bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA27: Advances in oligonucleotide chemistry for the treatment of neurodegenerative disorders and brain tumors
Authors: Khvorova Anastasia 
Published: May 2016

Abstract
RNA interference has revolutionized human functional genomics and therapeutics, but its impact on the development of new therapies for cancer has been surprisingly limited, due mainly to the lack of simple and efficient methods to deliver oligonucleotides to tumors, especially those located in the brain.
Our research shows that many cell types, including tumor, glial and neuronal, rapidly internalize fully stabilized, hydrophobically modified siRNAs (hsiRNAs) added directly to the culture medium and that hsiRNAs induce potent and long-lasting silencing in vitro. A single injection of unformulated hsiRNA (cholesterol-conjugated) into mouse brain silences locally with great potency and longevity in primary tumor, glial and neuronal cells. Limited distribution from the site of administration interferes with addressing metastasis, thus limiting the clinical utility to treatment of primary tumors only.
Using fully chemically modified siRNA scaffolds, we systematically screened a wide range of bioactive conjugates and demonstrated that the chemical nature of the conjugation modality has a major impact on brain tissue retention, distribution and selectivity of cellular uptake. We have identified several novel chemical classes of conjugates that demonstrate markedly improved brain distribution and robust in vivo efficacy, with some showing selective tumor, glia or neuronal uptake. Direct conjugation of a fully chemically modified siRNA to docosahexaenoic acid (DHA), the most abundant poly-unsaturated fatty acid in the brain, results in improved tissue retention with wide distribution and robust efficacy in the striatum and cortex after a single injection. Most importantly, DHA-hsiRNA conjugates do not induce neural cell death or measurable innate immune activation following the administration of concentrations 20-fold over the efficacious dose. Interestingly, variants of DHA-based conjugates support preferential delivery to glia cells, establishing a new approach toward targeted development of RNAi-based therapeutics for glioblastomas and other glia-associated cancers.
Citation Format: Anastasia Khvorova. Advances in oligonucleotide chemistry for the treatment of neurodegenerative disorders and brain tumors. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr IA27.
Abstract A12: Microenvironmental Interleukin-6 induced activation of STAT3 signaling in medulloblastoma: Implications for molecular pathology and therapy
Authors: Yan Shuang , Chatterjee Sampurna , Vardam Trupti , Kitahara Shuji , Hato Tai , Roberge Sylvie , Askoxylakis Vasileios , Duquette Mark , Fukumura Dai , Xu Lei , Jain Rakesh 
Published: May 2016

Abstract
Aberrant activation of Janus kinase (JAK) / signal transducer and activator of transcription (STAT) 3 pathway has been implicated in tumor initiation, progression and metastasis which make it a potential therapeutic target in human malignancies. In vitro STAT3 inhibition exhibited anti-tumor effect in medulloblastoma (MB) cell lines; however, little has been reported about the mechanisms of STAT3 activation in medulloblastoma (MB). We found that STAT3 was constitutively activated in both medulloblastoma patient samples and 3 mice models that were clinically classified as SHH subgroup, Group 3 and Group 4 in pediatric MB patients. By using PCR arrays we investigated the early expression profile of local cytokines in host cerebellum during MB pathogenesis and found increased IL17B, IL6 and TNFα in the microenvironment of MB mice models. In vitro cytokine stimulation assay indicated that IL6 was the major activator of STAT3 in D283 MB cells. Confocal immunofluorescence staining of different cell components in the cerebellum in D283 xenografts showed that the endothelial cells and Purkinje cells were the two major sources of IL6 secretion. Our data provides molecular and cellular clue for the activation of STAT3 signaling during MB tumorigenesis and might help to develop more effective therapeutic targets for STAT3 blockade in MB.
Citation Format: Shuang Yan, Sampurna Chatterjee, Trupti Vardam, Shuji Kitahara, Tai Hato, Sylvie Roberge, Vasileios Askoxylakis, Mark Duquette, Dai Fukumura, Lei Xu, Rakesh Jain. Microenvironmental Interleukin-6 induced activation of STAT3 signaling in medulloblastoma: Implications for molecular pathology and therapy. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr A12.
Abstract A32: Urine as a potential liquid biopsy for detecting tumor DNA in Wilms tumor patient: Detection of somatic mutations in urine opens perspectives of monitoring chemotherapy response in WT patients
Authors: Miguez Ana C. K. , Ramalho Rodrigo F. , Ferreira Elisa N. , Barros Bruna D. F. , Paula Claudia A. A. de , Valieris Renan , Mota Louise D. C. , Souza Jorge E. , Cunha Isabela W. , Costa Cecília L. , Souza Sandro J. de , Carraro Dirce M. 
Published: May 2016

Abstract
Detection of tumor DNA in urine has been shown as viable method of diagnosis not only for urinary tract (e.g., kidney and bladder) cancers but also for other types, e.g. prostate. Applications of such method, resemble those which use plasma DNA and include cancer detection, monitoring of tumor growth or recurrence and response to chemotherapy or radiation therapy. As far as we know, there is a lack of studies applying urine DNA detection in Wilms tumor (WT), an embryonary kidney cancer type.
Here we show evidences of detection for two somatic variants in the urine DNA of one WT patient. By using NGS exome sequencing of tumor tissue and leukocytes samples of the same patient we were able to find new somatic variants: a frame-shift indel in TNRC18 and a misssense SNV in INTS1 gene. Target sequencing applied to the DNA from the patient's urine revealed the presence of these two somatic variants. More interestingly, both variants could not be found in the urine DNA of this patient after treatment (chemotherapy and nephrectomy). Additionally, these genes are poorly characterized in WT contributing for the comprehension of the cellular processes that are operating in tumorigenesis of WT. Altogether, our findings contribute with the mutational repertoire of WT and reveals the potential of using urine DNA sequencing as a noninvasive cancer screening approach.
Citation Format: Ana C. K. Miguez, Rodrigo F. Ramalho, Elisa N. Ferreira, Bruna D. F. Barros, Claudia A. A. de Paula, Renan Valieris, Louise D. C. Mota, Jorge E. Souza, Isabela W. Cunha, Cecília L. Costa, Sandro J. de Souza, Dirce M. Carraro. Urine as a potential liquid biopsy for detecting tumor DNA in Wilms tumor patient: Detection of somatic mutations in urine opens perspectives of monitoring chemotherapy response in WT patients. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr A32.
Abstract B05: Improved therapy for neuroblastoma using small molecule inhibitors in combination with chemotherapy
Authors: Chaturvedi Nagendra K. , Timothy McGuire R. , Coulter Don W. , Shukla Ashima , McIntyre Erin M. , Sharp J. Graham , Joshi Shantaram S. 
Published: May 2016

Abstract
Neuroblastoma is the most common pediatric malignancy with poor response to current therapy. The NF-kB/mTOR, hedgehog and PLK1 pathways/molecules are aberrantly expressed and activated in high-risk neuroblastoma, thereby targeting these pathways/molecules is an attractive therapeutic strategy. Therefore, we investigated the efficacy and associated molecular mechanism(s) of NF-kB/mTOR dual inhibitor 13-197, hedgehog inhibitor Vismodegib and PLK1 inhibitor BI2536 alone or in combination with Topotecan against high-risk neuroblastoma in vitro and in vivo. Using three neuroblastoma cell lines, the in vitro efficacy of the inhibitors as single agents or in combination with Topotecan on cell growth and apoptosis along with associated molecular mechanism(s) were investigated. In addition, the combined efficacy of Vismodegib and Topotecan was determined in vivo using a xenograft mouse model. Results showed that 13-197, BI2536 and Vismodegib significantly decreased neuroblastoma cell growth and induced apoptosis by targeting associated pathways and molecules in vitro. The 13-197 and BI2536 as single agents showed similar efficacies and were most potent in inhibiting cell growth and survival of neuroblastoma cells. In combination with Topotecan, BI2536 or Vismodegib further significantly decreased neuroblastoma cell growth/survival and neurospheres formation. Corresponding changes in the expression of targeted molecules following therapy were observed. Together, in vitro data demonstrated that hedgehog pathway inhibitor Vismodegib was most efficacious in potentiating Topotecan-induced antineuroblastoma effects. Therefore, as a next logical step, we tested the combined efficacy of Vismodegib and Topotecan against neuroblastoma in vivo using NOD-SCID Gamma deleted (NSG) mice. Our in vivo results showed that Vismodegib combined with Topotecan significantly (p&lt;0.001) reduced tumor growth and increased survival of xenograft mice compared to single agent activity. This combination not only significantly reduced tumor growth and increased survival of the mice but also significantly enhanced antineuroblastoma efficacy by targeting hedgehog pathway components in neuroblastoma in vivo. Thus our studies lay a foundation for taking this therapeutic strategy to clinical setting to determine their efficacies in high-risk neuroblastoma patients.
Citation Format: Nagendra K. Chaturvedi, McGuire R. Timothy, Don W. Coulter, Ashima Shukla, Erin M. McIntyre, J. Graham Sharp, Shantaram S. Joshi. Improved therapy for neuroblastoma using small molecule inhibitors in combination with chemotherapy. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr B05.
Abstract B16: NR5A2 as a potential therapeutic target for hepatoblastoma
Authors: Jin Jingling , Patel Roma , Jin Nan Ge , Shi Yan , Sun Wenjing , Yang Jianhua , Nuchtern Jed G. , Vasudevan Sanjeev A. 
Published: May 2016

Abstract
Hepatoblastoma (HB) is the most common malignant liver tumor in very young children. Because of multidrug resistance and severe side effects of anti-HB drugs during HB chemotherapy, it is urgent and important to develop new effective therapeutic agents with less toxicity for the treatment of pediatric patients with liver cancer. Nuclear Receptor Subfamily 5 Group A Member 2 (NR5A2; LRH-1) has been linked to various types of malignancies, and it is an emerging therapeutic target for many cancers. However the role of NR5A2 in liver cancer remains elusive. In this study, we found that both mRNA and protein expression levels of NR5A2 were significantly higher in HepG2 and HuH6 human HB cell lines and mouse orthotopic HB liver than the normal liver cell and normal liver tissue. Lentiviral-Mediated Short Hairpin RNA (shRNA) knockdown of NR5A2 inhibited HepG2 and HuH6 cell proliferation and colony formation compared with control cells. Furthermore, we found that silencing of NR5A2 induced downregulation of cell cycle gene CCND1 and the regulator gene c-myc. Similar to the effects of shRNA, we found the NR5A2 antagonist treatment also inhibited the proliferation of human HB cell lines (HepG2, HuH6 and HepT1 cells), reduced colony formation and CCND1 and c-Myc expression. Finally, flow cytometry results showed that the NR5A2 antagonist treatment induced a decreased percentage of cells in S phase which resulted in a significant decrease in the rate of cell proliferation and tumorigenicity, and induced an increased number of cells in the G2/M phase, leading to HB cell cycle arrest at G2/M phase. Collectively, our results suggest that NR5A2 play an important role in HB cancer cell proliferation. Interference of NR5A2 by shRNA or the NR5A2 antagonist inhibits HB cell proliferation and colony formation by inhibiting the cell cycle process through downregulation of CCND1 and c-Myc expression. By targeting NR5A2 signaling pathway, NR5A2 antagonist has promising therapeutic potential in the treatment of HB cancer.
Note: This abstract was not presented at the conference.
Citation Format: Jingling Jin, Roma Patel, Nan Ge Jin, Yan Shi, Wenjing Sun, Jianhua Yang, Jed G. Nuchtern, Sanjeev A. Vasudevan. NR5A2 as a potential therapeutic target for hepatoblastoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr B16.
Abstract B24: Targeting promoter regions of oncogenic drivers in pediatric AML cells using G-quadruplex Interacting Drugs (GQIDs)
Authors: Patel Apurvi , Montoya Justin J. , Turnidge Megan , Sabir Marya , Wai Daniel H. , Lee David W. , Gokhale Vijay , Aleem Eiman , Hurley Laurence J. , Arceci Robert J. , Azorsa David O. 
Published: May 2016

Abstract
Cancer is primarily a disease characterized by aberrant gene expression that is manifested by the overexpression of key genes that support tumor development and maintenance. In many instances, oncogenic drivers are frequently ‘undruggable’ because of structural challenges, the inability to effectively inhibit high concentrations of overexpressed proteins, and the development of drug resistance mutations. An alternative therapeutic approach is to directly inhibit gene transcription by targeting unique secondary DNA structures, called G-quadruplexes, that are associated with subsets of promoters. Our laboratory investigated the activity of a class of compounds termed G-quadruplex Interacting Drugs (GQIDs) that are able to shut down the expression of specific genes used by tumor cells for growth and survival. We tested the activity of two GQIDs GQC-05 and GSA-1103 on cell growth of a panel of eight pediatric and eight adult AML cell lines. Drug dose response analysis showed IC50 values ranging from approximately 10 nM to 1 µM for GQC-05 and from 40 nM to 2 µM for GSA-1103. The AML cell lines had different sensitivities to each GQID indicating a different mechanism of action for each compound. Three AML cell lines that were highly resistant to cytarabine were among the more sensitive to GQC-05. Four cell lines sensitive to GQC-05 had high expression of either c-myc and/or bcl-2, both of which are potential targets of these two GQIDs. Furthermore, treatment of cells with the GQC-05 decreased expression of c-myc and bcl-2. These studies will help define a novel approach of repressing key drivers of leukemia by targeting selective promoter structures. Validation of such an approach for AML will have important implications for testing this therapeutic approach to other childhood cancers in order to improve the length and quality of survival.
Citation Format: Apurvi Patel, Justin J. Montoya, Megan Turnidge, Marya Sabir, Daniel H. Wai, David W. Lee, Vijay Gokhale, Eiman Aleem, Laurence J. Hurley, Robert J. Arceci, David O. Azorsa. Targeting promoter regions of oncogenic drivers in pediatric AML cells using G-quadruplex Interacting Drugs (GQIDs). [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr B24.
Abstract B37: Detection of sarcoma circulating tumor cells using a size based microfiltration device
Authors: Hayashi Masanori , Zhu Peixuan , Albert Catherine M. , Steppan Diana , McCarty Gregory , Jackson Kyle W. , Tang Cha-Mei , Loeb David M. 
Published: May 2016

Abstract
The inability to effectively treat hematogenous metastasis remains the largest challenge of sarcoma therapy. The ability to isolate, quantify, and study circulating tumor cells (CTC) in sarcomas has the potential to enhance our understanding of the biology of metastasis, altering the way we treat patients with high grade sarcomas. Using a size based filtration device, CellSieve™, we were able to successfully identify and quantify CTC in a metastatic xenograft model as well as in blood samples from patients with high grade sarcomas. In mice, we utilized our orthotopic implantation/amputation model of metastasis. Using a TdTomato-expressing Ewing sarcoma cell line and a cocktail of fluorescently labeled antibodies to vimentin and CD45, we were able to detect both CTC and circulating tumor clusters (CTCL) in mice with growing tumors and with metastatic disease, but not in mice immediately post-amputation. These experiments were augmented with samples collected from patients with high grade sarcomas. In 18 samples from 15 patients, we were able to identify both CTC and CTCL. Furthermore, we were also able to validate the presence of CTC by PCR amplification of sarcoma-associated chromosomal translocations. Future work will use this system to explore the biology of sarcoma metastasis by studying genetic, transcriptional, and epigenetic characteristics of CTC and CTCL and comparing these cells to those in the bulk primary tumor. We will also further explore the possibility that CTC and/or CTCL might serve as a biomarker of disease burden, response to treatment, or metastatic risk.
Citation Format: Masanori Hayashi, Peixuan Zhu, Catherine M. Albert, Diana Steppan, Gregory McCarty, Kyle W. Jackson, Cha-Mei Tang, David M. Loeb. Detection of sarcoma circulating tumor cells using a size based microfiltration device. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr B37.
Abstract IA13: Mechanisms of chromatin regulation by the EWS-FLI1 fusion protein in Ewing sarcoma
Authors: Rivera Miguel N. 
Published: May 2016

Abstract
Our laboratory uses genomic approaches to identify and characterize abnormalities in gene regulation in cancer. Large scale sequencing studies have shown that transcriptional regulators, including transcription factors, chromatin modifiers and histones, are frequently altered in cancer and may thus contribute to transformation through widespread changes in gene expression programs. This is particularly evident in pediatric tumors, which have low numbers of recurrent genetic events and where alterations in a transcriptional regulator may be the sole genetic “driver”. In the case of Ewing sarcoma, the second most common pediatric bone cancer, translocations involving EWS and the ETS transcription factor FLI1 generate a fusion protein that has been shown to be essential for the growth and survival of tumor cells. We recently used genome-wide chromatin profiling to study the mechanisms of action of EWS-FLI1 and found that it utilizes two distinct patterns of chromatin remodeling to either activate or repress enhancers. At repeats of the GGAA ETS recognition motif, which are poorly conserved in evolution, EWS-FLI1 multimers induce chromatin opening and create active enhancers de novo. These repeat enhancers can loop to physically interact with target promoters, as demonstrated by chromosome conformation capture assays. In contrast, at conserved enhancers containing canonical ETS motifs, EWS-FLI1 displaces wild-type ETS transcription factors and leads to significant reductions in enhancer activity. These different chromatin remodeling mechanisms are associated with the repression of tumor suppressors and mesenchymal lineage genes and the activation of oncogenes and potential therapeutic targets. Our studies thus illustrate how chromatin profiling can reveal mechanisms of chromatin regulation that are critical in establishing an oncogenic regulatory program in cancer.
Citation Format: Miguel N. Rivera. Mechanisms of chromatin regulation by the EWS-FLI1 fusion protein in Ewing sarcoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr IA13.
Abstract CS1-3: Contemporary role of radiotherapy in axillary management
Authors: Jagsi R 
Published: May 2016

Abstract
Sentinel lymph node evaluation is an innovation that has radically transformed the surgical approach to the axilla in many patients with breast cancer. This revolution in surgical management has important implications for the optimal use of radiotherapy. The context of decision-making has changed dramatically with the recent maturation of studies that have demonstrated low rates of axillary failure in select patients with clinically negative axillae and 1-2 nodes positive on sentinel node biopsy, even without completion axillary dissection. Optimizing the radiotherapeutic management of the axilla in this modern context requires sophisticated understanding of the characteristics of patients who enrolled on trials such as ACOSOG Z0011 and IBSCG 23-01, including their risk factors and systemic management, as well as the radiation fields actually treated. Many patients treated on these trials received substantial incidental radiation to axillary levels I and II from tangential radiotherapy fields, and some even received directed nodal irradiation, but others did well with little or no radiation at all to the axilla. Understanding how to apply the results of these trials to guide current practice requires the radiation oncologist to integrate the insights of these studies with those from other recent studies evaluating the role of more comprehensive regional nodal radiotherapy that included the supraclavicular and internal mammary regions. Recognizing how the patient populations treated on the NCIC MA20 and EORTC 22922 trials may have differed from those on ACOSOG Z0011 and IBSCG 23-01 is necessary to help reconcile the findings of these studies and guide us in optimizing our patients' radiotherapeutic management decisions. In addition, the landmark AMAROS study, in which patients with clinically negative axillae were randomized to axillary dissection versus axillary radiation after a positive sentinel node biopsy, adds to a long history of clinical trials evaluating the question of optimal axillary management. These studies must be considered in detail in order to determine how best to individualize the use of radiation therapy to maximize disease control and minimize treatment-related morbidity. These issues will be the focus of this clinical science symposium lecture, which will provide a radiation oncologist's perspective on regional nodal management for patients diagnosed with invasive breast cancer, with a specific focus on the axilla.
Citation Format: Jagsi R. Contemporary role of radiotherapy in axillary management. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr CS1-3.