bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4751: Correlating the genomic and transcriptomic profiles of pre-treatment cervical tumor biopsies with patient recurrence after definitive chemoradiation
Authors: Ruiz Fiona J. , Schwarz Julie K. 
Published: July 2017

Abstract
Purpose: The purpose of this study was to identify genomic mutations that correlate with patient recurrence after curative intent chemoradiation therapy in advanced stage cervical cancer patients.
Methods: Pre-treatment cervical tumor biopsies and normal blood were prospectively collected from patients treated at Washington University in St. Louis. DNA and RNA was isolated from the fresh frozen tumor biopsies and sent for next-generation sequencing and RNAseq respectively. Targeted exome sequencing was done using a panel of 127 known cancer associated genes, and an additional 8 genes previously reported to be mutated in cervical cancer. Gene tiling was done to probe for 30 different HPV subtypes.
Results: The mutational signatures of single nucleotide polymorphisms were an APOBEC cytidine deaminase and CpG site cytidine deamination mutagenesis pattern. The non-silent somatic mutations were analyzed by online prediction algorithms to assess the mutation’s putative effect on protein function. Univariate COX regression was used to correlate patient recurrence with non-silent putatively functional mutations. In our patient cohort 88% of samples were HPV positive, with 74% being the high-risk HPV 16 and 18 subtypes. Patient’s with HPV positive tumors had increased progression-free survival when compared to the HPV negative patient tumors; and the HPV positive patients with HPV 16 had increased progression-free survival over the other HPV subtypes. Complete gene tiling of the HPV 16 and 18 subtypes allowed us to determine whether the HPV DNA was integrated in the host genome or retained episomally. In our patient cohort less than 30% of samples had integrated HPV DNA, and there was no significant difference in progression-free survival between patients with integrated or episomal HPV.
Conclusions: The genomic analysis of our advanced staged cervical cancer patient cohort found that epigenetic modifiers were frequently mutated and that cytidine deamination mutagenesis was primarily responsible for the generation of the SNP mutations. Our study identified NSD1 mutations as being correlated with tumor recurrence, indicating that histone modifications and chromatin structure may play an important role in tumor response to ionizing radiation therapy. Gene expression analysis is currently ongoing.
Citation Format: Fiona J. Ruiz, Julie K. Schwarz. Correlating the genomic and transcriptomic profiles of pre-treatment cervical tumor biopsies with patient recurrence after definitive chemoradiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4751. doi:10.1158/1538-7445.AM2017-4751
Abstract 476: MicroRNA mediated regulation of ATF5 contributes to homeostasis and benign to malignant transformation in breast cancer cells
Authors: Gaither Kari Ann , Madarampalli Bhanupriya , Liu David X. 
Published: July 2017

Abstract
The transcription factor ATF5 modulates survival, proliferation, differentiation, and homeostasis. In unstressed conditions, ATF5 has a short half-life and is rapidly degraded due to post-translational modifications. Conversely, ATF5 is upregulated in cells under cellular stress. Furthermore, we have found that ATF5 is elevated and is a survival factor in transformed C6 glioma and MCF7 breast cancer compared to non-transformed cells. Regulation of ATF5 expression is not fully understood. We hypothesized that microRNA (miRNA) play a role in regulating the expression of ATF5 at the 3’ UTR and sought to better understand the role of ATF5 in the transformation to a malignant cell phenotype. To date, no studies have examined the regulation of ATF5 by miRNA. MiRNAs are endogenous small non-coding RNAs 20-25 nucleotides in length that contribute to regulation of gene expression at the translational level. We used in silico modeling programs to identify miRNAs predicted to bind to the 3’ UTR of ATF5. We then aimed to identify the presence of specific miRNA and their ability to downregulate ATF5 during cellular stress and other physiological conditions in vitro. Luciferase reporter assays and immunoprecipitations of ATF5 3’ UTR mRNA and cell lysate were performed and microRNA quantity analyzed via qPCR analysis. Subsequently, transfections of precursor microRNA were carried out in human MCF10A breast epithelial, MCF7 mammary epithelial, and breast adenocarcinoma MDA-MB-231 cell lines, and expression levels of ATF5 were measured under varying physiological conditions via Western Blot analysis. In vitro migration and invasion assays were performed and transformation was studied via MCF10A mammary epithelial cells with inducible SRC. We demonstrate that miRNA are bound to the 3’ UTR of ATF5 and that miRNAs 433-3p and 520b help to regulate the expression of ATF5 under varying stress conditions and at steady state in MCF10A, MCF7, and MDA-MB-231 cells. Additionally, preliminary data indicate that ATF5 is upregulated during transformation of MCF10A cells with inducible SRC and is overexpressed in MDA-MB-231 cells as compared to MCF7 and MCF10A cell lines, and suggest that ATF5 may enhance migration and invasion. Further studies are necessary to elucidate the role of ATF5 in transformation, migration, and invasion. Better understanding of the regulation of ATF5 could have implications in a broad range of human malignancies.
Citation Format: Kari Ann Gaither, Bhanupriya Madarampalli, David X. Liu. MicroRNA mediated regulation of ATF5 contributes to homeostasis and benign to malignant transformation in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 476. doi:10.1158/1538-7445.AM2017-476
Abstract 4761: BCL2 induced by LAMTOR3-MAPK is a druggable target of chemoradioresistance in mesenchymal lung cancer
Authors: Kwon Ok-Seon , Hong Soon-Ki , Cha Hyuk-Jin 
Published: July 2017

Abstract
Metastasis and chemoresistance, which are main causes of lung cancer related death, have been major interest in cancer research. Recently, Epithelial-Mesenchymal Transition (EMT) a foremost process for acquiring metastatic properties has been demonstrated to be strongly link to chemoresistance. Due to limited understanding of mechanism for EMT mediated chemoresistance, druggable targets for chemoresistance remained unidentified yet. In this study, we established the mesenchymal like cancer cells (MLCCs) from A549 lung cancer cells with chronic exposure of TGFβ. With clinicogenomics database analysis and following validation with MLCC model, we determined that BCL2, of which expression was clearly induced and indicated a poor prognosis in the mesenchymal cancer patients, was responsible for high chemoresistance in MLCCs. Therefore combined treatment of chemotherapeutic drug and BH3 mimetic such as ABT-263 or ABT-737, remarkably sensitized MLCCs to chemo and radio therapy. Furthermore, BCL2 expression was governed by sustained ERK1 activity in MLCCs, which resulted from high level of MEK partner-1 (MP1) protein expression. Therefore, combined chemotherapy with small molecules (approved by FDA or clinically tested) targeting for MEK1 or BCL2 would be a clinically feasible approach to overcome EMT related chemoresistance.
Citation Format: Ok-Seon Kwon, Soon-Ki Hong, Hyuk-Jin Cha. BCL2 induced by LAMTOR3-MAPK is a druggable target of chemoradioresistance in mesenchymal lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4761. doi:10.1158/1538-7445.AM2017-4761
Abstract 4762: New device for radiation delivery in breast cancer patients - double balloon applicator for optimal dose distribution
Authors: Subramanian Manny R. , Cutrer Mike , Mehta Rohit 
Published: July 2017

Abstract
Currently available applicators for delivery of accelerated partial breast irradiation using a high dose afterloader, have treatment catheters close to the center of the balloon in fixed positions, restricting one’s ability to modify the dose to critical organs. Recently we developed a novel, dual balloon brachytherapy applicator using which one could optimize radiation dose by shaping the resection cavity with an outer balloon and allowing an inner balloon to selectively position the treatment catheters away from the central axis of the balloon based on cavity size.
The Double Balloon Breast Brachytherapy applicator offers a unique design with adjustable treatment catheters, allowing for both optimized dose delivery and conformal avoidance of critical structures. This applicator is a single entry (1 cm incision), multi-channel high dose rate afterloader (HDR) accessory device. The treatment catheters can be expanded to an optimal location greater than or equal to 50% of the outer balloon diameter(&gt; 1 cm diameter) - thereby optimizing dose delivery to the patient. The Conformal Double Balloon Breast Brachytherapy Device has the ability to optimize either conformality or homogeneity by allowing expansion of an inner polyurethane balloon to selectively position multiple treatment catheters significantly away from the central axis of an expanded outer polyurethane balloon.
A model study of the Double Balloon Breast Brachytherapy Device was performed with a wide range of volumes of the lumpectomy cavity. Each case is scanned in a CT scanner and the data transported to a treatment planning system. Dosimetric parameters such as dose delivered to treatment site, different organs such as skin, ribs, etc are evaluated and compared against existing breast brachytherapy applicator devices.
Both ultrasound and CT images clearly indicate that the quality of the Double Balloon Device images are comparable to other commercial devices. All catheters are distinguishable and can be reconstructed for treatment planning, and the balloon volume can be clearly delineated. Planning Treatment Volume (PTV) based on balloon volume can be easily generated and optimized dosimetry performed. Initial patient studies also indicate that using the double balloon applicator optimized dosimetry can be obtained thereby reducing the dose to critical structures such as skin and rib while maintaining the dose to the target.
Citation Format: Manny R. Subramanian, Mike Cutrer, Rohit Mehta. New device for radiation delivery in breast cancer patients - double balloon applicator for optimal dose distribution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4762. doi:10.1158/1538-7445.AM2017-4762
Abstract 4763: Metronomic chemotherapy prevents therapy-induced stromal activation and induction of cancer stem cells
Authors: Tsai Kelvin K. , Chan Tze-Sian , Hsu Chung-Chi , Pai Vincent C. , Huang Shenq-Shyang , Weaver Valerie M. 
Published: July 2017

Abstract
Whilst traditional chemotherapy kills a fraction of tumor cells, it also activates the stroma and can promote the growth and survival of residual cancer cells to foster tumor recurrence and metastasis. Accordingly, overcoming the host response induced by chemotherapy could substantially improve therapeutic outcome and patient survival. Treatment resistance and metastasis have been attributed to expansion of cancer stem-like cells (CSCs). Molecular analysis of the tumor stroma in neoadjuvant chemotherapy-treated human desmoplastic cancers and orthotopic tumor xenografts revealed that traditional maximal tolerated dose chemotherapy, regardless of the agents used, induces persistent STAT-1 and NF-κB activity in carcinoma-associated fibroblasts that induces the expression and secretion of ELR-motif-positive (ELR+) chemokines, which signal through CXCR-2 on carcinoma cells to trigger their phenotypic conversion into CSCs and promote their invasive behaviors, leading to paradoxical tumor aggression following the therapy. By contrast, the same total accumulated dose administered as a low-dose-metronomic chemotherapy regimen largely prevented the therapy-induced stromal ELR+-chemokine paracrine signaling for CSCs, thereby substantially enhancing treatment response and extending survival of mice carrying desmoplastic cancers (Chan et al, J. Exp. Med. 2016). These studies illustrate the importance of stroma in cancer therapy and how its impact on treatment resistance could be tempered by altering the dosing schedule of systemic chemotherapy.
Note: This abstract was not presented at the meeting.
Citation Format: Kelvin K. Tsai, Tze-Sian Chan, Chung-Chi Hsu, Vincent C. Pai, Shenq-Shyang Huang, Valerie M. Weaver. Metronomic chemotherapy prevents therapy-induced stromal activation and induction of cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4763. doi:10.1158/1538-7445.AM2017-4763
Abstract 4766: Translation from unconventional 5' start sites drives tumor initiation
Authors: Sendoel Ataman , Dunn Joshua G. , Rodriguez Edwin H. , Naik Shruti , Gomez Nicholas C. , Hurwitz Brian , Levorse John , Dill Brian D. , Schramek Daniel , Molina Henrik , Weissman Jonathan S. , Fuchs Elaine 
Published: July 2017

Abstract
How translational control impacts tumor-initiation and malignancy is just beginning to unfold. Here, we devise an epidermis-specific, in vivo ribosome profiling strategy to interrogate the translational landscape during the transition from normal homeostasis to malignancy. Inducing SOX2, broadly expressed in oncogenic RAS-associated cancers, we find that despite widespread reductions in translation and protein synthesis, certain oncogenic mRNAs are spared. Seeking mechanism, we find that during tumor-initiation, the translational apparatus is redirected towards unconventional upstream initiation sites, enhancing translational efficiency of oncogenic mRNAs. An in vivo RNAi screen of translational regulators revealed that dampening conventional EIF2 complexes has dire consequences for normal but not oncogenic growth. Conversely, we identify alternative initiation factors essential for cancer progression, where they mediate initiation at these upstream sites, differentially skewing translation and protein expression. Our findings unveil a hitherto unappreciated role of 5’UTR translation in cancer, and expose new targets for therapeutic intervention.
Citation Format: Ataman Sendoel, Joshua G. Dunn, Edwin H. Rodriguez, Shruti Naik, Nicholas C. Gomez, Brian Hurwitz, John Levorse, Brian D. Dill, Daniel Schramek, Henrik Molina, Jonathan S. Weissman, Elaine Fuchs. Translation from unconventional 5' start sites drives tumor initiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4766. doi:10.1158/1538-7445.AM2017-4766
Abstract 4775: PTHrP regulate CSC and promote EMT in the PyMT model of breast cancer progression
Authors: Zhang Rui , Li Jiarong , Karaplis Andrew C. , Kremer Richard 
Published: July 2017

Abstract
PTH-related peptide (PTHrP) was first discovered in cancer patients as the primary cause of humoral hypercalcemia of malignancy (HHM). We previously showed that PTHrP ablation in the MMTV-PyMT murine model of breast cancer progression can dramatically prolongs tumor latency, slows tumor growth & metastases suggesting that PTHrP may regulate cancer stem cells (CSCs). CSCs & epithelial-mesenchymal transition (EMT) have been recognized as driving forces in tumor initiation & progression, & have been characterized previously using ALDH & CD49/EpCAM markers. Here, we aim to determine the role of PTHrP in CSCs & EMT regulation. For this purpose, we analyzed tumor cells derived from Pthrpflox/flox;Cre- (Control) & Pthrpflox/flox;Cre+ (KO) tumors. Cells were incubated with ALDH reagent followed by CD49f/EpCAM antibody labelling & subjected to FACS analysis. Using CD49f/EpCAM labelling, cells separated into two distinct populations, luminal progenitor cells (CD49f+EpCAM+) & EMT cells (CD49f+EpCAM-). In control tumors, ~85% of cells were characterized as luminal progenitor and ~15% as EMT. In contrast, in KO tumors, ~97% of cells were characterized as luminal progenitor whereas only ~2% were EMT. Using ALDH staining alone, ~8% & ~10% of the cells from the control & KO tumor were ALDH+, respectively. Furthermore, the majority of the ALDH+ cells were predominately contained within the luminal progenitor population in both the control & KO tumors cells. Next, we confirmed the dividing capacity of the two cell populations using a lipophilic fluorescent dye, PKH26. As expected, luminal progenitor cells exhibited a fast-dividing phenotype, whereas EMT cells displayed a slow dividing phenotype. However, using mammosphere assay, we did not see any significant difference in mammosphere forming efficiency between control & KO tumor. In summary, PTHrP ablation significantly diminishes the EMT population in KO compared to the control tumor. In conclusion, PTHrP may shift the tumor cell phenotype towards EMT, which suggests a mechanism underlying PTHrP - driven metastases.
Citation Format: Rui Zhang, Jiarong Li, Andrew C. Karaplis, Richard Kremer. PTHrP regulate CSC and promote EMT in the PyMT model of breast cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4775. doi:10.1158/1538-7445.AM2017-4775
Abstract 478: Regulation of cross talk between AR and wnt/beta-catenin pathways in prostate cancer
Authors: Plaga Alexis , Shukla Girish C. 
Published: July 2017

Abstract
Prostate Cancer (PCa) is the second most commonly diagnosed cancer in the United States with 180,890 males diagnosed and is predicted to cause approximately 26,000 deaths in 2016. The current treatment of androgen deprivation therapy (ADT) initially depletes circulating androgens; however, intratumoral androgens rescue androgen receptor (AR) signaling and promotes the development of castration resistant prostate cancer (CRPC). The dysregulation of the Wnt/β-catenin signaling pathway has been implicated in the development of many cancers including PCa. The disruption of this signaling leads to the stabilization of β-catenin which upregulates many genes involved in tumorigenesis. Additionally, β-catenin acts as AR cofactor. Our previous studies show that AR is a direct target of miR-644a. We hypothesized that targeting the expression of both the β-catenin pathway and AR by conventional drugs and/or tumor suppressor miR-644a would have synergistic therapeutic benefits. In this
study, we are investigating miR-644a mediated posttranscriptional downregulation of GSK3-β and β-catenin in the wnt/β-catenin signaling pathway. The effect of miR-644a in combination with inhibitors (β-catenin or GSK3-β) was also assessed using proliferation assays and a significant downregulation was observed. We will further study the posttranscriptional effects of tumor suppressor miR-644a on the wnt/β-catenin pathway and also the processing and regulation of miR-644a in PCa.
Citation Format: Alexis Plaga, Girish C. Shukla. Regulation of cross talk between AR and wnt/beta-catenin pathways in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 478. doi:10.1158/1538-7445.AM2017-478
Abstract 479: Modeling miRNA induced silencing in breast cancer with PARADIGM
Authors: Sedgewick Andrew J. , Benos Panayiotis V. , Rabizadeh Shahrooz , Soon-Shiong Patrick , Vaske Charles J. 
Published: July 2017

Abstract
Introduction: MicroRNAs play an important role in regulation of gene expression and are known biomarkers for breast cancer as well as other malignancies. PARADIGM is a pathway based algorithm that allows for integration of multiple genomic data types with a curated pathway database to make pathway activity predictions. We added a model of gene silencing due to miRNA to the PARADIGM algorithm in order to study miRNA expression in a pathway context.
Results: We curated a set of 7751 miRNA-mRNA interactions from the intersection of 3 target prediction algorithms. These interactions involved 66 miRNA and 2814 mRNA transcripts. We ran this model on global DNA copy number, RNAseq and miRNAseq data from 697 patients in the TCGA breast cancer cohort, and studied changes in the interactions between miRNAs and their targets between different tumor subtypes. The median activity of the RNA-induced silencing complex (RISC) predicted by our model is significantly higher in Basal tumors than other subtypes. In addition, RISC activity is significantly associated with overall survival of patients with Luminal A tumors. The miRNA-target pairs with the largest correlation changes between Basal and Luminal A subtypes were enriched for putative oncogenes and oncomirs. The mRNA targets are involved in a number of important signaling pathways including PI3K-AKT, JAK-STAT, and Ras. Many of these highly differential links involved the miR-16 family of miRNAs which are known tumor suppressors. miR-16 shows significantly lower activity in basal tumors than other subtypes.
Conclusions: By looking at changes in miRNA-target links between tumor subtypes, our algorithm was able to identify both miRNAs and target genes involved in pathways relevant to breast cancer. Our predictions of overall RNA-induced silencing activity show prognostic value in both determining subtype and predicting overall survival within subtypes.
Citation Format: Andrew J. Sedgewick, Panayiotis V. Benos, Shahrooz Rabizadeh, Patrick Soon-Shiong, Charles J. Vaske. Modeling miRNA induced silencing in breast cancer with PARADIGM [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 479. doi:10.1158/1538-7445.AM2017-479