bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4440: TRAF4 is a key molecule for lung cancer through regulating AKT ubiquitination and activation
Authors: Peng Cong , Li Wei , Chen Xiang , Dong Zigang 
Published: May 2015

Abstract
TRAF4 is a member of TRAF family. Although TRAF4 was reported to be overexpressed in cancer tissues, the role of TRAF4 in tumorigenesis remains unclear. Here, we found TRAF4 is over expressed in lung cancer cell lines as well as lung cancer tissues. Knockdown TRAF4 dramatically attenuated lung cancer malignant phenotype including cell proliferation, anchorage independent growth and tumor development in a xenograft mouse model . To our surprised, it is that TRAF4, but not skp2 is required for Akt activation through ubiquitination in lung cancer. Overall, our study suggests that TRAF4 might be a potential molecular target for lung cancer prevention and therapy.
Citation Format: Cong Peng, Wei Li, Xiang Chen, Zigang Dong. TRAF4 is a key molecule for lung cancer through regulating AKT ubiquitination and activation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4440. doi:10.1158/1538-7445.AM2014-4440
Abstract 4483: IO125, a novel Pt-based supramolecular therapeutic exhibits increased anti-cancer efficacy compared with oxaliplatin
Authors: Roy Monideepa , Hossain Sk Samad , Sarkar Arindam , Sengupta Aniruddha , Gupta Nimish , Hussain Sajid , Ansari Aasif , Mylavarapu Sanghamitra , Sengupta Shiladitya 
Published: May 2015

Abstract
Despite the widespread use of platinum chemotherapy, only few drugs have been approved in this class of molecules. Here, we describe a novel supramolecular chemistry-based platform technology to engineer more potent oxaliplatin analogues. In IO125, a unique platinum (II) is tethered to a cholesterol backbone via a monocarboxylato bond and an N→Pt coordination environment, releasing diaminocyclohexane (DACH)-platinum in a sustained pH-dependent manner. The molecule facilitates assembly into defined nanoscale supramolecular structures of uniform size distribution as measured using dynamic light scatter and electron microscopy. Such a supramolecular therapeutic demonstrates enhanced activity compared with oxaliplatin in 4T1 and MDA-MB-231 triple negative breast cancer lines. The uptake of IO125-based supramolecular therapeutic was 10-20 fold greater than free oxaliplatin in these cells. In addition, the nanoparticles exhibited significantly lower IC50 values in comparison to oxaliplatin in primary colorectal carcinoma lines generated from patient tumor sample. Nanostructures have been shown to exhibit superior pharmacokinetics profile and biodistribution to tumors due to an enhanced permeability and retention (EPR) effect. Based on these observations, we anticipate an IO125-based supramolecular therapeutic may emerge as a novel next-generation platinum-based potent anti-cancer agent.
Citation Format: Monideepa Roy, Sk Samad Hossain, Arindam Sarkar, Aniruddha Sengupta, Nimish Gupta, Sajid Hussain, Aasif Ansari, Sanghamitra Mylavarapu, Shiladitya Sengupta. IO125, a novel Pt-based supramolecular therapeutic exhibits increased anti-cancer efficacy compared with oxaliplatin. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4483. doi:10.1158/1538-7445.AM2014-4483
Abstract 4490: A novel tumor-targeting construct aimed at c-Met
Authors: mastali mitra , Sims Jessica D , Taguiam Jan M , Hanson Chris , Valenteen Felix Alonso , Medina-Kauwe Lali K. 
Published: May 2015

Abstract
C-Met is a receptor tyrosine kinase (RTK) that is activated by the binding of its ligand, hepatocyte growth factor (HGF). The HGF/c-Met pathway contributes to embryonic development, wound healing, cell proliferation and survival, motility and morphogenesis. It is also one of the most frequently dysregulated pathways in a variety of human cancers, including breast, ovarian, prostate, lung, and pancreatic. Importantly, cell surface elevation of c-Met has been associated with drug-resistance, including acquired resistance to current signal-blocking therapies.
Tumor-targeting strategies that do not require signal inhibition may prove more effective on c-Met positive cancer cells. This may be addressed by ligands that recognize c-Met to trigger cell uptake of attached therapeutics, thus bypassing the need to block signaling. HGF has the potential to accomplish this but its requirement for tetramerization and disulfide bonding presents technical complications for therapeutics development. An alternative, and potentially superior ligand for c-Met targeting may possibly be derived from a bacterium that causes food-poisoning.
The human pathogen, Listeria monocytogenes, binds c-Met to invade host cells through its surface proteins called Internalins. Specifically, Internalin B (InlB) triggers receptor-mediated endocytosis after c-Met binding. InlB and HGF recognize different regions of c-Met, and InlB does not require tetramerization or disulfide bonds for binding. Consequently, InlB is more suitable for recombinant protein production than HGF.
We have previously shown that PBK10, a recombinant protein derived from the adenovirus capsid penton base, can mediate gene and drug delivery into cells through the membrane penetrating activity of the penton base. Moreover, PBK10 can be targeted to tumor cells via recombinant fusion to tumor-homing ligands. Here, we explore the possibility of fusing the receptor-binding site of InlB to PBK10 for targeting attached cytotoxic agents to c-Met positive cancer cells, and transporting such agents directly into these cells via receptor-mediated endocytosis and membrane penetration.
Citation Format: mitra mastali, Jessica D Sims, Jan M Taguiam, Chris Hanson, Felix Alonso Valenteen, Lali K. Medina-Kauwe. A novel tumor-targeting construct aimed at c-Met. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4490. doi:10.1158/1538-7445.AM2014-4490
Abstract 4550: Differential PARP inhibitors' effects on cell cycle and consequently homologous DNA damage repair
Authors: Jelinic Petar , Levine Douglas A. 
Published: May 2015

Abstract
Background: Poly (ADP)-ribose polymerase (PARP) inhibition has been explored in pre-clinical and clinical studies with greatest successes demonstrated in homologous DNA damage repair (HDR) pathway-deficient cancer patients. PARP inhibitor's (PARPis) potency to inhibit PARP's catalytic activity is well established; however non-catalytic effects that may add to their therapeutic properties are not fully understood. Our objective was to comparatively evaluate non-catalytic effects of olaparib and veliparib, the two most widely used PARPis in clinical trials, with a particular focus on cell cycle effects and HDR.
Methods: To measure DNA damage repair activity upon PARPi treatment, we used a well-established DR-GFP reporter assay in two model cell lines, U2OSDR-GFP and H1299DR-GFP. Cell cycle progression was assessed by propidium iodide and monitored by flow cytometry. Depletion of targeted mRNAs was performed by standard siRNA knock-down technique using electroporation for transfection. Immunoblotting was used to confirm cell cycle results and demonstrate replicative stress on the protein expression levels.
Results: We found a dramatic decrease in DNA damage repair activity in olaparib- versus veliparib-treated U2OSDR-GFP p53 wild type cells, regardless of inhibitory potency. This decrease in HDR activity was a result of olaparib triggering a cell cycle arrest-like effect as a response to strong replicative stress. Lack of the same effect in p53-null cells suggests that olaparib's effect is p53-dependent, which was confirmed in U2OSDR-GFP cells depleted of p53. Finally, CHK1 is strongly phosphorylated in cells treated with olaparib but not veliparib, confirming cells differential response to these two PARPis.
Conclusion: These data demonstrate that olaparib and veliparib differ in their non-catalytic inhibitory effects, with olaparib but not veliparib mitigating DNA damage repair activity via cell cycle arrest-like effects in a p53-WT background. Moreover, olaparib but not veliparib triggers CHK1 phosphorylation, which suggests differential levels of replicative stress. This new insight into olaparib's and veliparib's mechanism of action should be considered when developing inclusion criteria for treatment of cancer patients with these PARP inhibitors.
Citation Format: Petar Jelinic, Douglas A. Levine. Differential PARP inhibitors' effects on cell cycle and consequently homologous DNA damage repair. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4550. doi:10.1158/1538-7445.AM2014-4550
Abstract 457: Expression, purification, and characterization of recombinant TAT-SALL4B protein
Authors: Yuan Mengru , Jiang Yongping , Dai Wei 
Published: May 2015

Abstract
SALL4 is an important transcription factor that supports expansion of hematopoietic stem cells. Several recent studies reveal that SALL4 and SALL4B (a major isoform) are heavily modified by post-translational mechanisms and that these modifications are critical for their stability, subcellular localization, and transcriptional activities. Given the importance of SALL4 and SAL4B in supporting stem cell self-renewal and expansion, we optimized a large scale expression and purification process to obtain SALL4B. Sf9 insect cells were transduced with the recombinant baculovirus expressing human SALL4B fused with 6His residues and a TAT sequence in the N-terminus. Recombinant TAT-SALL4B was purified by nickel affinity chromatography under native conditions. Immuno-blotting confirmed that recombinant SALL4B was highly expressed and purified. As the first step to test the biological activity of purified TAT-SALL4B, we investigated whether TAT-SALL4B, directly supplemented to the culture medium, was capable of entering into cells through the protein transduction process. Immuno-fluorescence microscopy revealed that recombinant TAT-SALL4B specifically localized to the nucleus in a concentration- and time-dependent manner. To further test the transcriptional activity of TAT-SALL4B protein, dual luciferase reporter assay was performed, which showed that TAT-SALL4B protein was transcriptionally active.Our results suggest that TAT-SALL4B may provide a promising cellular factor for supporting ex vivo expansion of hematopoietic stem cells.
Citation Format: Mengru Yuan, Yongping Jiang, Wei Dai. Expression, purification, and characterization of recombinant TAT-SALL4B protein. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 457. doi:10.1158/1538-7445.AM2014-457
Abstract 4982: Characterization of novel α-ketoamide derivatives as potent inhibitors against cathepsin S induced by acidic extracellular pH in pancreatic cancer cells
Authors: Chang Wun-Shaing Wayne , Chang Tzu-Yuan , Wu Tzu-Chin , Liao Chien-Yu , Lin Chun-Cheng 
Published: May 2015

Abstract
Extracellular acidification is known to be a driving force in pancreatic cancer growth and metastasis. Thus, manipulation of acidic peritumoral pH or blockage of key proteins stimulated by acidic extracellular microenvironment may offer considerable potential for pancreatic cancer therapy. Cathepsin S, also known as CTSS or CatS, is a critical proteolytic enzyme found to be up-regulated in malignant cells and secreted into the extracellular milieu to degrade surrounding matrix components. By examining the effect of low pH (6.7) on various pancreatic tumor cell lines, we detected a consistently increased CTSS expression associated with augmented cell migration and invasion. Other features such as CTSS-mediated proteolysis and ECM degradation were also observed under mildly acidic condition. Based on these findings, we designed and synthesized some new small molecules bearing an α-ketoamide warhead to evaluate their ability to inhibit CTSS. Kinetic study revealed these compound inhibitors possess very low Ki values and high specificity against target CTSS enzyme. Further in vitro and in vivo analyses demonstrated these agents not only could protect fibronectin from CTSS-mediated degradation but also induce tumor cell autophagy under extracellular acidification. Together these results indicate the potential of α-ketoamide derivatives as antitumor agents against pancreatic cancer.
Citation Format: Wun-Shaing Wayne Chang, Tzu-Yuan Chang, Tzu-Chin Wu, Chien-Yu Liao, Chun-Cheng Lin. Characterization of novel α-ketoamide derivatives as potent inhibitors against cathepsin S induced by acidic extracellular pH in pancreatic cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4982. doi:10.1158/1538-7445.AM2014-4982
Abstract 5037: Targeting MICA with therapeutic antibodies for the treatment of cancer
Authors: Blery Mathieu , Bonnafous Cécile , Peri Valentine , Trichard Sylvia , Perrot Ivan , Cornen Stéphanie , Thielens Ariane , Breso Violette , Morel Yannis , Romagne François , Rossi Benjamin , Paturel Carine , Gauthier Laurent 
Published: May 2015

Abstract
MICA and MICB, along with ULPBs, are ligands for the activating receptor NKG2D expressed on NK cells and subsets of T cells in Human. NKG2D ligands are induced by cellular stress and pathogen infections. Their expression is tightly regulated by complex mechanisms both at the mRNA and protein levels. In the case of MICA and MICB, more than 65 and 30 alleles respectively were described with different properties regarding to their cellular location adding to the complexity of this recognition system. Nevertheless, as markers of cellular stress, in particular in tumorigenesis, MICA and the closely related MICB proteins are candidates of choice to be targeted by a cytotoxic therapeutic antibody. We first evaluated MICA/B expression by immunohistochemistry on healthy tissues and tumors to validate these antigens as therapeutic targets. Then, using mouse immunization, we generated a panel of chimeric human IgG1 monoclonal antibodies targeting MICA and MICB. These mAbs have the ability to bind to several structurally different alleles and to cross-react on MIC proteins from cynomolgus macaques. Their capacity to block the MICA/NKG2D interaction was assessed by surface plasmon resonance as well as by using cell-based assays. In vitro efficacy was measured by the capacity to mediate complement-dependent cytotoxicity (CDC) and antibody-dependent cell cytotoxicity (ADCC) towards MICA expressing cells. In vivo efficacy of the anti-MICA mAbs was measured in both a preventive and a curative setting using MICA expressing cell lines. Altogether, we have generated a panel of anti-MICA mAbs with diverse functional properties. Ongoing work aims to choose the best candidate for humanization and further clinical development.
Citation Format: Mathieu Blery, Cécile Bonnafous, Valentine Peri, Sylvia Trichard, Ivan Perrot, Stéphanie Cornen, Ariane Thielens, Violette Breso, Yannis Morel, François Romagne, Benjamin Rossi, Carine Paturel, Laurent Gauthier. Targeting MICA with therapeutic antibodies for the treatment of cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5037. doi:10.1158/1538-7445.AM2014-5037
Abstract 5099: Automated rapid and accurate cell cycle analysis
Authors: Yurlova Larisa , Gregor Jacqueline , Sirenko Oksana , Cromwell Evan , Zolghadr Kourosh 
Published: May 2015

Abstract
It is essential to have detailed information about compounds identified in screening campaigns during drug discovery and to know their influence on cell cycle progression or DNA repair. The discovery of Chromobodies® and advancements in High Content Imaging systems with improved optical properties and live cell capabilities has opened the door for new reliable and robust screening assays that provide these relevant high quality data.
Chromobodies are a novel class of fluorescent antibodies, based on special heavy chain antibodies from camelids (VHHs). These unique nanoprobes can be transfected into cells as plasmid DNA similar to any conventional fusion protein. The cell expresses the fluorescent antibody-fragment thus enabling the non-invasive imaging of endogenous proteins and processes in real time. Therefore Chromobodies avoid any deleterious side effects from the traditional over-expression of a tagged protein. This is especially true for the essential components of the DNA replication, DNA repair and DNA methylation machinery: Proliferating Cell Nuclear Antigen (PCNA) and DNA Methyltransferase 1 (Dnmt1) . It has been shown that high over-expression of theses proteins can have adverse effects on normal progression through S phase.
In this study we present a new method to evaluate cell cycle and DNA methylation. We developed Chromobodies directed against PCNA and Dnmt1. Transfecting these Chromobodies into cells circumvents the laborious and error-prone staining procedure with conventional antibodies. We demonstrate the flexible use of the Cell Cycle Chromobody cell line in conjunction with different automated high content imaging platforms. We show dose-dependent cell cycle inhibition caused by a number of anti-cancer drugs, DNA damage and apoptosis inducing compounds. Multiple analysis protocols enable the fast and accurate analysis with quantitative information on each sub phase of DNA replication for each individual cell. Moreover, by continuing to film cells, the exact length the cell cycle stages can also be extrapolated, thereby providing detailed temporal information on G1, S, G2 and M phase.
Citation Format: Larisa Yurlova, Jacqueline Gregor, Oksana Sirenko, Evan Cromwell, Kourosh Zolghadr. Automated rapid and accurate cell cycle analysis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5099. doi:10.1158/1538-7445.AM2014-5099
Abstract 5219: MicroRNA-874 impedes angiogenesis in non-small cell lung cancer
Authors: Chetty Chandramu , Maddirela Dilip R. , Gogineni Venkateswara R. , Chittivelu Subramanyam , Rao Jasti S. , Moorthy Bhagavatula 
Published: May 2015

Abstract
MicroRNAs (miRs) are short (20-24nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in eukaryotes by affecting both the stability and translation of mRNAs. MicroRNAs play crucial roles in normal biological processes and are commonly dysregulated in human diseases. Thus far, miRs have been shown to act as either tumor suppressor genes or oncogenes in driving critical gene expression pathways in cancer stem cells in a wide range of human malignancies, including non-small cell lung cancer (NSCLC).We previously found that miR-874 could suppress tumor growth and metastasis of NSCLC. Since angiogenesis is important for tumor growth and metastasis, in this study, we further investigated the possible roles of miR-874 in tumor angiogenesis. Attenuation of miR-874 expression in histological sections of NSCLC tumors and the CD133 positive population of NSCLC cells (NSCLC-initiating cells; NSCLC-ICs), as compared to its normal counterparts, was observed by in situ hybridization and real time quantitative PCR, respectively. Tumor-conditioned medium from NSCLC-ICs induced significantly high levels of endothelial cell capillary network and neovascularization in vivo; whereas, re-expression of miR-874 in NSCLC-ICs inhibited this capillary network formation ability by suppressing the protein levels of VEGF, Stat3, MMP-2, uPA and PI3K. Further, miR-874-treatment decreased in vivo angiogenesis and pre-established orthotopic tumor growth in nude mice as compared to mock- and control-miR-treatments. Immunohistochemical analysis revealed a significant decrease in the expression of VEGF, Stat3 and microvessel density (CD31 levels) in xenograft tumor sections from miR-874-treated mice. In conclusion, our study highlights the possible anti-angiogenic role of miR-874 in NSCLC-initiating cells and presents a new, hopeful therapeutic target and prognostic marker for NSCLC.
Citation Format: Chandramu Chetty, Dilip R. Maddirela, Venkateswara R. Gogineni, Subramanyam Chittivelu, Jasti S. Rao, Bhagavatula Moorthy. MicroRNA-874 impedes angiogenesis in non-small cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5219. doi:10.1158/1538-7445.AM2014-5219