bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3185: Use of whole slide digital imaging for determination of caPCNA and Ki-67 labeling index in normal breast reductions and DCIS: Comparison of the two biomarkers using the Aperio image-based positive pixel algorithm
Authors: Sandusky George E. , Rodgers Matt S. , John Karla , Gulley Patty , Malkas Linda , Hickey Robert 
Published: June 2012

Abstract
While mitotic rates as well as proliferation indices have been reported as significantly different among normal breast and different grades of breast cancer, a reproducible cut-off value has not emerged. The goal of this study was to determine whether more reproducible algorithms using whole slide digital images (WSDI) can define better cut-off values for the normal breast vs. DCIS.
Design: Whole tissue sections from 10 normal breast reductions and 10 cases of DCIS were evaluated by immunohistochemistry for caPCNA and Ki67 (Mib-1). Having identified an isoform of PCNA that was uniquely expressed by cancer cells (caPCNA) and distinct from the isoform expressed by non-malignant and normal cells (nmPCNA), antibody selectively binding to caPCNA was developed and used for these studies. Stained slides were scanned using the Aperio (Vista, California) automated whole slide scanning system (Scanscope CS) and were viewed using ImageScopeTM. Single fields of view from each WSDI measuring ∼420,000 µ2 and representing the highest density of caPCNA and Ki-67 positive nuclei were selected for analysis. Different areas were analyzed in a subset of slides to determine the variability in each case, and the total nuclear labeling index was generated using the Aperio positive pixel algorithm.
Results: We analyzed the labeling indices in 10 normal breast reductions and 10 DCIS cases. Both caPCNA and Ki-67 were nuclear specific with minimal cytoplasmic staining. The mean labeling indices for the Aperio automated positive pixel counts were caPCNA (0.15) and Ki-67 (0.12) for normal breast and caPCNA (0.52) and Ki-67 (0.29) for DCIS. The correlation coefficients between automated counts were 0.653 for normal breast and 0.616 for DCIS, with an overall correlation coefficient of 0.708 for the entire series.
Conclusions: Our analysis of both biomarkers yielded a similarly increasing labeling index for DCIS cases when compared to their expression in normal breast expression. The positive pixel algorithm method has a sampling bias due to subjective selection of the area being counted. In summary, the present results show similar findings for caPCNA and Ki-67 in normal breast reductions with no evidence of breast disease and in DCIS clinical cases. Comparing caPCNA with Ki-67, and unlike traditional PCNA, caPCNA can potentially better differentiate between normal breast and DCIS, and may be a useful biomarker for early stage cancer diagnosis.
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 3185. doi:10.1158/1538-7445.AM2011-3185
Abstract 3220: Application of GastroPlus™ modeling and simulation for predicting mouse and human pharmacokinetic profiles in oncology research and development
Authors: Hosea Natilie 
Published: June 2012

Abstract
Pharmacokinetic modeling plays an integral role in the drug discovery and development process. In particular, modeling and simulation has broad application to predict pharmacokinetics for human and non-clinical species, and as such drug concentration at the site of action, optimal dosing regimen with respect to safety and efficacy, food effects, inter-individual variability, drug-drug interaction potential and other scenarios, all with the aim of increasing understanding of a molecule and enabling informed decisions during the drug discovery and development process. GastroPlus™ is an “off the shelf” application that has been reported to accurately predict the absorption and pharmacokinetic profile of small drug-like molecules. Herein, three case studies are described where GastroPlus™ modeling and simulation was employed to predict the absorption and pharmacokinetic profile. In the first case study, GastroPlus™ was employed to predict the pharmacokinetic profile in mouse following oral administration to facilitate dose selection for in vivo pharmacological testing in tumor bearing mice. The second case study employed the parameter sensitivity analysis mode within GastroPlus™ to determine the critical parameters limiting oral exposure of the compound in mouse. The third case study employed GastroPlus™ to predict the implication of food on the human oral exposure of a compound in exploratory development in oncology patients. In all 3 case studies, the results obtained from the modeling and simulation provided key information that led to decisions on either dose selection, chemistry strategy to improve lead matter or clinical protocol design, thus demonstrating the value of modeling and simulation in both early discovery and exploratory development for predicting absorption and pharmacokinetic profiles in the area of oncology research and 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 3220. doi:10.1158/1538-7445.AM2011-3220
Abstract 323: Use of triple combination array analysis to identify STEAP family member 4 (STEAP4), a novel tumor suppressor gene in hepatocellular carcinoma
Authors: Nomoto Shuji , Okamura Yukiyasu , Hayashi Masamichi , Takeda Shin , Sugimoto Hiroyuki , Fujii Tsutomu , Nakao Akimasa 
Published: June 2012

Abstract
Background: Hepatocellular carcinoma (HCC) is one of the most common cancers world-wide, but the molecular mechanisms underlying hepatocarcinogenesis are not clear. Array technology has made it possible to identify novel genes with alterations in liver cancer. In this study, we performed triple combination array analysis, expression profiling, karyotyping analysis using SNP array, and array-based DNA methylation profiling in the same HCC sample and attempted to find a novel tumor suppressor gene as a prognostic marker.
Materials & Methods: A 68-year-old woman with chronic hepatitis C was diagnosed with HCC. The tumor and corresponding normal tissues were used for extraction of DNA and RNA. SNP chip array experiments were performed according to the standard protocol of Affymetrix GeneChip Mapping 500K arrays for DNA. mRNA expression profiles were determined using Affimetrix HGU133A and B Gene-Chips. Bisulphite-converted genomic DNA was analyzed using Illumina's Infinium Human Methylation27 Beadchip Kit. We consequently analyzed the identified gene using quantitative RT-PCR, methylation and un-methylation-specific PCR in nine HCC cell lines and in 48 primary HCC tissues and corresponding non-cancerous tissues collected at Nagoya University Hospital, and then compared these results with clinico-pathological data.
Results: The STEAP4 gene, is located on 7q21.12, and expression was decreased at a Log2 ratio of -4.2 to -2.0 in cancerous tissue. There were two copies of 7q21.12, indicating no loss of heterozygosity (LOH) in the SNP array. The methylation value (0-1.0) in the tumor sample was 0.870 compared to 0.234 in non-cancerous tissue, indicating high methylation in tumor tissue in the Methylation array. Re-activation of STEAP4 expression was seen after 5-aza-dC treatment in HCC cell lines. Moreover, we found that 32 of 48 (67%) HCC samples showed promoter hypermethylation. In 32 methylated cases, the expression values of STEAP4 gene in tumor tissues by real-time RT-PCR were tended to decrease compared to corresponding normal samples. In addition, methylated cases were significantly correlated with positive results for Hepatitis B and α-feto protein and had a tendency for poor prognosis (p=0.098).
Conclusion: The STEAP4 gene is a tumor suppressor gene in HCC and might be a marker of poor prognosis. The triple combination array was a useful technique to identify the novel methylated tumor suppressor gene in HCC.
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 323. doi:10.1158/1538-7445.AM2011-323
Abstract 3231: In vitro cross species metabolism of a novel RAF kinase inhibitor phosphate prodrug, ARQ 736
Authors: Hall Terence , Bresciano Karen , Volak Laurie , Wang Yunxia , Zhong Caiyun , Liu Yanbin , Lapierre Jean-Marc , Savage Ronald E. , Chan Thomas C.K. 
Published: June 2012

Abstract
ARQ 736 is a highly-soluble phosphate prodrug that readily undergoes conversion to ARQ 680 in the presence of phosphatases. The active drug, ARQ 680, is a pan-RAF inhibitor that is effective, both in vitro and in vivo, in inhibiting proliferation of cancer cell lines expressing mutant-BRAF (V600E). During preclinical development, the metabolic fate of ARQ 736 and ARQ 680 was evaluated in human, rat, and dog in vitro systems. Based on the data generated, metabolic pathways were proposed for ARQ 736 and ARQ 680. Cross-species metabolic stability studies were conducted in microsomes and hepatocytes. CYP450 reaction phenotyping using 6 recombinant CYP isozymes was conducted to identify the CYP isozyme(s) responsible for the phase one metabolism of ARQ 736 and ARQ 680. ARQ 736 and ARQ 680 were incubated in hepatocytes and liver fractions to evaluate the phase one and phase two metabolites produced in humans rats, and dogs. Additional studies in microsomes and hepatocytes were conducted to evaluate the potential for ARQ 736 or ARQ 680 to inhibit or induce various CYP450 isozymes. Cross-species NADPH-dependent metabolism studies revealed that ARQ 736 and 680 were highly stable in, rat, dog, and human liver microsomes with half-life values &gt;30 min. CYP450 reaction phenotyping indicated that CYP3A4 is the predominant CYP450 isozyme responsible for phase one metabolism of ARQ 736 and 680. Detailed metabolite ID work in hepatocytes identified multiple phase one and two metabolites as a result of oxidations, demethylation and glucuronidation. Metabolic pathways appeared to be similar across all species tested. In conclusion, this research is the first characterization of the metabolism of ARQ 736, a novel pan-RAF inhibitor currently being tested in phase one clinical trial in cancer patients.
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 3231. doi:10.1158/1538-7445.AM2011-3231
Abstract 3239: Shp2 inhibitor activity of estramustine phosphate and its triterpenoid analogues
Authors: Scott Latanya M. , Chen Liwei , Daniel Kenyon G. , Urlam Murali K. , Brooks Wesley H. , Guida Wayne C. , Lawrence Harshani R. , Sebti Said M. , Lawrence Nicholas J. , Wu Jie 
Published: June 2012

Abstract
Shp2 is a non-receptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene. Shp2 mediates proliferative signaling induced by growth factors. Gain-of-function PTPN11 mutations that encode constitutively active Shp2 are leukemic oncogenes. In a continuing effort to identify new Shp2 PTP inhibitors, we screened a small molecule library comprising the National Cancer Institute (NCI) Approved Oncology Drug set and the NIH Clinical Collection. After evaluation of initial hits, estramustine phosphate was verified as a Shp2 PTP inhibitor. A focused structure-activity relationship study indicated that the 17-phosphate group is required for the Shp2 PTP inhibitor activity of estramustine phosphate. A search for estramustine phosphate analogs led to identification of two triperpenoids, enoxolone and celastrol, having Shp2 PTP inhibitor activity. With the previously reported PTP1B inhibitor trodusquemine, our study reveals steroids and triterpenoids with negatively charged phosphate, carboxylate, or sulfonate groups as novel pharmacophores of selective PTP inhibitors. These findings point to a rich natural source for discovery of lead compounds of novel PTP inhibitors.
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 3239. doi:10.1158/1538-7445.AM2011-3239
Abstract 325: Mutation analysis of PIK3CA, KRAS, BRAF and Corresponding EGFR status in head and neck squamous cell carcinoma
Authors: Suda Toshihito , Hama Takanori , Okano Susumu , Seino Youichi , Yuza Yuki , Kato Takakuni , Moriyama Hiroshi 
Published: June 2012

Abstract
Background: KRAS, BRAF, PIK3CA activate protein kinase signaling and an important pathway in cancer development. Recent reports show that these downstream signaling molecules are mutated in a number of cancers. However, in head and neck squamous cell carcinoma (HNSCC), the frequency and positions of these molecules mutations are not clear. In this study we detected mutations from the clinical specimens of HNSCC by High-Throughput sequencing KRAS, BRAF, PIK3CA. Next we also intended to discover whether these mutations in downstream signaling molecules of EGFR are corresponding with EGFR status.
Patients and Method: The ninety-six tumors for this study were obtained from HNSCC patients surgically treated at the Department of head and neck surgery, Jikei University School of Medicine, Tokyo. The hot-spot regions in exons 1 and 2 of K-RAS, exon 15 of BRAF, exon 9 and 20 of PIK3CA were amplified by PCR and sequenced directly using DNA from samples. Next, we analyzed expression and phosphorylation of the EGFR protein by Western blotting as well as mutations encoding the hot-spot regions in exons 18 to 21.
Results: We identified mutations in 6 of the 96 patients (6.2%). 3 mutations (G12A) were found in exon 1 of K-RAS. In PIK3CA, 2 mutations were found in exon 9 (E545K) and one was in exon 20(H1047R). No other mutation was found in BRAF. Overexpression of EGFR protein was observed in all clinical samples with these mutations. On the other hand, hyper-phospholyation of EGFR was confirmed in only one sample. Finally, we tried to elucidate associations between these molecular status and patient characteristics and disease-free survival to asses the prognostic values of these molecules factors.
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 325. doi:10.1158/1538-7445.AM2011-325
Abstract 3254: Novel bivalent Smac mimetics as a new class of anticancer agents
Authors: Sun Haiying , Lu Jianfeng , Liu Liu , McEachern Donna , Bai Longchuan , Yang Chao-Yie , Wang Shaomeng 
Published: June 2012

Abstract
Second mitochondria-derived activator of caspase (Smac) is a protein released from mitochondria in response to apoptotic stimuli which functions as an endogenous inhibitor of several members of inhibitor of apoptotic proteins (IAPs), including XIAP, cIAP-1 and cIAP-2. Smac interacts with IAPs by binding of its N-terminal AVPI tetrapeptide to one or more BIR domains in IAPs. We designed and synthesized a series of non-peptidic, cell-permeable, bivalent small-molecules which mimic the dimeric Smac protein for targeting IAPs (bivalent Smac mimetics) and performed extensive evaluations of these bivalent Smac mimetics for their interaction with IAP proteins and their activity and mechanism of function in cancer cells. Our studies show that these Smac mimetics bind to XIAP, cIAP-1 and cIAP-2 with low nano-molar affinities. They function as extremely potent XIAP antagonists by concurrently targeting both the BIR2 and BIR3 domains of XIAP and nullify its inhibition to both caspase-9 and caspase-3/-7 and potently and effectively induce rapid degradation of these two proteins in cancer cells. The most potent bivalent Smac mimetics inhibit cell growth with IC50 values at low nanomolar and effectively induce apoptosis in a subset of cancer cell lines through TNFα dependent mechanism. Furthermore, bivalent Smac mimetics can dramatically enhance the antitumor activity of TRAIL in both TRAIL-sensitive and -resistant cancer cell lines. The combination of one such bivalent Smac mimetic, SM-164 with TRAIL induces rapid tumor regression in vivo in a breast cancer xenograft model in which either agent is ineffective. Mechanistic studies demonstrate that while RIP1 plays a minimal role in TRAIL's activity as a single agent, it is required for the synergistic interaction between TRAIL and SM-164. XIAP and cIAP1 work in concert to attenuate the activity of TRAIL and SM-164 strongly sensitizes TRAIL by concurrently targeting XIAP and cIAP1. Taken together, our data suggest that bivalent Smac mimetics may have a great therapeutic potential for the treatment of human cancer by targeting multiple IAPs, either alone or in combination with TRAIL.
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 3254. doi:10.1158/1538-7445.AM2011-3254
Abstract 3256: New retinoid derivatives as backups of adarotene
Authors: Giannini Giuseppe , Cabri Walter , Brunetti Tiziana , Battistuzzi Gianfranco , Alloatti Domenico , Quattrociocchi Gianandrea , Dallavalle Sabrina , Cincinelli Raffaella , Nannei Raffaella , Vesci Loredana , Pisano Claudio 
Published: June 2012

Abstract
Adarotene (ST1926) (WO03/011808) belongs to a so-called class of atypical retinoids. It represents a new first-in-class potent proapoptotic and cytodifferentiating agent, and was selected by Sigma-Tau for clinical development as a “chemotherapy enhancer” in solid tumors (ovarian ca.).
In pre-clinical models of haematological as well as solid tumors, Adarotene induced a DNA damage response and affected the modulation of cancer cell survival pathways. When used in combination with other anticancer agents, Adarotene showed a significant synergistic effect in most of the combinations and models tested.(1-4) A possible mechanism has also been described.(5-6)
The presence of the phenolic hydroxyl group on Adarotene structure, allowed a rapid O-glucuronidation as a major mechanism of elimination of the drug, favoring a fast excretion of its glucuronide metabolite in the urines.
In order to protect the phenolic hydroxyl and improve the “drug-like” properties of the drug, a series of new derivatives have been synthesized. According to chemical structure, these can be grouped into three classes: ether-, carbamate- and ester-derivatives. All of them have been studied and evaluated for their stability at different pH (1.2 – 6.8 – 7.4). The cytotoxic activity in vitro on NCI-H460 non-small cell lung carcinoma and A2780 ovarian tumor cells was also tested.(7)
A potential back-up of Adarotene has been selected to be evaluated in vivo tumor models.
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(2) Blood, 2004, 103, 194-207
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(6) J. Comput. Aided Mol. Des. 2010, 24, 943-956
(7) WIPO Patent Application WO2010/072727
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 3256. doi:10.1158/1538-7445.AM2011-3256
Abstract 3259: An efficient total synthesis of Tubulysin B
Authors: Vlahov Iontcho R. , Groaning Michael , Kleindl Paul , Santhapuram Hari Krishna R. , You Fei , Wang Yu , Xu Lecun , Stanford Katheryn , Ritter Allen , Leamon Christopher P. 
Published: June 2012

Abstract
The tubulysins are members of a new class of natural products isolated from myxobacterial species.[1] As cytoskeleton interacting agents, the tubulysins are mitotic poisons that inhibit tubulin polymerization and lead to cell cycle arrest and apoptosis.[2-4] Tubulysins are extremely potent cytotoxic molecules, exceeding the cell growth inhibition of any clinicaly relevant traditional chemotherapeutic e.g. paclitaxel, vinblastine, and epothilones. Furthermore, they are potent against multidrug resistant cell lines.[5]
Structurally, tubulysins are closely related linear tetrapeptides comprised of distinctive, unusual, or hydrophobic amino acid segments: D-N-methyl pipecolinic acid, L-isoleucine, the heterocyclic tubuvalin, and the γ-amino acid tubutyrosine/tubuphenylalanine. The most prominent feature in the molecular architecture of these natural occurring compounds is the acid and base sensitive N-acyloxymethyl substituent (or a N,O-acetal of formaldehyde).
In this poster we present an efficient yet simplified synthesis of Tubulysin B. The optimized synthetic protocol relyes on chemical as well as enzymatic steps and is readily scalable to industrial meaningful quantities. All the synthesized intermediates and final compound are well charectreized by several analytical methods including HPLC, MS, 1H and 13C NMR, etc. Biological activty of synthetic tubulysin B is identical with natural tubulysin B. This synthetic protocol is amenable to all other natural tubulysins and analogs.
[1] F. Sasse, H. Steinmetz, G. Höfle, H. Reichenbach, J. Antibiot. 2000, 53, 879-885.
[2] H. Steinmetz, N. Glasser, E. Herdtweck, F. Sasse, H. Reichenbach, G. Höfle, Angew. Chem. Int. Ed. 2004, 43, 4888-4892.
[3] M. Khalil, F. Sasse, H. Lünsdorf, Y. Elnakady, H. Reichenbach, ChemBioChem. 2006, 7, 678-683.
[4] G. Kaur, M. Hollingshead, S. Holbeck, Schauer-Vikašinovic, R. Camalier, A. Dömling, S. Agarwal, Biochem. J. 2006, 396, 235-242.
[5] For a review see: A. Dömling, W.Richter, Mol. Diversity 2005, 9, 141-147 and references therein.
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 3259. doi:10.1158/1538-7445.AM2011-3259