bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2811: Silver nanoparticles protect human keratinocytes from deleterious effects of ultraviolet radiation: Implications for skin cancer chemoprevention
Authors: Arora Sumit , Tyagi Nikhil , Bhardwaj Arun , Rusu Lilia , Palanki Rohan , Singh Ajay P. , Carter James E. , Singh Seema 
Published: August 2015

Abstract
Skin cancer is the most common form of cancer worldwide and its incidence has been increasing at an alarming rate in the United States. A solar ultraviolet (UV) radiation, particularly UVB, is the main etiological cause of skin carcinogenesis due to its DNA damaging ability. Therefore, multidisciplinary scientific research has placed specific emphasis on finding novel ways for skin cancer chemoprevention. Here, we provide first experimental evidence for chemopreventive efficacy of silver-nanoparticles (AgNPs) against UVB-induced DNA damage and apoptosis in immortalized human epidermal keratinocytes (HaCaT). AgNPs synthesized by chemical reduction method were characterized for their physicochemical properties. The nanoparticles were spherical (&gt; 90%) in shape, in the size range of 20-50 nm, and had net negative surface charge with an average zeta potential of - 47.7 mV. AgNPs were largely non-toxic to HaCaT cells and their pretreatment protected them from UVB-induced apoptosis. Significant reduction in cyclobutane pyrimidine dimer (CPD) formation upon UVB exposure was also observed in AgNPs-pretreated HaCaT cells. In addition, AgNPs pre-treatment leads to G1 phase arrest of cell cycle in UVB-exposed HaCaT cells thus allowing sufficient time for CPDs repair. Moreover, enhanced AgNPs internalization and localization into cytoplasmic and nuclear compartments was observed by UVB irradiated HaCaT cells. Furthermore, AgNPs pretreatment altered the expression of various genes involved in cell-cycle, apoptosis and nucleotide-excision repair in UVB-irradiated HaCaT cells. Together, these findings clearly suggest the potential utility of AgNPs as novel chemopreventive agents against UVB-induced skin carcinogenesis.
Citation Format: Sumit Arora, Nikhil Tyagi, Arun Bhardwaj, Lilia Rusu, Rohan Palanki, Ajay P. Singh, James E. Carter, Seema Singh. Silver nanoparticles protect human keratinocytes from deleterious effects of ultraviolet radiation: Implications for skin cancer chemoprevention. [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 2811. doi:10.1158/1538-7445.AM2015-2811
Abstract 2831: Development of selective GRP94 inhibitors for the treatment of cancer
Authors: Ochiana Stefan O. , Taldone Tony , Patel Hardik J. , Patel Pallav , Pengrong Yan , Sun Weilin , Rodina Anna , Shah Smit , Gewirth Daniel T. , Chiosis Gabriela 
Published: August 2015

Abstract
Glucose Regulated Protein 94 (Grp94) is an Hsp90 paralog localized in the lumen of the endoplasmic reticulum (ER) of higher eukaryotes. While the mechanisms associated with Grp94-pathogenic expression are still actively studied, the focus thus far of most cancer related studies has been primarily on the immunogenic activity of Grp94/peptide complexes and the involvement of this protein in the secretion of IGF-I and IGF-II and the regulation of Toll-like receptors and integrins. This status quo has recently changed when work from our lab has shown that in certain breast cancers the maintenance of a high density HER2 species at the plasma membrane and its associated aberrant signaling also requires Grp94, rendering these tumors highly sensitive to Grp94 inhibition. The discovery of selective and potent Grp94 inhibitors has been hindered due to the high similarity of the ATP-binding regulatory pocket of the Hsp90 paralogs. However, recent work from our lab has shown that this apparent roadblock can be overcome by using library screening and structural and computational analysis to discover purine-based molecules that show 100-fold selectivity for the Grp94 isoform. Herein, we detail for the first time the structure activity relationship of the selective purine derived Grp94 molecules. This work provides insights on how to overcome the high structural similarity of Hsp90s in the ligand binding pocket, and also reports selective and therapeutically relevant Grp94 inhibitors based on a purine scaffold. These initial inhibitors have potent activity against cancer cells providing an important platform for the development of Grp94 inhibitors with drug-like features and potential for clinical translation.
Citation Format: Stefan O. Ochiana, Tony Taldone, Hardik J. Patel, Pallav Patel, Yan Pengrong, Weilin Sun, Anna Rodina, Smit Shah, Daniel T. Gewirth, Gabriela Chiosis. Development of selective GRP94 inhibitors for the treatment of 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 2831. doi:10.1158/1538-7445.AM2015-2831
Abstract 2846: Ultrasensitive detection of actionable subclones in chronic myeloid leukemia
Authors: Schmitt Michael W. , Aminov Bella , Radich Jerald P. , Loeb Lawrence A. 
Published: August 2015

Abstract
Targeted Abl inhibitors such as imatinib have vastly improved survival in chronic myeloid leukemia (CML). However resistance occurs in many patients, most frequently due to point mutations in the Abl kinase. At the time of diagnosis, resistance mutations may already exist in a small fraction of the malignant cells. Second-generation inhibitors have been developed which can overcome specific resistance mutations. Identification of pre-existing resistance mutations would thus have important therapeutic implications, as it could inform which therapy would result in the most durable response in a given patient.
Prior searches for pre-existing Abl mutations in CML have used methods such as allele-specific PCR or next-generation DNA sequencing; these methods are prone to background errors resulting in frequent false positive mutations. For example, next-generation sequencing has an error rate of 0.1%-1%, which results in a large number of erroneous mutations that obscure true variants. Enrichment of the Abl gene is also a major limitation. Nearly all prior reports have used PCR amplification for dozens of cycles to enrich the Abl gene prior to mutation detection; this process introduces thousands of PCR errors which make differentiation of true mutations from artifactual mutations challenging.
We have developed a protocol for DNA sequencing, Duplex Sequencing, that separately tags and sequences each of the two strands of single DNA molecules. True mutations are present at the same position in both strands and are complementary, while PCR or sequencing errors occur in only one of the strands and are not scored. Duplex Sequencing has a calculated error rate of less than one artifactual mutation per billion nucleotides sequenced. To apply Duplex Sequencing to the Abl oncogene, we established a new, extremely efficient targeted capture approach that utilizes sequential rounds of capture with biotinylated DNA probes. This protocol results in &gt;1,000,000 fold enrichment, with up to 99.8% of reads corresponding to the Abl gene. Duplex Sequencing was carried out at high depth (&gt;100,000 fold), resulting in an average of 2,000 duplex reads per nucleotide position. The estimated accuracy for mutation identification was 99.9999%.
We are in the process of sequencing samples from CML at the time of diagnosis and relapse to assay for drug resistance mutations below the limit of detection of conventional assays. Our approach could be extended to any targeted molecular agent for which mutation of the target confers resistance to the drug.
Citation Format: Michael W. Schmitt, Bella Aminov, Jerald P. Radich, Lawrence A. Loeb. Ultrasensitive detection of actionable subclones in chronic myeloid leukemia. [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 2846. doi:10.1158/1538-7445.AM2015-2846
Abstract 286: Coordinated activation of TLR8 and NLRP3 by VTX-2337 (motolimod) ignites tumoricidal NK cell activity
Authors: Dietsch Greg , Lu Haling , Yang Yi , Morishima Chihiro , Chow Laura Q. , Disis Mary L. , Hershberg Robert 
Published: August 2015

Abstract
VTX-2337 (motolimod) is a selective toll-like receptor 8 (TLR8) agonist in clinical development as an immunotherapy for multiple oncology indications, including squamous cell carcinomas of the head and neck (SCCHN). Activation of TLR8 has been found to enhance natural killer (NK) cell activation, increase antibody-dependent cell-mediated cytotoxicity (ADCC), and induce Th1 polarizing cytokines. Further characterization of VTX-2337 reveals the release of mature IL-1β and IL-18 from monocyte cell populations through coordinated actions on both TLR8 and NLRP3. In vitro, VTX-2337 primes monocytes to produce pro-IL-1β, pro-IL-18 and caspase 1, while activating the NLRP3 inflammasome, leading to the release of mature IL-1 family cytokines. Inflammasome activation by VTX-2337 is blocked by inhibiting caspase 1, with little impact on the production of other TLR8 induced mediators such as TNFα. The release of IL-18 stimulates NK cells, and augments other activation pathways including: FcγRIII and NKG2D receptors, resulting in IFNγ production and induction of CD107α. NLRP3 activation in vivo was confirmed by a dose-related increase in plasma levels of IL-1β and IL-18 in cynomolgus monkeys administered VTX-2337. This pathway for NK activation was subsequently assessed in SCCHN patients treated with VTX-2337 in combination with cetuximab, a clinically approved epidermal growth factor receptor (EGFR) specific monoclonal antibody (mAb). Cetuximab can activate NK cells through an interaction with FcγRIII, and facilitate ADCC of tumor cells. Preliminary data from a Phase I clinical trial found that prior to treatment, patient NK cells did not effectively activate in response to ex vivo stimulation by NKG2D or FcγRIII. However, following VTX-2337 treatment, patient NK cells become more responsive to these activating signals. These results show that TLR8 stimulation and inflammasome activation by VTX-2337, can complement FcγRIII engagement, and may augment clinical responses in SCCHN patients treated with cetuximab.
Citation Format: Greg Dietsch, Haling Lu, Yi Yang, Chihiro Morishima, Laura Q. Chow, Mary L. Disis, Robert Hershberg. Coordinated activation of TLR8 and NLRP3 by VTX-2337 (motolimod) ignites tumoricidal NK cell 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 286. doi:10.1158/1538-7445.AM2015-286
Abstract 2864: Acetylation regulates TET2 stability and enzymatic activity
Authors: Zhang Yang , Cai Yi , Xie Wenbing , Easwaran Hariharan , Baylin Stephen B. 
Published: August 2015

Abstract
DNA methylation, one of the key epigenetic modifications in the mammalian genome, plays fundamental roles in development and disease. Although DNA methylation and DNA methyltransferases (DNMTs) have been studied intensively, our knowledge about DNA demethylation is just starting to emerge. The Ten-eleven translocation (TET) family of proteins are newly identified methylcytosine dioxygenases/demethylases that can oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), and promote DNA demethylation either passively through DNA replication, or actively via thymine DNA glycosylase (TDG)-mediated base excision repair. TET-mediated DNA demethylation has also been shown to play important roles in diverse biological processes and tumorigenesis.
Human TET2 is frequently mutated in myeloid malignancies, while loss of 5hmC and TETs expressions have been broadly observed in many other cancer types. Recent studies suggested that TETs may be regulated by microRNAs and calpain proteases, but, overall, the regulation of TET activities is not well outlined. Here we show, in human ovarian cancer cells, that TET2 activity may be significantly modulated by post-translational modifications. TET2 is acetylated by p300/CBP at K110/111, and this acetylation can be reversed by HDAC1/2 and SIRT1/2 deacetylases. Acetylation increases TET2 stability by protecting it from ubiquitination and proteasome-mediated degradation. Interestingly, DNMT1 physically associates with and stabilizes TET2 protein, and a TET2 acetylation deficient mutant (2KR) disrupts this association, indicating that acetylation of TET2 may stimulate DNMT1 binding which prevents TET2 from degradation. In addition, we show that acetylation increases TET2 enzymatic activity. Treatment of cells with HDAC inhibitors TSA/NAM, or knocking down HDAC1/2, significantly increases global 5hmC levels. Consistent with these latter observations, the 2KR mutant almost completely abolishes TET2 catalytic activity, and this mutant protein is less efficient in forming dimer with wild type TET2. Thus acetylation events may increase the activity of TET2 through enhanced dimerization of the protein. Taken together, our study reveals a novel acetylation-dependent regulatory mechanism controlling the function of TET2.
Citation Format: Yang Zhang, Yi Cai, Wenbing Xie, Hariharan Easwaran, Stephen B. Baylin. Acetylation regulates TET2 stability and enzymatic 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 2864. doi:10.1158/1538-7445.AM2015-2864
Abstract 2865: Characterization of histone deacetylases in embryonal rhabdomyosarcoma
Authors: Phelps Michael , Vleeshouwer-Neumann Terra , Bailey Jenna , Hickman Nicole , Chen Eleanor 
Published: August 2015

Abstract
Histone acetylation and deacetylation are key epigenetic modifications that influence gene expression in both normal and neoplastic cells. Histone deacetylases (HDACs) have been the target for cancer therapeutics due to their demonstrated role in modulating tumor onset and progression in a subset of cancers. We have shown that treatment with pan HDAC inhibitors leads to reduced tumor growth and increased tumor cell differentiation of cultured Embryonal Rhabdomyosarcoma (ERMS) cells. However, the role of specific HDACs in ERMS remains unknown. To determine the function specific to each HDAC in ERMS, we have employed the Clustered Regularly Interspersed Short Palindrome Repeats (CRISPR)/Cas9 nuclease-mediated genome editing technology to enable effective knockout of individual HDAC genes in ERMS. Our CRISPR/Cas9 system uses a transient and multiplex gene targeting approach that induces loss-of-function mutations with high efficiency and allows rapid phenotypic analysis. Combining this system with stable selection of mutant clones with null mutations, we have systematically targeted all class I HDAC genes in ERMS cells. Initial characterization reveals distinct functions of class I HDAC genes in ERMS tumorigenesis. HDAC1 loss-of-function in ERMS cells promotes tumor growth. By contrast, HDAC3 or HDAC8 loss-of-function reduces tumor cell viability. HDAC2 loss-of-function does not affect tumor growth but induces robust differentiation of ERMS cells. In future studies, candidate genes/pathways regulated by HDACs will be identified by an integrated approach of Chromatin Immunoprecipitation (ChIP) and gene expression profiling studies. To validate HDAC mutant phenotypes observed in vitro and assess pre-clinical efficacy of targeted HDAC therapies, CRISPR/Cas9 inducible ERMS lines are currently being developed to facilitate tumor xenograft studies in vivo. Overall, our initial gene targeting results reveal distinct roles of class I HDAC genes in modulating ERMS tumor growth and differentiation. Our results suggest that therapeutic efficacy of pan HDAC inhibitors may be compromised by simultaneously inhibiting tumor-promoting and tumor-suppressive functions of HDACs. Targeted HDAC therapies therefore, may have more potent therapeutic benefits.
Citation Format: Michael Phelps, Terra Vleeshouwer-Neumann, Jenna Bailey, Nicole Hickman, Eleanor Chen. Characterization of histone deacetylases in embryonal rhabdomyosarcoma. [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 2865. doi:10.1158/1538-7445.AM2015-2865
Abstract 2869: SChLAP1 mediated epigenetic modifications in prostate cancer
Authors: Singhal Udit , Sahu Anirban , Prensner John R. , Cao Qi , Chinnaiyan Arul M. 
Published: August 2015

Abstract
Prostate cancer is the leading cancer diagnosis in men, but only a subset of patients die from the disease. Understanding the molecular basis of aggressive prostate cancer remains elusive and few genomic biomarkers exist to guide clinical management. Long non-coding RNAs (lncRNAs) have emerged as a class of regulatory genes that play a role in several biological and disease processes, including cancer.
Recently, we identified SChLAP1, a novel, prognostic lncRNA expressed in a subset of prostate tumors. Mechanistically, SChLAP1 interacts with and inhibits genome-wide binding of the SWI/SNF nucleosome-remodeling complex. Additionally, SWI/SNF plays a key role in the epigenetic control of gene expression and has been shown to have tumor suppressive ability. Given the emerging role of SChLAP1 in the pathogenesis of aggressive prostate cancer and its interaction with the tumor suppressive SWI/SNF complex, exploring the detailed mechanism of action of SChLAP1 warranted further investigation.
To identify the regions of SChLAP1 necessary for its function, we created 250 base pair deletion constructs of SChLAP1 and measured RNA-enrichment following SWI/SNF pull-down as well as cell invasion using a Boyden chamber matrigel assay. To investigate whether SChLAP1 preferentially interacts with specific components of the SWI/SNF complex, we performed RNA immunoprecipitation assays using antibodies targeting various enzymatic subunits of SWI/SNF. SChLAP1 enrichment was measured by qPCR.
Our results indicate that there is a 250bp region of SChLAP1 that mediates its interaction with SWI/SNF and promotes an invasive phenotype. Furthermore, SChLAP1 shows binding specificity for certain SWI/SNF subunits. Future studies to elucidate the details of this interaction will provide a more comprehensive understanding of the biological and therapeutic consequences of SChLAP1 in prostate cancer progression.
Citation Format: Udit Singhal, Anirban Sahu, John R. Prensner, Qi Cao, Arul M. Chinnaiyan. SChLAP1 mediated epigenetic modifications in prostate 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 2869. doi:10.1158/1538-7445.AM2015-2869
Abstract 2881: Systemic Chromosome Instability (CIN) resulted in transcriptomic changes in metabolic and proliferation regulators in colonic mucosal tissue of Sgo1-/+ mice
Authors: Rao Chinthalapally V. , Sanghera Saira , Zhang Yuting , Biddick Laura , Reddy Arun , Lightfoot Stan , Mohammed Altaf , Dai Wei , Yamada Hiroshi Y. 
Published: August 2015

Abstract
(a) Colon cancer is the second most lethal cancer and is predicted to claim 50,310 lives in 2014. Chromosome Instability (CIN) is observed in 80-90% of colon cancers and is thought to contribute to colon cancer progression and recurrence. We developed animal models focusing on mitotic error-induced CIN, Shugoshin-1 (Sgo1) haploinsufficient (-/+) mice, to investigate the impact of CIN on colon cancer development. Sgo1-/+ mice showed altered profiles in colonic lesions and cancer development. In this study, we analyzed signature changes in the colonic transcriptome of Sgo1-/+ mice to investigate underlying molecular events in the altered carcinogenesis profiles.
(b) We treated control and Sgo1-/+ mice with colonic carcinogen azoxymethane (AOM), and tracked colon cancer development 12, 24, and 36 weeks after AOM treatments. We performed Next Generation Sequencing (NGS)-based transcriptome analysis at 24 weeks.
(c) There were 349 hits with 2-fold expression difference threshold, P&lt;0.05 (217 upregulated genes, 132 downregulated genes). In normal-looking colonic mucosal tissue from Sgo1 mice, we observed notable transcriptomic changes in the lipid metabolism, Notch signaling, insulin signaling, and peroxisome proliferator-activated receptor (PPAR) pathways. The profile had partial overlap with the colon tumor transcriptome, consistent with high prevalence of CIN in colon cancer. By applying secondary selection criteria, we also identified cell surface markers that may be used to selectively target colonic CIN cells with antibody-based or vaccine approaches.
(d) Systemic Chromosome Instability resulted in transcriptomic changes in metabolic and proliferation regulators in the colon. We propose that the CIN effect may be countered through manipulation of these pathways.
Citation Format: Chinthalapally V. Rao, Saira Sanghera, Yuting Zhang, Laura Biddick, Arun Reddy, Stan Lightfoot, Altaf Mohammed, Wei Dai, Hiroshi Y. Yamada. Systemic Chromosome Instability (CIN) resulted in transcriptomic changes in metabolic and proliferation regulators in colonic mucosal tissue of Sgo1-/+ mice. [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 2881. doi:10.1158/1538-7445.AM2015-2881