bluuebunny/crossref_metadata_2025_split huggingface dataset:
Electrode Composite LiFePO4@Carbon: Structure and Electrochemical Performances
Authors: Huynh Le Thanh Nguyen , Nguyen Hoang Hai Au , Tran Thi Thuy Dung , Nguyen Thi Thu Trang , Nguyen Thi My Anh , La Thi Hang , Tran Van Man , Le My Loan Phung 
Published: February 2019

This work aimed at preparing the electrode composite LiFePO4@carbon by hydrothermal and the calcination process was conducted at 600, 700, and 800°C. The structure and morphology were determined by X-ray diffraction (XRD), SEM, Raman spectroscopy, X-ray photon spectroscopy (XPS), and thermal analysis. The XRD refinement’s results point out the orthorhombic structure without impurity phase and the high crystalline of synthesized olivines. The results of Raman spectroscopy and XPS confirmed the pure olivine phase as well as the successful carbon coating on the surface of olivines’ powders. Moreover, the calcinated temperature affected the morphology as well as the electrochemical performance of synthesized olivines. The electrochemical measurements were conducted by cyclic voltammetry and galvanostatic cycling test. The diffusion coefficients were calculated from cyclic voltammetry curves and reached 1.09 × 10−12 cm2/s for LFP600, 2.28 × 10−11 cm2/s for LFP700, and 3.27 × 10−12 cm2/s LFP800. The cycling test at rate C/10 exhibited an excellent cyclability with discharge capacity of 145 mAh/g for LFP600, 170 mAh/g for LFP700, and 160 mAh/g for LFP800.
Novel Third-Generation EGFR Tyrosine Kinase Inhibitors and Strategies to Overcome Therapeutic Resistance in Lung Cancer
Authors: Murtuza Ayesha , Bulbul Ajaz , Shen John Paul , Keshavarzian Parissa , Woodward Brian D. , Lopez-Diaz Fernando J. , Lippman Scott M. , Husain Hatim 
Published: February 2019

Abstract
EGFR-activating mutations are observed in approximately 15% to 20% of patients with non–small cell lung cancer. Tyrosine kinase inhibitors have provided an illustrative example of the successes in targeting oncogene addiction in cancer and the role of tumor-specific adaptations conferring therapeutic resistance. The compound osimertinib is a third-generation tyrosine kinase inhibitor, which was granted full FDA approval in March 2017 based on targeting EGFR T790M resistance. The compound has received additional FDA approval as first-line therapy with improvement in progression-free survival by suppressing the activating mutation and preventing the rise of the dominant resistance clone. Drug development has been breathtaking in this space with other third-generation compounds at various stages of development: rociletinib (CO-1686), olmutinib (HM61713), nazartinib (EGF816), naquotinib (ASP8273), mavelertinib (PF-0647775), and AC0010. However, therapeutic resistance after the administration of third-generation inhibitors is complex and not fully understood, with significant intertumoral and intratumoral heterogeneity. Repeat tissue and plasma analyses on therapy have revealed insights into multiple mechanisms of resistance, including novel second site EGFR mutations, activated bypass pathways such as MET amplification, HER2 amplification, RAS mutations, BRAF mutations, PIK3CA mutations, and novel fusion events. Strategies to understand and predict patterns of mutagenesis are still in their infancy; however, technologies to understand synthetically lethal dependencies and track cancer evolution through therapy are being explored. The expansion of combinatorial therapies is a direction forward targeting minimal residual disease and bypass pathways early based on projected resistance.
Genome-Wide Screening and Functional Analysis Identifies Tumor Suppressor Long Noncoding RNAs Epigenetically Silenced in Hepatocellular Carcinoma
Authors: Xu Feiyue , Li Chi Han , Wong Chi Hin , Chen George G. , Lai Paul Bo San , Shao Shengwen , Chan Stephen L. , Chen Yangchao 
Published: February 2019

Abstract

Long noncoding RNAs (lncRNA) play critical roles in the development of cancer, including hepatocellular carcinoma (HCC). However, the mechanisms underlying their deregulation remain largely unexplored. In this study, we report that two lncRNAs frequently downregulated in HCC function as tumor suppressors and are epigenetically silenced by histone methyltransferase EZH2. lncRNAs TCAM1P-004 and RP11-598D14.1 were inhibited by EZH-mediated trimethylation of H3K27me3 at their promoters. Downregulation of TCAM1P-004 and RP11-598D14.1 was frequently observed in HCC tumors compared with adjacent normal tissues. Both lncRNAs inhibited cell growth, cell survival, and transformation in HCC cells in vitro as well as tumor formation in vivo. Using RNA pull-down and mass spectrometry, we demonstrated that TCAM1P-004 bound IGF2BP1 and HIST1H1C, whereas RP11-598D14.1 bound IGF2BP1 and STAU1. These lncRNA–protein interactions were critical in regulating p53, MAPK, and HIF1α pathways that promoted cell proliferation in HCC. Overexpression of EZH2 was critical in repressing TCAM1P-004 and RP11-598D14.1, and EZH2-TCAM1P-004/RP11-598D14.1–regulated pathways were prevalent in human HCC. Aberrant suppression of TCAM1P-004 and RP11-598D14.1 led to loss of their tumor-suppressive effects by disrupting the interaction with IGF2BP1, HIST1H1C, and STAU1, which in turn promoted HCC development and progression. Collectively, these findings demonstrate the role of TCAMP1P-004 and RP11-598D14.1 in suppressing tumor growth and suggest that EZH2 may serve as a therapeutic target in HCC.

Significance:
EZH2-mediated loss of lncRNAs TCAM1P-004 and RP11-598D14.1 hinders the formation of tumor suppressor lncRNA–protein complexes and subsequently promotes HCC growth.
Abstract A02: Targeting EWS-FLI1 dose-dependent epithelial-to-mesenchymal transition
Authors: Katschnig Anna M. , Kauer Maximilian O. , Schwentner Raphaela , Tomazou Eleni M. , Aryee Dave N.T. , Kovar Heinrich 
Published: February 2019

Abstract
Reversible transitions from a proliferative to a nonproliferative but highly migratory and invasive phenotype, widely known as epithelial-to-mesenchymal transition (EMT), is a prerequisite for wound healing and organ development but also a hallmark of cancer. Recently, phenotypic changes resembling EMT were described to occur in Ewing sarcoma upon modulation of expression of the driver oncogene EWS-FLI1. Evidence was provided for the presence of highly migratory EWS-FLI1-low cells in Ewing sarcoma cell lines as well as in about 20% of primary tumors at low frequency (Franzetti et al., 2017). Importantly, when injected into the tail vein of immunosuppressed mice, EWS-FLI1-low cells were more likely to result in lung metastases than EWS-FLI1-high cells upon re-expression of the oncogene. In our study, we identified a mechanism for the cytoskeletal reprograming underlying EWS-FLI1 dose-dependent phenotypic transitions in Ewing sarcoma. We provide evidence for EWS-FLI1 blocking access of the transcriptional coactivators MRTFB and TAZ to the YAP/TEAD transcription factor complex on enhancers of EWS-FLI1 anti-correlated genes. Upon modulation of EWS-FLI1 expression, TEADs get activated downstream of Rho signaling through recruitment of MRTFB/YAP/TAZ, leading to the expression of key cytoskeletal components and regulators involved in the reorganization of the actin cytoskeleton. Based on these findings, we hypothesized that small-molecule inhibitors of the YAP/TAZ/TEAD pathway should interfere with the migratory phenotype of EWS-FLI1-low cells. In fact, the YAP/TAZ inhibitor verteporfin (Visudyne®), which is clinically used as a photosensitive drug in the treatment of age-related macular degeneration, was able to block Ewing sarcoma cell migration at low nanomolar concentrations without affecting tumor cell proliferation. These results suggest that YAP/TAZ inhibitors may be considered as a promising add-on to conventional combination treatments to prohibit tumor cell dissemination and metastasis.
Citation Format: Anna M. Katschnig, Maximilian O. Kauer, Raphaela Schwentner, Eleni M. Tomazou, Dave N.T. Aryee, Heinrich Kovar. Targeting EWS-FLI1 dose-dependent epithelial-to-mesenchymal transition [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr A02.
Abstract A08: TGFβb inhibition improves oncolytic herpes viroimmunotherapy in murine models of rhabdomyosarcoma
Authors: Hutzen Brian , Chen Chun-Yu , Wang Pin-Yi , Sprague Les , Hayley Swain M. , Love Julia , Conner Joe , Boon Louis , Cripe Timothy P. 
Published: February 2019

Abstract
Oncolytic viruses are an emerging class of cancer therapeutics that couple cytotoxicity with the induction of an antitumor immune response. Host-virus interactions are complex and modulated by a tumor microenvironment whose immunosuppressive activities can limit the effectiveness of cancer immunotherapies. In an effort to improve this aspect of oncolytic virotherapy, we combined the oncolytic herpes virus HSV1716 with the TGFβR1 inhibitor A8301 to treat syngeneic models of murine rhabdomyosarcoma. Mice that received HSV1716 or A8301 alone showed little to no benefit in efficacy/survival over controls. Conversely, mice given combination therapy exhibited tumor stabilization throughout the treatment regimen, which was reflected in significantly prolonged survival times including some complete responses. In vitro cell viability and virus replication assays showed that the rhabdomyosarcoma cell lines were generally insensitive to HSV1716 and A8301. Likewise, in vivo virus replication assays showed that HSV1716 titers moderately decreased in the presence of A8301. The enhanced efficacy instead appears to be dependent on the generation of an improved antitumor T-cell response as determined by its loss in athymic nude mice and following in vivo depletion of either CD4+ or CD8+ cells. These data suggest that TGFβ inhibition can augment the immunotherapeutic efficacy of oncolytic herpes virotherapy.
Citation Format: Brian Hutzen, Chun-Yu Chen, Pin-Yi Wang, Les Sprague, Swain M. Hayley, Julia Love, Joe Conner, Louis Boon, Timothy P. Cripe. TGFβb inhibition improves oncolytic herpes viroimmunotherapy in murine models of rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr A08.
Abstract A22: Identification of gene expression differences between primary pediatric tumors and their PDX models
Authors: Pfeil Jacob J. , Lee Alex G. , Sayles Leanne C. , Kephart Ellen T. , Beale Holly C. , Sanders Lauren M. , Morozova Olena , Salama Sofie R. , Sweet-Cordero Alejandro , Haussler David 
Published: February 2019

Abstract
Molecularly targeted therapies inhibit specific cancer pathways and have fewer harmful side effects than cytotoxic chemotherapies; however, the development of targeted therapies for childhood cancers has lagged behind that of adult cancers. Although adult and childhood cancers have different molecular mechanisms, similar druggable cancer pathways may be activated. We propose using gene expression analysis to identify opportunities to reposition FDA-approved targeted therapies for childhood cancer patients. We developed an N-of-1 gene expression approach that leverages a compendium of ~11,000 cancer gene expression profiles. To evaluate the utility of this approach for identifying cancer driver pathways, we analyzed gene expression data for 9 patient-derived xenograft (PDX) tumors. PDXs were tested for sensitivity to selected targeted therapies. Our analysis correctly predicted drug sensitivity in 8 of the 9 PDXs based on overexpression of specific cancer pathways. We also compared gene expression between PDX and matched primary tumor samples (n=7). Using TumorMap analysis, we found that PDX tumors cluster with their matched primary tumor and other samples with a similar cancer diagnosis. We also ran differential expression analysis and found 260 overexpressed genes and 630 underexpressed genes in PDX tumors. Underexpressed genes were associated with immune functions, extracellular matrix proteins, and growth factor signaling. Overexpressed genes were involved in TNF-α; signaling. This analysis confirmed expected changes in gene expression while also identifying TNF-α; signaling as a potential biologic artifact of PDX tumors. These features may influence the results of PDX experiments and should be accounted for when using this model. Overall, the PDX model recapitulates gene expression features of pediatric cancer and is a powerful tool for evaluating novel precision medicine approaches.
Citation Format: Jacob J. Pfeil, Alex G. Lee, Leanne C. Sayles, Ellen T. Kephart, Holly C. Beale, Lauren M. Sanders, Olena Morozova, Sofie R. Salama, Alejandro Sweet-Cordero, David Haussler. Identification of gene expression differences between primary pediatric tumors and their PDX models [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr A22.
Abstract A39: Characterizing the epigenetic effects of the histone 3.3 G34W mutation in giant cell tumors of bone
Authors: Deshmukh Shriya , Khazaei Sima , Marchione Dylan , Harutyunyan Ashot , Garcia Benjamin , Jabado Nada 
Published: February 2019

Abstract
Introduction: Pediatric glioblastomas (pGBM) are malignant brain tumors associated with a dismal prognosis. A subset of pGBMs carry mutations of either the Lysine 27 or Glycine 34 (G34) amino acid residues of histone 3 variant genes. The same G34 residue is also mutated in 85-95% of giant cell tumors of bone (GCTs), albeit to Tryptophan (G34W) in GCTs rather than to Arginine or Valine (G34R/V) as in pGBMs. The G34 mutation is predicted to impede access of histone methyltransferases like SetD2 to the nearby Lysine 36 residue, thereby altering the epigenome and transcriptome.
Methods: To elucidate the tumorigenic effect of G34 mutations, we used the gene-editing technology CRISPR/Cas9 to correct the G34W mutation to wild-type in 2 GCT cell lines. We then investigated CRISPR-edited cell lines using functional assays, proteomic, epigenomic, and transcriptomic analyses.
Results: Correction of the G34W mutation to wild-type in CRISPR-edited GCT cells results in phenotypic and functional changes suggestive of reduced tumorigenicity. By mass spectrometry, G34W-mutant GCT cell lines display decreased level of Lysine 36 trimethylation (H3K36me3) on the mutant G34-peptide, similar to G34-mutated pGBM cell lines. However, unlike pGBMs, GCTs display increased levels of Lysine 36 dimethylation (H3K36me2) on the mutant G34W-peptide.
Ongoing Experiments and Analyses: We are currently comparing the level and distribution of multiple histone marks by performing chromatin immunoprecipitation followed by next-generation sequencing (ChIP-Seq) of CRISPR-edited wild-type clones relative to the parent G34W-mutant GCT line. We are also assessing differential gene expression by RNA-Seq and characterizing the methylation signature by 850K DNA methylation array of G34W-mutant GCTs and edited clones.
Conclusion: The G34W-mutation clearly has an impact on tumorigenic potential, as evidenced by in vitro functional assays. The G34W-mutant peptide of GCT cell lines features a distinct profile of post-translational histone modifications compared to G34R- or G34V-mutant peptides of pGBM cell lines. Further investigation could elucidate the epigenetic mechanism(s) through which the G34W mutation confers its tumorigenic properties.
Citation Format: Shriya Deshmukh, Sima Khazaei, Dylan Marchione, Ashot Harutyunyan, Benjamin Garcia, Nada Jabado. Characterizing the epigenetic effects of the histone 3.3 G34W mutation in giant cell tumors of bone [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr A39.
Abstract A41: Role of UHRF1 in tumorigenesis and metastasis of osteosarcoma
Authors: Wu Stephanie C. , Benavente Claudia A. 
Published: February 2019

Abstract
Osteosarcoma is the eighth most common form of childhood cancer, with very limited advances in treatment over the past three decades. Osteosarcoma is a highly metastatic cancer, with 15-20% of osteosarcoma patients diagnosed after the cancer has already metastasized, causing the survival rate to be little over 50%. Common sites of metastasis include lung and liver. Loss of the retinoblastoma protein (RB) is associated with poor prognosis in osteosarcoma, as defined by shorter life span and heavier tumor burden. Ubiquitin Like with PHD and Ring Finger Domains 1 (UHRF1) has been identified as a critical downstream effector of the RB/E2F pathway that is overexpressed in various cancers. We have confirmed using human mesenchymal stem cells (MSCs) and osteosarcoma cell lines that UHRF1 is directly regulated by the RB/E2F pathway in the bone lineage, and found that the UHRF1 gene is upregulated and its protein overexpressed in osteosarcoma. Using gain/loss-of-function assays to study the role of UHRF1 in osteosarcoma, we observed that UHRF1 is involved in promoting cell migration. To study the role of UHRF1 in osteosarcoma tumor development, we generated Uhrf1 conditional knockout mice. In this system, we use an Osterix-driven Cre recombinase (Osx-cre) to facilitate preosteoblast-specific loss of various combinations of genes. Osx-cre Tp53; Rb1 double knockout mice give rise to osteosarcoma and have a median survival of 26.7 weeks. Additional loss of Uhrf1 in Osx-cre Tp53; Rb1 double knockout mice (Osx-cre Tp53; Rb1; Uhrf1 triple knockout mice) significantly delays the age of tumor onset to &gt;47 weeks. Furthermore, triple knockout mice have a decreased frequency and number of lung and liver metastasis. In conclusion, we have strong evidences both in vitro and in vivo that UHRF1 is a crucial component in aiding osteosarcoma progression, and have identified its novel role in tumor metastasis. The high metastatic rate and low 5-year survival rate following metastasis of osteosarcoma make UHRF1 a promising target for therapeutics. Further studies on the mechanism by which UHRF1 overexpression contributes to osteosarcomagenesis, including tumor growth and dissemination, will strongly aid the process of drug development for anticancer treatment.
Citation Format: Stephanie C. Wu, Claudia A. Benavente. Role of UHRF1 in tumorigenesis and metastasis of osteosarcoma [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr A41.
Abstract A45: Tumor suppressor miR-584-5p regulates MYC and sensitizes MYC-amplified medulloblastoma to vincristine and ionizing radiation
Authors: Abdelfattah Nourhan , Rajamanickam Subapriya , Timilsina Santosh , Subbarayalu Panneerdoss , Onyeagucha Benjamin , Rao Manjeet 
Published: February 2019

Abstract
Despite recent improvements in the overall survival of medulloblastoma (MB), only a modest percentage of patients survive high-risk disease. Furthermore, the toxicity associated with current therapies inflicts debilitating lifelong side effects on surviving MB patients. Using an unbiased microRNA screen, we identified miR-584-5p as a potent tumor suppressor that uniquely sensitizes MB to both ionizing radiation (IR) and vincristine (VCR), which are commonly used in combination to treat MB. Our studies revealed that miR-584-5p inhibited MB stem cell proliferation and consequently growth in vivo. Notably, we discovered that miR-584-5p imparts its tumor-suppressor and therapy-sensitizing effects by inhibiting histone deacetylase 1 (HDAC1), eukaryotic translation initiation factor 4e family member 3 (eIF4E3), and C-MYC. We demonstrated that miR-584-5p overexpression or the knockdown of its target genes including eIF4E3 and HDAC1 resulted in G2-M arrest, DNA damage, spindle defects, and apoptosis in MB cells. Meta-analysis of normal brain and MB tumor samples showed that while miR-584-5p is highly expressed in normal brain and cerebellum, it is highly downregulated across all MB subtypes. miR-584-5p targets, on the other hand, are highly overexpressed in MB tumors compared to normal cerebellum. Taken together, this study highlights a previously unidentified role for miR-584-5p, eIF4E3, and HDAC1 in regulating microtubule dynamics and DNA repair pathways. In addition, our study identifies novel targets that can affect the therapeutic efficacy of VCR and IR in MB and sets the stage for a new paradigm of treating medulloblastoma using microRNA-based therapeutics.
Citation Format: Nourhan Abdelfattah, Subapriya Rajamanickam, Santosh Timilsina, Panneerdoss Subbarayalu, Benjamin Onyeagucha, Manjeet Rao. Tumor suppressor miR-584-5p regulates MYC and sensitizes MYC-amplified medulloblastoma to vincristine and ionizing radiation [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr A45.
Abstract A47: Inhibition of histone methyltransferase with novel epipolythiodioxopiperazines (ETP) alkaloids in pediatric high-grade glioma
Authors: Dombrowski Stephen , Abou-Antoun Thamara , Mansour Anthony , Arar Rewa , Movassaghi Mohammad , Murphy Erin , Banerjee Shuvojit , Li Xiao-Nan , Houghton Peter , Bigner Darell , Carcaboso Angel Montero , Rich Jeremy , Recinos Violette 
Published: February 2019

Abstract
Pediatric high-grade glioma (HGG), which ranks among the most lethal of cancers among children, contain two recurrent mutations within the histone H3 gene H3F3A (K27M and G34R/V). It is not known whether these mutations directly alter specific epigenetic regulatory mechanisms that may be involved in tumor proliferation and growth, or contribute to their therapeutic resistance and rapid recurrence. Preliminary findings from our lab have identified that Chaetocin (CH), a pan histone methyltransferase (HMT) inhibitor, and two newly synthesized epipolythiodioxopiperazines (ETP) alkaloids that are structurally and functionally distinct HMT inhibitors can effectively kill pediatric HGG (N=7), including three that contain the H3 K27M mutation. In addition, CH and ETPs can also inhibit tumor sphere formation and cell migration at low concentrations (&lt;0.5uM) through in vitro studies. In H3 K27M tumors, these HMTi were shown to reverse hypomethylation of K27me3 transiently (&lt;48 hours). We also found these HMTis to decrease tumor stem cell expression (Sox2, Oct4), and increase tumor-suppressor activity (PTEN, p53) for three pediatric HGG up to 72 hours. These results suggest ETP effectiveness that acts through direct HMT inhibition may also influence other tumorigenic pathways, which may in part contribute to their aggressive nature. Results from this investigation have advanced our understanding of epigenetic regulation of solid brain tumors, and identified drugs that may specifically target pediatric H3 K27M tumor subtypes and could ultimately improve overall survival in pediatric patients with high-grade glioma.
Citation Format: Stephen Dombrowski, Thamara Abou-Antoun, Anthony Mansour, Rewa Arar, Mohammad Movassaghi, Erin Murphy, Shuvojit Banerjee, Xiao-Nan Li, Peter Houghton, Darell Bigner, Angel Montero Carcaboso, Jeremy Rich, Violette Recinos. Inhibition of histone methyltransferase with novel epipolythiodioxopiperazines (ETP) alkaloids in pediatric high-grade glioma [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr A47.