bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1998: A novel luminescent system for monitoring intracellular protein:protein interactions
Authors: Binkowski Brock , Dixon Andrew S. , Schwinn Marie K. , Hall Mary P. , Zimmerman Kris , Otto Paul , Lubben Thomas , Butler Braeden , Kirkland Thomas , Wood Monika G. , Encell Lance P. , Fan Frank , Wood Keith V. 
Published: August 2015

Abstract
Protein:protein interactions (PPIs) are essential to the cellular signal transduction pathways that contribute to cancer. Although numerous approaches exist to monitor protein:protein interactions in vitro, methods for intracellular detection have been more limited. We developed a system for the detection of PPIs based on NanoLuc luciferase. Proteins are fused to either an 18 kDa or 1 kDa subunit. PPI facilitates interaction of the subunits, leading to increased luminescence. Intracellular PPIs are measured using a non-lytic assay protocol by providing a cell permeable substrate. The interaction status can be monitored at a single time point or followed continuously over 1-2 hours. Unlike related approaches where a luciferase enzyme is simply split, the subunits of this system were optimized for structural stability and minimal binding affinity. The result is a luminescence signal that is orders of magnitude brighter than approaches using split luciferase, allowing use of fusion protein expression levels at or near physiological levels. The low affinity interaction between subunits (Kd ∼200 μM) minimizes assay background by preventing non-specific association, and the system shows rapid reversibility using model systems such as protein kinase A catalytic and regulatory subunits. We have successfully applied this system to several PPIs related to cancer research, including TP53:MDM2, MYC:MAX, and members of the RAS-RAF signaling pathway.
Citation Format: Brock Binkowski, Andrew S. Dixon, Marie K. Schwinn, Mary P. Hall, Kris Zimmerman, Paul Otto, Thomas Lubben, Braeden Butler, Thomas Kirkland, Monika G. Wood, Lance P. Encell, Frank Fan, Keith V. Wood. A novel luminescent system for monitoring intracellular protein:protein interactions. [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 1998. doi:10.1158/1538-7445.AM2015-1998
Abstract 2012: Accurate measurement of free and complexed PSA concentrations in serum of women using a novel technology with fg/mL sensitivity
Authors: Nikolenko Galina N. , Stengelin Martin K. , Sardesai Laukik , Glezer Eli N. , Wohlstadter Jacob N. 
Published: August 2015

Abstract
Measurement of free and complexed PSA (prostate specific antigen; complexed with ACT) in certain patient groups such as prostatectomy patients and women at risk of breast and ovarian cancer has been limited by the sensitivity of current immunoassay technology (5-30 pg/mL for common clinical analyzers). Fifth generation assays for total PSA with detection limits of 0.05 to 0.1 pg/mL have been described (McDermet 2009; Thaxton 2009; Wilson 2011). We developed a next-generation assay format based on MSD's MULTI-ARRAY® electrochemiluminescence technology with detection limits of 2 fg/mL (0.002 pg/mL) for complexed PSA (cPSA) and 20 fg/mL for free PSA (fPSA), requiring only 25 μL of serum or plasma per measurement.
Assays were calibrated against the WHO standards 96/668 (free PSA) and 98/670 (90% complexed, 10% free PSA). The dynamic range of both assays was three to four orders of magnitude. Typical intra-plate coefficients of variation ranged from 5% to 15%. LLOQ's of cPSA and fPSA assays were 5 fg/mL and 55 fg/mL, respectively. Spike recovery and dilution linearity were between 80% and 120%. Approximately 100 serum samples from women were evaluated. Free PSA was detectable in 95% of samples and cPSA was detectable in all samples.
Multiple literature reports indicate that free PSA might be a marker for early detection of breast cancer; however, the concentrations of many samples were close to or below the detection limits of the assays used for the studies. We tested 48 serum samples from patients with breast cancer and 37 serum samples from apparently healthy women. As the table below shows, there was no clear difference between PSA concentrations in cases and controls.
Free PSA [fg/mL] (Median, IQR)cPSA [fg/mL] (Median, IQR)Free/cPSA (Median, IQR)Apparently Healthy (n = 37)150 (80-260)560 (210-1,500)0.29 (0.18-0.73)Breast Cancer (n = 48)90 (50-260)180 (90-480)0.36 (0.17-0.77)Breast Cancer, ER positive (n = 10)160 (80-660)170 (120-13,000)0.62 (0.22-1.8)Breast Cancer, HER2 positive (n = 10)160 (50-290)460 (110-8,300)0.10 (0.03-0.44)Breast Cancer, triple negative (n = 10)90 (40-370)140 (50-300)0.68 (0.34-1.9)
In conclusion, we developed a next-generation assay format that is 100 to 1000 times more sensitive than the currently available clinical PSA assays. This enables accurate determination of free PSA and cPSA concentrations in the serum of females.
Citation Format: Galina N. Nikolenko, Martin K. Stengelin, Laukik Sardesai, Eli N. Glezer, Jacob N. Wohlstadter. Accurate measurement of free and complexed PSA concentrations in serum of women using a novel technology with fg/mL sensitivity. [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 2012. doi:10.1158/1538-7445.AM2015-2012
Abstract 2031: RRD-251 enhances retinoic acid induced differentiation of myeloblastic leukemic cells
Authors: Wallace Aaron S. , Geil Wendy M. , Yen Andrew 
Published: August 2015

Abstract
All-trans-retinoic acid (RA) is known to induce terminal granulocytic differentiation and cell cycle arrest in HL-60 cells. This is driven by sustained activation of the MAPK pathway, where Raf-1 (MAPKKK) acts as a critical signaling molecule. RRD-251 is a small molecule that binds to the Rb protein and prevents its interaction with Raf-1. Hyperphosphorylation of Rb leads to a conformational change, inhibiting its ability to sequester the E2F family of transcription factors. To determine the effect of RRD-251 on RA-induced differentiation, cells were treated with RA and/or RRD-251 and then analyzed for proliferation, expression of key markers of differentiation, cell cycle arrest, and modifications in protein levels. RRD-251 by itself significantly inhibited proliferation, but cells treated with both RA and RRD-251 showed even further reduction in cellular growth. Similarly, both RA and RRD-251 induce cell cycle arrest, but cells treated with both show higher levels of G0/G1 than singly treated cells. Expression of CD11b is used a late classical marker for differentiation in HL-60. RRD-251 does not induce expression of CD11b, but cultures treated with RRD-251 and RA have nearly double the amount of cells expressing CD11b as compared to RA treated cells alone 72 hours after treatment. Additionally, we had wanted to see the relationship between specific Rb phosphorylation, the cell cycle, and treatment of RA and RRD-251. At 72 hours after treatment, RA induces the formation of a population of cells with no phosphorylation at serine 608 of Rb, which was 99.9% in G0/G1. The appearance of two populations for Rb phosphorylation was unique to serine 608 out of the four phospho-sites that we studied: serine 608, serine 780, serine 795, serine 807/811. Cells treated with both RA and RRD-251 had more cells in the no-phosphorylation population at 72 hours, as well as the appearance of this population at 48 hours. Finally, we observed the changes in protein amounts and localizations by western blotting. RA is known to cause the phosphorylation of Raf-1 at serine 621 and its translocation to the nucleus at 48 hours. This was observed on our blots and that cells treated with both RA and RRD-251 had increased amounts of total nuclear Raf-1 and of pS621 Raf-1 at 48 and 72 hours. The results reported here further support the usefulness of RRD-251 as an anti-cancer drug, from reducing tumor size and preventing angiogenesis in drug-resistant melanoma, to enhancing retinoic acid-induced differentiation in myeloblastic leukemic cells.
Citation Format: Aaron S. Wallace, Wendy M. Geil, Andrew Yen. RRD-251 enhances retinoic acid induced differentiation of myeloblastic leukemic cells. [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 2031. doi:10.1158/1538-7445.AM2015-2031
Abstract 2038: A novel role for the NLRP3 inflammasome in lung cancer
Authors: Petrilli Virginie , Bodnar Mélanie , Guey Baptiste , Hacot Sabine , Lantuejoul Sylvie 
Published: August 2015

Abstract
Although significant advances have been made in the diagnosis and treatment of lung cancer, it remains the most fatal cancer worldwide. This poor outcome is mainly due to the limited curative options available especially for advanced cancer stages. About 80% of lung cancers are Non Small Cell Lung Cancers (NSCLC). Although several mutations in oncogenes and tumor genes have been identified in NSCLC, the oncogene K-ras and the Receptor Tyrosine Kinases (RTK) being the most frequently mutated, about 40% of cancers are driven by unidentified mutations. Many cancer cells activate a proinflammatory program to manipulate the host immune system to support their growth. Inflammasomes are crucial effectors of the innate immunity. Upon activation, inflammasomes assemble into multiprotein complexes controlling the activation of the inflammatory caspase-1 and the maturation of the pro-Interleukin-1beta (pro-IL-1b) and the pro-IL-18 into active cytokines. The NLRP3 inflammasome detects pathogens, airborne pollutants but also self-danger signals released by dying cells. In the lung, hyperactivation of this complex upon bleomycin or asbestos exposure drives an inflammatory response resulting in lung fibrosis.
Published large-scale genomic analyses of NSCLC identified somatic mutations in the NLRP3 gene and scored NLRP3 as a putative oncogene. Little is known about the role of the NLRP3 inflammasome in lung cancer. We speculated that the NLRP3 inflammasome could play a prominent role in NSCLC and studied the function of NLRP3 inflammasome in human non-transformed and transformed lung epithelial cells. Our data unravel new functions for the NLRP3 inflammasome in DNA damage sensing and unexpectedly suggest that NLRP3 could act as a tumor suppressor gene in lung cancer.
Citation Format: Virginie Petrilli, Mélanie Bodnar, Baptiste Guey, Sabine Hacot, Sylvie Lantuejoul. A novel role for the NLRP3 inflammasome in lung 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 2038. doi:10.1158/1538-7445.AM2015-2038
Abstract 2052: The transcriptional co-regulator and emerging cancer drug target C-terminal binding protein (CtBP) is a transforming oncogene
Authors: Sumner Evan T. , Grossman Steven R. 
Published: August 2015

Abstract
The paralogous C-terminal binding proteins (collectively CtBP) 1 and 2 are evolutionarily conserved transcriptional co-regulators which demonstrate oncogene-like properties such as allowing for the progression of EMT and cellular invasion/migration, and supporting cellular survival through suppression of tumor suppressors (PTEN, p16, E-cadherin, BRCA-1) and pro-apoptotic genes (Bik, Puma, Noxa). Overexpression of CtBP is found in colon, ovarian, breast, and prostate cancers, and often correlates with loss of the tumor suppressors ARF and APC and with poorer prognosis for the patient. CtBP is also an emerging cancer drug target, encoding a dehydrogenase domain that can be targeted with small molecule inhibitors to kill cancer cells. CtBP appears to fit the criteria for a driver oncogene, though has never been fully characterized as such. To investigate the hypothesis that CtBP is a transforming oncogene, we subjected CtBP2 to multiple assays for cellular oncogenic activity including loss of contact inhibition, invasion, and anchorage independent growth. Previously immortalized NIH 3T3 mouse fibroblasts expressing CtBP2 or mutant H-Ras as a positive control were analyzed for focus formation, Matrigel-invasion, and soft agar colony formation. Consistent with the hypothesis that CtBP exhibits properties of an oncogene, CtBP2 potently induced focus formation, Matrigel-invasion, and soft agar colony formation with similar potency to oncogenic mutant H-Ras. Moreover, CtBP2 cooperated with the adenovirus E1A oncoprotein but not H-Ras to transform primary mouse embryonic fibroblasts (MEFs). Taken together, the 3T3 and MEF transformation data suggest CtBP2 acts as a “Ras-like” oncogene in rodent cell transformation assays. Previous research from our lab has shown that CtBP's ability to induce migration in HCT116 cells depends in part on its activation of T-cell lymphoma invasion and metastasis 1 (Tiam1). Work is ongoing to characterize critical downstream targets for CtBP's transforming activity. Targeting CtBP and its dehydrogenase domain in cancers where the protein is found to be overexpressed, or where its regulators, ARF and APC are found to be inactive, could lead to a therapeutic approach specific for an emerging driver oncogene.
Citation Format: Evan T. Sumner, Steven R. Grossman. The transcriptional co-regulator and emerging cancer drug target C-terminal binding protein (CtBP) is a transforming oncogene. [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 2052. doi:10.1158/1538-7445.AM2015-2052
Abstract 2053: Overexpressed Rab1A is associated poor prognosis and promotes oncogenic growth and metastasis through mTORC1 activation in hepatocellular carcinoma
Authors: Xu Bi-Hong , Li Xiao-Xing , Wang Hui-yun , Zheng X.F. Steven 
Published: August 2015

Abstract
Background: The mammalian target of rapamycin complex 1 (mTORC1) is a pivotal regulator of cell growth and proliferation in response to nutrition and various factor. In recent years, studies have focus on over-activation of mTORC1 in normal cells leading to tumorigenesis and malignant tumor development. However, the precise factors of mTORC1 hyperactivation to promote the growth of hepatocellular carcinoma (HCC) or other cancers are still not well characterized. Thus, in this study, we aimed to clarify a novel gene -Rab1A, and it's expression and functional role in mTORC1 signal in of HCC. Methods: We analyzed the Rab1A protein in HCC and para-cancer samples from 143 patients and the correlation with its survival. To identify Rab1A's role in tumor progression, a serious of functional study were applied including overexpression and knockdown Rab1A in different cell lines both in vivo and in vitro. For mechanism research, western bolt was demonstrated to identify the signal dysregulation between Rab1A abnormity and mTORC1 pathway under involvement of irritants. Results: Our results showed that, compared with normal livers, Rab1A was frequently overexpressed in HCC and significantly associated with HCC prognosis. Functional study demonstrated that overexpression of Rab1A in HCC cells increased cell growth, cell migration, cell cycle progression and tumor formation in vivo and/or in vitro, all of which were effectively inhibited when Rab1A was silenced by shRNA. We further provided evidences that Rab1A promotes HCC growth and migration through phosphorylation of S6K, the consequence of activating mTORC1 signaling pathway. Mechanism research of the signal pathway between Rab1A and mTORC1 suggest that Rab1A is likely to stimulate mTORC1 directly, with the cooperation of Amino acid stimulation but not depend on the pathway of PI3K/AKT and MAPK/ERK..
Citation Format: Bi-Hong Xu, Xiao-Xing Li, Hui-yun Wang, X.F. Steven Zheng. Overexpressed Rab1A is associated poor prognosis and promotes oncogenic growth and metastasis through mTORC1 activation in hepatocellular carcinoma. [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 2053. doi:10.1158/1538-7445.AM2015-2053
Abstract 2055: Overexpression of nuclear met activates NF-κB signaling to promote tumorigenesis and metastasis in hepatocellular carcinoma
Authors: Tey Sze Keong , Tse Edith Yuk Ting , Ko Frankie Chi Fat , Yam Judy Wai Ping 
Published: August 2015

Abstract
Met is a surface receptor tyrosine kinase which upon hepatocyte growth factor (HGF) induction, triggers a diversity of downstream signaling cascades that modulates different cellular processes. Frequently, Met signaling pathway is hijacked in human cancers, resulted in abberant expression and activity. Emerging evidence has shown the presence of nuclear Met (nMet) in some cancerous tissues and cell lines, postulating that nMet could have unexplored functions within nucleus. Up to date, therapeutic antibodies and kinase inhibitos that undergoing clinical trial are all targeting Met surface receptor, which in this case exhibit limitation in acting against nMet. Althought Met is well known of its oncogenic role in hepatocellular carcinoma (HCC), existence and functions of nMet in HCC are yet to be reported. Our present study aim to examine the clinical association and functions of nMet in HCC. Immunohistochemistry of 103 human HCC paired samples showed that nMet was overexpressed in nearly 90% of cases. We also found that nMet overexpression was progressively increased along HCC development, from non-tumorous liver tissue to advanced HCC. Nonetheless, nMet overexpression was significantly associated with venous invasion and poorer overall survival in HCC patients. This suggests that nMet may play a pivotal role in HCC tumorigenesis and metastasis. As revealed by immunoblot and immunofluorescence, we found that nMet is about 48kDa and comprises of cytoplasmic domain of Met, as it can only be detected by an antibody against the carboxyl terminal of Met (C28). To study the functions of nMet, we employed a lentiviral based inducible exression system that tightly controlled by doxycycline to express the cytoplasmic region of Met. Immunofluorescence microscopy showed that juxtamembrane deletion of Met accumulates in the nucleus whereas truncated tyrosine kinase domain accumulates in the cytoplasm, implying a region necessary for nuclear localization of the cytoplasmic fragment. In vitro functional assay showed that nMet significantly promoted HCC cell proliferation and anchorage independent growth. It also significantly augmented HCC cell migration and invasiveness. Besides that, nMet also enhanced HCC tumor formation in animal model. Furthermore, we showed that nMet activates NF-κB reporter activity which might enhances the pro-metastatic gene expression to promote tumor invasiveness and aggressiveness.
Citation Format: Sze Keong Tey, Edith Yuk Ting Tse, Frankie Chi Fat Ko, Judy Wai Ping Yam. Overexpression of nuclear met activates NF-κB signaling to promote tumorigenesis and metastasis in hepatocellular carcinoma. [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 2055. doi:10.1158/1538-7445.AM2015-2055
Abstract 208: Novel intracellular Doppler imaging predicts therapeutic efficacy for personalized medicine
Authors: Turek John J. , Merrill Dan , Custead Michelle , Childress Michael , Nolte David D. , Yakubov Bakhtiyor , An Ran , Matei Daniela 
Published: August 2015

Abstract
This study reports first application of biodynamic imaging (BDI), a novel Doppler imaging technology, in studies of ovarian cancer xenografts and preclinical trials of canine multicentric lymphoma responding to doxorubicin.
In a study of A2780 human ovarian cell lines implanted in mice, an unexpected and large difference was discovered between mouse tumor explants versus A2780 cells grown as 3D tumor spheroids. The biopsied explants from mice were three times more sensitive to platinum, applied in vitro, than were multicellular tumor spheroids. A preclinical trial has been completed for canine non-Hodgkins lymphoma using BDI to predict patient outcome under doxorubicin therapy. The 3D imaging capability of BDI enabled the measurement of tumor heterogeneity in response to the therapy. The biodynamic assay took only 24 hours to complete, while the clinical outcome was often unknown for one to several months. The therapeutic efficacy of doxorubicin was predicted by BDI with 90% accuracy. Based on this success, biodynamic imaging is entering human pilot trials in ovarian, pancreatic, and esophageal cancer.
Biodynamic imaging is a radically different approach to the prediction of therapeutic efficacy for personalized medicine with higher accuracy and more biological relevance than standard cell-based assays. Supported in part by NIH NIBIB 1R01EB016582-01.
Citation Format: John J. Turek, Dan Merrill, Michelle Custead, Michael Childress, David D. Nolte, Bakhtiyor Yakubov, Ran An, Daniela Matei. Novel intracellular Doppler imaging predicts therapeutic efficacy for personalized medicine. [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 208. doi:10.1158/1538-7445.AM2015-208