bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5223: A novel molecular inversion probe (MIP) system for the streamlined identification of germline and somatic sequence variants in cancer
Authors: Jefferson Keynttisha , Halvensleben Heather , Green Dawn , Bannen Ryan , Brockman Michael , Richmond Todd , Burgess Daniel 
Published: July 2016

Abstract
Characterization of the somatic sequence variations that accrue in cells is critical for understanding the pronounced cellular and clinical heterogeneity observed in cancer. The ability to efficiently detect variations in tumors can help to identify biomarkers which may be relevant to clinical trials, support more accurate prognosis, and help guide more effective choices of therapy. Next-generation sequencing (NGS) has become a valuable tool for discovering somatic mutations in cancers. Here we present an alternative approach to current methodologies for addressing these needs.
HEAT-Seq (High Efficiency Amplification of Targets for Sequencing) is a targeted NGS method based on optimized, multiplexed molecular inversion probes (MIPs). This is a convenient, sensitive and cost-effective target enrichment technology for SNP discovery and SNP validation in cancer-related genes. HEAT-Seq probes target both DNA strands and were designed to facilitate bioinformatic error correction. Molecule identifiers (UIDs) incorporated into the probes tag PCR duplicates and support ultra-sensitive detection of low frequency variants, reduction of false positives, and accurate assessment of molecular complexity free of amplification bias. Sensitivities for allele detection have been measured to below 1%.
The HEAT-Seq workflow from input DNA to sequence-ready sample can be completed in ≤8 hours without any requirement for a separate library preparation step, which saves both time and cost. Additionally, the capture, amplification and sample clean up steps are performed in a single reaction tube. This eliminates the need to transfer samples to subsequent reaction tubes, preserves sample identity, prevents cross contamination, limits sample loss, and makes the HEAT-Seq protocol easy to automate. A comparison of current PCR-based targeted sequencing with the new HEAT-Seq technology indicates significant advantages for HEAT-Seq in the accurate quantification of low frequency cancer variants.
In summary, HEAT-Seq technology offers a rapid, convenient, automatable option to identify genomic DNA variants and enable advances in cancer research.
Citation Format: Keynttisha Jefferson, Heather Halvensleben, Dawn Green, Ryan Bannen, Michael Brockman, Todd Richmond, Daniel Burgess. A novel molecular inversion probe (MIP) system for the streamlined identification of germline and somatic sequence variants in cancer. [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 5223.
Abstract 5237: Protection of tocopherols against estrogen-induced breast cancer via mechanisms targeting cancer stem cells
Authors: Bak Min Ji , Das Gupta Soumyasri , Wahler Joseph , Lee Mao-Jung , Lin Yong , Joe Shih Weichung , Yang Chung S , Suh Nanjoo 
Published: July 2016

Abstract
Estrogens have been implicated to be complete carcinogens through mechanisms involving increased proliferation, oxidative stress and DNA damage. Although the importance of estrogen in breast cancer is well established, the effects of estrogen on breast cancer stem cells are not fully understood. Due to the role of breast cancer stem cells in tumor initiation, maintenance, and progression, targeting cancer stem cells has become important for understanding estrogen-mediated breast carcinogenesis. The vitamin E family, which is consisted of four different forms of tocopherols and tocotrienols, has been shown to exert anti-tumor effects in animal models of various cancers. In the present study, we examined the protective effects of α-, γ-, δ-tocopherol as well as a natural γ-tocopherol rich mixture of tocopherols (γ-TmT) against estrogen-induced expansion of cancer stem-like cells and estrogen-mediated tumor growth. To determine the effects of tocopherols on breast cancer stem cells, the MCF-7 mammosphere cell culture system, which enriches for mammary progenitor cells and putative breast cancer stem cells, was utilized. Treatment of MCF-7 mammosphere with estrogen for six days resulted in an increase in CD44+/CD24- stem-like cell populations as well as the number and size of mammosphere. α-, γ-, δ-Tocopherol, and most significantly γ-TmT, inhibited estrogen-induced mammosphere formation, indicating that tocopherols reverse estrogen-induced expansion of breast cancer stem cells. In MCF-7 xenograft tumor study, MCF-7 cells (5 × 106 cells/mouse) were injected into the mammary fat pad in immunodeficient mice after subcutaneous implantation with 0.72 mg of estrogen pellet. Mice were then administered with diets containing 0.2% α-, γ-, δ-tocopherol and γ-TmT for 5 weeks. Treatment of α-, γ-, δ-tocopherol or γ-TmT reduced the tumor volume by 71% (p&lt;0.05), 55% (p&lt;0.05), 59% (p&lt;0.05) and 42% (p&lt;0.01) as well as tumor weight by 80%, 63% (p&lt;0.05), 61% (p&lt;0.05) and 48% (p&lt;0.05), respectively. Our results suggest that tocopherols significantly repress the expansion of breast cancer stem cell-like population and tumor development. Tocopherols, in particular a naturally occurring tocopherol mixture rich in γ and δ-tocopherols, could thus be effective natural agents for the prevention and treatment of estrogen-induced breast cancer.(This work was supported by NIH R01 AT007036)
Citation Format: Min Ji Bak, Soumyasri Das Gupta, Joseph Wahler, Mao-Jung Lee, Yong Lin, Weichung Joe Shih, Chung S Yang, Nanjoo Suh. Protection of tocopherols against estrogen-induced breast cancer via mechanisms targeting cancer stem cells. [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 5237.
Abstract 5247: Caffeic acid phenethyl ester (CAPE) reverses aggressive breast cancer in the radiation chimera model
Authors: Omene Coral O. , Patel Manan , IllaBochaca Irineu , Barcellos-Hoff Mary Helen 
Published: July 2016

Abstract
CAPE is the major active component of propolis, a widely available, safe, honeybee natural product with anti-inflammatory, antioxidant, and antitumor properties. We have previously shown diverse effects of CAPE in breast cancer. We postulated that CAPE may be useful in chemoprevention for women at high risk for triple-negative breast cancers (TNBC) and evaluated this in a radiation chimera mouse model in which the tumor spectrum is shifted to TNBC.
The radiation chimera model consists of surgically clearing the mammary epithelium from the inguinal glands of 3-week old BALB/c mice, the mice were irradiated with 1 Gy or sham irradiated at 10-12 weeks of age, and bilaterally transplanted 3 days later with syngeneic Trp53 null mammary fragments. Mice were placed on a CAPE diet or a control diet at 1 month post transplantation that was maintained for the course of the experiment. Mammary tumor development was monitored by palpation for up to 18 months. The first tumor was resected at 1cm3 and mice monitored for tumor recurrence or second tumor formation. Tumors were immunostained for estrogen receptor (ER) status and ER negative tumors were selected from all the groups for RNA sequencing.
No difference in body weight or tumor incidence was observed between mice on the CAPE versus control diet. Host irradiation significantly accelerated tumor growth rate compared to the control sham irradiated mice. CAPE treatment blocked this effect, but did not affect the control tumor growth rate. Resected tumors in CAPE treated mice recurred at significantly longer intervals (average of 40 days in the control group versus 90 days with CAPE treatment) and much less frequently than tumors from mice on a control diet. Mean expression analysis showed that CAPE induces a distinct gene expression pattern in ER negative tumors from irradiated mice. As previously described, the transcriptional profile of ER negative tumors was enriched in immune response genes in tumors from irradiated mice on a control diet. Interestingly, this difference was abrogated in mice on the CAPE diet.
These findings support the potential use of CAPE to modify the aggressive behavior of TNBC. This may be due to effects on the immune system in which CAPE acts to re-establish anti tumor immunity. Thus, CAPE may be useful in chemoprevention both for women at high risk for TNBC and to prevent or delay TNBC breast cancer recurrence.
Citation Format: Coral O. Omene, Manan Patel, Irineu IllaBochaca, Mary Helen Barcellos-Hoff. Caffeic acid phenethyl ester (CAPE) reverses aggressive breast cancer in the radiation chimera model. [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 5247.
Abstract 5250: Photopreventive effect and mechanism of AZD4547 and curcumin C3 complex on UVB-induced epidermal hyperplasia
Authors: Khandelwal Alok R. , Xiaohua Rong , Moore-Medlin Tara , Ekshyyan Oleksandr , Fleurette Abreo , Gu Xin , Nathan Cherie-Ann O. 
Published: July 2016

Abstract
Aggressive cutaneous squamous cell carcinoma (cSCC) of the skin is the second most common type of skin cancer in the USA due to high exposure to ultraviolet-B (UVB) radiation. In our previous studies Curcumin C3 complex (C3), a standardized preparation of three curcumonoids, delayed UVB-induced tumor incidence and inhibited multiplicity. Exposure to UVB activates mTOR and FGFR signaling both of which play a key role in skin tumorigenesis. The purpose of this study was to investigate the efficacy of C3 complex to afford protection against UVB-induced hyper proliferation by targeting the mTOR and FGFR signaling pathways. Pre-treatment with C3 complex significantly inhibited UVB-induced FGF-2 induction, FGF-2-induced colony formation, mTORC1 and mTORC2 activation and FGFR2 phosphorylation in promotion sensitive JB6 epithelial cells. Further, FGFR2 was required for UVB-induced mTOR activation suggesting an important role of FGFR2 in UVB-induced mTOR signaling. SKH-1 mice pre-treated with C3 (15mg/kg/b.w) for 2 weeks followed by a single exposure to UVB (50mj/cm2) significantly attenuated UVB-induced mTOR and FGFR activation. To further assess the role of FGFR in UVB-induced hyper proliferation, SKH-1 mice were pre-treated with AZD4547; a selective pan-FGFR kinase inhibitor followed by single exposure to UVB (50mj/cm2). AZD4547 significantly inhibited UVB-induced mTORC1 and mTORC2 activation, epidermal hyperplasia and hyper proliferation. Our studies underscore the importance of FGFR signaling in UVB-induced acute skin changes and the role of FGFR/mTOR pathway in mediating the effects of C3 complex in the pathogenesis of skin cancer.
Citation Format: Alok R. Khandelwal, Rong Xiaohua, Tara Moore-Medlin, Oleksandr Ekshyyan, Abreo Fleurette, Xin Gu, Cherie-Ann O. Nathan. Photopreventive effect and mechanism of AZD4547 and curcumin C3 complex on UVB-induced epidermal hyperplasia. [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 5250.
Abstract 5252: Skin cancer prevention by traditional Chinese medicinal formula Si-Wu-Tang and its constituents
Authors: Huang Kevin , Liu Mandy , Zhang Suhui , Yeung Steven , Chang Andy , Qian Li , Chatterjee Payal , Li Rui , Zhou Su , Mei Nan , Wang Zhijun , Parsa Cyrus , Orlando Robert , Luo Yun , Huang Ying 
Published: July 2016

Abstract
Si-Wu-Tang (SWT), comprising the combination of four herbs, Rehmanniae, Angelica, Chuanxiong and Paeoniae, is one of the most popular Chinese medicines for women's diseases. Previously we showed that SWT was able to upregulate genes in the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, suggesting a potential application for cancer chemoprevention. The present study examined the chemopreventive activity of SWT using models of skin carcinogenesis. In JB6 P+ cells, a non-cancerous murine epidermal cell line for studying skin tumor promotion, SWT inhibited epidermal growth factor (EGF)-induced neoplastic transformation. In a 7,12-dimethylbenz(a)anthracene (DMBA)-induced murine skin tumorigenesis model, both topical and oral treatment of SWT inhibited epidermal hyperplasia, proliferating cell nuclear antigen expression, and H-ras mutations induced by DMBA treatment. In addition, SWT exhibited a significant antimutagenic activity against DMBA-induced mutagenicity, determined by the Ames Test using Salmonella typhimurium TA100 in the presence of metabolic activator S9 system. To identify active components in SWT, among nine compounds previously reported in commercial SWT products, in silico molecular docking analysis predicted some as potential Nrf2 activators due to an ability of interfering the forming of Nrf2-Keap1 complex. Three of these compounds, gallic acid, Z-liguistilide and senkyunolide A, were confirmed with highest potency of increasing the antioxidant response element luciferase reporter activity, inducing Nrf2-regulated genes Hmox1, Slc7A11 and Nqo1, and inhibiting EGF-induced JB6 P+ transformation. Further mechanistic studies showed that SWT and the three compounds suppressed EGF-induced activation of the activator protein 1 (AP-1), an essential transcription factor involved in skin carcinogenesis. The antimutagenic activity for the three compounds was also confirmed with the Ames Test. In conclusion, these results provide evidence that SWT and its constituents are able to prevent skin cancer, at least partly, by activating the Nrf2 pathway and blocking the activation of AP-1. Thus, this widely used Chinese medicinal formula may provide a promising option toward preventing skin cancer or may be other types of cancer.
Citation Format: Kevin Huang, Mandy Liu, Suhui Zhang, Steven Yeung, Andy Chang, Li Qian, Payal Chatterjee, Rui Li, Su Zhou, Nan Mei, Zhijun Wang, Cyrus Parsa, Robert Orlando, Yun Luo, Ying Huang. Skin cancer prevention by traditional Chinese medicinal formula Si-Wu-Tang and its constituents. [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 5252.
Abstract 5257: Upregulation of glutathione S-transferase P1 by green tea polyphenols: A novel transcriptional target of p53 tumor suppressor gene
Authors: Thakur Vijay S. , Deb Gauri , Jackson Mark W. , Gupta Sanjay 
Published: July 2016

Abstract
Green tea polyphenols (GTPs) and its major constituent (-)-epigallocatechin-3-gallate (EGCG) reactivate epigenetically silenced genes in cancer cells. Glutathione S-transferase P1 (GSTP1), an enzyme involved in detoxification process, is frequently inactivated in prostate cancer due to epigenetic modifications. The mechanisms underlying the re-expression of GSTP1 expression by GTP/EGCG in prostate cancer is currently not well understood. Earlier we demonstrated the ability of GTP/EGCG to increase p53 transcriptional activity through suppression of class I histone deacetylases (Carcinogenesis 33(2):377-84, 2012). Here we report that the GSTP1 gene is an unrecognized downstream transcriptional target of the tumor suppressor p53, and that GTP/EGCG has ability to increase GSTP1 expression mediated through p53. Treatment of human prostate cancer LNCaP cells with 5μg/ml GTP and 20μM EGCG, activate p53 through acetylation at the Lys373 and Lys382 residues along with consequent increase in GSTP1 protein expression in time-dependent manner. To study the possible interaction between GSTP1 and p53, LNCaP cells stably-transfected with short hairpin-RNA against p53 (LNCaPshp53) and control vector (LNCaPshV) for generation of p53 knockout cells. GTP/EGCG treatment induced p53 activation and acetylation at p53 Lys373 and Lys382 specifically in LNCaPshV cells in time-dependent manner, but not in LNCaPshp53. This increase in p53 acetylation led to activation of GSTP1 in LNCaPshV cells both at protein and message levels. GTP/EGCG-mediated increase in GSTP1 expression is caused by increase binding of p53 to its consensus binding site on the intron 4 of GSTP1 gene as analyzed by electrophoretic mobility shift binding assay. Furthermore, this association was validated by ChIP assay where GTP/EGCG treatment led to an increase in the amount of acetylated p53-Lys373 associated within the intron site of GSTP1, compared to untreated controls. Taken together, our findings indicate the ability of p53 to transcriptionally activate the human GSTP1 gene, which defines a novel mechanism of protection of the genome by green tea polyphenols.
Citation Format: Vijay S. Thakur, Gauri Deb, Mark W. Jackson, Sanjay Gupta. Upregulation of glutathione S-transferase P1 by green tea polyphenols: A novel transcriptional target of p53 tumor suppressor gene. [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 5257.
Abstract 5265: Cloud-based somatic analysis platform for populations with paired tumor normal samples
Authors: Lou Melanie , Beale Holly 
Published: July 2016

Abstract
Maverix Biomics introduces its cloud-based somatic analysis platform, a scientifically sound, end-to-end analysis solution that begins with quality control of fastq reads and leads to somatic variant calling, annotation and interactive analysis and has been validated using paired tumor normal cancer samples from the COSMIC cell line project (CLP). In addition to providing the ability to call somatic variants for cancer populations and features to explore characteristics within each of these populations, another strength of the Maverix Analytic Platform is the ability to compare multiple cancer populations - a limitation in other existing platforms. To support this functionality, our cloud-based platform has been optimized using the biological expectations of COSMIC CLP data and outfitted with interactive features within Maverix's Variant Explorer. Specifically, we maximized the sensitivity and minimized the percentage of unvalidated variants of two COSMIC cancer cell lines - small cell lung carcinoma and renal cell carcinoma. Then interactive analysis of this data using Maverix's Variant Explorer has identified somatic variants and affected genes specific to each cancer population and shared among both cancer populations. Our platform expedites data exploration and the ability to identify similarities and differences among cancer populations which is useful for tumor reclassification and for repurposing targeted therapies based on discovering similar genetic profiles across different types of cancer.
Citation Format: Melanie Lou, Holly Beale. Cloud-based somatic analysis platform for populations with paired tumor normal samples. [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 5265.
Abstract 527: Myeloid PTEN deficiency impairs tumor immune surveillance via immune checkpoint inhibition
Authors: Kuttke Mario , Sahin Emine , Pisoni Julia , Percig Sophie , Vogel Andrea , Kraemmer Daniel , Hanzl Leslie , Brunner Julia Stefanie , Paar Hannah , Soukup Klara , Halfmann Angela , Dohnal Alexander , Steiner Carl-Walter , Blüml Stephan , Basilio Jose , Hochreiter Bernhard , Salzmann Manuel , Hoesel Bastian , Lametschwandtner Günther , Eferl Robert , Schmid Johannes , Schabbauer Gernot 
Published: July 2016

Abstract
In the current study we are investigating the effects of PTEN-deficient myeloid cells on tumor immune surveillance. We could previously show that hyper-activation of the PI3K signaling cascade by genetic knock-out of the counteracting phosphatase PTEN induced an anti-inflammatory phenotype in myeloid cells. This resulted in protection of conditional knock-out mice in models of acute infection and inflammation.
A reduction in pro-inflammatory responses could however increase tumor burden. To address this question we induced colitis associated colon cancer in conditional PTEN-KO mice and found an increase in tumor burden and a reduction in survival in male KO mice. This was accompanied by increased numbers of splenic antigen-presenting cells (APC) expressing the immune checkpoint regulators PD-L1 and PD-L2. Furthermore, transcriptome analysis in these cells revealed a shift towards gene expression profiles found in professional APCs capable of cross-presentation. As expected, ex-vivo stimulated T-cells from KO-mice showed a reduction in proliferative capacity. These findings were further substantiated by findings in a second tumor model using implanted B16 melanoma cells. In this model myeloid PTEN-deficient mice showed a decrease in T-cell activation and a reduction in melanoma cell killing capacity.
Taken together, our findings show that genetic deletion of PTEN in cells of myeloid origin increases splenic APCs expressing immune checkpoint regulators resulting in a decrease in tumor immune surveillance. Our study shows that PI3K-inhibitors which are currently tested as anti-cancer drugs might have additional beneficial effects on immune cells by shifting their inflammatory phenotype.
Citation Format: Mario Kuttke, Emine Sahin, Julia Pisoni, Sophie Percig, Andrea Vogel, Daniel Kraemmer, Leslie Hanzl, Julia Stefanie Brunner, Hannah Paar, Klara Soukup, Angela Halfmann, Alexander Dohnal, Carl-Walter Steiner, Stephan Blüml, Jose Basilio, Bernhard Hochreiter, Manuel Salzmann, Bastian Hoesel, Günther Lametschwandtner, Robert Eferl, Johannes Schmid, Gernot Schabbauer. Myeloid PTEN deficiency impairs tumor immune surveillance via immune checkpoint inhibition. [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 527.