bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3632: Adaptive operations and technology platform for nation-scale precision oncology
Authors: Abaan Ogan , Basu Amrita , Deal David , Hultner Michael 
Published: July 2016

Abstract
Precision oncology requires predictive models for therapy selection using variety of biomarkers and clinical features as input. Building and validating these models requires analysis of large numbers of diverse cases in order to relate markers and treatments to positive outcomes. The -omics technologies provide a rich source of genetic and epigenetic markers but demand large compute and storage systems to process the data. Thus, there is an urgent need for scalable and reliable information systems to support nation-scale research and delivery of precision oncology.
At Lockheed Martin, we deliver operational solutions to complex problems. Here, we present our vision for a precision oncology platform. This solution integrates best-in-class capabilities from multiple sources/vendors to support innovation, research and clinical care for a whole nation. We not only thought about the basic -omics based data collection, but also an infrastructure to collect and store data within a compliant privacy and security framework that also facilitates collaborative analytics and data sharing for deeper insight.
Taking a systems engineering approach, we have examined some of the challenges to implement such a platform. For instance, running the basic genomic data processing pipelines to yield variant calls, which in turn will feed the variant store, should be a single scalable workflow. Accounting for multiple data sources, various use cases and selections of tools are at the core of an adaptable workflow. A variant store design that can scale and support a national cohort with an overlaying cohort selection tool are all part of this intricate design.
It is our vision that a systems engineering and integration approach can deliver a unified solution for the national precision oncology roadmap. It is paramount that all the individual pieces should be well tuned to deliver scalability and reliability and simultaneously work in complete harmony. Only then we can process data at-scale needed for finding actionable mutations, designing effective treatments and implementing prevention strategies, affordably and reliably.
Citation Format: Ogan Abaan, Amrita Basu, David Deal, Michael Hultner. Adaptive operations and technology platform for nation-scale precision oncology. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3632.
Abstract 3648: Resolving copy number variations from existing exome SNP data without the need for sophisticated software
Authors: Hansen Marcus C. , Herborg Laura L. , Roug Anne S. , Chotirat Sadudee , Auewarakul Chirayu U. , Kjeldsen Eigil , Hokland Peter 
Published: July 2016

Abstract
Several tools exists to evaluate copy-number variation (CNV) from sequencing read data. Here, the aim is to investigate whether larger CNVs in leukemia can be extracted directly from already called variants - without specialized algorithms.
Methods: 12 cases of leukemia, with 6 paired and 6 unpaired, were included (Table 1). Following exome sequencing and reference alignment variants were called with GATK to produce recalibrated sets in variant call format (VCF). Passed single nucleotide polymorphisms (SNPs) were limited to depth of coverage &gt; 29x. Each chromosome were visualized as frequency scatter plot and smoothened histograms of frequency distribution in order to inspect frequency bands and number of peaks in histograms. Kolmogorov-Smirnov test was employed to compare distributions between paired samples.
Results: None of the AML cases with normal karyotype displayed CNVs and no significant changes in frequency distributions were detected. In the relapse of paired T-ALL a Chr 4 trisomy and a 33×10−6 bp copy-number neutral loss of heterozygosity (CN-LOH) on Chr 9 were detected. Collectively, 7 aberrations confirmed standard cytogenetics, 8 new aberrations were added to the cytogenetical profile and 5 could not be detected as shown in Table 1. The aberrations not detected were, as expected, balanced translocations (3) and microdeletions (2).
Discussion: No previously found large aberrations escaped detection, when disregarding translocations. In addition, other CNVs not detected by conventional cytogenetics were found by SNP analysis. Moreover, the added information is in agreement with the literature: 5% of T-ALL patients display del(11)(p12p13) and +12 is one of the most common cytogenetic changes of CLL, e.g.
Thus, we suggest that CNV profiling can be initiated by directly evaluating frequencies from existing variant calls. This may ease implementation of “closed toolboxes”, enable analysis of single unpaired samples and function as a direct complement to array-CGH or FISH to detect CN-LOH. Table 1SamplesPairedCytogeneticsCNV detectedNK-AML5YesNormal karyotypeNoneT-ALL relapse1Yes4+, 3p26.2 and Xp22.2 micro-deletions+4, partial del(9p)AML M01YesNormal karyotypePartial del(11p)AML M31Not(15;17)NoneCML1Not(9;22)NoneT-ALLNodel(5) t(7;14)Partial del(5q), +4q, +9p, del(11p), del(12q)CLL1NoNot analyzed+12AML M01NoNormal karyotypePartial +11
Citation Format: Marcus C. Hansen, Laura L. Herborg, Anne S. Roug, Sadudee Chotirat, Chirayu U. Auewarakul, Eigil Kjeldsen, Peter Hokland. Resolving copy number variations from existing exome SNP data without the need for sophisticated software. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3648.
Abstract 3649: Targeted sequencing of 409 cancer-related genes for somatic mutations and copy number variations in human cancer using the semiconductor sequencers
Authors: Sasaki Yasushi , Koyama Ryota , Nakagaki Takafumi , Tamura Miyuki , Idogawa Masashi , Tokino Takashi 
Published: July 2016

Abstract
Next-generation sequencing technologies have revolutionized cancer genomics research by providing a comprehensive method of detecting somatic cancer genome alterations. In this study, we describe a next-generation semiconductor sequencing protocol for rapid (2 days), standardized, and cost-effective gene analysis for human cancer specimens including FFPE samples. DNA was extracted from 19 human cancer cell lines and 61 human cancer specimens and their corresponding non-cancerous tissues, including oral squamous cell carcinomas and multiple myelomas. Using the Ion Ampliseq Comprehensive Cancer Panel, we sequenced 15992 loci from 409 tumor suppressor genes and oncogenes frequently cited and frequently mutated in human cancers (covered regions = 95.4% of total). Each sample underwent on average 8.3 million sequencing reads after quality filtering. The mean read depths were 461x, and &gt;95% of targeted bases were represented by at least 20 reads. We also detected copy number variations in which segments of the genome can be duplicated or deleted from sequencing data. We found several genetic alterations that may have been associated with the poor prognosis and poor response to chemotherapy of cancer patients. Pathway assessment has shown that somatic aberrations within myeloma genomes are mainly involved in several important pathways, including cell cycle regulation, RTK-MAPK-PI3K and NF-kB. This study demonstrates the utility of using a semiconductor-based sequencing to efficiently identify human cancer mutations. The targeted next generation sequencing using low amounts of FFPE DNA is a valuable tool for high-throughput genetic testing in research and clinical settings.
Citation Format: Yasushi Sasaki, Ryota Koyama, Takafumi Nakagaki, Miyuki Tamura, Masashi Idogawa, Takashi Tokino. Targeted sequencing of 409 cancer-related genes for somatic mutations and copy number variations in human cancer using the semiconductor sequencers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3649.
Abstract 3652: Identification of cancer-specific signaling networks: what is “normal” control
Authors: Anjanappa Manjushree , Hao Yangyang , Edenberg Howard J. , Liu Yunlong , Nakshatri Harikrishna 
Published: July 2016

Abstract
Success of precision medicine depends on definitive identification of cancer-specific alterations in signaling pathways. However, identifying cancer-specific signaling networks is challenging because of lack of proper control tissue for differential gene expression analyses. Most studies in breast cancer utilize tumor-adjacent normal tissue or reduction mammoplasty samples as “normal” controls. We recently reported that breast epithelial cells from healthy donors as well as tumor-adjacent normal are in different differentiation states compared with tumor cells and the differences in differentiation status alone could account for major transcriptome variations between normal and tumor. To overcome these limitations, we propagated breast epithelial cells from three healthy donors (healthy-normal), two high-risk patients, two tumor-adjacent normal (HR/AD-normal) and five tumor samples of different molecular subtypes. Phenotypically defined (CD49f+/EpCAM+) luminal progenitor cells were sorted from these cultures and subjected to RNA-seq analyses. Pathway analysis revealed activation of cell-intrinsic pro-inflammatory signaling in HR/AD-normal cells compared with healthy-normal cells. This signaling network was further amplified in tumor cells. The pro-inflammatory chemokine CCL2, which is overexpressed in highly aggressive breast cancer, and the cytokine TNFRSF11B were elevated in HR/AD-normal luminal progenitor cells. Despite using phenotypically defined cells in the transcriptome analyses, cancer-specific signaling network identification was directly influenced by the type of controls used; healthy-normal or HR/AD-normal. While cancer-enriched PI3K and NF-κB activation was observed when compared to any kind of control, SRC kinase activation was noted only when cells from healthy-normal were used as a control. In general, the number of tumor signaling networks identified using healthy-normal as a control was higher than when compared with HR/AD-normal as a control. These results suggest that considerable attention should be placed on the type of tissues used as control for definitive identification of cancer-specific signaling networks and therapies to target such pathways. Additionally, these data show that non-cancer tissues of breast cancer patients acquire a cell intrinsic pro-inflammatory phenotype, which may be prerequisite for cancer development and potentially an early-detection tool.
Citation Format: Manjushree Anjanappa, Yangyang Hao, Howard J. Edenberg, Yunlong Liu, Harikrishna Nakshatri. Identification of cancer-specific signaling networks: what is “normal” control. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3652.
Abstract 3655: Suppression of Plk3 expression by nickel may contribute to lung carcinogenesis
Authors: Li Cen , Park Soyoung , Dai Wei , Xu Dazhong 
Published: July 2016

Abstract
Exposure to nickel (Ni) compounds is known to induce human lung malignancies. Research shows that Ni induces lung cancer mainly through epigenetic and metabolic pathways. Polo-like kinase 3 (Plk3) is a multifunctional protein kinase that involves in tumor initiation and progression. Plk3−/− mice tend to develop highly vascularized lung tumors at an advanced age. Reduced expression of Plk3 was reported in human lung cancers. In this study, we examined the effect of Ni on Plk3 expression in A549 lung carcinoma cells. Western blot showed that NiCl2 reduced the Plk3 protein level in a time- and dose-dependent manner. We then treated A549 cells with cycloheximide for various times to examine the effect of NiCl2 on the half-life of Plk3 protein. We observed a shortened half-life of Plk3 in the presence of NiCl2. A reduced level of Plk3 protein was also found in hypoxia-treated A549 cells. In addition, MG132, a specific proteasome inhibitor, could partially reverse the effect of NiCl2 or hypoxia on the Plk3 protein level. Our cell fractionation experiments showed that majority of the endogenous Plk3 protein is located in the cytoplasm where degradation of Plk3 likely occurs. Transfection of A549 cells with FLAG-tagged ubiquitin (FLAG-Ub) followed by treatment with NiCl2 and/or MG132, immunoprecipitation (IP) with an anti-FLAG antibody, and Western blot with an anti-Plk3 antibody showed that Plk3 was poly-ubiquitinated and that the ubiquitination was significantly enhanced by NiCl2 and/or MG132 treatments. The elevated ubiquitination of Plk3 in response to NiCl2 was further confirmed in 293T cells with co-transfection of Plk3 and FLAG-Ub. Furthermore, overexpression of USP28, a deubiquitinase known to be inhibited by Ni or hypoxia, partially restored the protein level of Plk3 suppressed by NiCl2. Moreover, real-time PCR analysis showed that NiCl2 also reduced the Plk3 mRNA level, in a time- and dose-dependent pattern. Taken together, our data show that NiCl2 suppresses Plk3 expressions by lowering the Plk3 mRNA level and promoting proteasome-mediated degradation of the Plk3 protein. Given the potential role of Plk3 as a tumor suppressor in the lung, suppression of Plk3 expression likely contributes to Ni-induced lung carcinogenesis and tumor progression.
Citation Format: Cen Li, Soyoung Park, Wei Dai, Dazhong Xu. Suppression of Plk3 expression by nickel may contribute to lung carcinogenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3655.
Abstract 3658: A novel microtubule associated RNA binding protein matrin 3 act as a tumor suppressor by regulating mitotic spindle organizing proteins in triple negative breast cancers
Authors: Subbarayalu Panneerdoss , Rajamanickam Subapriya , Viswanadhapalli Suryavathi , Onyeagucha Benjamin C. , Eedunuri Vijay K. , Dybdal-Hargreaves Nicholas , Timilsina Santosh , Bansal Hima , Bansal Sanjay , Mohammad Tabrez , Chen Yidong , Herr John C. , Mooberry Susan L. , Rao Manjeet K. 
Published: July 2016

Abstract
Microtubule-targeting drugs are widely used as cancer chemotherapeutic agents and they have been shown to inhibit mitotic progression and interphase signaling. Despite their use as a first line treatment for cancer, many patients develop resistance to microtubule-targeting drugs leading to early relapse and shorter survival. Moreover, the quality of life for patients who do survive is often substantially reduced due to the toxicity associated with these drugs. Therefore, identification of new factors that determine the effectiveness of microtubule-targeting agents will not only facilitate a better understanding of the mechanisms of acquired drug resistance but will also be amenable to therapeutic interventions. We discovered a novel microtubule associated protein “Matrin 3 (MATR3)” that is known to bind to RNA and play a critical role in RNA transport and RNA stabilization. Our results revealed that MATR3 acts as a potent tumor suppressor as it inhibits long-term growth, migration, invasion as well as tumor growth of triple negative breast cancer (TNBC) cells in vivo. We demonstrated that MATR3 overexpression induced cell cycle arrest and apoptosis in TNBC cells. Furthermore, analysis of breast cancer samples showed a significantly lower expression of MATR3 when compared to normal adjacent tissues. Importantly, our RNA immunoprecipitation (RIP)-seq analysis showed that MATR3 controls expression of several mitotic spindle organizing proteins by binding to their RNA. Interestingly, we found that these MATR3 regulated proteins were highly altered in breast cancer patients. In conclusion, we identified a novel RNA-binding protein that inhibits breast cancer growth and progression suppressor by regulating microtubule dynamics.
Citation Format: Panneerdoss Subbarayalu, Subapriya Rajamanickam, Suryavathi Viswanadhapalli, Benjamin C. Onyeagucha, Vijay K. Eedunuri, Nicholas Dybdal-Hargreaves, Santosh Timilsina, Hima Bansal, Sanjay Bansal, Tabrez Mohammad, Yidong Chen, John C. Herr, Susan L. Mooberry, Manjeet K. Rao. A novel microtubule associated RNA binding protein matrin 3 act as a tumor suppressor by regulating mitotic spindle organizing proteins in triple negative breast cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3658.
Abstract 3681: Nischarin disruption promotes breast tumor development in mouse models
Authors: Dong Shengli , Alahari Suresh K. 
Published: July 2016

Abstract
Nischarin is a novel tumor suppressor that was first discovered and characterized in our laboratory. The accumulating evidence suggests that Nischarin is a critical regulator of cell migration and breast tumor growth, metastasis and invasion. However, little is known about the exact function of Nischarin in in vivo physiological conditions, probably due to lack of any transgenic Nischarin animals. We recently generated Nischarin knockout mouse. This Nischarin knockout mouse has a dramatic unusual phenotype of mammary development and overall growth defect. Nischarin knockout mice do not spontaneously develop breast tumors. To determine the importance of Nischarin in regulation of breast cancer development, we bred Nischarin knockout virgin mice with PyMT (polyoma middle T antigen) and Neu background mice and the progeny produced tumors exclusively in the mammary gland. We found Nischarin knockout virgins with PyMT accelerated breast cancer onset and progression, which further suggests Nischarin inhibits tumor growth. Mammary epithelial cells (MECs) are surrounded by basement membrane, which mainly consists of extracellular matrix. We noted that the basement membrane of Nischarin knockout virgins contain much more collagen and fibronectin than those of wild type virgins. In addition, we observed that Nischarin disruption significantly changed extracellular acidification rates (ECAR) in mouse primary breast tumour cells. We suspected that this changed acidic microenvironment might facilitate breast tumor progression. Recent studies indicated that clinical anti-diabetic drug Metformin, an AMPK activator, inhibits breast cancer cell growth. Our data show that Het-PyMT and Null-PyMT primary cells were much more sensitive for metformin treatment. Thus we examined the importance of AMPK signaling in our mouse models. Interestingly, both tumor tissues and primary cells derived from Null-PyMT breast tumors had lower AMPK activity. Together, our data strongly support that Nischarin disruption promotes breast tumor development and AMPK signaling is important for Nischarin-mediated suppression of breast tumor.
Citation Format: Shengli Dong, Suresh K. Alahari. Nischarin disruption promotes breast tumor development in mouse models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3681.
Abstract 3682: Phosphorylation mediated conformational changes defines nuclear role of phosphatase and tensin homology (PTEN) in tumor suppression
Authors: Malaney Prerna , Semidey-Hurtado Jonathan , Hardee Jamaal , Patel Deepal , Hennessey Daniel , Stanford Kate , Palumbo Emily , Tian Zhi , Allen-Gipson Diane , Davé. Vrushank 
Published: July 2016

Abstract
Loss of function of tumor suppressor PTEN (Phosphatase and tensin homolog) causes cancer in various tissues. PTEN C-terminal phosphorylation (pPTEN) inactivates PTEN, leading to multiple malignancies with increased severity. However, little is known about the molecular mechanisms underlying such inactivation. Therefore, the objective of our work is to ascertain the molecular mechanisms by which PTEN phosphorylation drives lung cancer. PTEN C-terminal phosphorylation at a serine-threonine cluster (Ser380, Thr382, Thr383 and Ser385) conformationally inactivates PTEN, abrogating its tumor suppressor function. Replacement of these serine/threonine residues with alanine generated an artificial phosphorylation-deficient mutant of PTEN (PTEN-4A), which is constitutively active. PTEN-4A suppressed cell proliferation and migration to a greater extent as compared to PTEN-WT. PTEN-4A preferentially localized to the nucleus and suppressed the E2F-mediated transcription of cell cycle genes. The nuclear localization sequence and phosphatase activity of PTEN-4A is critical for this transcriptional suppression. Immuno-precipitation assays show that PTEN physically associates with the transcription factor E2F1, a likely mechanism for its suppressive effect on E2F1 related genes. Further, deletion analysis of PTEN-4A protein revealed that the C2 domain is indispensable for suppression of E2F-related genes. Systematic transcriptional assays identify disease-associated C2 domain mutations that lose their ability to suppress E2F-mediated transcription, supporting the concept that these mutations are oncogenic in patients. Taken together, we reveal nuclear functions of PTEN-4A in tumor suppression that can be therapeutically leveraged for developing adjunctive cancer therapies. Small molecule inhibitors that hinder PTEN phosphorylation maybe utilized to activate PTEN nuclear function in tumors. Such adjunctive therapy has a high likelihood to reduce toxic doses of chemotherapeutic agents and targeted inhibitors, including kinase inhibitors that are being used in clinical settings.
Citation Format: Prerna Malaney, Jonathan Semidey-Hurtado, Jamaal Hardee, Deepal Patel, Daniel Hennessey, Kate Stanford, Emily Palumbo, Zhi Tian, Diane Allen-Gipson, Vrushank Davé. Phosphorylation mediated conformational changes defines nuclear role of phosphatase and tensin homology (PTEN) in tumor suppression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3682.