bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5364: ATF3 contributes to the DNA damage response by regulating the histone acetyltransferase Tip60
Authors: Cui Hongmei 
Published: May 2015

Abstract
Activating transcription factor 3 (ATF3) is a common stress mediator, and its expression is rapidly induced upon DNA damage. Although we have demonstrated that ATF3 can activate the tumor suppressor p53 and regulate expression of p53 target genes, the consequences of ATF3 induction by DNA damage remain elusive. Tat-interactive protein 60 (Tip60) belongs to the MYST family of histone acetyltransferase, and plays important roles in regulating chromatin remodeling, transcription, and the DNA damage response. While Tip60-mediated p53 acetylation promotes pro-apoptotic gene expression, Tip60 can also catalyze acetylation of ATM resulting in increased ATM kinase activity thereby mobilizing DNA repair machinery. Here we report that ATF3 can directly bind Tip60 and regulates its function in the DNA damage response. ATF3 binds Tip60 via its leucine zipper domain, and can increase Tip60 stability by blocking its ubiquitination. This effect is achieved through ATF3 binding to Tip60 as an ATF3 mutant devoid of Tip60 binding fails to block Tip60 ubiquitination and stabilize Tip60. Consistent with these results, knockdown of ATF3 expression decreases the level of Tip60 protein, but not its mRNA. Interestingly, ATM phosphorylation, a marker for ATM activation, is significantly suppressed in ATF3 knockdown cells. Therefore, we identified that ATF3 as a novel regulator of Tip60 in the DNA damage response. Our results suggest that, consistent with its tumor suppressor role, ATF3 may contribute to the DNA damage response by activating ATM signaling.
Citation Format: Hongmei Cui. ATF3 contributes to the DNA damage response by regulating the histone acetyltransferase Tip60. [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 5364. doi:10.1158/1538-7445.AM2014-5364
Abstract 5366: Mutation signature of TP53 gene in H. pylori-associated inflamed gastric mucosa during gastric carcinogenesis
Authors: Shimizu Takahiro , Marusawa Hiroyuki , Chiba Tsutomu 
Published: May 2015

Abstract
Helicobacter pylori (H. pylori) infection and the resultant chronic gastric inflammation is an important etiologic factor for gastric cancer development. To explore the genetic basis of gastric cancer that develops in inflamed gastric mucosa, we investigated genetic aberrations that latently accumulate in non-tumorous gastric epithelium with H. pylori infection. Whole exome sequencing on gastric cancer, non-cancerous gastritis tissues and peripheral lymphocytes of 5 patients revealed that somatic mutations accumulated in various genes in inflamed gastric tissues. Additional deep sequencing analyses of selected tumor-related genes in 34 gastritis mucosa samples from patients with, or without, gastric cancer revealed non-synonymous low-abundance mutations in TP53 in 15 cases (44.1%) and ARID1A in 5 cases (14.7%). The mutation signature of whole exome sequences in gastric cancer genomes as well as low-abundance TP53 mutations latently accumulated in H. pylori-inflamed gastritis mucosa were predominantly biased to C:G&gt;T:A transitions in the context of GpCpX motifs, the typical footprints of cytidine deamination triggered by activation-induced cytidine deaminase (AID). In vivo studies with a human TP53 knock-in mouse model revealed that constitutive AID expression in the gastric mucosa caused the emergence of human TP53 mutations at the amino acid positions identical to those detected in human gastric cancers. These findings provide novel evidence that somatic mutations latently accumulated in various genes in inflamed gastric mucosa with H. pylori infection, and cytidine deaminase activity might provide a putative genetic basis for the increased susceptibility to gastric carcinogenesis in patients with H. pylori infection.
Citation Format: Takahiro Shimizu, Hiroyuki Marusawa, Tsutomu Chiba. Mutation signature of TP53 gene in H. pylori-associated inflamed gastric mucosa during gastric carcinogenesis. [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 5366. doi:10.1158/1538-7445.AM2014-5366
Abstract 5375: Enhanced permeability of nanoscale chemotherapeutic agents for the treatment of breast cancer
Authors: Molina Oliver , Yu Eugena , Abdulabbas Sarah , Lopez Steve 
Published: May 2015

Abstract
Nanotechnology is becoming increasingly successful in advancing site-specific drug delivery to cancer tissues. The ability to deliver drugs more effectively to a region of interest translates into less harmful side effects and more beneficial therapeutic action. This technology is currently in use in treating a number of human cancers. Certain therapeutic limitations are encountered, such as short circulation life, poor drug permeability, and drug resistance. These limitations can be addressed with the use of nanoscale particles that allow for controlled release of the drug. This presentation will educate the audience about approaches to treating cancer using new technologies.
Objectives
The main objective of this strategy is to minimize the side effects associated with chemotherapy, while enhancing the overall efficacy of the treatment of breast cancer, and other cancers.
- Tackle drug limitations by combining nanotechnology and chemotherapeutic methods that have been shown to increase therapeutic efficacy
- Measure the effects of this combinatorial strategy using a mouse model bearing human breast tumors
- Assemble the drug into a nanoscale shell in order to form a polymeric nanoparticle capable of providing controlled drug release.
- Create leaky vasculature in the vicinity of tumor tissue without affecting normal tissue
Methods
1st Method: Synthesis of a nanoparticle which encapsulates two chemotherapeutic agents, Paclitaxel and Cisplatin. The nanoparticle formed is a lipid-polymer hybrid whose main components are as follows: a core encapsulating the two drugs; a biocompatible shell to promote drug retention inside the core; and a polymer stealth layer outside the lipid shell to enhance nanoparticle stability and systemic circulation lifetime.
2nd Method: The tumor will be starved by limiting vascular growth using the drug, Endostatin. In addition, the permeability of the vasculature surrounding the tumor will be made more permeable for drug uptake by using a permability enhancing agent, iRGD.
Note: This abstract was not presented at the meeting.
Citation Format: Oliver Molina, Eugena Yu, Sarah Abdulabbas, Steve Lopez. Enhanced permeability of nanoscale chemotherapeutic agents for the treatment of breast 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 5375. doi:10.1158/1538-7445.AM2014-5375
Abstract 5376: Systematic analysis of peptide linker length and liposomal polyethylene glycol coating on cellular uptake of peptide-targeted liposomal nanoparticles
Authors: Stefanick Jared , Ashley Jonathan , Kiziltepe Tanyel , Bilgicer Basar 
Published: May 2015

Abstract
In an effort to improve tumor targeting and cellular uptake of nanoparticle-based drug carriers, nanoparticles are functionalized with active targeting molecules such as antibodies, antibody fragments, small ligands, and peptides. However, active targeting approaches have not consistently shown successful outcomes. Nanoparticle design factors including: traditional methods of generating active targeting nanoparticles, PEG coatings, linkers used to conjugate targeting ligands, and various types of targeting ligands used further contribute to the inconsistencies observed with targeted nanoparticle therapies. In order to dissect the individual effects of these parameters, we employed a multifaceted synthetic strategy to prepare peptide-targeted liposomal nanoparticles with high purity, reproducibility, and precisely controlled stoichiometry of functionalities to evaluate the role of liposomal PEG coating, peptide EG-linker length, and peptide valency on cellular uptake in a systematic manner. We analyzed these parameters in two distinct disease models where the liposomes were functionalized with either HER2- or VLA-4-antagonistic peptides to target HER2-overexpressing breast cancer cells or VLA-4-overexpressing myeloma cells, respectively. When targeting peptides were tethered to nanoparticles with an EG45 (∼PEG2000) linker in a manner similar to a more traditional formulation, their cellular uptake was not enhanced compared to non-targeted versions regardless of the liposomal PEG coating used. Conversely, reduction of the liposomal PEG to PEG350 and the peptide linker to EG12 dramatically enhanced cellular uptake by ∼9-fold in breast cancer cells, while an EG6 peptide linker enhanced cellular uptake by ∼150-fold in multiple myeloma cells. Uptake efficiency is highly dependent on peptide valency, reaching a maximum and a plateau with ∼2% peptide density in the breast cancer model. Taken together, these results demonstrate the significance of using the right design elements such as the appropriate peptide EG-linker length in coordination with the appropriate liposomal PEG coating and optimal ligand density in efficient cellular uptake of liposomal nanoparticles.
Citation Format: Jared Stefanick, Jonathan Ashley, Tanyel Kiziltepe, Basar Bilgicer. Systematic analysis of peptide linker length and liposomal polyethylene glycol coating on cellular uptake of peptide-targeted liposomal nanoparticles. [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 5376. doi:10.1158/1538-7445.AM2014-5376
Abstract 5381: VLA-4 targeted nanoparticles deliver a cMYC-MAX prodrug antagonist extends survival a metastatic myeloma mouse model
Authors: Soodgupta Deepti , Pan Dipanjan , Cui Grace , Senpan Angana , Yang Xiaoxia , Wickline Samuel A. , Prochownik Edward V. , Weilbaecher Katherine N. , Tomasson Michael H. , Lanza Gregory M. 
Published: May 2015

Abstract
Background: While it is well known that MYC oncoprotein drives multiple myeloma (MM) pathogenesis, the development of several small-molecule inhibitors of the c-MYC/MAX interaction has been limited by rapid systemic metabolism, poor bioavailability and the inability of the drug to reach inhibitory concentrations in the tumor.
Objective: The goal of this study was to develop and deliver an effective VLA-4-targeted Sn 2 lipase-labile Myc-inhibitor nanotherapy.
Experimental Methods: A novel Sn 2 phosphatidylcholine-cMyc-Max antagonist prodrug (M1-PD) was designed, synthesized, characterized and evaluated in vitro and in vivo. In vitro, titrated free M1-PD was compared to free Myc-antagonist in human MM cell lines (H929 and U266) and mouse MM (5TGM1). M1-PD was incorporated into two lipid-based nanoparticle genera (&lt;20nm and ∼200nm) that were functionalized for MM targeting using a peptidomimetic VLA-4-lipid ligand. The nanoparticles were physico-chemically characterized and evaluated for their relative pharmacokinetics in vivo. Effectiveness of the two VLA-4-targeted M1-PD nanotherapies were evaluated in MM cell cultures, correlated with VLA-4 expression levels, and then studied in C57BL/KaLwRij mice with metastatic 5TGM1.
Results: Bioactivity of free M1-PD was several orders magnitude more potent that the free cMyc antagonist in cell culture. Binding and efficacy of M1-PD nanoparticles correlated with integrin expression in target cells. VLA-4-M1-PD nanoparticles (&lt;20nm and ∼200nm) equivalently inhibited MM cell growth in vitro compared to controls. In C57BL/KaLwRij mice with metastatic 5TGM1, VLA-4-MI1-PD 20nm micelles conferred significant survival benefit (T/D) over the 20nm targeted no drug (T/ND) or untreated controls (NT/ND) (52 days vs. 29 days, p=0.001) and versus the 200nm VLA-4-MI1-PD nanocolloid and its controls.
Conclusion: These finding support the feasibility of a new VLA-4-directed nanotherapy to deliver lipase-labile cMyc prodrug to disrupt MYC-MAX dimerization and improve MM survival.
Citation Format: Deepti Soodgupta, Dipanjan Pan, Grace Cui, Angana Senpan, Xiaoxia Yang, Samuel A. Wickline, Edward V. Prochownik, Katherine N. Weilbaecher, Michael H. Tomasson, Gregory M. Lanza. VLA-4 targeted nanoparticles deliver a cMYC-MAX prodrug antagonist extends survival a metastatic myeloma mouse model. [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 5381. doi:10.1158/1538-7445.AM2014-5381
Abstract 5383: The plasmonic photothermal therapy efficacy of Au NRs in vivo using a SCCHN xenograft mouse model
Authors: Peng Xianghong , Mackey Megan A. , Oyelere Adegboyega , Zhang Jun , Chen Georgia , Nie Shuming , El-Sayed Mostafa A , Shin Dong M 
Published: May 2015

Abstract
The plasmonic photothermal therapy (PPTT) is promising for the treatment of cancer because it overcomes the challenges in conventional treatments by avoiding drug resistance, surgery infections, and minimizing healthy cell destruction. It is well suited for the treatment of the squamous cell carcinoma of the head and neck (SCCHN) as this type of cancer is readily accessible to NIR light. We have synthesized the Au nanorods (NRs) with different sizes (25nm and 40nm) and modified the particle surface with PEG stabilizer, and conjugated Au NRs with SCCHN-targeted HNSCP peptides. The new Au NRs -assisted PPTT was tested in a SCCHN xenografted tumor model. The SCCHN xenograft tumors were inoculated by injection of 1x106 Tu212 cells subcutaneously into the right flank of nude mice and allowed to grow to approximately 100 mm3. Fifty nude mice were divided into ten groups (n=5) in a way to minimize weight and tumor size differences among the groups: control group treated with PBS (A), laser treatment (diode laser, 808 nm, 1-2 W/cm2, 1cm diameter, 2 min) (B), non-targeted AuNRs ( 25nm size) with (C)or without laser treatment(D), HNSCP-Au NRs(25 nm size) with (E) or without laser treatment( F), non-targeted Au NRs (40 nm size) with (G) or without laser treatment (H), HNSCP-Au NRs(40 nm size) with (I) or without laser treatment (J). Au NRs (25 μL) at concentration of, 25 nM in PBS buffer were injected into mice via intratumoral injection. Our results showed that the Au NRs with laser treatment could significantly inhibit the tumor growth in vivo compared with that of control and laser treatment only groups (without Au NRs). In addition, the tumor targeted Au NRs didn't show enhanced antitumor efficacy compared with the non-tumor targeted Au NRs. The mice showed complete response to the PPTT didn't have tumor relapse after 15 weeks of the treatment. There are no remarkable toxicities observed. (This research was supported by the National Cancer Institute award 5U01CA151802 )
Citation Format: Xianghong Peng, Megan A. Mackey, Adegboyega Oyelere, Jun Zhang, Georgia Chen, Shuming Nie, Mostafa A El-Sayed, Dong M Shin. The plasmonic photothermal therapy efficacy of Au NRs in vivo using a SCCHN xenograft mouse model. [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 5383. doi:10.1158/1538-7445.AM2014-5383
Abstract 5386: Disrupting p53:Mdm2 and p53:Mdm4 - Comparative cell-based assays for drug screening
Authors: Yurlova Larisa , Brown Christopher J. , Derks Maarten , Ghadessy Farid John , Hickson Ian , Lane David P. , Krausz Eberhard , Zolghadr Kourosh 
Published: May 2015

Abstract
The important interconnected protein-protein interactions between the tumor suppressor p53 and its regulatory binding partners Mdm2 and Mdm4 (= MdmX/ HdmX) are implicated in pathogenesis of various cancers. However, until now there is a lack of reversible cell-based assays for concurrent analysis for both PPIs: p53/Mdm2 and p53/Mdm4. Our aim was to develop two comparative assays based on the Fluorescent 2-Hybrid (F2H) assay principle, which enable side-by-side analysis of antagonistic compounds.
The F2H assay is a fully reversible microscopy-assisted assay for the direct intracellular analysis of PPIs. It offers a fast and straight-forward readout: an interaction-dependent co-localization of two fluorescent signals at a defined spot in the nucleus of mammalian cells.
With these assays we analyzed a set of newly developed stapled peptides as potent p53:Mdm2 and/ or p53:Mdm4 inhibitors. Live cell data generated by the F2H assays enabled us to discriminate and describe the peptides according to their ability to penetrate into the cells, their efficacy on the PPIs and their cytotoxic side effects in one single assay.
In parallel we performed a pilot F2H screen with a sub-set or 20 small molecule compounds (including Nutlin-3) that exhibited activity against one or both interactions at various potencies in ELISAs before. We could identify 5 potent compounds, which were dramatically reducing the number of p53:Mdm2 interactions. However, none of the small molecules, but only the stapled peptides exhibited an intracellular activity on p53:Mdm4. Furthermore, we were able to expand these assays and to identify mutants of Mdm2 resistant to Nutlin inhibition.
In summary, we show that the p53:Mdm2 and p53:Mdm4 F2H assays described here,
- enable side-by-side analysis of substances' dual Mdm2-Mdm4 activity
- are suitable for screening and testing various types of compounds, such as peptidic inhibitors or small molecules
- concurrently provide initial data on compound cell-permeability and cytotoxicity
- allow real-time visualization of PPI dynamics in living cells.
Citation Format: Larisa Yurlova, Christopher J. Brown, Maarten Derks, Farid John Ghadessy, Ian Hickson, David P. Lane, Eberhard Krausz, Kourosh Zolghadr. Disrupting p53:Mdm2 and p53:Mdm4 - Comparative cell-based assays for drug screening. [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 5386. doi:10.1158/1538-7445.AM2014-5386
Abstract 539: Downregulation of hnRNP A1 by miRNAs as a new mechanism of survival in ovarian cancer
Authors: Rodriguez-Aguayo Cristian , Monroig Paloma , Almeida Maria I. , Ivan Cristina , Gonzalez-Villasana Vianey , Shah Maitri Y. , Sood Anil K. , Calin George , Lopez-Berestein Gabriel 
Published: May 2015

Abstract
Background. Posttranscriptional regulation is a critical control point for the expression of genes that promote or retard tumor growth. The mRNA-binding protein hnRNP A1 is required for the processing of miR-18a, an inhibitor of k-ras expression. In this study we hypothesized that downmodulation of hnRNP A1 by miR-25 and miR-15a controls the expression of miR-18a and k-ras by modulating nuclear and cytoplasmic miRNA processing at the posttranscriptional level. Methods. In this study, we determined the expression of hnRNP A1 at mRNA and protein levels in three parental ovarian cancer cells lines (Skov3ip1, HeyA8, and A2780) and their chemotherapy-resistant derivatives (Skov3-TR, HeyA8 MDR, and A2780 cp20). We also predicted in silico which miRNAS can target hnRNP A1 and confirmed the miRNA expression by real-time PCR. Moreover, we inhibited miR-25 and mir-15a to determine their tumorigenic potential in vitro. We also correlated the expression of miR-25 and miR-15a and/or miR-18a and k-ras expression in the TCGA data. Results. Downregulation of hnRNP A1 at the RNA and protein levels was observed in the taxane-resistant cell lines but not in the cisplatin-resistant cell line. Furthermore, we predicted in silico that miR-25and miR-15a can target hnRNP A1 and confirmed the overexpression of these microRNAs in SKOV3-TR (5- and 3-fold, respectively) and HeyA8 MDR (3-fold) by real-time PCR. We also analyzed overall survival, trying to find a correlation between k-ras and miR-15a (high 23.77, low 33.97 months), k-ras and miR-25 (high 16.95, low 35.21 months), and the combination of k-ras, miR-25, and miR18a (k-ras high, miR25 high, mir18a low, 20.73 months; k-ras low, miR25 low, mir18a high, 31.49 months). Comparison of these data with a validation set yielded similar results. Conclusion. These results underscore the importance of a previously uncharacterized circuit of posttranscriptional regulation between miR-25 or -15a and RNA-binding protein hnRNP A1 that regulates miR-18a and k-ras expression. This circuit represents a unique opportunity for novel therapeutics approaches.
Citation Format: Cristian Rodriguez-Aguayo, Paloma Monroig, Maria I. Almeida, Cristina Ivan, Vianey Gonzalez-Villasana, Maitri Y. Shah, Anil K. Sood, George Calin, Gabriel Lopez-Berestein. Downregulation of hnRNP A1 by miRNAs as a new mechanism of survival in ovarian 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 539. doi:10.1158/1538-7445.AM2014-539
Abstract 5391: MT-MMP cleavage profiling using rapid endopeptidase profiling library (REPLi)
Authors: Mitchell Andrew , Giménez-Warren Javier , Shnyder Steven D. , Gill Jason H. , Falconer Robert A. , Loadman Paul M. 
Published: May 2015

Abstract
Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that are associated with the metastatic process. Relative to non-diseased tissue, the increased expression and activity of Membrane-type matrix metalloproteinases (MT-MMPs) such as MMP-15 within the prostate tumour microenvironment can be exploited in order to selectively activate highly toxic chemotherapeutics. The main advantage to such a targeted drug delivery system is a significant reduction of systemic toxicity, resulting in a highly efficacious and successful treatment for prostate cancer.
We have screened 3375 peptides with a variety of residue combinations using Rapid Endopeptidase Profiling Library (REPLi). A ‘small but smart’ design, the REPLi library template: MCA-Gly-Gly-Gly-Xaa-Xaa-Xaa-Gly-Gly-DPA-Lys-Lys contains a donor (MCA) and quenching acceptor (DPA) FRET pair. No fluorescence indicates the molecules within the pools are intact, however, upon cleavage, the tri-variable cores can be assessed via auto fluorescence of the MCA molecule.
By analysing the 512 distinct substrate pools we have identified combinations of Phe/Tyr and Asn/Gln residues as having a greater MMP-15 cleavage bias over MMP-14, with the opposite being true for variable cores with Ile/Leu and Lys/Arg combinations. Since most known substrates show little (if any) MMP selectivity this is a novel finding, and as such, provides us with insights that are essential for designing prodrugs targeted to specific MMPs.
Through detailed metabolic studies, this information is being utilised in a bid to maximise the successful development of novel MMP-15 targeted paclitaxel conjugated prostate cancer prodrugs.
Citation Format: Andrew Mitchell, Javier Giménez-Warren, Steven D. Shnyder, Jason H. Gill, Robert A. Falconer, Paul M. Loadman. MT-MMP cleavage profiling using rapid endopeptidase profiling library (REPLi). [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 5391. doi:10.1158/1538-7445.AM2014-5391