bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3762: Second generation PIM inhibitors exhibit improved activity in solid tumor models
Authors: Foulks Jason M. , Xu Yong , Saunders Michael , Liu Xiao-Hui , Brenning Benjamin , Clifford Adrianne , Wilkes Marcus , Luo Bai , Lai Shuping , Merx Shannon , Chan Ashley , Huang Liwen , Vollmer David , Senina Anna , Liu Jihua , Ho Koc-Kan , McCullar Michael V. , Kanner Steven B. 
Published: August 2012

Abstract
The proto-oncogene PIM kinase family (PIM-1, -2 and -3) includes constitutively active serine/threonine kinases upregulated in multiple cancer indications, including lymphomas, leukemias, multiple myeloma, prostate and bladder cancers. Overexpression of one or more PIM family members in patient tumors frequently correlates with poor prognosis. The PIM kinases function by inhibiting apoptosis in MYC-driven tumors, and promoting tumor cell survival and proliferation. In the HEK-293T cell line, enhanced PIM kinase substrate BAD phosphorylation (pBAD) was observed following PIM and BAD overexpression. Enhancement of pBAD was inhibited by SGI-1776, a well-described PIM inhibitor, and more effectively by second generation PIM inhibitors exhibiting 4-10 fold improved potency against the PIM kinase family. The current PIM inhibitors display sub-µM activity in pharmacodynamic marker, proliferation and 2D colony formation assays using the UM-UC-3 human bladder cancer cell line. PIM1 and PIM2 overexpression models were established in the human prostate cancer cell line 22RV-1 and the non-tumorigenic mouse NIH-3T3 cell background. Overexpression of PIM kinases led to enhanced cell growth and tumorigenicity in both NIH-3T3 and 22RV-1 cell lines. In vivo xenograft studies using both PIM overexpression models and a clinically relevant solid tumor model facilitated identification of a lead candidate with demonstrated efficacy and favorable toxicity. IND-enabling studies with a lead candidate are underway.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3762. doi:1538-7445.AM2012-3762
Abstract 3764: SC-1, a sorafenib derivative, induces apoptosis in epidermal growth factor receptor wild type non-small cell lung cancer through the inhibition of signal transducers and activators of transcription 3
Authors: Wang Cheng-Yi , Chao Ting-Ting , Shiau Chung-Wai , Yuan Ang , Yu Chong-Jen , Chen Kuen-Feng 
Published: August 2012

Abstract
Background: Lung cancer is the leading cause of cancer-related death worldwide, but currently there are no available target therapies for EGFR wild type NSCLC patients. Sorafenib, a multiple kinase inhibitors, shows therapeutic effects in renal carcinoma (RCC) and hepatocellular carcinoma (HCC). Our data shows that the inhibition of signal transducers and activators of transcription 3 (STAT3), a transcription factor involving in cell proliferation and survival, represents a major mechanism whereby sorafenib induces apoptosis in HCC cells (Clin Cancer Res 2010). Therefore, we design and synthesize a sorafenib derivative, SC-1, which is devoid of kinase activity (J Hepatol 2011). SC-1 shows higher potency in inducing apoptosis than sorafenib. Here, we tested efficacy of SC-1 to EGFR wild type NSCLC and examined the drug mechanism. Methods: EGFR wild type NSCLC cell lines, A549 H292 H322 and H460, were used for in vitro studies. Apoptosis was examined by both flow cytometry and western blot. Signal transduction pathways in cells were assessed by western blot. Results: SC-1 induced apoptosis in association with reducing the phosphorylation of STAT3 (p-STAT3) in a dose- and time-dependent manner in four NSCLC cells lines (A549 H292 H322 and H460). SC-1 demonstrates dose-dependent anti-proliferation effects on cell viability in NSCLC cell lines on MTT assay. Increased amount of SC-1 represented improvement cell apoptosis by FACS in NSCLC cells. Western blot analysis showed SC-1 exhibit dose-dependent and time-dependent effect on cell apoptosis through inhibition of STAT3 with reducing p-STAT3 and the STAT3-regulating protein, Mcl-1, survivin and cyclinD1. Conclusions: SC-1 provides a proof of concept that targeting STAT3 signaling pathway is a novel approach for the treatment of EGFR wild type NSCLC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3764. doi:1538-7445.AM2012-3764
Abstract 3794: Inhibition of prostate cancer bone metastases by the dickkopf-1 neutralizing antibody BHQ880
Authors: Sottnik Joseph L. , Hall Christopher , Karatsinides Andreas , Keller Andrew L. , Ettenberg Seth A. , Keller Evan T. 
Published: August 2012

Abstract
Advanced prostate carcinoma (PCa) is usually complicated by the presence of bone metastases. Current therapies targeting bone metastases are suboptimal as the metastases progress in spite of therapy. Accordingly, novel therapeutics are needed to target these lesions. The Wnt inhibitor Dickkopf-1 (DKK-1) appears to play an important role in progression of PCa bone metastases. Overexpression of DKK-1 by PCa promotes tumor growth and bone lysis in laboratory studies and DKK1 is present in clinical PCa bone metastases. Development of a fully humanized anti-DKK-1 neutralizing antibody, BHQ880 (Novartis), provides a potential therapeutic strategy to target PCa bone metastases. The goal of this study was to test if BHQ880 could impact PCa bone metastases. PC-3-luc cells (2.5x105) were injected intratibially into mice. Treatment with anti-DKK-1 or isotype control antibody (n=12 mice per group) was initiated 0, 7, or 14 days post-tumor injection. Mice were treated three times weekly by intraperitoneal injection with 200 μg/mouse (approximately 10 mg/kg) Tumor growth and bone lysis were assessed by weekly bioluminescence and bi-weekly radiography, respectively. All mice were euthanized 31 days post-tumor injection, tumor bearing limbs were formalin fixed and serum was obtained. Tumor bearing limbs were analyzed by dual energy x-ray absorptiometry (DEXA) and histology. Serum was assayed for the bone turnover biomarkers alkaline phosphatase (ALP), osteocalcin (OC), and tartate-resistant acid phosphatase 5b (TRAP5b). BHQ880 was well tolerated with no significant side effects observed. Significant inhibition of tumor growth was observed in mice where treatment was initiated 7 or 14 days post-tumor challenge when established tumors were present. Two mice from the 14-day treatment group had tumor regressions after treatment with BHQ880. Treatment with BHQ880 resulted in decreased bone lysis as determined using DEXA. Furthermore, increased serum concentrations of ALP and OC in mice treated with BHQ880 suggest increased bone production; no significant difference in TRAP5b concentration between treated and untreated mice was found. Treatment with the DKK-1 neutralizing antibody BHQ880 was found to inhibit tumor growth, tumor-induced osteolysis and increase serum bone remodeling markers associated with increased bone production in a murine model of PCa bone metastasis. These data suggest that anti-DKK-1 treatment is a plausible mechanism for inhibition of progression of PCa bone metastases. These data suggest that inhibition of DKK-1 may be an effective strategy to inhibit PCa growth in bone.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3794. doi:1538-7445.AM2012-3794
Abstract 3973: Developing a public resource for structural biology and cancer pathway plasmids
Authors: Cormier Catherine Y. , Park Jin , Fiacco Michael , Steel Jason , Kramer Jason , LaBaer Joshua 
Published: August 2012

Abstract
Understanding the structure and function of the genes involved in cancer is crucial to dissecting the underlying mechanisms of cancer development, progression and treatment. The Protein Structure Initiative:Biology-Materials Repository (MR; http://psimr.asu.edu) connects researchers with both the genetic raw materials and the structural knowledge to better understand the roles of individual genes in cancer pathways. As a centralized plasmid repository, the MR is responsible for sequence-verification, archival, and distribution of plasmids created by the high throughput structural genomics efforts of the Protein Structure Initiative (PSI). Plasmid annotations such as the full length sequence, vector information, and associated publications are stored in a freely available, searchable database called DNASU (http://dnasu.asu.edu). Each plasmid also links to external resources, including the PSI Structural Biology Knowledgebase (http://sbkb.org) facilitating cross-referencing of plasmids to additional protein annotations and experimental data. In addition to the 50,000 protein expression plasmids and empty vectors from the PSI, DNASU distributes over 151,000 plasmids including collections of human kinases, 1,000 breast cancer-related genes, over 10,000 human genes in several cloning and expression vectors, and over 800 glyco-enzyme plasmids that were created by or in collaboration with the MR, the ORFeome Collaboration, or individual laboratories. Furthermore, the MR strives to expedite and simplify plasmid requests through its expedited material transfer agreement (EP-MTA) network, where researchers from network institutions can order and receive PSI plasmids without institutional delays. By providing these plasmids to the research community, the MR is able to facilitate and accelerate the study of the biological function of proteins involved in cancer and whose structures have been solved by the PSI.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3973. doi:1538-7445.AM2012-3973
Abstract 3981: Evaluation of mutation detection sensitivity in exome sequencing and other genotyping platforms
Authors: Wulur Isabella H. , Wong Swee Seong , Yu Kun , Barber Thomas D. , Yue Yong Gang 
Published: August 2012

Abstract
An evaluation was performed to compare mutation calls from exome capture sequencing data to publicly available data sets derived from Sequenom MassARRAY and Sanger sequencing methods. We compared hot-spots KRAS and BRAF mutations using Sanger sequencing method in patient-derived tumor grafts. Mutation data of the tumor grafts were also generated with Sequenom MassARRAY using the OncoCarta panel. We also evaluated the sensitivity of mutation detection for a panel of cancer genes in &gt;100 cancer cell lines against the data from the Cancer Cell Line Encyclopedia Project (OncoMap mutation panel) as well as the Sanger's Cancer Genome Project. Overall, we observed high sensitivity and concordance of the mutation calls from the exome sequencing with the other platforms and technologies. The above comparisons support the use of exome sequencing as a sensitive mutation detection method for patient-derived tumor grafts and cancer cell lines.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3981. doi:1538-7445.AM2012-3981
Abstract 3986: Science Exchange: An integrated platform for experiment outsourcing
Authors: Connolly Jay , Abbott Ryan , Knox Dan , Iorns Elizabeth J. 
Published: August 2012

Abstract
Introduction: Scientific research is becoming increasingly specialized, necessitating greater use of collaborations and outsourcing to draw on experimental expertise. To facilitate this, many research institutions have established core facilities to help reduce the inefficiencies associated with the historical system of ‘bartering’ to gain access to specialized equipment and expertise. However, the current core facility system is fragmented: researchers have varying degrees of access to services, quality is hard to evaluate and pricing is not transparent. Researchers who need to collaborate outside of their institution lack an easy way to find providers, evaluate them, coordinate logistics and pay for work. Similarly, core facilities lack a robust mechanism for promoting their expertise and services to relevant researchers outside their institution. Methods: Science Exchange, an online marketplace accessible at www.ScienceExchange.com, was launched in August 2011 to address these issues. Science Exchange works by signing up core facilities as “providers” of different experiment types. Researchers can search for an experiment type they wish to outsource and choose a facility to perform the work, or post an open project and receive bids from qualified facilities. Science Exchange acts as a centralized hub for provider information and reviews, and assists with project management, including billing and payment. The goal of Science Exchange is to create an integrated and accessible marketplace for experimental services. Results: As of October 2011 more than 3,000 scientists from over 500 research institutions have registered with Science Exchange. The top 10 most searched for experiment types are, in descending order: DNA sequencing, Bioinformatics, Microarray, DNA analysis, electron microscopy, protein extraction/ purification, confocal microscopy, realtime qPCR, microRNA microarray, and NMR. On average, experiments outsourced through the platform have saved users 54% of the value of their experiment ($4,664 per experiment). Conclusions: Science Exchange has begun to address the barriers to effective experiment outsourcing. As with any marketplace, awareness and participation by key players is essential to increase utility. Experience also provides data necessary to make outsourcing as frictionless as possible for the particulars of each experiment type. Our team has an enduring commitment to making the platform as useful for researchers and providers as possible.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3986. doi:1538-7445.AM2012-3986
Abstract 4010: New AXIN2 germline variant in a Spanish family with an attenuated form of FAP without oligondontia or ectodermal dysplasia signs
Authors: Rivera Barbara , Perea Jose , Sanchez Eloy , Villapun Manuel , Sanchez-Tome Eva , Mercadillo Fatima , Robledo Mercedes , Benitez Javier , Urioste Miguel 
Published: August 2012

Abstract
Familial Adenomatous Polyposis (FAP) is a colorectal cancer syndrome caused mainly by mutations in the APC gene (50-80% of the cases), and some mutations in MUTYH, usually in recessive and milder cases. Additionally, the genetic cause of 20% of classic forms and 50% of attenuated forms of the disease remain unclear. AXIN2 is a partner of the APC protein in the b-catenin destruction complex. Mutations in AXIN2 have been described in patients with oligodontia and other ectodermal dysplasia features in association with colorectal neoplasia or adenomatous polyps. We studied the AXIN2 gene in a series of APC/MUTYH mutation negative families and identified a novel variant, c.1387C&gt;T;p.R463P, as the possible genetic cause of an attenuated FAP phenotype (AFAP). The autosomal dominant AFAP phenotype was not associated with any extracholonic manifestations or ectodermal dysplasia features. However, hyperplastic polyps were observed in some AXIN2-variant carriers. Thus, from a clinical point of view this family displayed some features that differ from previously described families with AXIN2 mutations. The variant c.1387C&gt;T;p.R463P is located in the b-catenin binding domain, an area highly conserved throughout evolution. The variant segregates with the affected family members and was not present in 800 healthy Spanish controls. We were able to confirm loss of heterozygosity in 3 out of 5 polyps from the proband and his affected sister. AXIN2 and b-catenin expression patterns were tested by inmunofluorescence staining: both proteins are overexpressed in adenomatous polyps compared with normal colorectal ephitelium from the proband. Moreover, no colocalization of the two proteins could be observed by confocal microscopy. These results support a possible pathogenic role for this AXIN2 variant in our family and highlight the implication of AXIN2 in some cases of FAP syndrome. We argue comprehensives and functional studies will be necessary to clarify the role of AXIN2 in familial colorectal cancer predisposition.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4010. doi:1538-7445.AM2012-4010
Abstract 4011: Why does this APC exon 9 mutation causes severe and not attenuated familial adenomatous polyposis (FAP)
Authors: Cheah Peh Yean , Wong Yu Hui , Loi Carol , Koh Poh Koon , Tang Choong Leong 
Published: August 2012

Abstract
Familial adenomatous polyposis (FAP), an autosomal dominantly inherited form of colorectal cancer (CRC), is characterized by up to thousands of adenomatous polyps in the colon and rectum of an affected individual by the second or third decade of life. The risk of cancer is virtually 100% if the polyps are not removed in time. Germline mutation in the tumor suppressor, adenomatous polyposis coli (APC) gene causes the majority (80%) of FAP. Point mutation in 5′end of exon 9 of APC usually results in an attenuated form of FAP (aFAP), characterized by later age of onset (forth or fifth decade of life) and much less (&lt;100) polyps. The presence of a physiological in-frame isoform with exon 8 spliced to 3′end of exon 9 (exon 9a) dilutes any deleterious effect of the mutation. We report here an interesting case of a proband with an APC mutation in 5′end of exon 9 that presented with 6 synchronous advanced CRC at age 37. The novel insertion-deletion (indel) mutation at codon 409 removes an exonic splice enhancer site that causes skipping of the whole of exon 9 in the mature transcript, resulting in a premature stop codon at exon 10 and a truncated protein that removes all of the β-catenin (CTNNB1) binding motifs, thus activating the downstream T-cell transcription factor (Tcf) pathway. This surprising consequence of the indel would not have been identified if the mutation screening has not begun with the protein truncation test and the APC transcript. The finding indicates the necessity of examining any point mutation in the 5′end of exon 9 for exonic splice enhancer or repressor site to avoid clinical mismanagement and counseling based on just the mutation site.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4011. doi:1538-7445.AM2012-4011
Abstract 4016: Epigenetic regulation of CXCR3 splicing in prostate cancer cells
Authors: Kumar Devi Sharanya Sampath , Wells Alan 
Published: August 2012

Abstract
Prostate cancer is the second leading cause of cancer death among men, with the metastasis of these tumors being the main reason for the high rates of mortality and morbidity. This tumor progression requires epithelial cell dedifferentiation, migration, invasion and growth in an ectopic site. CXCR3 is a G-protein coupled receptor whose splicing was found to be differentially regulated in prostate cancer. We have found over-expression of the CXCR3A splice isoform in prostate cancers and cell lines whereas normal prostate epithelium expresses by and large only the CXCR3B isoform, representing a possible switch in the expression between the CXCR3 splice variants. As these variants link differentially to pro- and anti-invasion signaling pathways, this may explain the relentless progression of the prostate carcinoma cells. The switch is present at both the RNA and the protein level which suggests that the altering factor is at the trancriptional control level. We hypothesized that a mutation in the gene or an epigenetic modification of the genome could possibly be regulating the splicing event and hence the switch in the expression. CXCR3 when scanned for mutations was found to be intact except for a polymorphism in the intronic region which coincided with the normal prostate cells. On the epigenetic regulation side, the CpG dinucleotides in the regulatory regions, the one intron and 5′ upstream region, susceptible to methylation changes were analysed for methylation differences. The upstream sequence does not show a differential methylation pattern whereas the intronic region shows differential methylation between the cancer and normal prostate cells at 3 different nucleotides. A possible explanation is that the methylation in the introns alters the speed of the transcription machinery allowing more time for a particular splice variant to be transcribed more than the other. A bichromatic reporter minigene has been designed for each of the differentially methylated CpG nucleotides, to study its effects on the splicing regulation of the CXCR3 gene. Further studies include expressing the minigene and documenting the splicing differences.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4016. doi:1538-7445.AM2012-4016