bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3214: C-seco taxanes with 7, 9-linkages exhibit better activity in drug-resistant tumor cells
Authors: Tang Yong , Cai Pei , Rodríguez-Salarisch Javier , Díaz J. Fernando , Fang Weishuo 
Published: May 2015

Abstract
Taxanes are a group of very successful MT stabilizing agents in cancer chemotherapy, although they suffer from tumor drug resistance, which compromises clinical efficacy. Many efforts were made in our labs to the structural modification of paclitaxel to improve efficacy against tumor drug resistance mediated by multiple mechanisms, with the emphasis on two clinically relevant ones: P-glycoprotein (Pgp) and β-III tubulin overexpression. While Pgp mediated multidrug resistance has been extensively explored and applied to the drug discovery projects, β-III tubulin overexpression related drug resistance was much less explored.
The β-III tubulin isotype was found to play an important role in conferring resistance to MT stabilizing agents only in recent decade. It has also been identified as a survival factor in several types of cancers, thus conferring resistance to various anticancer agents, such as MT destabilizing agents and DNA interacting agents.
We have found some high affinity taxanes (e.g. LX2-32C, Yg-3-46a) exhibited their activity toward Pgp efflux pump and also β-III tubulin mediated drug resistance. However, they did not show greater specificity for the β-III tubulin isotype. Based on a C-seco taxane IDN5390 which was reported to be more selectively interacted with β-III tubulin than paclitaxel, we have succeeded in the design and synthesis of 7,9-O-linked C-seco taxanes with different linkages. Some of them exhibited better activity than IDN5390, and the activities were found sensitive to the structural changes of the linkers.
Citation Format: Yong Tang, Pei Cai, Javier Rodríguez-Salarisch, J. Fernando Díaz, Weishuo Fang. C-seco taxanes with 7, 9-linkages exhibit better activity in drug-resistant tumor 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 3214. doi:10.1158/1538-7445.AM2014-3214
Abstract 3215: Role of pterostilbene on proliferation, invasion, and migration in ovarian and uterine cancer cells
Authors: Lowe Gina , Wen Wei , Roberts Cai , Finlay James , Glackin Carlotta , Han Ernest , Dellinger Thanh H. 
Published: May 2015

Abstract
PURPOSE: To determine the functional effects of the resveratrol analog, pterostilbene (PTE), and its potential adjuvant role with cisplatin, in ovarian and uterine cancer cells.
EXPERIMENTAL DESIGN: The human ovarian cancer cell lines (OVCAR8, SKOV3) and uterine cancer cell lines (HEC1A, ECC1) were obtained from ATCC, and grown according to standard protocols using recommended media. Standard proliferation (MTT) and migration assays were performed in routine fashion, with or without PTE +/- cisplatin treatment. For the in-vitro Cell Proliferation Assay, different concentrations of cisplatin (3 - 50 μM), pterostilbene (PTE) (30 - 500 μM), or both in combination were added for 72 hours. Cell migration was assayed using 24-mm diameter chambers with 8-μm pore filters, with or without treatment of PTE and cisplatin, and migrated cells were counted using Image-pro program. A synergistic analysis from the MTT assay results was calculated via the CompuSyn for Windows computer program based on the combination index (CI) theorem of Chou-Talalay, to determine the presence of synergy between cisplatin and PTE.
RESULTS: PTE reduces proliferation in OVCAR8, SKOV3, HEC1A, and ECC1 cells, and its anti-proliferative effect approaches that of cisplatin. Addition of PTE to cisplatin potentiates the anti-proliferative effects of cisplatin in HEC1A, ECC1, SKOV3, and OVCAR8 cells. The combined effect of PTE and cisplatin is synergistic in OVCAR8 cells based on synergy calculations (CI&lt;1). PTE reduces cell migration in HEC1A and OVCAR8 cells, and its addition to cisplatin treatment improves the anti-migratory effect.
CONCLUSIONS: Pterostilbene, a resveratrol analog with improved bioavailability, reduces proliferation and migration in ovarian and uterine cancer cells, and potentiates the anti-proliferative and anti-migratory effects of cisplatin, thus presenting as an attractive non-toxic alternative for potential adjuvant chemotherapy in ovarian and uterine cancer.
Citation Format: Gina Lowe, Wei Wen, Cai Roberts, James Finlay, Carlotta Glackin, Ernest Han, Thanh H. Dellinger. Role of pterostilbene on proliferation, invasion, and migration in ovarian and uterine 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 3215. doi:10.1158/1538-7445.AM2014-3215
Abstract 3221: Covalent inhibitors of S100B (SBiXs) in malignant melanoma
Authors: Cavalier Michael C. 
Published: May 2015

Abstract
Summary: The calcium binding protein, S100B, has been directly linked to malignant melanoma (MM) and has long been used as a prognostic indicator. Studies have proven S100B to not only be a clinical marker within MM, but that it binds to the tumor suppressor p53, and promotes its degradation. p53 is typically found as wild-type in MM, and inhibition of S100B expression restores both p53 protein levels and normal transcriptional activation/apoptosis activities. Subsequently, we have made it our long-term goal to discover S100B inhibitors (SBiXs) in order to restore the p53 tumor suppression function in patients with MM, and have already identified many SBiXs.
Purpose: It is our purpose to discover/synthesize and/or to improve existing inhibitors of S100B to restore p53 activity in human malignant melanoma. Amongst these SBiXs are compounds which covalently modify S100B. The effects of covalent SBiXs on S100B in Malignant Melanoma are to be investigated.
Results and conclusions: The development of S100B inhibitors (SBiXs) is ongoing at the University of Maryland Schools of Pharmacy and Medicine with the goal of improving affinity and specificity towards inhibiting S100B. Fluorescent Polarization Completion Assays have identified compounds that bind S100B and inhibit melanoma cell growth. S100B binding by these SBiXs was confirmed using NMR spectroscopy. The crystallographic structures of the SBiX:S100B complexes were solved revealing covalent modifiers occupying persistent binding site 2. The compounds offer potential bridging scaffolds between sites 1 and 3. All five SBiXs demonstrated the ability to kill malignant melanoma with some killing in a S100B dependent manner. TheS100B-SBiX complexes presented will act as the basis for the design of improved SBiXs. SBiXs may also have therapeutic value for treating other cancers with elevated S100B and wt p53 such as astrocytoma, renal tumors, and some forms of leukemia.
Citation Format: Michael C. Cavalier. Covalent inhibitors of S100B (SBiXs) in malignant melanoma. [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 3221. doi:10.1158/1538-7445.AM2014-3221
Abstract 3222: Structural evaluation of several antitumor Tencon variants
Authors: Cardoso Rosa , Goldberg Shalom , Luo Jinquan , Barnakov Alexander , Swift Edward , Jacobs Steven , Gilliland Gary 
Published: May 2015

Abstract
Tencons are engineered alternative scaffold proteins that combine the affinity and specificity of antibodies with the biophysical features of smaller molecules and hold high promise as biotherapeutic agents. We present the crystal structures and antigen binding data of several anti-Tumor Tencon variants. The structures of the variants show a switch of the FG loop conformation from α-helical at the tip to mostly β-strands. This conformational change prompts differential exposure of potential binding residues and a finger-like shape for the FG region that may facilitate its access to binding pockets on the target protein, thus likely accounting for the observed differences in KD.
Citation Format: Rosa Cardoso, Shalom Goldberg, Jinquan Luo, Alexander Barnakov, Edward Swift, Steven Jacobs, Gary Gilliland. Structural evaluation of several antitumor Tencon variants. [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 3222. doi:10.1158/1538-7445.AM2014-3222
Abstract 3227: JNK2 oligomerization regulates its activation through non-canonical pathways
Authors: Kaoud Tamer S. , Riggs Austin F. , Dalby Kevin N. 
Published: May 2015

Abstract
C-Jun N-terminal kinases (JNKs) regulate various cellular functions. Their activation is mediated cooperatively by both MKK4 and MKK7. The c-Jun N-terminal kinase 2 (JNK2) isoform is constitutively activated in glial tumor cell lines and human glioblastoma models. We investigated the regulation of JNK2 self-activation in vitro in both cell-free and cell-based experiments. Light scattering analysis suggested that unphosphorylated recombinant JNK2α2 exists in solution as a mixture of monomers, dimers and tetramers. JNK2α2 self-phosphorylates more rapidly in vitro when assayed at low concentration leading to its activation. However, at a slightly higher concentration, the formation of a tetramer is favored, whose ability to self-phosphorylate is suppressed. HEK293T cells that were transfected with varying amounts of pcDNA-JNK2α2 showed that an increased concentration of JNK2α2 (54 kDa) could suppress the appearance of activated JNK2α2 in mammalian cells. A mutant of JNK2 (F170R) thought to stabilize the DFG-out conformation appears to stabilize the formation of a JNK2 tetramer. Taken together our data suggest that oligomerization may regulate non-canonical (self-activation) activation of JNK2.
Citation Format: Tamer S. Kaoud, Austin F. Riggs, Kevin N. Dalby. JNK2 oligomerization regulates its activation through non-canonical pathways. [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 3227. doi:10.1158/1538-7445.AM2014-3227
Abstract 3230: Genome-wide localization of anti-cancer drugs
Authors: Anders Lars , Guenther Matthew G. , Qi Jun , Fan Zi Peng , Marineau Jason J. , Rahl Peter B. , Lovén Jakob , Sigova Alla A. , Smith William B. , Lee Tong Ihn , Bradner James E. , Young Richard A. 
Published: May 2015

Abstract
A vast number of small-molecule ligands, including therapeutic drugs under development and in clinical use, elicit their effects by binding specific proteins associated with the genome. An ability to map the direct interactions of a chemical entity with chromatin genome-wide could provide new and important insights into the mechanisms by which such small molecules interfere with tumor cell functions. We have developed a method that couples affinity capture of chemical entities and massively parallel DNA sequencing (Chem-seq) to identify the sites bound by small molecules throughout the human genome. Using Chem-seq, we have uncovered the full repertoire of the genomic sites bound by a BET bromodomain inhibitor, a cyclin-dependent kinase (CDK) inhibitor and a DNA intercalating drug. Moreover, by combining Chem-seq with ChIP-seq, we have characterized the interactions of drugs with their targets throughout the genome of tumor cells. These methods provide a powerful approach to enhance understanding of therapeutic action and characterize the specificity of drugs that interact with DNA or genome-associated proteins.
Citation Format: Lars Anders, Matthew G. Guenther, Jun Qi, Zi Peng Fan, Jason J. Marineau, Peter B. Rahl, Jakob Lovén, Alla A. Sigova, William B. Smith, Tong Ihn Lee, James E. Bradner, Richard A. Young. Genome-wide localization of anti-cancer drugs. [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 3230. doi:10.1158/1538-7445.AM2014-3230
Abstract 3234: Covalent capture of protein binding partners using an azide-tagged, photo-reactive stapled alpha helical p53 peptide
Authors: Whiting Amanda L. , Mitala Joe J. , Headley Kathryn M. , Reilly Joe , Morrison Bethanie L. , Murray Kevin A. , Bernal Federico 
Published: May 2015

Abstract
Mutations in the DNA binding region of tumor suppressor p53 render it transcriptionally inactive (dominant negative) but can also manifest in transcriptionally-independent gain-of-function (GOF) effects, possibly due to mutp53 interacting with other, as yet, unknown targets. Identification of these targets would help to elucidate the pathways and vulnerabilities involved in mutp53 GOF. Covalently linking a known handle to these unknown proteins is one method to aid in their isolation and identification. A hydrocarbon-stapled alpha helical peptide of the p53 transactivation domain (residues 14-29), SAH-p53-8, has been shown to strongly interact with known p53 targets that utilize this domain for binding (HDM2, Kd = 55 nM, HDMX, Kd = 2.3 nM). Substitution of a key interacting residue for the unnatural amino acid benzoylphenylalanine (Bpa) results in a stapled peptide that retains the biochemical properties of SAH-p53-8 (affinities of 38.1 nM and 58.3 nM, respectively) and can covalently capture known targets via photochemical reaction. The introduction of an azido group - a versatile, biochemically-inert capping group - to the N-terminus of this photo-reactive peptide allows for the attachment of various tags to the covalently bound protein(s) via a copper-catazlyzed azide alkyne cycloaddition. Tags include both fluorophores for visualization and affinity tags for protein isolation. This poster will cover the biochemical proof-of-principle of this protein isolation method and exploration into more complex cell lysate environments.
Citation Format: Amanda L. Whiting, Joe J. Mitala, Kathryn M. Headley, Joe Reilly, Bethanie L. Morrison, Kevin A. Murray, Federico Bernal. Covalent capture of protein binding partners using an azide-tagged, photo-reactive stapled alpha helical p53 peptide. [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 3234. doi:10.1158/1538-7445.AM2014-3234
Abstract 3252: A regulatory variant in CYP2E1 affects the risk of lung squamous cell carcinoma
Authors: Cao Lei , Lin Jia , He Bing , Wang Hongge , Rao Juan , Liu Yingwen , Zhang Xuemei 
Published: May 2015

Abstract
Background: Cytochrome P450 2E1 (CYP2E1), an ethanol-inducible enzyme, has been shown to metabolically activate various carcinogens, which is critical for the development of cancers. It has demonstrated that CYP2E1 polymorphisms alter the transcriptional activity of the gene. However, studies on the association between CYP2E1 PstI polymorphism and non-small cell lung cancer have reported conflicting results. Thus, the gain of the present study was to investigate whether CYP2E1 PstI polymorphism is associated with the development of non-small cell lung cancer in Chinese population.
Method: A case-control study was conducted in which CYP2E1 PstI polymorphism was analyzed in 526 Chinese patients with non-small cell lung cancer and 526 age-matched healthy controls by PCR-RFLP. Odds ratios were estimated by multivariate logistic regression.
Result: For CYP2E1 PstI polymorphism, C allele carriers (OR=0.67; CI=0.51-0.87; P=0.002) was associated with a decreased risk of non-small cell lung cancer when compared with GG homozygotes. In the group analyses by pathological types, for lung SCC and other types the ORs of the C allele carriers were (OR=0.60; CI=0.41-0.88; P=0.009) and (OR=0.54; CI=0.30-0.99; P=0.045), respectively. In the group analyses by smoking status, there was a significant association among nonsmokers (OR=0.57; CI=0.40-0.81; P=0.002), but not smokers. In the group analyses by TNM stage, there was no significance between CYP2E1 PstI polymorphism and the grade of non-small cell lung cancer.
Conclusion: CYP2E1 PstI polymorphism is associated with decreased risk of development of non-small cell lung cancer and lung SCC or other types in Chinese patients.
Key Words: lung cancer; CYP2E1; gene polymorphism; susceptibility; genetic variant
Citation Format: Lei Cao, Jia Lin, Bing He, Hongge Wang, Juan Rao, Yingwen Liu, Xuemei Zhang. A regulatory variant in CYP2E1 affects the risk of lung squamous cell carcinoma. [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 3252. doi:10.1158/1538-7445.AM2014-3252
Abstract 3253: Id4 and FKBP52 interaction regulates androgen receptor activity in normal prostate and prostate cancer
Authors: Joshi Jugal B. 
Published: May 2015

Abstract
The androgen receptor (AR) is a ligand activated transcription factor and important member of the steroid hormone nuclear receptors. Androgen signaling through AR plays a critical role in prostate tumorigenesis. AR transcriptional enhancement normally requires FKBP52 mediated peptidyl-prolyl cis-trans isomerase (PPIase) activity as well as HSP90-binding ability. FK506 binding protein 4 (FKBP52) is an AR folding factor that has critically important physiological roles in male reproductive tissues. Despite several experimental evidences, the molecular mechanism by which FKBP52 promotes AR signaling in prostate cancer still remains to be investigated. Our previous lab studies have demonstrated that Id4 is regulated by androgens in normal prostate epithelial and LNCaP cells. However, the interaction of Id4 and with the androgen receptor pathway in regulating the development and function of the normal prostate still remains elusive. Here we demonstrate that Id4 (inhibitor of differentiation-4) a dominant negative regulator of bHLH transcription factors can physically interact with AR, FKBP52 and HSP90 in early stage prostate cancer LNCaP cells and thereby selectively regulating AR transcriptional activity. Id4 is highly expressed in the normal prostate and decreased in prostate cancer due to promoter hypermethylation. Loss of Id4 in LNCaP cells resulted in ligand independent AR activation characterized by increased AR nuclear translocation and expression of PSA, FKBP51, FKBP52 and ARD1, the transcriptional targets of AR. Differential protein expression between LNCaP and LNCaP-Id4 demonstrated that loss of Id4 cells significantly elevated the levels of FBKP52 and Hsp27, the two known transcriptional regulators and nuclear transporters of AR. More importantly, LNCaP-Id4 cells were able to synthesize significantly higher levels of testosterone as compared to the androgen-dependent LNCaP cells. In conclusion, we demonstrate that loss of Id4 in LNCaP cells elevates FKBP52 levels, transcriptionally potentiates AR activity which in turn then leads to progression of androgen-independent prostate cancer. NIH grant #R01CA128914
Citation Format: Jugal B. Joshi. Id4 and FKBP52 interaction regulates androgen receptor activity in normal prostate and prostate 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 3253. doi:10.1158/1538-7445.AM2014-3253
Abstract 3259: Evaluation of the aromatase inhibition potential of standardized grape extract
Authors: Olson Janet E. , Allen Summer V. , Suman Vera J. , Hoskin Tanya L. , Vachon Celine M. , Ingle James N. 
Published: May 2015

Abstract
OBJECTIVE: To determine the role of grape extract as a potential aromatase inhibitor by testing of plasma hormone levels.
PROCEDURE: A six-week study was conducted involving postmenopausal women during which 94 grams of grape extract was consumed in addition to their usual diet. Plasma hormones were measured before and after treatment.
RESULTS: Of the 18 women involved in the study, average age and BMI were 61.4 years and 24.4, respectively. For the hormone levels studied, the following median (IQR) percent change from baseline to 6 weeks values were found: estradiol +11.8% (-34.4%,+44.2%), p = 0.42; estrone +3.4% (-15.7%,+12.9%), p = 0.64; estrone sulfate +5.3% (-19.9%,+56.3%), p = 0.35; testosterone -1.5% (-14.7%,+10.7%), p = 0.97; androstenedione +12.6% (-17.1%, +49.1%), p = 0.15. The hormone levels did not significantly change between baseline and six weeks. Further, the changes that were observed did not tend to go in the hypothesized direction (estrogens and conjugates increased slightly, testosterone decreased slightly). Only androstenedione showed a trend toward change in the hypothesized direction.
CONCLUSION: In this study, there was no evidence that plasma hormone levels are altered by 6 weeks of daily consumption of 94 grams of grape extract powder.
Citation Format: Janet E. Olson, Summer V. Allen, Vera J. Suman, Tanya L. Hoskin, Celine M. Vachon, James N. Ingle. Evaluation of the aromatase inhibition potential of standardized grape extract. [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 3259. doi:10.1158/1538-7445.AM2014-3259
Abstract 3262: Windows of susceptibility to endocrine disruptors and gene expression in mammary tissue
Authors: Gopalakrishnan Kalpana , Li Qian , Ma Yula , Lambertini Luca , Chen Jia , Teitelbaum Susan L. , Manservisi Fabiana , Belpoggi Fiorella , Bua Luciano , Falcioni Laura 
Published: May 2015

Abstract
Breast cancer is hormonally driven. Endocrine disruptors (EDs) are exogenous substances that mimic or antagonize endogenous hormone action and disrupt endocrine system function. While EDs have been shown to modulate the risk for mammary tumors in animal models, their effects at biologically relevant doses and during critical developmental windows remain poorly understood. We sought to examine the individual and combinatorial effects of three common EDs, diethyl phthalate, methyl paraben and triclosan in rats exposed at five distinct developmental windows of susceptibility - prenatal, neonatal, prepubertal, pubertal and parous/nulliparous. Pathological features and whole genome expression of normal rat mammary tissues were profiled to provide both qualitative and quantitative biological effects of EDs. ED exposure at levels comparable to human exposure resulted in profound changes in both gross phenotypes (e.g. reproductive mortality and mammary gland morphology) as well as in molecular genome profiles. Specifically, ED exposure appeared to hamper normal breast development and resulted in increased mortality in the offspring, possibly due to reduced milk production. Whole genome expression profiling of mammary tissues revealed that in the course of development, the number of differentially expressed genes was lower in ED-exposed rats compared to controls, suggesting developmental delay or suppression by EDs. Pathway enrichment analysis indicated that several processes including inflammation, metabolism and development were disrupted by ED exposure. Taken together, our findings reveal novel mechanisms of ED action in mammary development and strongly suggest the importance of taking into account the timing of exposure when studying the relationship between environment and disease.
Citation Format: Kalpana Gopalakrishnan, Qian Li, Yula Ma, Luca Lambertini, Jia Chen, Susan L. Teitelbaum, Fabiana Manservisi, Fiorella Belpoggi, Luciano Bua, Laura Falcioni. Windows of susceptibility to endocrine disruptors and gene expression in mammary tissue. [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 3262. doi:10.1158/1538-7445.AM2014-3262