bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3199: Ceramide restores the expression of wild-type p53 tumor suppressor in mRNA splicing through PP1 and ASF/SF2.
Authors: Liu Yong-Yu , Patwardhan Gauri A. 
Published: August 2014

Abstract
p53 mutants that have been detected in approximately 50% of tumors loss the activity in stabilizing the genome and tumor suppression, and further exhibit oncogenic function in cancer cells. Most tumors that exhibit disrupted p53 signaling pathways remain addicted to p53 mutants, and p53 mutants have emerged as perhaps the most important target to improve cancer treatment. Most works in restoring p53 activity focus on either altering protein conformations of the mutants or introducing foreign p53 gene into cells. Using gene silencing strategy and mass spectrometry, here we demonstrated that ceramide modulates the RNA splicing to restore the expression of wild-type p53 in p53 deletion-mutant ovarian cancer cells. Enhanced endogenous long-carbon chain ceramide species (C16- to C24-ceramides) and exogenous C6-ceramide, but not other sphingolipids, restored wild-type p53 mRNA (intact exon-5), phosphorylated p53 protein (Ser15 in exon-5) and p53-responsive proteins (p21, Bax) in cells that dominantly expressed a deleted p53-mRNA and protein in exon-5. Thus, the restored p53 sensitized the cells to induced apoptosis. Furthermore, ceramide activated protein phosphatase 1 (PP1), rather than PP2a, increased the translocation of alternative splicing factor ASF/SF2 from cytoplasm to nucleus and thus determined the pre-mRNA splicing for wild-type p53. Alternative pre-mRNA splicing not only generates more than one protein isoform from single gene, it also results in gene mutants in cancer and other diseases. Our study elucidates a previous unrecognized mechanism in regulating the expression of wild-type versus mutant protein of
p53 and indicates mutants can be restored in posttranscriptional levels by using an epigenetic approach.
Citation Format: Yong-Yu Liu, Gauri A. Patwardhan. Ceramide restores the expression of wild-type p53 tumor suppressor in mRNA splicing through PP1 and ASF/SF2. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3199. doi:10.1158/1538-7445.AM2013-3199
Abstract 32: Single and multiple dose-ranging evaluation of safety, pharmacokinetics, and pharmacodynamics of GS-9973, a novel pSYK inhibitor.
Authors: Ramanathan Srini , DiPaolo Julie A. , Doan Tom , Burge Dan 
Published: August 2014

Abstract
Background: GS-9973 is a selective, reversible, ATP-competitive small molecule spleen tyrosine kinase (Syk) inhibitor that blocks BCR-mediated activation/ proliferation, Fc receptor signaling/ function, and inhibits immune complex-mediated inflammatory cytokine production, including TNFα. The safety, pharmacokinetics (PK), and pharmacodynamics (PD) of GS-9973 were evaluated in a double-blind, single/multiple ascending dose study.
Methods: In sequential cohorts (n=8 active, 2 placebo), subjects (fasted) received GS-9973 (25 mg to 1200 mg) as a single dose (Part A) or multiple twice-daily doses for 7 days (Part B). Along with PK, PD sampling Parts A and B assessed functional inhibition of ex vivo αIgE-stimulated CD63 expression on basophils. Safety and tolerability were assessed throughout the study, with dose-escalation gated by pre-specified stopping criteria. PK-PD was evaluated using GS-9973 concentrations vs CD63 inhibition.
Results: Across dose cohorts, subjects were ≥ 60% white, ≥ 50% male, with mean age of 28 to 37 years. Adverse events (AEs) were generally mild to moderate, with no AE-driven study drug discontinuations noted. GS-9973 exposures (Table 1) reached a plateau at ≥ 600 mg BID (due to solubility-limited absorption), provided &gt; 90% CD63 inhibition at peak levels, and &gt; 60% inhibition over the dosing interval, due to 10-14 hr plasma half-life. PK-PD analyses indicated a sigmoidal exposure-response relationship, with EC50 of ∼ 400-450 ng/ml and hill slope &gt; 1.
Single and Multiple dose PK of GS-9973 Part A Single Dose (mg) AUCinf (ng.h/ml) Cmax (ng/ml) 25 231 (80) 42.3 (76) 75 413 (98) 67.8 (84) 200 4250 (64) 534 (56) 600 5960 (90) 779 (70) 1200 9740 (111) 1060 (101) Part B Multiple Dose (mg) AUCtau Cmax Ctrough T1/2 (hr) 25 356 (65) 57.8 (68) 11.9 (65) 8.7 (7.7, 9.5) 75 1880 (48) 273 (52) 79.2 (64) 8.9 (6.9, 10.8) 200 7650 (57) 1050 (59) 380 (63) 10.0 (8.4, 14.9) 600 21500 (64) 2960 (61) 1240 (66) 15.4 (12.8, 19.7) 900 23900 (62) 2810 (58) 1470 (67) 13.5 (11.7, 16.9) 1200 26800 (77) 3430 (77) 1470 (80) 13.9 (9.8, 16.4) Values presented as mean (%CV) except for T1/2 (median (Q1,Q3)); Part B: Cmax, Ctrough units ng/ml; AUCtau: ng.h/ml
Conclusions: GS-9973 was generally well tolerated over a 48-fold dose range. GS-9973 exposures plateaued ≥ 600 mg and provided robust exposure-dependent PD activity over the dosing interval. The overall safety, PK, and PD profile of GS-9973 support further clinical evaluation of doses with strong PD activity.
Citation Format: Srini Ramanathan, Julie A. DiPaolo, Tom Doan, Dan Burge. Single and multiple dose-ranging evaluation of safety, pharmacokinetics, and pharmacodynamics of GS-9973, a novel pSYK inhibitor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 32. doi:10.1158/1538-7445.AM2013-32
Abstract 3203: The tri-snRNP spliceosome complex is required for MYC-dependent cancer growth.
Authors: Adler Adam , Jiang Zhaoshi , McCleland Mark , Blackwood Elizabeth , Yee Sharon , Haley Benjamin , Stephan Jean-Philippe , Hussain Sofia , Chopra Vivek , Firestein Ron 
Published: August 2014

Abstract
Spliceosome coordinated RNA splicing is an essential cellular process that can generate an immensely diverse repertoire of RNA. While cancer cells have been known to hijack this process to generate splice forms with oncogenic function, the specific role of spliceosome components in this process is not well understood. In this study, we use an integrative genomic approach to identify PRPF6, a member of the tri-snRNP spliceosome complex as essential for colon cancer growth. We show that, in addition to PRPF6, other tri-snRNP components are coordinately overexpressed or amplified in cancer cells. Inhibition of the tri-snRNP complex, but not other spliceosome components, abrogated cancer cell growth only in dependent cancer cell lines in vitro and in vivo. High resolution transcriptome analysis reveals that the tri-snRNP complex binds and regulates the splicing of a relatively small number of genes, many of which are transcriptional targets of the c-MYC oncogene. Intriguingly, many components of the tri-snRNP complex are mutated in a genetic form of Retinitis Pigmentosa. This genetic corollary suggests that the tri-snRNP complex is necessary in specific cellular contexts that may depend on the proper transcription and splicing of a tri-snRNP regulated set of genes.
Citation Format: Adam Adler, Zhaoshi Jiang, Mark McCleland, Elizabeth Blackwood, Sharon Yee, Benjamin Haley, Jean-Philippe Stephan, Sofia Hussain, Vivek Chopra, Ron Firestein. The tri-snRNP spliceosome complex is required for MYC-dependent cancer growth. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3203. doi:10.1158/1538-7445.AM2013-3203
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 321: Sunitinib alternated with everolimus in renal cell carcinoma: a sequential combination strategy for antitumor efficacy in mice clinical trial.
Authors: Dos Santos Célia , Tijeras-Raballand Annemilaï , Serova Maria , Dreyer Chantal , Slimane Khemaies , de Gramont Armand , Faivre Sandrine , Raymond Eric 
Published: August 2014

Abstract
Background: Sunitinib (VEGFR/PDGFR inhibitor) and everolimus (mTOR inhibitor) are approved for advanced renal cell carcinoma (RCC), as first-line and second-line therapy, respectively. No data have been reported on programmed sequential strategies combining alternative use of sunitinib and everolimus prior to progression. Such strategy is expected to delay the emergence of first-line acquired resistance and improve tumor control. The aim of our study was to assess the effects of three sequences administration of sunitinib and everolimus.
Methods: Nude mice (n=5/group) were engrafted with human RCC cells (CAKI-1) then randomized to vehicle, everolimus, sunitinib, sunitinib alternated with everolimus every week (S1), every two weeks (S2), and every three weeks (S3). Median time to tumor progression (mTTP) was determined in each group. Angiogenesis and necrosis were evaluated using CD31 and HE staining. Inhibition of mTOR pathway was evaluated using phospho-S6 (pS6) and e-cadherin/vimentin expressions were analyzed by immunofluorescence staining.
Results: The S1, S2 and S3 regimens increased mTTP by 30 to 80% relative to sunitinib or everolimus alone. The vascular surface areas (vessels size and number) in tumors were reduced in all treated groups relative to control, especially S1 and S2. All three sequential therapies induced larger necrosis areas in tumors as compared to control. In each group, tumor response seemed associated with a decrease in pS6 expression and changes in epithelial-mesenchymal phenotype with a decrease in vimentin and an increase in e-cadherin expression
Conclusion: Sunitinib and everolimus programmed sequential regimens prior to progression yielded longer mTTP than sunitinib and everolimus monotherapies. The sequential combinations of these two agents in a RCC mouse clinical trial, increased antiangiogenic effects, leading potentially to tumor necrosis, especially with the S1 and S2 regimens.
mTTP for each group and effects of sequential treatments in tumors angiogenesis and necrosis Treatment groups mTTP (in days) Vascular Surface Area per field (% vs control) Number of vessels per field % of necrosis surface per field Control 24 100 22 23 Sunitinib 36 30 5 47 Everolimus 50 28 7 27 S1 64 15 5 37 S2 59 20 4 51 S3 59 42 5 37
Citation Format: Célia Dos Santos, Annemilaï Tijeras-Raballand, Maria Serova, Chantal Dreyer, Khemaies Slimane, Armand de Gramont, Sandrine Faivre, Eric Raymond. Sunitinib alternated with everolimus in renal cell carcinoma: a sequential combination strategy for antitumor efficacy in mice clinical trial. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 321. doi:10.1158/1538-7445.AM2013-321
Abstract 3210: Proteomic study of 5-fluorouracil resistance in colon cancer cell lines.
Authors: Guerrero-Valero Marta , Marin-Vicente Consuelo , Zubarev Roman A. , Visa Neus 
Published: August 2014

Abstract
The anticancer drug 5-fluorouracil (5-FU) is a chemotherapy agent that has been in use against colon cancer for about 40 years. However, inherent and acquired drug resistance phenomena often limit the effectiveness of 5-FU chemotherapy, which makes it necessary to explore the underlying resistance mechanisms. In addition, it is important to identify useful markers to predict the sensitivities of different tumors to 5-FU therapy.
In order to study the mechanism of 5-FU resistance, we used three 5-FU-resistant cell lines (HCT116/5-FU, H630/5-FU and RKO/5-FU) and their parental cell lines (HCT116, H630 and RKO). The proteomes of the untreated cells and of cells treated with 5-FU for 24 h were analyzed by label-free mass spectrometry using a nano-LC-ESI-LTQ Orbitrap Velos. When we compared the untreated proteomes, we could detect significant differences among resistant and parental cell lines, and we identified 21 proteins overexpressed and 12 underexpressed in the three resistant cell lines. Many of these proteins were associated with the mitochondria or were involved in carboxylic acid metabolism, in response to chemical stimuli, in regulation of programmed cell death, in oxidoreductase ativity or in DNA repair/cell cycle control pathways.
The observed differences among the 5-FU resistant and the parental proteomes were even more pronounced in cells treated with 5-FU for 24 h. The numbers of proteins overexpressed and underexpressed in the resistant cell lines rose to 25 and 17, respectively. Moreover, many of the differentially expressed proteins were associated to the ribosome and were involved in translation and RNA metabolism.
The mass spectrometric results were validated by semi-quantitative Western blotting and complemented with cell proliferation assays and with pathway analysis. Altogether, our results not only led to the identification of potential protein markers of 5-FU resistance, but also provided information about the underlying resistance mechanisms.
Citation Format: Marta Guerrero-Valero, Consuelo Marin-Vicente, Roman A. Zubarev, Neus Visa. Proteomic study of 5-fluorouracil resistance in colon cancer cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3210. doi:10.1158/1538-7445.AM2013-3210
Abstract 3211: Proteomic analysis of nuclei dissected from FFPE tissue using expression microdissection.
Authors: Blackler Adele R. , Tangrea Michael A. , Pohida Tom , Morgan Nicole , Bonner Robert , Mora Keshia , Kakareka John , Markey Sanford , Emmert-Buck Michael R. 
Published: August 2014

Abstract
Currently, proteomic analysis of formalin-fixed, paraffin-embedded (FFPE) tissue (the most common method of storing tissue specimens) are limited by the overwhelming complexity of the cellular proteome, which makes disease related changes in protein expression difficult to detect. Expression Microdissection (xMD) allows for automated, operator-independent dissection of specific cells or subcellular organelles in FFPE tissue, resulting in the enrichment of specific, selectable protein populations. In xMD, tissue slices that have been stained for specific cellular markers using immunohistochemical (HC) methods are placed under a layer of ethylene vinyl acetate (EVA) polymer film. When the stack is uniformly illuminated (using a rastering laser or a light pulse), the EVA melts and makes contact only over the stained tissue, enabling specific capture and transfer of these areas for further biochemical analysis, while leaving unstained tissue behind.
As a proof of principle, we are using the xMD technique to enrich for nuclei in FFPE rat brain tissue sections followed by proteomic analysis. Shotgun proteomic analysis of these samples show a significant enrichment in nuclear localized proteins, with an average 18% of recovered proteins localized to the nucleus-versus 11% of recovered proteins in whole tissue scrapes. Targeted mass spectrometry, using Multiple Reaction Monitoring (MRM), also shows an enrichment of nuclear markers such as histones and DNA-binding proteins, and a de-enrichment of non-nuclear proteins. The enrichment for nuclei allows for the identification of methylated lysines on histones that are not detected in whole tissue scrapes, most likely due to their low abundance.
The evolving methodology may allow researchers to profile the sub-cellular proteome of patient samples to identify potential new disease biomarkers and drug targets. This novel technology could also be used to advance our understanding of the biomolecular changes responsible for a specific disease state.
Citation Format: Adele R. Blackler, Michael A. Tangrea, Tom Pohida, Nicole Morgan, Robert Bonner, Keshia Mora, John Kakareka, Sanford Markey, Michael R. Emmert-Buck. Proteomic analysis of nuclei dissected from FFPE tissue using expression microdissection. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3211. doi:10.1158/1538-7445.AM2013-3211
Abstract 3235: Characterization of tumor explant models using next-generation sequencing.
Authors: Lai Zhongwu , Bradford James , Zhang Qi , Dempster Sara , Dougherty Brian , D'Cruz Celina , Dry Jonathan 
Published: August 2014

Abstract
Tumor explant models (human tumor tissue directly transplanted into mice) are believed to conserve original tumor characteristics, including molecular heterogeneity and tumor architecture. Thus, they better represent patient population and can provide more relevant predictive insight into clinical outcome. They potentially offer a clinically relevant model in which to compare drug response to genomic and molecular profiles. So called next generation sequencing (NGS) technologies (Exome sequencing and RNA-seq) are becoming the standard choices for genetic profiling due to the rich information they can provide. The sequence based nature of these technologies offers the potential to differentiate results by species and remove mouse derived stromal ‘contamination’ when assessing tumor cells directly. This also presents a unique opportunity to differentiate and assess molecular interaction between the tumor and the stromal tissue.
To this aim, we have developed algorithms to differentiate NGS sequences between human and mouse. Using mixtures of human and mouse derived cell lines we demonstrated that the algorithm achieved high sensitivity (99.8%) and specificity (99.5%). More than 90% of sequence reads mapped to both human and mouse can be effectively differentiated. We applied the approach to differentiate human and mouse sequences for several explant models derived from both exome sequencing and RNA-seq. We demonstrated that the process resulted in more accurate expression quantification, and reduction of false positives in variance calling. In addition, we compared the variance calling between paired exome and RNA-seq and found that the two methods are complimentary to each other where genes were expressed. We also highlighted a number of interesting features and anomalies between RNAseq and exome data.
In summary, we demonstrated the feasibility of using exome and RNA-seq to effectively differentiate human and mouse sequences in tumor explants models. We highlight the value of this approach to rationally guide their application in drug discovery.
Citation Format: Zhongwu Lai, James Bradford, Qi Zhang, Sara Dempster, Brian Dougherty, Celina D'Cruz, Jonathan Dry. Characterization of tumor explant models using next-generation sequencing. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3235. doi:10.1158/1538-7445.AM2013-3235
Abstract 3254: Discovery of S3I-1757, a STAT3-STAT3 dimerization disruptor that inhibits STAT3 activity, tumor survival, migration and invasion.
Authors: Zhang Xiaolei , Sun Ying , Pireddu Roberta , Yang Hua , Urlam Murali K. , Lawrence Harshani R. , Guida Wayne C. , Lawrence Nicholas J. , Sebti Said M. 
Published: August 2014

Abstract
The ability of STAT3 to translocate to the nucleus, bind DNA and transcriptionally regulate STAT3 target genes depends on tyrosine phosphorylation STAT3-STAT3 dimerization. Our chemistry efforts led to the discovery of S3I-1757 that disrupts STAT3-STAT3 dimerization. Fluorescence polarization assays and molecular modeling show that S3I-1757 interacts with Y-705 binding site in the STAT3-SH2 domain and displaces fluorescein-labelled GpYLPQTV phosphotyrosine peptide from binding to STAT3. Furthermore, using co-immunoprecipitation and co-localization studies we show that S3I-1757 inhibits STAT3 dimerization and STAT3-EGF receptor binding in intact cells. Treatment of human cancer cells with S3I-1757 (but not a closely related analogue, S3I-1756, that does not inhibit STAT3 dimerization), inhibits selectively the phosphorylation of STAT3 over Akt and Erk1/2, nuclear accumulation of P-Y705-STAT3, STAT3-DNA binding and transcriptional activation and suppresses the expression levels of STAT3 target genes such as Bcl-xL, survivin, cyclin D1 and MMP9. Furthermore, S3I-1757 but not S3I-1756 inhibits anchorage-dependent and -independent growth, migration and invasion of human cancer cells which depend on STAT3 selectively over those that do not. Finally, STAT3-C, a genetically engineered mutant of STAT3 that forms a constitutively dimerized STAT3, rescues from S3I-1757 effects. Our results warrant further development of S3I-1757 as a STAT3-STAT3 dimerization inhibitor capable of blocking hyper activated STAT3 and suppressing malignant transformation of STAT3-dependent human tumors.
Citation Format: Xiaolei Zhang, Ying Sun, Roberta Pireddu, Hua Yang, Murali K. Urlam, Harshani R. Lawrence, Wayne C. Guida, Nicholas J. Lawrence, Said M. Sebti. Discovery of S3I-1757, a STAT3-STAT3 dimerization disruptor that inhibits STAT3 activity, tumor survival, migration and invasion. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3254. doi:10.1158/1538-7445.AM2013-3254
Abstract 3257: Targeting small cell lung cancer harboring PIK3CA mutation with a selective oral PI3K inhibitor, PF-4989216.
Authors: Walls Marlena , Baxi Sangita M. , Mehta Pramod P. , Epps Elizabeth , Estrella Heather , Liu Kevin KC , Zhu JinJiang , Li Chunze , Smeal Tod , Yin Min-Jean 
Published: August 2014

Abstract
Aberrant PI3K/AKT signaling occurs commonly in cancer. Gene mutation, amplification, and copy number gains in the catalytic p110α of PI3K have been shown in a variety of human cancers. Tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN) dephosphorylates the 3-phosphoinositides and is frequently mutated, deleted, or down-regulated in many human cancers to constitutively activate the PI3K pathway. Small cell lung cancer (SCLC) patients have poor prognosis; response to second-line chemotherapy for patients with refractory disease is less than 10%, and survival is 3-4 months. Multiple phase III trials have been conducted, however the survival of SCLC patients has not significantly improved over the years. In this study, we characterized a selective PI3K inhibitor, PF-4989216, in preclinical SCLC models to investigate whether targeting the PI3K pathway may be a potential therapy for SCLC. PF-4989216 inhibits phosphorylation of PI3K downstream molecules and subsequently leads to induction in apoptosis and cell cycle block, as well as inhibition of cell proliferation, transformation, and xenograft tumor growth in SCLCs harboring a PIK3CA mutation. Moreover, our results suggest that there may be different mechanisms of tumorigenesis between PIK3CA mutation and PTEN loss in SCLCs, and indicate that PF-4989216 is a potential cancer drug candidate for small-cell lung cancer patients harboring a PIK3CA mutation.
Citation Format: Marlena Walls, Sangita M. Baxi, Pramod P. Mehta, Elizabeth Epps, Heather Estrella, Kevin KC Liu, JinJiang Zhu, Chunze Li, Tod Smeal, Min-Jean Yin. Targeting small cell lung cancer harboring PIK3CA mutation with a selective oral PI3K inhibitor, PF-4989216. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3257. doi:10.1158/1538-7445.AM2013-3257