bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 386: Rapid in situ RNA analysis of circulating tumor cells using magnetic micropore-based sorting and Turbo FISH
Authors: Ko Jin A , Bhagwat Neha , Yee Stephanie S. , Carpenter Erica , Stanger Ben , Issadore David 
Published: August 2015

Abstract
Pancreatic cancer is the fourth most common cause of cancer-related death in the US, with a five year survival rate of only 6%. Recently, we have shown that circulating pancreatic cells can be detected at the onset of the disease cycle (pre-Stage 1). Thus, there is both a great need for early diagnosis and an opportunity, due to the early presence of circulating tumor cells (CTCs).
Currently, the gold standard for CTC detection cannot resolve these extremely sparse, heterogeneous CTCs, which do not have any single surface marker that allows them to be targeted. Additionally, conventional downstream analyses are limited to either protein expression of individual cells on-chip, which has limited sensitivity to relevant biomarkers, or genetic testing off-chip, which has limited practical clinical use.
To address these challenges, we have developed a rapid (&lt; 40 minute) clinical diagnostic for pancreatic cancer detection. Our approach combines magnetic micropore based negative selection of immunomagnetically labeled leukocytes with on-chip RNA fluorescence in situ hybridization (Turbo RNA FISH) to profile individual cells. With the high-specificity of FISH and its ability to be multiplexed, combined with the high sensitivity of track-etched magnetic micropore (TEMPO) to rare cells, we have demonstrated the potential to diagnose pancreatic cancer early in the disease cycle.
A key innovation is the development of our magnetic micropore based sorting technique, which preserves the low cell-loss and specificity of microfluidic sorting but at &gt;10x greater flow rates and an insensitivity to clogging, enabling use directly on whole blood. The TEMPO filter consists of an electroplated 1.25 μm NiFe, 30 μm pores, and 5.1×10E5 pores total.
Using this chip, we have demonstrated extremely high sensitivity to rare cells (LOD ∼ 1 cell / 7.5 mL blood) and exponentially improved sorting efficiency by stacking multiple TEMPO filters in series. Furthermore, single molecules of targeted RNA in each individual CTC could be resolved.
Citation Format: Jin A Ko, Neha Bhagwat, Stephanie S. Yee, Erica Carpenter, Ben Stanger, David Issadore. Rapid in situ RNA analysis of circulating tumor cells using magnetic micropore-based sorting and Turbo FISH. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 386. doi:10.1158/1538-7445.AM2015-386
Abstract 3876: Actionable somatic mutations in head and neck cancer prognosis
Authors: Nelson Omar L. , Wu Evan S. , Park Jong Y. , Zeitouni Joseph , Gomez Carmen R. , Reis Isildinha M. , Zhao Wei , Lee Eunkyung , Lin Hui-Yi , Franzman Elizabeth J. , Savell Jason , McCaffrey Thomas V. , Goodwin W. Jarrard , Hu Jennifer J. 
Published: August 2015

Abstract
Head and neck squamous cell carcinoma (HNSCC) is a devastating illness with racial/ethnic disparities in survival. Using a retrospective study design, we evaluated 210 somatic mutation sties of 10 cancer genes (i.e., CDKN2A, EGFR, FGFR3, HRAS, KRAS, MET, NOTCH1, PIK3CA, STK11, and TP53) in 214 HNSCC patients: 98 Non-Hispanic Whites (NHW; 46%), 72 Hispanic Whites (HW; 34%), and 44 African Americans (AA; 20%). HW and AA had significantly higher mutation rates for EGFR, HRAS, KRAS, and TP53 compared to that in NHW. Significantly higher proportions of HW (30%) and AA (18%) had at least 3 mutations compared to that in NHW (p&lt;0.001). In logistic regression models using 2-year as the cut-off for early death, we evaluated the overall and racial/ethnic-specific somatic mutations that are associated with early death. Although there was no significant association between somatic mutation and early death in the total population, NOTCH1 mutations were significantly associated with early death in NHW (odds ratio [OR] = 5.51, 95% confidence internal [CI] = 1.22, 24.83). More importantly, the NOTCH1 mutation C6814T (P2272S) within the PEST domain was associated with early death (OR = 13.13 (95%CI = 1.61, 107.36). TP53 mutations were significantly associated with early death in HW (OR = 3.84; 95%CI = 1.08, 13.68) in multivariate analysis after adjustment for age, gender, tumor site, and tumor stage. With limited sample size, no association was observed in AA. This is the first pilot study evaluating the association between somatic mutations and HNSCC early death in a tri-racial/ethnic population. Our data suggest that HW and AA have higher EGFR mutations and these patients may benefit from mutation-targeted precision medicine to improve survival.
Citation Format: Omar L. Nelson, Evan S. Wu, Jong Y. Park, Joseph Zeitouni, Carmen R. Gomez, Isildinha M. Reis, Wei Zhao, Eunkyung Lee, Hui-Yi Lin, Elizabeth J. Franzman, Jason Savell, Thomas V. McCaffrey, W. Jarrard Goodwin, Jennifer J. Hu. Actionable somatic mutations in head and neck cancer prognosis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3876. doi:10.1158/1538-7445.AM2015-3876
Abstract 3890: Whole-genome mutational landscape of liver cancers displaying biliary phenotype reveals hepatitis impact and molecular diversity
Authors: Nakagawa Hidewaki , Fujimoto Akihiro , Furuta Mayuko , Gotoh Kunihito , Nakamura Toru , Yamamoto Masakazu , Yamaue Hiroki , Chayama Kazuaki , Miyano Satoru , Tsunoda Tatsuhiko 
Published: August 2015

Abstract
Primary liver cancer is the third leading cause of cancer death worldwide. Virus infection is the most common and strongest etiological factor for liver cancer development. Pathologically, primary liver cancer can be classified into ∼90% hepatocellular carcinoma (HCC), and 5∼10% intrahepatic cholangiocarcinoma (ICC), and the combined hepatocellular-cholangiocarcinoma (cHCC/CC) representing only a small portion. Clinically, ICC and cHCC/CC show much more aggressive behavior with poorer prognosis than HCC, and no standard treatment currently exists, other than surgical resection. ICC and cHCC/CC show varying degrees of biliary epithelial differentiation, which can be defined as liver cancer displaying a biliary phenotype (LCB). To gain insight into molecular alterations of LCBs, we performed whole genome sequencing analysis on 30 LCBs. Here we show the genome-wide substitution patterns of LCBs developed in chronic hepatitis livers overlapped with those of 60 HCCs, while those of hepatitis-negative LCBs diverged. The subsequent validation study on 68 LCBs identified recurrent mutations in TERT promoter, chromatin regulators (BAP1, PBRM1 and ARID2), a synapse organization gene (PCLO), IDH genes and KRAS. The frequencies of KRAS and IDHs mutations, which are associated with poor disease-free survival, were significantly higher in hepatitis-negative LCBs. This study reveals the strong impact of chronic hepatitis on the mutational landscape in liver cancer and the genetic diversity among LCBs.
Citation Format: Hidewaki Nakagawa, Akihiro Fujimoto, Mayuko Furuta, Kunihito Gotoh, Toru Nakamura, Masakazu Yamamoto, Hiroki Yamaue, Kazuaki Chayama, Satoru Miyano, Tatsuhiko Tsunoda. Whole-genome mutational landscape of liver cancers displaying biliary phenotype reveals hepatitis impact and molecular diversity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3890. doi:10.1158/1538-7445.AM2015-3890
Abstract 3894: The importance of matched tumor and normal DNA for somatic mutation discovery and clinical interpretation
Authors: Jones Siân , Sausen Mark , Anagnostou Valsamo , Angiuoli Samuel V. , Chesnick Bryan , Galens Kevin , Kadan Maura , Kann Lisa , Lytle Karli , Murphy Derek , Nesselbush Monica , Papp Eniko , Parpart-Li Sonya , Riley David , Shukla Manish , Zhang Theresa , Diaz Luis A. , Velculescu Victor E. 
Published: August 2015

Abstract
Massively parallel sequencing approaches are beginning to be used clinically to characterize individual patient tumors and to identify targeted therapies based on mutations identified. A major question in these analyses is the extent to which these methods identify clinically actionable alterations in patients and whether the examination of the tumor tissue alone is sufficient or whether matched normal DNA should also be analyzed to accurately identify tumor-specific (somatic) alterations. To address these issues, we comprehensively evaluated tumor-normal paired samples from 753 cancers from fourteen tumor types. We analyzed somatic alterations using whole exome or targeted next generation sequencing approaches that were validated with high sensitivity and specificity. These analyses revealed an average of 140 and 4.34 somatic changes per exome and targeted analyses, respectively. Approximately 65% of cases had somatic alterations in genes associated with known therapies or current clinical trials. In contrast, a tumor-only sequencing approach followed by bioinformatic removal of common germline variants from existing databases led to a 36% and 58% false discovery rate in alterations identified in targeted and exome analyses, respectively, including in potentially actionable genes. These data suggest that matched tumor-normal sequencing analyses are essential for precise identification and interpretation of somatic alterations and have important implications for the diagnostic and therapeutic management of cancer patients.
Citation Format: Siân Jones, Mark Sausen, Valsamo Anagnostou, Samuel V. Angiuoli, Bryan Chesnick, Kevin Galens, Maura Kadan, Lisa Kann, Karli Lytle, Derek Murphy, Monica Nesselbush, Eniko Papp, Sonya Parpart-Li, David Riley, Manish Shukla, Theresa Zhang, Luis A. Diaz, Victor E. Velculescu. The importance of matched tumor and normal DNA for somatic mutation discovery and clinical interpretation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3894. doi:10.1158/1538-7445.AM2015-3894
Abstract 3910: Acetylation of ΔNp63α by Tip60 affects its stability
Authors: Stacy Andrew J. , Smith Zachary J. , Zhang Jin , Kadakia Madhavi 
Published: August 2015

Abstract
p63, a member of the transcription factor p53 family, exists as six different isoforms due to the usage of alternative promoter sites and splicing. ΔNp63α is the most abundant and predominant isoform and is identified to being involved in epithelial morphogenesis. ΔNp63α expression is up-regulated in non-melanoma skin cancers. We have identified ΔNp63α as a potential target for acetylation by the Tat Interacting Protein 60 kDa (TIP60) histone acetyltransferase (HAT) by mass spectometry. Co-expression of ΔNp63α with Tip60 leads to stabilization of ΔNp63α protein levels. The change in protein levels are not due to an increase in transcription or translation, and is likely the result of stabilization by post-translational modification as confirmed by half-life studies in presence of cycloheximide and measurement of transcript levels by quantitative reverse transcriptase PCR. This was further supported by our observations that ΔNp63α and Tip60 interact using immunoprecipitation studies. ΔNp63α levels are not affected by Tip60 HAT mutant, but increased with Tip60 double sumoylation mutant which retains its acetyltransferase ability. These results identify a possible biologically important interaction between ΔNp63α and Tip60, warranting further investigation.
Citation Format: Andrew J. Stacy, Zachary J. Smith, Jin Zhang, Madhavi Kadakia. Acetylation of ΔNp63α by Tip60 affects its stability. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3910. doi:10.1158/1538-7445.AM2015-3910
Abstract 3921: TGFβ sensitizes hepatocellular carcinoma cells to growth factors, preventing sorafenib-induced apoptosis
Authors: Ungerleider Nathan , Han Chang , Wu Tong 
Published: August 2015

Abstract
Many hepatocellular carcinoma (HCC) patients have a poor prognosis due to an acquired resistance of tumors to chemotherapeutic treatment. Transforming growth factor β (TGFβ) has important roles in the control of cell differentiation, cell cycle progression, and apoptosis. An upregulation in the TGFβ signalling pathway is associated with poor prognosis in HCC patients. In this study, we aim to investigate the mechanisms by which TGFβ contributes to HCC tumor progression. We found that TGFβ significantly increases mRNA and protein levels of several mitogenic receptor tyrosine kinases, including insulin-like growth factor 1 receptor (IGF1R) and epidermal growth factor receptor (EGFR) in both time-dependent and dose-dependent manners in PLC/PRF/5 cells. Furthermore, TGFβ pretreatment significantly increases the acute cellular response to IGF1, IGF2, and EGF treatment, as measured by levels of pAKT and pERK also in both time-dependent and dose-dependent manners. We hypothesized that this increase in growth factor sensitivity would render cells resistant to sorafenib, the only approved targeted HCC chemotherapeutic agent. To test this, we pretreated PLC/PRF/5 cells with TGFβ for 48 hours then incubated the cells with sorafenib for up to 24 hours. We found that TGFβ pretreatment led to a reduction of cleaved caspases 3, 7, 9, and PARP, which are cleaved as cells undergo apoptosis. We confirmed an increase in cell viability via WST-1 assays and by counting viable cells. Lastly, we found that the TGFβRI kinase inhibitor, LY2157299, synergized with sorafenib to promote apoptosis. Taken together, our data suggests that TGFβ can enhance the survival of HCC cells by upregulating cell sensitivity to pro-survival growth factors. Furthermore, the use of both sorafenib and an inhibitor of the TGFβ signalling pathway may one day prove to be a more effective therapy for patients with advanced HCC.
Citation Format: Nathan Ungerleider, Chang Han, Tong Wu. TGFβ sensitizes hepatocellular carcinoma cells to growth factors, preventing sorafenib-induced apoptosis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3921. doi:10.1158/1538-7445.AM2015-3921
Abstract 3935: CDKN2A/p16 is inactivated by the combination of inversion and translocation
Authors: Norris Alexis L. , Kamiyama Hirohiko , Hruban Ralph H. , Eshleman James R. 
Published: August 2015

Abstract
Homozygous deletions (HDs) are a common mechanism by which tumor suppressor genes (TSG) are inactivated in cancer. Cyclin-Dependent Kinase Inhibitor 2A (CDKN2A/p16) is the most commonly deleted TSG, with HDs in 40% of pancreatic ductal adenocarcinomas (PDAC) harboring p16 deletions. HDs create novel junctions, which can be exploited for sensitive early detection and minimal residual disease testing, using the PAtient-specific REarrangement (PARE) method.
Here we characterize the underlying structural rearrangements that produce p16 HDs in a panel of PDAC cancer cell lines using pair-end whole genome sequencing (WGS) and high density SNP microarray analyses. Rearrangements were defined as simple interstitial deletions when the segment of a chromosome arm was deleted and the ends joined. The complex rearrangements causing the HD were categorized at both breakpoints as inversions and/or translocations. Sanger sequencing confirmed novel junctions, and breakpoints were assessed for non-templated base insertions and microhomology.
We report that complex rearrangements underlie half of p16 HDs in PDAC (3 of 5). Most striking, the combination of an inversion and inter-chromosomal translocation (INV+TRANS) was exclusively responsible for these complex rearrangements. Inversions ranged in size from 47 to 3,373bp and translocations were non-recurrent and were often non-reciprocal (2 of 3). All HDs were resolved (either by interstitial deletion or INV+TRANS) without the addition of any non-templated bases inserted at the novel junction, arguing against the involvement of error-prone non-homologous end joining (NHEJ). Microhomology was seen at most rearrangement junctions (8 of 9), but with a median of only 2 bases. Further work is needed to elucidate the mechanism responsible for INV+TRANS rearrangements.
Citation Format: Alexis L. Norris, Hirohiko Kamiyama, Ralph H. Hruban, James R. Eshleman. CDKN2A/p16 is inactivated by the combination of inversion and translocation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3935. doi:10.1158/1538-7445.AM2015-3935
Abstract 3952: BRE: a genetic interactor of BRCA2
Authors: Biswas Kajal , Chang Suhwan , Philip Subha , Sharan Shyam K. 
Published: August 2015

Abstract
Mutations in breast cancer susceptibility genes BRCA1 and BRCA2 predispose individuals to breast and ovarian cancers. Though BRCA associated tumor tissues showed inactivation of both alleles, in primary cells mutations in both copies affect cell viability. This suggests that BRCA1 or 2 loss mediated tumorigenesis process needs other factors. In this study, MSCV (Murine Stem Cell Virus) retroviral mediated insertional mutagenesis approach was used in conditional Brca2 mutant mES (mouse embryonic stem) cells to identify and characterize genetic interactors of BRCA2. One of the factors identified in this screen is brain and reproductive organ expressed protein BRE. BRE is an anti-apoptotic protein and also a component of the BRCA1-A complex that specifically recognizes ‘Lys-63′-linked ubiquitinated histones H2A and H2AX at DNA lesions sites. Overexpression of BRE results into perturbation of DNA damage induced G1/S cell cycle checkpoint by preventing DNA damage induced degradation of CDC25a phosphatase. Further it was found that the stabilization of CDC25a phosphatase in BRE overexpressing cells on DNA damage is mediated via ubiquitin-specific-processing protease 7 (USP7). We are now examining the expression of BRE and CDC25a in BRCA2 deficient tumors.
Citation Format: Kajal Biswas, Suhwan Chang, Subha Philip, Shyam K. Sharan. BRE: a genetic interactor of BRCA2. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3952. doi:10.1158/1538-7445.AM2015-3952
Abstract 3967: miRNA reference samples for interlaboratory study
Authors: Pine P. Scott , Sorbara Lynn R. , Srivastava Sudhir , Salit Marc 
Published: August 2015

Abstract
The biomarkers of interest in this study are microRNA (miRNA), small non-coding RNAs involved in the regulation of gene expression. Currently, over 1000 human miRNAs have been identified. Several laboratories within the Early Detection Research Network are currently profiling miRNA as potential biomarkers. The reference sample paradigm presented and evaluated here is designed to provide measurement assurance in the earliest phases of a cancer biomarker development pipeline.
Three commercially available samples of human total RNA (brain, liver, and placenta) were selected for detectable differences in miRNA expression based upon previously reported miRNA microarray experiments. For each round of this study, replicate samples of each tissue were aliquoted, blinded, and distributed to participating laboratories. The samples were then profiled using the standard workflows of each laboratory. This was repeated over multiple rounds of measurement. Raw data were processed in pair-wise comparisons between tissue types.
Log2 transformed ratios were calculated for each detectable miRNA. For each of these miRNA ratios, the results among laboratories were compared to the consensus value to provide a measure of concordance and help identify laboratories that might need to make adjustments to their process. Results demonstrated repeatability within labs and reproducibility among labs with respect to direction and magnitude of differential miRNA expression between tissues for a set of miRNAs of interest (MOI). For the first round, 79% of reported results for all log2 ratio combinations and MOI were in agreement with the consensus values.
Subsequent rounds demonstrated increased concordance, with 91 and 100% agreement, respectively. The data from the nine “neat” tissue total RNA samples were also used for in silico modeling to predict the values for two complex mixtures based on three components. The two mixture designs provide a pair of reference samples with designed-in reciprocal ratios of 2:1 for brain and placenta, as well as a shared 1:1 liver component. For two brain-selective and two placenta-selective MOI, 91% of reported values were in close agreement with the target values. Overall, measurement results were harmonious for a set of miRNAs of interest measured by all participants, both within rounds and between rounds. The laboratories were also able to demonstrate the ability to resolve the 2-fold differences created with complex mixtures. These results suggest that endogenous miRNAs present within total RNA may be suitable as QA/QC process controls.
Citation Format: P. Scott Pine, Lynn R. Sorbara, Sudhir Srivastava, Marc Salit. miRNA reference samples for interlaboratory study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3967. doi:10.1158/1538-7445.AM2015-3967