bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1326: Systems approach to identifying potential environmental exposures playing a role in ovarian carcinogenesis
Authors: States J. Christopher , Ouyang Ming , Helm C. William 
Published: June 2012

Abstract
Other than an association of a small fraction with inherited mutations in BRCA1 and BRCA2, most cases of ovarian cancer (OvCa) are sporadic with cause unknown. Identifying environmental exposures that may contribute to ovarian carcinogenesis would provide the basis for epidemiological studies to determine other causes of OvCa. Environmental exposures are capable of inducing epigenetic changes that result in changes in gene expression. Most importantly, changes in microRNA expression may cause permanent changes in regulation of gene expression patterns leading to altered cellular phenotypes. These alterations in microRNAs represent dysregulation in the cancer cells and may be a manifestation of environmental exposures. Thus, we hypothesized that circulating microRNAs associated with OvCa are biomarkers of exposure and could be used to identify gene expression changes resulting from environmental exposures. We employed a systems approach utilizing publicly available data for elevated levels of circulating microRNAs associated with OvCa and for altered gene expression in ovarian cancers in conjunction with associations between chemical exposures and gene expression compiled in the Comparative Toxicogenomics Database (CTD) to identify chemicals that may play a role in ovarian carcinogenesis. Intersection of genes with altered expression in ovarian cancer and putative gene targets of microRNAs identified in plasmas of OvCa patients gave a list of candidate genes for chemical interactions. Ingenuity Pathway analyses of these genes show that they participate in pathways involved in cancer and other chronic diseases. This list of genes was submitted to the CTD and a list of chemicals with known interactions with these genes was collected. The list of chemicals interacting with the OvCa specific genes included known carcinogens (arsenic, asbestos, benzo[a]pyrene), co-carcinogens (tetrachlorodibenzodioxin, tetradecanoylphorbol acetate), peroxides, heavy metals (Cu, Zn), epigenotoxicants (hydralizine, valproic acid), inflammation inducers (zymosan, lipopolysaccharide), steroid hormones (estradiol, progesterone, dexamethasone), dietary chemopreventives (indole-3-carbinol, curcumin) and chemotherapeutics (doxorubicin, tamoxifen). While some of these chemicals and pathways have been implicated previously in ovarian carcinogenesis, many have not and their identification will enable the development of targeted epidemiological studies to determine the role of their exposure in inducing or preventing OvCa. This systems approach may be useful to identify environmental exposures contributing to cancer of other organs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1326. doi:10.1158/1538-7445.AM2011-1326
Abstract 1328: Replication inhibition and mutagenicity of 8,5’-cyclopurine-2’-deoxynucleosides in Escherichia coli
Authors: Basu Ashis K. , Jasti Vijay P. , Das Rajat S. , Weerasooriya Savithri 
Published: June 2012

Abstract
8,5’-Cyclopurine-2’-deoxynucleosides are unique tandem DNA lesions formed by oxidation or ionizing radiation, which are repaired only by nucleotide excision repair. They have been suspected to be responsible for neurodegeneration and other diseases. But their replication properties are little studied. In the current work, we have evaluated replication of a pMS2 plasmid containing a single (5's)-8,5’-cyclo-2’-deoxyadenosine (5's-cdA) or (5's)-8,5’-cyclo-2’-deoxyguanosine (5's-cdG) at a preselected site in Escherichia coli. In the wild type E. coli cells, viability of 5's-cdA and 5's-cdG plasmids dropped to approximately 1% and 0.5%, respectively, relative to control. The viability of each was further reduced in pol II-deficient strain, but it was most pronounced in a pol V-deficient strain, where it dropped ten-fold. By contrast, viability increased 4-7-fold in a pol IV-deficient strain. Upon induction of SOS functions, viability increased ten-fold in the wild type strain. Though less pronounced, viability increased in the other strains as well. We conclude that pol V is necessary for translesion synthesis of the cyclopurines and that it may work cooperatively with pol II, which is also needed for bypass. In addition, it appears that although pol IV competes with the other bypass polymerases, it is inefficient in bypassing these lesions. In the absence of SOS, 5's-cdA-to-G mutations occurred at a low frequency, whereas 5's-cdG-to-A events were detected at a much higher frequency. With SOS, 5's-cdA-to-T and 5's-cdG-to-T were also detected. [Supported by NIEHS grant ES-013324]
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1328. doi:10.1158/1538-7445.AM2011-1328
Abstract 1329: Up-regulation of FOXM1b promotes low doses of arsenite-induced lung carcinogenesis
Authors: Liu Youhong , Sullivan Con , Li Xiong 
Published: June 2012

Abstract
Long-term exposure to low doses of arsenic from environmental sources has been associated with increased incidence of skin, lung, liver, bladder, and prostate cancers. A paradox is that arsenic has not been shown conclusively to be an initiator or a promoter of carcinogenesis in animal models. After E6/E7/hTERT immortalized human airway epithelial cell line NuLi-1 was exposed at 1μM arsenite continuously for 24 weeks, the cells exhibited malignant transformation in the anchorage independent growth assay. Because this cell line is null for p53 and Rb, these data indicated that inactivation of p53 and pRb pathways alone was not sufficient to induce malignant transformation, the addition of long-term exposure of low dose arsenite resulted in malignant transformation. Using a high-throughput method, we detected up-regulated expressions of CDC6, CDC25A and Cyclin D1 (which are critical for cell cycle regulation at G1 and S) when the cells were exposed to 0.1μM arsenite for 24∼72 hours CDC6, CDC25A and Cyclin D1 were expressed over time until cell transformation occurred. Arsenite steadily increased the expression levels of CDC6, CDC25A and Cyclin D1 with time at both transcription and protein levels. Interestingly, the expression of a proliferation-specific transcription factor FOXM1b correlated with increased expression of CDC6, CDC25A and Cyclin D1. FOXM1b is a key regulator of both G1/S and G2/M cell cycle transitions, and mitotic spindle integrity and plays an important role in lung carcinogenesis. Ectopic upregulation of FOXM1b in NuLi-1 cells significantly promoted arsenite-induced malignant transformation; in reverse, knockdown of FOXM1b in the transformed NuLi-1 cells and lung adenocarcinoma cell line A549 significantly decreased malignant transformation. Collectively, the study indicated that upergulation of FoxM1b, of the absence of p53 and pRb in immortalized human airway epithelial cells, promotes low dose arsenite-induced malignant transformation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1329. doi:10.1158/1538-7445.AM2011-1329
Abstract 1340: Examination of in vivo mutagenicity and carcinogenicity in the gpt delta rat with Dammar resin
Authors: Tajiri Masaki , Wei Min , Obo Yumi , Ishii Naomi , Yamano Shotaro , Wanibuchi Hideki 
Published: June 2012

Abstract
Dammar resin is a food additive as a thickening agent. The purposes of this study are to evaluate carcinogenicity and in vivo mutagenicity of Dammar resin in gpt delta rats. 6 week-old male gpt delta rats were divided into 5 groups. Groups 1-3 were treated with five carcinogen (DMBDD) during the first 4 weeks of experiment as follows: diethylnitrosamine (100 mg/kg b.w. i.p.), N-methyl-N-nitrosourea (20mg/kg b.w. i.p.), 1,2-dimethylhydrazine (40 mg/kg b.w. s.c.), 0.05% N-butyl-N-(4-hydroxypropyl) nitrosamine in the drinking water from week 1 to 2, and 0.1% dihydroxybutyl-di-N-propylnitrosamine in the drinking water from week 3 to 4. Groups 4-5 were given vehicle. From experimental week 5, groups 1-3 were treated with Dammar resin in diet at doses of 0, 0.03, and 2% for 13 weeks. Groups 4-5 were treated with Dammar resin in diet at doses of 0, and 2%, respectively. At 18 weeks after starting the experiment, quantitative analysis of glutathione S-transferase placental form (GST-P) positive foci, which are preneoplastic lesions in the rat liver and mutation assays (gpt and Spi- mutation assays) were performed. Both numbers and area of GST-P positive foci were significantly increased in rats administered DMBDD with 2% Dammar resin (group 3) compared to rats administered DMBDD alone (group 1). 0.03% Dammar resin (group 2) had no effects on the development of GST-P positive foci. There were no significant differences in mutant frequencies of gpt and red/gam genes in the livers between rats administered basal diet (group 4) and 2% Dammar resin (group 5). These findings indicated that Dammar resin exerts promotion effect on liver carcinogenesis but lack of in vivo mutagenicity in the livers of gpt delta rats.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1340. doi:10.1158/1538-7445.AM2011-1340
Abstract 1342: Effects of the plasticizer metabolite 2 ethyl-1-hexanol on human lymphoblast cells
Authors: Rosado-Berrios Carlos A. , Vélez Christian , Zayas Beatriz 
Published: June 2012

Abstract
The study main objective was to determine the toxicity of 2-ethyl-1-hexanol (EH) and to compare them to its precursor di-ethylhexyl phthalate (DEHP) on the TK6 human lymphoblast cell line. EH is an organic alcohol produced in cells as result of the biotransformation of DEHP. Release of EH from lung cancer cells was also reported recently. Environmental human exposure to the parent DEHP can result through interaction with personal care products, paint lacquer, inks, rubber, dry cleaning and plasticizers such as PVC. Analyzed effects in this study included doses that inhibit cell growth (IC50), damage to the mitochondrial membrane, generation of Reactive Oxygen Species (ROS), and activation of caspase 3 and 7. TK6 cells were cultured on 12.5cm2 flasks with modified RPMI 1640 culture media with 10% FBS, and incubated at 37°C with 5% CO2. IC50 was determined by trypan blue exclusion and mitochondrial membrane permeability applying the Mito PT JC-1 assay from Immunochemistry. For ROS determination the fluorescent dye 2,7-dichlorofluorescein diacetate (DCFH-DA) was applied. For caspases 3 and 7 analysis the Magic RedTM assay from Immunochemistry was applied. Results indicated that IC50s of DEHP and EH on TK6 cells were 234 μM and 75nM respectively. Cells where then exposed to the identified IC50 for 48 hours to measure effects on mitochondria and ROS generation. ROS results indicated that EH generated an average of 96.31 Fluorescence Standard Units (FSU), the negative control Dimethyl Sulphoxide (DMSO) generated 58.22 FSU, the compound used as positive control cis-Di ammine platinum (II) dichloride (Cisplatin) generated 1309.67 FSU and for DEHP the ROS analysis resulted on 793.27 FSU. The level of ROS generated between the parent and this metabolite are not consistent with the degree of toxicity observed. Determination and comparison of the mitochondrial membrane permeabilization as well as Caspases 3 and 7-activation assays of EH are still developing. The preliminary results, however indicates a wide difference in citotoxicity between the parent compound and its metabolite clearly supporting the need for prevention strategies reducing exposure to these controversial plasticizer and therefore potential health effects.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1342. doi:10.1158/1538-7445.AM2011-1342
Abstract 1353: Hydrogen sulfide-releasing naproxen inhibits HT-29 human colon cancer cell growth: Modulation of NF-κB
Authors: Nesbitt Diandra E. , Chattopadhyay Mitali , Kodela Ravinder , Boring Daniel , Crowell James A. , Kashfi Khosrow 
Published: June 2012

Abstract
Introduction: Chronic inflammation is widely recognized as an underlying etiological factor in carcinogenesis; there is enough evidence to support the use of non-steroidal anti-inflammatory drugs (NSAIDs) as chemopreventive agents. However, their wide use is precluded due to significant toxicity. Recently, a new class of hydrogen sulfide-releasing NSAIDs have been described in which the parent NSAID is covalently linked to a dithiolethione moiety (5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione) which release hydrogen sulfide. HS-NSAIDs have enhanced safety and efficacy compared to their traditional counterparts. Since NSAIDs are regarded as prototypical chempreventive agents, here we compared naproxen and its hydrogen sulfide-releasing (HS-naproxen) analog using a human colon cancer cell line and also evaluated its effect on NF-κB whose induction is strongly implicated in some cancers.
Methods: HS-naproxen was synthesized and purified at our lab with 1H-NMR verification. Cell line: HT-29 human adenocarcimoma; Cell growth: MTT; Cell cycle phase distribution: Flow cytometry; Apoptosis: subdiploid (sub-G0/G1) peak in DNA content histograms; Proliferation: PCNA; NF-κB: enzyme-linked immunosorbent assay (ELISA). GSH levels: colorimetric method.
Results: HS-naproxen inhibited the growth of HT-29 cells with an IC50 of 72 ± 5 µM whereas for naproxen the IC50 was 2800 ± 190 µM at 24h. HS-naproxen treatment of HT-29 cells at 0.5xIC50, 1xIC50, and 2xIC50 for 24 hrs induced apoptosis (12 ± 1%, 54 ± 3%, 71 ± 3%), inhibited proliferation (PCNA, 71 ± 3%, 49 ± 5%, 26 ± 4%), and caused a G0/G1 cell cycle block. Activation of NF-κB was inhibited as demonstrated by ELISA, at 0.5xIC50, 1xIC50, and 2xIC50 the reduction was 22 ± 3%, 47 ± 2%, and 62 ± 4% respectively. Cellular GSH levels were also reduced dose-dependently by HS-naproxen, suggesting a condition of oxidative stress.
Conclusions: HS-naproxen inhibits HT-29 cell growth and inhibits NF-κB activation. These data suggest that HS-naproxen may be useful as chemopreventive agent against colon cancer and merits further evaluation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1353. doi:10.1158/1538-7445.AM2011-1353
Abstract 1354: New chemical tools for disrupting the Mcl-1/BH3 protein-protein interaction
Authors: Pernazza Daniele , Doi Kenichiro , Lawrence Harshani , Sebti Saïd , Wang Hong-Gang , Lawrence Nicholas 
Published: June 2012

Abstract
Anti-apoptotic members of the Bcl-2 protein family, such as Bcl-2, Bcl-xL and Mcl-1, are among the most effective inhibitors of apoptosis and are frequently upregulated in various types of human cancer. A number of pro-apoptotic proteins share only the BH3 domain with other members of the Bcl-2 family, so called BH3-only proteins, and appear to function essentially as transdominant inhibitors by binding to anti-apoptotic Bcl-2 family proteins and neutralizing their cell-survival activity. The development of small molecules to mimic the BH3 proteins has been an intense area of research. However, to date available Bcl-2 family proteins inhibitors are either pan-inhibitors such as (−)-gossypol (which simultaneously inhibits Bcl-xl/BH3, Bcl-2/BH3 and Mcl-1/BH3 interactions) or are selective for the Bcl-xl/BH3 and Bcl-2/BH3 interactions. Hence a selective Mcl-1/BH3 inhibitor would greatly aid investigating the role of Mcl-1 in cancer and in drug resistance. Our current study is centered on the identification and the synthesis of small molecule selective inhibitors of the Mcl-1/BH3 interaction. To this aim we interrogated the hit-list from inhibitors of the MLSCN screen of the Mcl-1-NOXA interaction [(Emory, AID 1417) TR-FRET screen for Mcl-1-NOXA inhibitors]. Selected compounds were purchased and assessed for activity in a fluorescence polarization and ELISA assay, to reveal the hit HLM050001 (FP IC50 0.8 ± 0.1 µM; ELISA IC50 19.3 ± 2.5 µM). HLM050001binding to Mcl-1 is currently being assessed via co-crystallization and other biophysical techniques. We will report the synthesis and biological evaluation of focused libraries based on the initial hit and designed by modeling and docking to Mcl-1. Structure activity relationship studies around the hit will be disclosed as well as the outcomes of further rounds of chemical design and biological assessment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1354. doi:10.1158/1538-7445.AM2011-1354
Abstract 1356: The Hinge (linker) region of the Hepatocyte Growth Factor (HGF) peptide sequence can act as Hepatocyte Growth Factor/c-Met inhibitor
Authors: Kawas Leen H. , Harding Joseph W. , Yamamoto Brent J. , Wright John W. 
Published: June 2012

Abstract
The central domain interface of the HGF referred to as the hinge region is critical for proper ligand (HGF) dimerization and activation. A peptide sequence representing the hinge region acts as a hinge region mimic, by binding directly to HGF and blocking its dimerization. Ligand dimerization is a critical step in activating the HGF/c-Met signaling pathway. And the interference of this unique structure with HGF dimerization translates into inhibition of HGF-dependent signaling, proliferation, and scattering in multiple cell types at concentrations reaching down into the picomolar range. Not only was the hinge peptide sequence capable of inhibiting HGF in-vitro, but it also showed anti-c-Met/anti-cancer activity in an in-vivo study. As expected, it significantly suppresses pulmonary colonization by B16-F10 murine melanoma cells (in C57BL/6 mice), which are characterized by an overactive HGF/c-Met system. This leads to the conclusion that the hinge peptide sequence exerts its anti-cancerous activity through interfering with the HGF/c-Met system, and that more effective HGF/c-Met antagonists can be designed using the hinge region peptide as the parent compound template. The project was funded by Autzen foundation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1356. doi:10.1158/1538-7445.AM2011-1356
Abstract 1358: Discovery and optimization of potent and selective benzonaphthyridinone analogs as dual mTOR/ATR small molecular inhibitors for treatment of cancer
Authors: Liu Qingsong , Zhou Danny , Shiotani Bunsho , Gray Nathanael S. , Elledge Stephen J. , Zou Lee 
Published: June 2012

Abstract
The Mammalian Target of Rapamycin is a highly conserved Serine/Threonine protein kinase that plays a key role in several fundamental cellular processes such as growth, proliferation and metabolism. As a key node in the PI3K/AKT/mTOR signal pathway, mTOR is currently being actively investigated as a therapeutic target for the treatment of a variety of human cancers. Structurally, mTOR shares high sequence identity in the catalytic domain with other PIKK family kinases including PI3Ks, ATR, ATM, DNA-PK and SMG-1. ATR is an apical kinase in a cell cycle checkpoint pathway that monitors DNA integrity. Upon DNA damage, ATR activation results in cell cycle arrest and the initiation of DNA repair processes. Numerous studies have demonstrated that impairment of ATR function sensitizes cells to death in the presence of chemotherapeutic drugs or ionizing radiation. We hypothesized that a dual mTOR/ATR dual inhibitor might produce a profound apoptotic response in cells with impaired DNA-repair pathways. Starting from the recently developed small molecular ATP competitive mTOR selective inhibitor Torin1, a focused medicinal chemistry exploration of the benzonaphthyridinone structure furnished a library of compounds which was screened in a functional cellular assay for ATR inhibition. Biochemical characterization of select compounds using an immunoprecipitation assays for ATR and mTORC1 kinase activity confirmed that the compounds are dual mTOR/ATR inhibitors. Select compounds were characterized in proliferation assays using p53-deficient HCT-116 cell lines alone and in combination with ionizing radiation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1358. doi:10.1158/1538-7445.AM2011-1358
Abstract 1362: Discovery of a novel structural class of compounds: HLM-030376 and its analogs as potent chymotrypsin-like proteasome inhibitors
Authors: Ge Yiyu , Ozcan Sevil , Kazi Aslamuzzaman , Marsilio Frank , Daniel Kenyon , Brooks Wesley , Guida Wayne , Lawrence Harshani , Sebti Said 
Published: June 2012

Abstract
The ubiquitin-proteasome pathway plays a critical role in the regulated degradation of proteins involved in cell cycle control and tumor growth. Proteasome inhibitors cause selective apoptosis of malignant cells and represent a new class of antineoplastic agents. In 2003 Bortezomib (peptide boronate), a proteasome inhibitor was approved by FDA for treatment of multiple myeloma. Toxicity and tumor cell resistance against Bortezomib demand development of less toxic proteasome inhibitors with broader spectrum of tumor activity. Our aim is to develop non-peptidic small drug-like molecules as proteasome inhibitors. To this end, we have identified through in-house screening efforts HLM-030376 as a small molecule proteasome inhibitor with phenanthridine pharmacophore. HLM-030376 showed in-vitro chymotrypsin like, trypsin like and PGPH inhibitory activities with IC50 values 0.26, 0.19 and 2.07 µM respectively. Extensive synthetic modifications around the HLM-030376 pharmacophore were undertaken to aid the cell activity of this class of compounds. We will describe the synthesis and activity of analogs of HLM-030376 as potent proteasome inhibitors. The analogs of HLM-030376 showed in-vivo CT-L inhibitory activities (IC50 between 0.6-6.0 µM) against MDA-MB 468 breast cancer cell line as well as improved (IC50 between 70-200 nM) in-vitro CT-L inhibitory activities. The detailed in-vitro structure activity relationship (SAR) data of HLM-030376 and analogs will be discussed to understand the structural moieties responsible for proteasome activity. The whole cell activity data of HLM-030376 as well as in-silico docking studies will be presented as potential proteasome inhibitors for further development.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1362. doi:10.1158/1538-7445.AM2011-1362