bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-314: The good drug, the bad barrier and the handy peptide: Improved treatment of experimental melanoma brain metastases using a synthetic peptide
Authors: Aasen Synnøve Nymark , Espedal Heidi , Holte Christopher Florian , Keunen Olivier , Karlsen Tine Veronica , Tenstad Olav , Baghirov Habib , Olberg Dag Erlend , Bjerkvig Rolf , Sarkar Gobinda , Thorsen Frits 
Published: August 2018

Abstract
Patients with brain metastases usually have a poor prognosis. Regardless of the constant progress in novel drug establishments, a crucial obstacle is the delivery of drugs across the blood brain barrier (BBB) and into the metastatic neoplasms. Different study designs to achieve temporary BBB opening have previously been studied. Here, we describe a synthetic peptide termed K16ApoE, which is able to transiently open the BBB for drug-delivery into experimental brain metastases.We conducted a systemic study of the ability of the peptide to open the BBB by dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) in nonobese diabetic/severe combined (nod/scid) mice. Further, we studied the mechanisms of the peptide using flow cytometry, electron microscopy and dynamic positron emission tomography (PET). The biodistribution of the peptide was studied in blood plasma and organs using I-125 labeled K16ApoE. Finally, a treatment study using the peptide in combination with the B-RAF inhibitor dabrafenib was conducted.An opening of the BBB for up to 60 mins was clearly demonstrated by DCE-MRI. Microscopy showed that the peptide disrupted brain endothelial cell monolayers by reducing the barrier properties of the cells. The treatment study demonstrated that the group of animals receiving K16ApoE followed by dabrafenib had smaller tumor volumes than the other two animal groups.In conclusion, the synthetic K16ApoE peptide in combination with dabrafenib decreased the number of experimental brain metastases. Thus, the current strategy could have the potential to improve the treatment of patients with brain metastatic disease. &lt;!–EndFragment–&gt;
Citation Format: Synnøve Nymark Aasen, Heidi Espedal, Christopher Florian Holte, Olivier Keunen, Tine Veronica Karlsen, Olav Tenstad, Habib Baghirov, Dag Erlend Olberg, Rolf Bjerkvig, Gobinda Sarkar, Frits Thorsen. The good drug, the bad barrier and the handy peptide: Improved treatment of experimental melanoma brain metastases using a synthetic peptide [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-314.
Abstract LB-324: A whole chromosome aberration phenotype in non-WNT/non-SHH tumors predicts outcome within standard-risk medulloblastomas from the HIT-SIOP-PNET4 clinical trial
Authors: Goschzik Tobias , Schwalbe Ed C. , Hicks Debbie , Figarella-Branger Dominique , Doz Francois , Rutkowski Stefan , Gustafsson Goran , Lannering Birgitta , Pietsch Torsten , Clifford Steve C. 
Published: August 2018

Abstract
Introduction: Standard-risk medulloblastoma (SR-MB; 50-60% of patients) is currently defined by the absence of high-risk (e.g. metastatic disease, large-cell/anaplastic histology, MYC amplification) disease features. 75-85% survival rates are achieved, however the identification and validation of novel prognostic biomarkers will be essential to improve risk-adapted therapies, aimed at increased survival and reduced treatment-related late-effects.
Experimental procedures: We undertook comprehensive analysis of the pan-European HIT-SIOP-PNET4 prospective clinical trial (2001-2006; age 4-21 years at diagnosis), encompassing central clinical and radiological review, and annotation of molecular pathological features to the WHO (2016) classification. Methods were developed and/or adapted to assess methylation-dependent molecular subgroup (MassArray), copy number aberrations (molecular inversion probe array) and mutational status in scant archival material previously refractory to analysis (n=136). Independent prognostic markers/predictive models for non-WNT/non-SHH patients (n=91) were identified by multivariate analyses, and validated in a representative independent cohort (n=70).
Results: WNT (n=28; 21%) and Group 4 (n=76; 56%) tumors were enriched in SR-MB compared to published disease-wide estimates. Favorable-risk WNT disease was confirmed in patients &lt;16.0 years at diagnosis. All events in SHH (4 of 17) occurred in tumors with TP53 mutation and/or chr17p loss. In non-WNT/non-SHH tumors, a novel whole chromosomal aberration (WCA) phenotype characterized by chr7 gain, chr8 loss, and/or chr11 loss, was identified in 42% of patients (38 of 91). This phenotype predicted an excellent prognosis (100% 5-year PFS) and its incorporation into novel survival models out-performed current risk-stratification schemes for SR-MB.
Conclusion: A favorable-risk WCA phenotype identifies a large proportion (42%) of non-WNT/non-SHH SR-MB patients for whom therapy de-escalation should be considered in future biomarker-driven risk-adapted clinical trials; remaining patients (58%; 68% 5-year PFS) might benefit from more intensive and/or novel therapies.
Citation Format: Tobias Goschzik, Ed C. Schwalbe, Debbie Hicks, Dominique Figarella-Branger, Francois Doz, Stefan Rutkowski, Goran Gustafsson, Birgitta Lannering, Torsten Pietsch, Steve C. Clifford. A whole chromosome aberration phenotype in non-WNT/non-SHH tumors predicts outcome within standard-risk medulloblastomas from the HIT-SIOP-PNET4 clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-324.
Abstract LB-357: Transcriptional landscape of stroma progression in the breast tumor microenvironment
Authors: Utama Raditya , Bastian Anja , Sadagopan Narayanan , Jin Ying , Antoniou Eric , Huang Yin , Lee Peter , Atwal Gurinder 
Published: August 2018

Abstract
The breast tumor microenvironment of primary and metastatic sites is a complex milieu of differing cell populations. However, the genomic expression landscape of the tumor stroma and its role in mediating cancer progression and informing effective therapies is not well understood. Here we obtained and cultured 52 cell-sorted stromal tissue samples across 37 patients from normal, primary tumor, and metastatic tumor sites. Deep RNA-seq was performed on poly(A)+ transcripts using a multiplexed barcoding sequencing strategy to increase yield and obviate batch effects. A conservative linear model of expression covariates revealed significant (q&lt;0.05) differential expression of protein-coding genes and lncRNAs in the stroma (80 transcripts in normal versus primary and 108 transcripts in primary versus metastatic). The majority of these genes were found to be associated with pattern formation, embryogenesis, and the epithelial-mesenchymal transition. Among the genes that were silenced in the epithelial cells, IHC staining was initially done for C2orf88, ALOX5AP, and UNC5C which are important in PKA binding, immune response, apoptosis, and neural development. Furthermore, survival analyses of 827 luminal breast tumor samples from TCGA demonstrated the predictive power of the stromal gene expression in informing clinical outcome. Together these results highlight the evolution of stromal gene expression in breast tumors and suggest novel therapeutic strategies targeting the microenvironment.
Citation Format: Raditya Utama, Anja Bastian, Narayanan Sadagopan, Ying Jin, Eric Antoniou, Yin Huang, Peter Lee, Gurinder Atwal. Transcriptional landscape of stroma progression in the breast tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-357.
Abstract LB-386: MicroRNA-164a activates the Wnt pathway to promote breast cancer metastasis
Authors: Kantono Melvin , Sun Wei , Guo Beichu 
Published: August 2018

Abstract
Breast cancer is the most common type of malignant tumor among women, and is the second leading cause of cancer-related death in women. The triple negative breast cancer (TNBC) remains is one of the major contributors of breast cancer mortality. TNBCs are a type of aggressive breast cancer that exhibits a high rate of distant metastasis and poor survival compared with other breast cancer subtypes. Although immunotherapy with PD-1 and PD-L1 blockade have achieved durable responses in a number of tumors, including TNBC. However, the overall response rates were low. Thus, elucidating the mechanisms responsible for tumor metastasis and the interaction of tumor cells with their microenvironments is critical for developing effective therapeutic approaches to treat metastatic breast cancer. Our results suggest that miR-146 can induce oncogenic transformation and tumor metastasis in the context of breast cancer. We found that miR-146a is highly expressed in TNBC cells, and is critical for the expansion of tumor-initiating cells in breast cancer growth and metastasis. Our preliminary data further indicate that miR-146a promotes breast tumorigenesis by targeting negative regulators of Wnt pathway, which is frequently altered in various tumors. The goal of this study to develop novel therapeutic approaches that could ultimately lead to effective treatment for breast cancer, particularly TNBC.
Citation Format: Melvin Kantono, Wei Sun, Beichu Guo. MicroRNA-164a activates the Wnt pathway to promote breast cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-386.
Abstract SY32-01: Knowledge management and decision support for commonly tested susceptibility mutations
Authors: Parmigiani Giovanni , Braun Danielle , Hughes Kevin S. 
Published: August 2018

Abstract
Challenges: Germline testing for inherited genetic susceptibility to cancer has become cheaper and widely used. Multigene panels now routinely test 25 to 123 genes. Health care providers, including clinicians and genetic counselors, must interpret results, assess the risk of various cancers, and advise on clinical management strategies. Aside from a small number of well-known genes, clinicians lack simple and reliable tools to personalize prevention decisions for individuals who test positive. Evidence on the types of cancer associated with susceptibility genes, and on the magnitude of increased risks associated with a mutation, is emerging at a fast rate. However, a large number of combinations of cancer type and gene variant needs to be considered. No comprehensive databases exist, information is dispersed over a vast number of published studies, the quality of the studies is uneven, and the data presented are seldom directly applicable to precision prevention decisions, which require absolute risk estimates. Thus, when assessing cancer risks for mutation carriers, clinical practice can take little advantage of the impressive scientific advancements in this field.
Approaches: This presentation describes ongoing work to develop tools that could facilitate the translation into clinical practice of research results that would otherwise be difficult to access, systematize, interpret, and convert into actionable knowledge. The long-term goal should be to develop a clinical decision-support system that allows a clinician to enter important factors about a patient with a mutation and immediately receive patient-specific absolute risk estimates. The foundation for the clinical decision-support system needs to be laid by systematically collecting and curating studies on gene cancer associations and, ideally, developing a public access knowledge base for researchers and health care providers. These steps need computational tools for efficient implementations of this plan and for sustainable long-term updating of the knowledge base and decision-support system. The ask2me.org project and the data science behind it are attempting to achieve some of these steps. This project will be used as an illustration throughout.
Impact: Progress in this area will have a direct clinical impact by providing patient-specific absolute risk estimates. These risk estimates will, in turn, lead to more carefully personalized prevention and management for individuals undergoing susceptibility testing, and will help us optimize screening and behavioral interventions to reduce risk.
Citation Format: Giovanni Parmigiani, Danielle Braun, Kevin S. Hughes. Knowledge management and decision support for commonly tested susceptibility mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr SY32-01.
Abstract SY36-02: Heterogeneity in molecular subtype of hepatocellular carcinoma
Authors: Hoshida Yujin 
Published: August 2018

Abstract
Hepatocellular carcinoma (HCC) mortality keeps rising with emerging etiologies such as nonalcoholic fatty liver disease and hepatitis C after viral cure. Through the efforts of high-throughput and comprehensive molecular characterization of HCC tumors, it has been revealed that HCC tumors can be classified into several subtypes (e.g., aggressive or indolent subtype) according to their molecular characteristics and clinical phenotypes. Ongoing basic and clinical studies have suggested their potential implication in therapeutic decision making. Systematic and integrative characterization of heterogeneity in intra/intertumor molecular features as well as host genetic, environmental, and socioeconomic factors is expected to facilitate development of precision care strategies for HCC patients.
Citation Format: Yujin Hoshida. Heterogeneity in molecular subtype of hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr SY36-02.
Abstract A18: Predictive and prognostic significance of RECQ1 expression in breast cancer
Authors: Parvathaneni Swetha , Lu Xing , Li Xiao Ling , Chaudhary Ritu , Lal Ashish , Madhusudan Srinivasan , Sharma Sudha 
Published: August 2018

Abstract
RECQ1, also known as RECQL or RECQL1, is critical for DNA replication and repair. Germline mutations in the RECQ1 gene predispose to hereditary breast cancers. Overexpression of RECQ1 has been reported in a variety of human cancers including breast cancers. Our recent studies have identified a novel function of RECQ1 in regulation of gene expression and suggest that RECQ1 contributes to tumor development and progression, in part through regulating the expression of key genes that promote invasion and metastasis of cancer cells. Additionally, our data suggest that RECQ1 expression may serve as a predictive marker of clinical outcome. Preclinically RECQ1 depletion in breast cancer cells resulted in doxorubicin sensitivity, DNA double-strand breaks accumulation, S-phase cell cycle arrest, and apoptosis. Utilizing METABRIC cohort to investigate clinicopathologic significance of altered RECQ1 expression in sporadic breast cancers, we found that in ER-positive tumors that received endocrine therapy, low RECQ1 was associated with poor survival; in contrast, in ER-negative tumors that received adjuvant anthracycline-based chemotherapy, high RECQ1 was associated with poor disease-free survival. Taken together, our data provide the first preliminary evidence that RECQ1 is a promising prognostic and predictive biomarker in breast cancers.
Citation Format: Swetha Parvathaneni, Xing Lu, Xiao Ling Li, Ritu Chaudhary, Ashish Lal, Srinivasan Madhusudan, Sudha Sharma. Predictive and prognostic significance of RECQ1 expression in breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A18.
Abstract A54: A cellular and molecular atlas of the human breast for dissecting mechanisms of cell and tissue function
Authors: Sayaman Rosalyn W. , Carr Ambrose , Thi Kate , Wan Zhenmao , Pe’er Dana , Bissell Mina J. , Hines Curt 
Published: August 2018

Abstract
A fundamental question in biology, central to our understanding of cancer, is determining how cells coordinate and cooperate to form and maintain tissues. Developing systems-wide knowledge of the numerous cell interactions within a tissue requires robust identification of the cell types it comprises. It demands comprehensive information about each of these cell types, including the genes they express and proteins they make. Unfortunately, the cellular composition and arrangement of cells in many complex tissue systems has yet to be fully resolved, and this includes the breast. This has resulted in a crucial knowledge gap where we know very little about the elaborate biology of how different normal cell types interact, and the consequences these interactions have on each other and the tissue as a whole. Using immunofluorescence and advanced flow cytometry, we have recently developed methods to resolve and isolate every known cell type in the normal human breast. This includes several different luminal and epithelial fractions, myoepithelial cells, adipocytes, leukocytes, pericytes, erythrocytes, adipose-derived mesenchymal stem cells, vascular smooth muscle cells, and both lymphatic and vascular endothelial cells—12 different types in all. Successful modification of this multiparameter FACS procedure allowed purification of enough cells and RNA to perform next-generation sequencing (NGS) from even the rarest of populations at high depth. Here, we present global transcriptome analysis of these different cell types. These data have clarified cell-type differences and revealed new insights, including the identification of genes and gene families contributing to the unique phenotype of each cell type and the delineation of lineage-specific marker expression. Our analysis has also exposed how the cell types each contribute to their individual microenvironments through production of extracellular matrix proteins and other secreted factors. Moreover, identification of cognate ligand and receptor pairs expressed by these cells has unveiled an elaborate paracrine and autocrine signaling network that has implications towards interpreting the biologic interactome underlying tissue homeostasis. Future studies are aimed at establishing coculture models and determining the biochemical processes essential for cell-coordination and tissue maintenance, and developing knowledge of how these processes go awry in breast cancer.
Citation Format: Rosalyn W. Sayaman, Ambrose Carr, Kate Thi, Zhenmao Wan, Dana Pe’er, Mina J. Bissell, Curt Hines. A cellular and molecular atlas of the human breast for dissecting mechanisms of cell and tissue function [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A54.
Abstract A58: Application of evolutionary principles to control ER+ breast tumors
Authors: Garcia Libia , Gillies Robert J. , Gatenby Robert A. 
Published: August 2018

Abstract
Introduction: Estrogen receptor-positive (ER+) breast cancers are initially treated with estrogen deprivation, usually using estrogen receptor modulator drugs (SERM) that are administered at near maximal dose until progression. However, in many of ER+ tumors, preexisting resistant populations that do not express ER on immunohistochemistry are observed. Furthermore, a number of other resistance mechanisms to SERM drugs have been observed including overexpression of MDR1 cell-membrane systems, which consume energy to extrude the drug from the cell. While the vast majority of ER+ tumors respond to SERM drugs, resistant populations can rapidly emerge due to preexisting or acquired phenotypic strategies. Herein, we examine nonconventional treatment strategies, based on the Darwinian evolutionary dynamics that govern tumor evolution, designed to maintain tumor control while delaying evolution of resistance.
Materials and Methods: Different cohorts (20, 24, 4, and 41) of Nu/nu mice were injected in the mammary fat pad with 5*106 MCF7 cells. Prior to the cell injections, an estrogen pellet was subcutaneously implanted in mice. When tumors reached 300 mm3, mice were randomly distributed in treatment groups using different algorithm that combined tamoxifen, paclitaxel, and periods of no treatment. Tumor volumes were monitored by MRI, using T2-weighted images. At the end of the experimental time, tumors were collected and stained for IHC studies with H&E, CD31, SMA, MDR1, and ER.
Results: Treatments in which tamoxifen therapy was interrupted by none-drug periods permitted tumor control equal to that of high-dose standard treatment while maintaining a large population of ER+ cells. Algorithms in which tamoxifen and paclitaxel were combined achieved tumor control equal to standard therapy and decreased MDR1 expressions.
Conclusions: Treatment algorithms designed to exploit evolutionary principles to delay or prevent emergence of resistant populations maintained tumor control using lower cumulative drug doses than the standard-of-care therapy while maintaining populations of cells that are sensitive to the therapy.
Note: This abstract was not presented at the conference.
Citation Format: Pedro M. Enriquez-Navas, Libia Garcia, Robert J. Gillies, Robert A. Gatenby. Application of evolutionary principles to control ER+ breast tumors [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A58.