bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A31: The long noncoding RNA lnc277 mediates a repressive gene signature in Ewing's sarcoma
Authors: Marques Michelle , Simpson David , Chen Ron , Vaka Dedeepya , Breese Marcus , Brunner Allayne , West Rob , Sweet-Cordero Alejandro 
Published: May 2015

Abstract
Ewing's sarcoma is a highly aggressive tumor characterized by a translocation between members of the FET family of RNA binding proteins and one of several ETS transcription factors, with the most common translocation being EWS-FLI1. Like many oncogenic translocations, EWS-FLI1 leads to changes in gene expression through mechanisms that are not completely understood. We performed RNA sequencing analysis on human mesenchymal progenitor cells (MPCs) expressing EWS-FLI1, which are thought to be the cell of origin of Ewing's sarcoma. This analysis identified lnc277 as a previously uncharacterized long non-coding RNA upregulated by EWS-FLI1 in MPCs. Expression of lnc277 in Ewing's sarcoma cell lines requires EWS-FLI1. In addition, inhibiting the expression of lnc277 diminished the ability of Ewing's sarcoma cell lines to proliferate and form soft agar colonies. Using RNA sequencing and shRNA knockdown, we defined the transcriptional changes induced by EWS-FLI1 and lnc277. This analysis revealed that both EWS-FLI1 and lnc277 repress far more genes that they induce and that a large fraction of EWS-FLI1 repressed targets are also modulated by lnc277. Thus, lnc277 is an oncogenic long non-coding RNA downstream of EWS-FLI1 that facilitates the formation of Ewing's sarcoma via the repression of target genes.
Citation Format: Michelle Marques, David Simpson, Ron Chen, Dedeepya Vaka, Marcus Breese, Allayne Brunner, Rob West, Alejandro Sweet-Cordero. The long noncoding RNA lnc277 mediates a repressive gene signature in Ewing's sarcoma. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A31.
Abstract A39: The novel atypical retinoid ST1926 is active against rhabdomyosarcoma and induces cell cycle arrest in S and G2/M phases
Authors: Basma Hussein , Dweik Loai , Darwiche Nadine , Pisano Claudio , Saab Raya 
Published: May 2015

Abstract
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children with two subtypes: embryonal rhabdomyosarcoma (ERMS) and alveolar rhabdomyosarcoma (ARMS). With current treatment strategies, most children with recurrent or high-risk disease fare poorly, identifying a need for novel therapeutic approaches. The novel retinoid, ST1926, is an orally available compound belonging to the class of synthetic atypical retinoids and is currently in clinical trials. ST1926 is showing promise because of its increased specificity and reduced toxicity and its unique antitumor mechanism of action that appears different from that of classical all-trans retinoic acid (ATRA). We are investigating the therapeutic potential of this novel synthetic retinoid ST1926, in treatment of RMS. Cell viability assessed by MTT assay showed that ST1926 was a much more potent inhibitor of cell proliferation than ATRA, in both ERMS and ARMS cell lines in vitro. In fact, ST1926 effectively inhibited cell proliferation in all tested cell lines, at concentrations as low as 0.5 micromolar, which is easily achievable in vivo. Unlike ATRA, ST1926 did not induce morphological differentiation in RMS cells. Further analysis showed that ST1926 induced accumulation of cells in S and/or in G2/M phases of the cell cycle, as well as induction of apoptosis in some cell lines, in a p53-independent manner. We are currently investigating the mechanistic details of the cell cycle inhibitory activities of ST1926 in RMS cells. This data identifies ST1926 as an interesting possible therapeutic agent in RMS, and in vivo preclinical studies utilizing this agent are currently underway.
Citation Format: Hussein Basma, Loai Dweik, Nadine Darwiche, Claudio Pisano, Raya Saab. The novel atypical retinoid ST1926 is active against rhabdomyosarcoma and induces cell cycle arrest in S and G2/M phases. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A39.
Abstract A44: Proprotein convertase furin in rhabdomyosarcoma progression: A potential target for pediatric sarcomas therapy?
Authors: Jaaks Patricia , D'Alessandro Valentina , Schäfer Beat W. , Bernasconi Michele 
Published: May 2015

Abstract
To improve therapies for embryonal pediatric tumors such as rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children, we have selected, by in vivo phage display, for peptides that bind to RMS with high specificity. We have shown that coupling of doxorubicin to RMS-P3, our lead RMS-targeting peptide, increases its therapeutic impact in a xenograft mouse model for RMS.
We have identified furin as potential target for RMS binding peptide RMS-P3. Furin is a member of the proprotein convertases (PC), a family of ten serine proteases, which convert inactive proproteins into their active form. We have found consistent expression of furin in a panel of RMS cell lines and in RMS biopsies at the mRNA level. To elucidate the contribution of furin to RMS growth we have generated a panel of RMS cell lines either overexpressing furin, or a specific intrinsic PC inhibitor called α1-PDX, as well as RMS cell lines were expression of furin has been stably reduced by shRNA. These cells have been tested for their growth, migration and invasion potential in vitro as well as for their growth in vivo as subcutaneous xenografts. The results suggest a direct correlation between furin activity and RMS cells migration and invasive properties in vitro as well as RMS tumor growth in vivo. Interestingly, alveolar RMS cells display a higher furin activity compared to embryonal RMS cells. Alveolar RMS cells growth in vivo cannot be further enhanced by furin overexpression, in contrast to embryonal RMS cells, suggesting a causal link between high furin activity and alveolar RMS malignant phenotype. Among the known furin substrates, which are processed and activated by furin, and involved in tumor growth, migration and invasion, we found a direct correlation between furin activity and IGFR1 activation.
Our results suggest that furin plays a relevant role in RMS progression through enhanced activation of the IGF1R pathway, among others, and that it might represent a viable target for therapeutic intervention in RMS. This warrants further studies in the development of novel therapeutic approaches for RMS based both on specific inhibition of its activity and on targeted drug delivery by furin targeting peptides.
Citation Format: Patricia Jaaks, Valentina D'Alessandro, Beat W. Schäfer, Michele Bernasconi.{Authors}. Proprotein convertase furin in rhabdomyosarcoma progression: A potential target for pediatric sarcomas therapy? [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A44.
Abstract A58: HMGA2 controls muscle stem cell activation and rhabdomyosarcoma progression
Authors: Li Zhizhong 
Published: May 2015

Abstract
Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children and it shares significant features with proliferating muscle progenitor (myoblast). In an effort to profile mechanistic changes that might control myogenesis and/or induce RMS, a group of genes were identified that are highly and specifically expressed in myoblasts and RMS, but not quiescent muscle stem cells or differentiated myofibers. One of these genes, HMGA2, maintains myoblast and RMS cellular proliferation and survival. Hmga2 knockout mice exhibit impaired muscle development and reduced myoblast proliferation. Similarly, targeting HMGA2 expression by shRNAs inhibited RMS proliferation and increased apoptosis. This perturbation in proliferation can be explained by the finding that HMGA2 directly regulates RNA-binding protein IGF2BP2 in both myoblast and RMS. IGF2BP2 in turn binds to and controls the translation of a set of mRNAs, including NRas, which is frequently mutated in RMS and critical for tumor progression. These data demonstrate that HMGA2-IGF2BP2 axis functions as a conserved regulator of myoblast and RMS growth and may provide a novel target for future drug development to treat this childhood cancer.
References:
Li Z, et.al. Oncogenic NRAS, required for pathogenesis of embryonic rhabdomyosarcoma, relies upon the HMGA2-IGF2BP2 pathway. Cancer Res. 2013 May 15;73(10):3041-50.
Li Z, et,al. An HMGA2-IGF2BP2 axis regulates myoblast proliferation and myogenesis. Dev Cell. 2012 Dec 11;23(6):1176-88.
Note: This abstract was not presented at the conference.
Citation Format: Zhizhong Li. HMGA2 controls muscle stem cell activation and rhabdomyosarcoma progression. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A58.
Abstract A63: YB-1 is critical for stress granule assembly and protects cells from oxidative stress
Authors: Somasekharan Syam Prakash , Leprivier Gabriel , Evdokimova Valentina , EI-Naggar Amal , Hajee Shamil , Gleave Martin , Sorensen Poul HB 
Published: May 2015

Abstract
Stress granules (SGs) are highly conserved cytoplasmic ribonucleoprotein complexes that modulate gene expression and cellular homeostasis under prototypical stress forms. SG formation protects cells under stress conditions by protecting untranslated mRNAs until stress relief, and cells that are incapable of forming SGs are more vulnerable to diverse stressors compared to cells that are proficient at SG formation. The transcription and translation regulation factor Y-box binding protein 1 (YB-1) is recruited to SG, but its exact contribution to formation of these structures is not clear. Using several stress inducing agents, arsenite, H2O2, piperlongumine, thapsigargin, heat shock, curcumin and hypoxia we demonstrate that YB-1 co-localizes to SG along with G3BP, TIA-1 and poly(A)+ mRNA in various human cancer cell lines. YB-1 inactivation by siRNA knockdown dramatically reduces the efficiency of SG assembly in two sarcoma cell lines, U2OS and Rh-30 and a prostate cancer cell line DU-145, with high YB-1 expression. We also found that si-YB-1 cells with an inefficient stress granule formation were more sensitive to stress induced by arsenite, H2O2, or piperlongumine compared to control cells. YB-1 influences SG assembly via two distinct mechanisms. First, it acts as a scaffold protein to recruit mRNA and SG associated RNA-binding proteins into SGs. Second, YB-1 regulates the mRNA translation of the essential nucleator SG proteins, G3BP and TIA-1, thus controlling their availability during SG assembly under oxidative stress. Finally, in vivo, downregulation of YB-1 significantly affected the formation of stress granules in primary tumors generated in mice. Taken together, YB-1 is critical in SG formation and cell survival.
Citation Format: Syam Prakash Somasekharan, Gabriel Leprivier, Valentina Evdokimova, Amal EI-Naggar, Shamil Hajee, Martin Gleave, Poul HB Sorensen. YB-1 is critical for stress granule assembly and protects cells from oxidative stress. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A63.
Abstract A67: Canonical WNT/β;-catenin pathway activation suppresses embryonal rhabdomyosarcoma growth and self-renewal
Authors: Chen Eleanor , DeRan Michael , Grandinetti Katherine Brooke , Ignatius Myron , Clagg Ryan , McCarthy Karin , Lobbardi Riadh , Wu Xu , Langenau David 
Published: May 2015

Abstract
Embryonal rhabdomyosarcoma (ERMS) is a common pediatric malignancy of muscle with relapse being the major clinical challenge. Self-renewing tumor-propagating cells (TPCs) drive cancer relapse and are confined to a molecularly definable subset of ERMS cells. To identify drugs that suppress TPC function, a large-scale chemical screen comprising of ∼40,000 compounds including 47% FDA-approved drugs was completed, identifying GSK3-inhibitors as potent suppressors of ERMS growth through inducing terminal differentiation of TPCs into myosin-expressing cells. In support of GSK3 inhibitors functioning through activation of the canonical WNT pathway, recombinant WNT3A and a stabilized β-catenin enhanced differentiation and reduced self-renewal in human ERMS cell lines. Moreover, treatment of tumor-bearing zebrafish with a GSK3 inhibitor activated the WNT/β-catenin pathway, resulting in suppressed ERMS growth, depleted TPCs, and diminished self-renewal capacity in vivo. As canonical WNT signaling is essential for transition from muscle stem cell proliferation to myogenic differentiation during regeneration, our findings suggest that the same developmental pathways that regulate muscle stem cell self-renewal also contribute to tumorigenesis in ERMS. GSK3 inhibitors are being assessed for their efficacy in inhibiting growth as well as inducing differentiation of human ERMS in xenograft mouse models. Our work has identified the vital role of canonical WNT pathway in regulating differentiation and self-renewal of ERMS and demonstrated the effective application of small molecule inhibitors to target differentiation of TPCs in ERMS.
Citation Format: Eleanor Chen, Michael DeRan, Katherine Brooke Grandinetti, Myron Ignatius, Ryan Clagg, Karin McCarthy, Riadh Lobbardi, Xu Wu, David Langenau. Canonical WNT/β;-catenin pathway activation suppresses embryonal rhabdomyosarcoma growth and self-renewal. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A67.
Abstract A75: A new, microRNA-regulated, epigenetic tumor-promoting pathway in Ewing sarcoma
Authors: Parrish Janet K. , Sechler Marybeth , Jedlicka Paul 
Published: May 2015

Abstract
Ewing Sarcoma is an aggressive pediatric bone and soft tissue malignancy driven by transcription factor oncogenic fusions, of which EWS/Fli1 is the most common. Our studies of the role of microRNAs in EWS/Fli1-driven oncogenesis have uncovered a new tumor-promoting pathway in Ewing Sarcoma. Specifically, we have found that EWS/Fli1 downregulates miR-22, which in turn results in increased expression of the H3K9 histone demethylase, and miR-22 target, KDM3A. Overexpression of miR-22 and stable depletion of KDM3A each results in impaired clonogenic and anchorage-independent growth of Ewing Sarcoma cells. KDM3A depletion further results in impaired tumorigenesis in a xenograft model, upregulation of the repressive H3K9 methyl histone mark, and diminished expression of multiple oncogenes in Ewing Sarcoma. Our studies thus identify a new, potentially targetable, tumor-promoting pathway in Ewing Sarcoma, involving modulation of H3K9 histone methylation downstream of EWS/Fli1.
Citation Format: Janet K. Parrish, Marybeth Sechler, Paul Jedlicka. A new, microRNA-regulated, epigenetic tumor-promoting pathway in Ewing sarcoma. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A75.
Abstract B24: Inhibition of mTOR induces multidrug resistance in B-progenitor acute lymphocytic leukemia
Authors: Vo Thanh-Trang , Lu Mengrou , Nguyen Duc , Lui Brandon , Maylla Sharmila , Fruman David 
Published: May 2015

Abstract
In B-progenitor acute lymphocytic leukemia (B-ALL), the current chemotherapeutic regimen can effectively cure most patients. However, some patients like those with the Philadelphia chromosome (Ph+) often relapse. Many of these Ph+ and some Ph- B-ALL have elevated signaling through the PI3K/AKT/mTOR pathway. The cancer proliferation and survival driven by this pathway provides these cancers an advantage that likely contributes to survival after chemotherapy, resulting in a high rate of relapse. The goal of this project is to test inhibitors of the various components of the PI3K/AKT/mTOR pathway to determine how to combine them with current chemotherapy to enhance leukemia killing and prevent relapse. Our pilot studies using Annexin-V and PI staining revealed that upstream PI3K inhibition often sensitizes B-ALL cell lines to chemotherapy but, surprisingly, downstream mTOR inhibition induces multidrug resistance. Using a novel assay called BH3 profiling we have found that mTOR inhibition actually sensitizes cells to triggers of mitochondrial apoptosis but an unknown resistance mechanism reverses the effects of this sensitization. This resistance is observed when using rapamycin as well as active-site mTOR inhibitors (MLN-0128 and AZD8055). The degree of drug resistance upon mTOR inhibition varies with different chemotherapeutic agents. mTOR inhibition best protects cells from killing by methotrexate and is least protective when combined with daunorubicin. Future work will focus on identifying the mechanism of drug resistance induced by mTOR inhibition. Thus far, we have found that resistance does not correspond with the effects on cell cycle. Identifying and finding mechanisms of reversing this protective effect could potentially augment the effectiveness of inhibiting the PI3K/AKT/mTOR pathway. Our results will lead to a better understanding of how to best utilize PI3K pathway inhibitors in combination with standard chemotherapy as an option for high-risk B-ALL cases driven by oncogenic PI3K signaling.
Citation Format: Thanh-Trang Vo, Mengrou Lu, Duc Nguyen, Brandon Lui, Sharmila Maylla, David Fruman. Inhibition of mTOR induces multidrug resistance in B-progenitor acute lymphocytic leukemia. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr B24.
Abstract B29: Increased vertebral marrow adiposity in long-term survivors of pediatric allogeneic hematopoietic stem cell transplant is associated with deficits in trabecular microarchitecture
Authors: Mostoufi-Moab Sogol , Sun Wenli , Magland Jeremy , Isaacoff Elizabeth , Bunin Nancy J. , Ginsberg Jill P. , Wehrli Felix , Shults Justine , Leonard Mary B. 
Published: May 2015

Abstract
Background: As treatment-related mortality following allogeneic hematopoietic stem-cell transplantation (alloHSCT) declines, a major unmet need is the identification and prevention of late effects. Long-term survivors of hematologic malignancies requiring alloHSCT show impaired bone density and structure with excess whole body adiposity (Mostoufi-Moab, JBMR, 2012). Marrow adipocytes share common mesenchymal stem cells (MSC) with bone-forming osteoblasts, with an inverse relation between MSC differentiation into osteoblasts or adipocytes. The impact of alloHSCT and total body irradiation (TBI) on marrow adipose tissue (MAT) and trabecular bone microarchitecture (TBA) has not been addressed.
Methods: Magnetic resonance spectroscopic imaging (MRSI) and high-resolution structural imaging were used to quantify vertebral MAT and distal tibia TBA on a 1.5 Tesla magnet. Twenty-five alloHSCT recipients with underlying diagnosis of acute leukemia, ages 12-24 years, were enrolled, a median of 11 years (range 5-19) after alloHSCT and TBI, and compared with age-, sex- and race-matched healthy controls.
Results: AlloHSCT survivors had lower height Z-scores (-1.39 ± 0.98 vs. -0.04 ± 0.98; p &lt; 0.001), compared with controls, while BMI Z-scores did not differ. Overall, greater MAT was associated with lower bone volume fraction (BVF), R = -0.57, p &lt; 0.001. AlloHSCT was associated with higher mean (± SD) vertebral fat fraction (59.0 ± 11.3 vs. 29.3 ± 9.9; p &lt; 0.001) and trabecular deficits including lower bone volume fraction (β -0.01; 95% CI -0.12, -0.00; p=0.02) and evidence of abnormal microarchitecture [greater erosion (p=0.01) with a more rod like structure (p=0.02)], vs. controls. TBA deficits were more pronounced in female alloHSCT recipients. Growth hormone deficiency was not associated with MAT or bone deficits.
Conclusion: Survivors of childhood alloHSCT after TBI demonstrate marked increases in vertebral MAT combined with abnormal trabecular bone microarchitecture. Future studies are needed to determine the metabolic effects and fracture implications of excess MAT, and to identify therapies for improved bone accrual following childhood alloHSCT.
Citation Format: Sogol Mostoufi-Moab, Wenli Sun, Jeremy Magland, Elizabeth Isaacoff, Nancy J. Bunin, Jill P. Ginsberg, Felix Wehrli, Justine Shults, Mary B. Leonard. Increased vertebral marrow adiposity in long-term survivors of pediatric allogeneic hematopoietic stem cell transplant is associated with deficits in trabecular microarchitecture. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr B29.
Abstract B39: IGF-IR regulation of osteoclastogenesis in neuroblastoma bone metastasis
Authors: Rivera-Pintado Chris A. , Shan Yufei , Golen Cynthia M. van 
Published: May 2015

Abstract
Neuroblastoma is a tumor that is responsible for 15% of cancer deaths in children and has a mortality rate greater than 90% percent upon metastasis to bone. Due to the high mortality rate and lack of effective treatment options, our laboratory is investigating potential new therapeutic targets in neuroblastoma bone metastases. Since, insulin-like growth factor I (IGF-I) production in the bone promotes neuroblastoma growth and survival, our hypothesis is that inhibiting IGF-I receptor (IGF-IR) will prevent metastasis of this tumor to bone. Furthermore, neuroblastoma with increased IGF-IR expression induces osteoclasts to differentiate, with the percentage of differentiated osteoclasts in vitro increasing to 30% in the presence of conditioned medium from high IGF-IR expressing cells. The addition of a monoclonal, neutralizing antibody to the IGF-IR decreases the percentage of mature osteoclasts formed by over 50%. We are testing the hypothesis that IGF-IR activation in neuroblastoma alters the levels of RANK, RANKL and OPG, proteins involved in osteoclast differentiation. This alteration in RANK, RANKL, and OPG may cause osteoclast differentiation and osteolysis. Neuroblastoma cells with high IGF-IR protein levels express low levels of the decoy receptor OPG, while some lines also express high levels of RANKL. Therefore, we are currently testing the effect of IGF-IR inhibition on RANKL and OPG levels and subsequent effect on osteolysis.
Citation Format: Chris A. Rivera-Pintado, Yufei Shan, Cynthia M. van Golen. IGF-IR regulation of osteoclastogenesis in neuroblastoma bone metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr B39.