overexpressed in oral squamous cell carcinoma, breast, non-small cell lung, colorectal, and other cancers and its expression is inversely correlated with survival. Unlike most other DUBs, USP22 exhibits robust activity only as a component of a multi-subunit complex. Initial studies reported activity solely as a member of the 2MDa SAGA complex, but more recently it has been demonstrated that USP22 exhibits similar activity in a four-protein DUB module derived from the SAGA complex. USP22 inhibitors are expected to have broad anti-cancer activities. Progenra's UbiProTM discovery platform was utilized to screen ∼200K member diversity based library of small molecules for identifying novel USP22 inhibitors. Data will be presented describing these results.
Citation Format: Feng Wang, Timothy R. Stanek, Leelabati Biswas, Matthew Kodrasov, James LaRocque, Jian Wu, David Sterner, Joseph Weinstock, Michael Mattern, Steven B. McMahon, Suresh Kumar. Discovery and characterization of USP22 inhibitors as novel anti-cancer agents. [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 5432. doi:10.1158/1538-7445.AM2015-5432
Abstract 5433: Discovery and development of novel USP2 inhibitors for cancer therapy
Authors: Kumar Suresh , LaRocque James P. , Marblestone Jeffrey G. , Wu Jian , Weinstock Joseph , Sterner David E. , Mattern Michael R. 
Published: August 2015

Abstract
Ubiquitylation and deubiquitylation control the stability, localization and activity of many cellular proteins. Deubiquitylation is performed by a family of ∼80 enzymes (DUBs) and many of these DUBs have been implicated in a wide range of diseases including cancer. In particular, USP2 removes ubiquitin selectively from Cyclin D1, Cyclin A1, Aurora A, MDM2 and FAS which are all implicated in oncogenic processes. Importantly, USP2 is overexpressed in prostate and ovarian cancers and inhibition of USP2 has been shown to sensitize prostate carcinoma cells to apoptosis. Therefore USP2 is an attractive therapeutic target. Progenra's unique UbiProTM discovery platform was utilized to screen ∼200K member diversity based library of small molecules for identifying novel USP2 inhibitors. Hits from the screen were subjected to orthogonal selectivity assays to identify USP2 specific inhibitors. Here we report discovery and hit to lead optimization of novel USP2 inhibitors showing cellular efficacy and anti-cancer activities against relevant cancer cell models. The most promising compounds are being further developed as novel anti-cancer agents.
Citation Format: Suresh Kumar, James P. LaRocque, Jeffrey G. Marblestone, Jian Wu, Joseph Weinstock, David E. Sterner, Michael R. Mattern. Discovery and development of novel USP2 inhibitors for cancer therapy. [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 5433. doi:10.1158/1538-7445.AM2015-5433
Abstract 5434: A high through-put bioluminescent assay to monitor the deamidation of asparagine and isomerization of aspartate residues in therapeutic proteins and antibodies
Authors: Goueli Said A. , Hsiao Kevin , Patel Rushikesh , Nashine Vishal 
Published: August 2015

Abstract
Spontaneous degradation reactions such as oxidation, glycation, deamidation, Isomerization, and racemization are non-enzymatic modifications and produce functionally damaged species reflecting aging effect at the molecular level. L-asparagine (Asn) and L-aspartate (Asp) are among the most unstable residues in proteins- linked to deamidation, isomerization and racemization Rx. Under physiological conditions, succinimide-linked deamidation of Asn occurs with t1/2as short as 6 hrs while that for isoaspartate are generally 10-fold longer. A number of biological peptides and proteins possess labile Asn and Asp residues and the formation of IsoAsp at these sites adversely affect their function. The degradation of Asn and Asp sites via succinimide pathway has significant effect on protein function. Loss of function associated with isoAsp formation are found in many biologically critical proteins and is a major source of antibody instability and micro heterogeneity, Thus it is critical to accurately determine both the levels and the site of Asn deamidation in therapeutic antibodies and proteins. Although mass Spectroscopic platforms have been at the forefront of technologies to quantitate and identify sites of isoAsp formation, it fails in accurately determining Asn level and has problems with Asp isomerization due to the various steps required for sample preparation such as denaturation, reduction, alkylation, and enzyme digestion of the Ab before analysis resulting in problems with Asp isomerization and Asn determination artifacts. Although peptide mapping is the most powerful tool in isoAsp analyses, it is very time consuming and may itself actually cause sample degradation during preparation and analysis and is not always practical when large number of samples are needed for analysis. To improve on and complement existing technologies, we have developed a bioluminescent, homogenous, robust, sensitive and easy to use assay to accurately monitor the deamidation of Asn and isomerization of aspartate. The assay is based on the use of protein isoaspartate methyltransferase to catalyze the methylation of isoaspartate using S-adenosylmethionine (SAM) and resulting in the formation of S-adenosylhomocysteine and methylated isoaspartate. The assay is very sensitive, it can detect as little as 100 fmol of IsoAsp in as little as 5-10 pmol of proteins.
Citation Format: Said A. Goueli, Kevin Hsiao, Rushikesh Patel, Vishal Nashine. A high through-put bioluminescent assay to monitor the deamidation of asparagine and isomerization of aspartate residues in therapeutic proteins and antibodies. [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 5434. doi:10.1158/1538-7445.AM2015-5434
Abstract 5435: A bioluminescent assay for measuring glucose uptake
Authors: Valley Michael P. , Sobol Mary , Vidugiriene Jolanta , Cali James J. 
Published: August 2015

Abstract
Glucose management is a key biological process. In adipose tissue and skeletal muscle, decreased rates of glucose uptake commonly associated with diabetes mellitus lead to chronic hyperglycemia and a wide array of physiological damage. In contrast, the overexpression of glucose transporters in cancer cells results in increased rates of glucose uptake to support their high rates of proliferation. Thus, activators and inhibitors of glucose uptake are useful for both diabetes management and anticancer therapies. The standard method of assaying glucose uptake involves addition of a radioactive glucose analog (2-deoxyglucose) and measurement of the accumulation of the stable and impermeable phosphorylated derivative, 2-deoxyglucose-6-phosphate (2DG6P). However, radioactive assays are laborious, costly, and require special handling of radioactive materials and waste. A simpler assay can be made by measuring the production of NADPH through the oxidation of 2DG6P by glucose-6-phosphate dehydrogenase. We have developed a bioluminescent glucose uptake assay that is both rapid and convenient and exhibits a larger signal window than comparable fluorescent or colorimetric approaches. The utility of this assay will be demonstrated with both cancer cells and insulin-sensitive 3T3L1 adipocytes and L6 myotubes.
Citation Format: Michael P. Valley, Mary Sobol, Jolanta Vidugiriene, James J. Cali. A bioluminescent assay for measuring glucose uptake. [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 5435. doi:10.1158/1538-7445.AM2015-5435