bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3175: Sulfated glycopeptide nanostructures activate and extend bone morphogenetic protein 4 ability to increase pediatric malignant glioma chemotherapeutic efficacy
Authors: Xi Guifa , Best Benjamin , Nayak Sonali , McClendon Mark , Mania-Farnell Barbara , Kessler John , James Charles David , Stupp Samuel , Tomita Tadanori 
Published: August 2018

Abstract
Pediatric gliomas, particularly high-grade gliomas, are among the most formidable and devastating cancers in children. These tumors have remained incurable, regardless of the many treatment approaches attempted. We recently identified a small population of glioma cells with stem-like features in pediatric gliomas (glioma stem cells: GSCs), that may be responsible, for therapeutic resistance in pediatric gliomas. Signaling by bone morphogenetic protein 4 (BMP4), an essential molecule for central nervous system (CNS) development, increases GSC therapeutic sensitivity, and whose activation is a promising adjuvant for glioma treatment. Mechanisms through which BMP4 increases therapeutic sensitivity need to be elucidated as this can lead to the identification of additional targets for treating malignant gliomas in children. Delivery systems for administering BMP4 in a clinical setting also need to be developed. Here, we show that BMP4 increases chemosensitivity by decreasing H3 lysine 4 trimethylation (H3K4me3) at the promoter of multidrug resistant gene 1 (MDR1) that, in turn, results in increased BMP4 expression. This appears to be the result of BMP4 decreasing levels of hSETD1A, a critical methyltransferase for H3K4me3. Our work also demonstrates the first use of a novel sulfated glycopeptide (glycol-PA) nanostructure as a vector for delivery of BMP4. Glycol-PA markedly extended and enhanced BMP4 function, and increased chemotherapeutic anti-tumor activity against pediatric malignant glioma cells in culture. Overall, our results expand understanding of how BMP4 brings about glioma therapeutic sensitization through epigenetic mechanisms, and show that highly bioactive glyco-PA nanostructures have potential as a novel delivery mechanism for treating pediatric malignant glioma, as well as other tumors.
Citation Format: Guifa Xi, Benjamin Best, Sonali Nayak, Mark McClendon, Barbara Mania-Farnell, John Kessler, Charles David James, Samuel Stupp, Tadanori Tomita. Sulfated glycopeptide nanostructures activate and extend bone morphogenetic protein 4 ability to increase pediatric malignant glioma chemotherapeutic efficacy [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 3175.
Abstract 3192: Aptamers, antibodies and radiotherapy for the treatment of DIPG
Authors: Martinez-Velez Naiara , Marigil Miguel , Aristu Javier , Ramos Luis , Pastor Fernando , Patiño-García Ana , García-Moure Marc , Fueyo Juan , Gomez-Manzano Candelaria , Diez-Valle Ricardo , Tejada Sonia , Alonso Marta M. 
Published: August 2018

Abstract
Diffuse intrinsic pontine gliomas (DIPGs) is one of the most aggressive pediatric brain tumors. Radiotherapy (RT) constitute the standard of care of these tumors being its therapeutic effect just palliative. There is plenty of evidence that RT is able to activate immune responses through the induction of immunogenic cell death. However, it also elicits immunosuppressive effects and enforces immunological tolerance. The result is that in DIPGs the RT effect is just transitory. In this context, immune costimulatory or inhibitory molecules with the capability to boost the immune effect of RT could be amenable agents to use in combination to treat DIPGs. Agonist antibodies has been widely used in immunotherapy. Aptamers are high-affinity single-stranded nucleic acid ligands that exhibit remarkable affinity and specificity to their targets, comparable or exceeding that of antibodies. 4-1BB is a major costimulatory receptor promoting the survival and expansion of activated T cells. TIM-3 is a negative regulator of lymphocyte function that is involved in T-cell exhaustion. To this end, we examined the effect of RT in combination with either an agonist 4-1BB antibody or an aptamer against TIM-3. Importantly, both combined treatments showed a safe profile. Moreover, combination treatment of 4-1BB agonist antibody or TIM-3 aptamer with RT resulted in a significant improvement in the median survival of mice bearing DIPG orthotopic tumors when compared with single treatment in around 20 days (P=0.001 and P=0.04, for the combination of RT and 4-1BB or TIM-3,respectively). In addition, both combination led to long-term survivors (90 days). Rechallenge experiments in these animals showed the generation of memory against the tumors in both combined treatment. Mechanistic studies performed on day 16 showed an increase in CD8 effector cells, a decrease in T-regulators Foxp3+ cells and an increase in INF-gamma expression suggesting the triggering of an antitumor-immune response. Our data underscore that combination of RT with immune-boosting strategies for DIPGs are worth exploring.
Citation Format: Naiara Martinez-Velez, Miguel Marigil, Javier Aristu, Luis Ramos, Fernando Pastor, Ana Patiño-García, Marc García-Moure, Juan Fueyo, Candelaria Gomez-Manzano, Ricardo Diez-Valle, Sonia Tejada, Marta M. Alonso. Aptamers, antibodies and radiotherapy for the treatment of DIPG [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 3192.
Abstract 3194: Development of an in vitro drug profiling platform with primary Rhabdomyosarcoma cells for tailoring patient-specific treatments
Authors: Wachtel Marco , Manzella Gabriele , Römmele Michaela , Zhang Luduo , Tchinda Joelle , Niggli Felix , Schäfer Beat 
Published: August 2018

Abstract
The paradigm of cancer therapy currently shifts from broadly used cytotoxic drug cocktails to patient specific precision therapies. These novel therapies are normally directed towards tumor specific driver oncogenes, identified by genomic analysis of individual tumors. In case of tumors with a very low mutational burden and/or currently undruggable driver oncogenes this approach is less suitable. There, direct drug profiling of in vitro cultured tumor cells represents a promising alternative for identification of patient specific therapies. Conditions to maintain primary tumor cells in culture for this purpose however are largely unknown for most tumor entities. Here, we aimed to establish an in vitro drug profiling platform for Rhabdomyosarcoma (RMS), a childhood cancer with above described characteristics. Towards this aim, we isolated cells from 6 alveolar and 8 embryonal RMS patient derived xenografts and systematically tested 18 different culture conditions in order to find suitable parameters for in vitro propagation of primary RMS cells. This approach revealed that cells from most tumors survive and proliferate only in serum-free medium, whereas in serum containing medium tumor cells are progressively lost over time. Importantly, cells preserve the clonal composition and phenotypic characteristics of the primary PDX under these conditions, as assessed by genomic and copy number analysis. Drug profiles established with a library of 204 drugs revealed, beside patient-specific vulnerabilities, a yet unrecognized sensitivity of a subgroup of alveolar RMS towards AKT inhibitors. Furthermore, screening with the same drugs for resensitization of resistant relapse samples identified the BCL-2 family inhibitor ABT-263 as most potent resensitizer towards standard-of-care chemotherapy. Detailed molecular analysis revealed that this effect is based on blockade of the BCL-XL-MCL-1 axis. Overall, our proof of concept study highlights the feasibility of in vitro drug profiling of primary RMS cells for patient-specific treatment selection in a co-clinical setting.
Citation Format: Marco Wachtel, Gabriele Manzella, Michaela Römmele, Luduo Zhang, Joelle Tchinda, Felix Niggli, Beat Schäfer. Development of an in vitro drug profiling platform with primary Rhabdomyosarcoma cells for tailoring patient-specific treatments [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 3194.
Abstract 3198: Comprehensive transcriptome analysis identifies integrated mRNA-lncRNA signature of triple-negative breast cancer treated with radiotherapy
Authors: CHEN Xingxing , YANG Zhaozhi , JIANG Yizhou , MA Jinli , YU Xiaoli , SHAO Zhimin , GUO Xiaomao 
Published: August 2018

Abstract
Triple-negative breast cancer (TNBC), with a lack expression of ER, PR, and HER-2 as potential treatment targets, is insensitive to the hormonal and trastuzumab therapies. Thus, local and regional treatment, such as radiotherapy is placed with more emphasis when treating TNBC patients. In the current study, expression profiles of mRNAs and long noncoding RNAs (lncRNAs) in TNBC patients, who received radiotherapy in our institute, was investigated to develop radiation-related gene signatures to facilitate individualized TNBC treatment. Specifically, 44 TNBC samples including 14 recurrences and 30 non-recurrences after radiotherapy were analyzed by using transcriptome microarrays. A total of 626 mRNAs were identified as differentially expressed (DEGs) between recurrent patients and non-recurrent patients (|fold change| &gt; 1.5, p &lt; 0.05). GeneOntology analysis showed that these DEGs were enriched in immune response, mitotic cell cycle, inflammatory response, cell adhesion as well as extracellular matrix organization, which indicated that these biological processes may exert significant impacts on the therapeutic effects of radiation. In addition, a total of 150 lncRNAs were identified as differentially expressed between recurrent patients and non-recurrent patients (|fold change| &gt; 1.5, p &lt; 0.05). The differentially expressed mRNAs and lncRNAs were confirmed by quantitative real-time PCR. Cox regression model was further applied to explore potential lncRNAs involved in certain signaling pathways such as JAK/STAT, EGRF/ATK/PI3K are highly co-expressed with mRNAs in these signaling pathways. Overall, our results revealed a panel of mRNAs and lncRNAs with significant impacts on evaluating the TNBC radio-therapeutic effects as well predicting the possibility of recurrence.
Citation Format: Xingxing CHEN, Zhaozhi YANG, Yizhou JIANG, Jinli MA, Xiaoli YU, Zhimin SHAO, Xiaomao GUO. Comprehensive transcriptome analysis identifies integrated mRNA-lncRNA signature of triple-negative breast cancer treated with radiotherapy [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 3198.
Abstract 3202: Radiation increases invasive activity of breast cancer cells via altering lysosome exocytosis
Authors: Wu Ping-Hsiu , Onodera Yasuhito , Giaccia Amato J. , Le Quynh-Thu , Shirato Hiroki , Nam Jin-Min 
Published: August 2018

Abstract
Radiotherapy is a standard treatment for many localized solid cancers. However, previous studies have shown that radiation may increase the invasive activity of cancer cells and potentially distant metastasis. Recently, lysosome exocytosis has been linked to cancer cell invasiveness and progression. In this study, we evaluate the role of lysosome exocytosis on invasive activity of breast cancer cells upon radiation.We used both human and murine breast cancer cell lines (MDA-MB-231 and 4T1). The cells were treated with a single radiation dose of 4 Gy. Cell invasive activity was measured by matrigel chemoinvasion assay. Lysosome exocytosis was quantified by fluorescein isothiocyanate conjugated dextran (FITC-dextran) intake assay, cell-surface lysosomal associated membrane protein 1 (LAMP1) expression and cellular lysosome distribution assay. To validate the lysosome function, lysosome inhibitors, bafilomycin A1 and chloroquine were used. Short hairpin RNA (shRNA) was used to knockdown ARL8B, which is a small GTPase protein that regulates lysosome distribution and exocytosis. The invasive activity and lysosome exocytosis of tested breast cancer cell lines were increased after radiation treatment. Treatment with lysosome inhibitor bafilomycin A1 or chloroquine decreased the invasive activity of cancer cells, with or without radiation treatment. The protein level of ARL8B increased in the lysosome fraction upon radiation. Down-regulation of ARL8B with shRNA led to a decrease in lysosome exocytosis with a concomitant inhibition radiation induced invasive activity of the breast cancer cells without affecting the basal invasiveness. In addition, overexpression of ARL8B increased the invasive activity of breast cancer cells, which was similar to the result obtained after radiation.In summary, radiation enhances lysosome exocytosis in breast cancer cells that can lead to their increased invasive activity. Our findings provide a novel mechanism to understand cancer invasion after radiotherapy and suggest novel approaches to counteract this undesirable effect of radiotherapy in the future.
Citation Format: Ping-Hsiu Wu, Yasuhito Onodera, Amato J. Giaccia, Quynh-Thu Le, Hiroki Shirato, Jin-Min Nam. Radiation increases invasive activity of breast cancer cells via altering lysosome exocytosis [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 3202.
Abstract 3212: Nuclear-targeted gold nanoparticles as radiosensitizers
Authors: Krishnan Sunil , Aliru Maureen 
Published: August 2018

Abstract
Purpose
Intracellular localization of gold nanoparticles has been shown to enhance the effects of radiation. However, few studies have investigated the effect of subcellular localization of these particles on enhancing the radiosensitization effect in cells treated with radiation of varying energies and linear energy transfer (LET) levels. Herein, we evaluate the radiosensitization potential of nuclear-targeted gold nanoparticles across a spectrum of energies and LETs.
Methods
Gold nanospheres (AuNSs) were functionalized with a nuclear localization sequence (NLS) peptide to enhance the nuclear accumulation of these particles. Internalization of the particles into the cells was achieved using a cell penetrating peptide (CPP). Cellular and nuclear internalization were assessed in Panc-1 human pancreatic adenocarcinoma cancer cells using western blot (WB), transmission electron microscopy, dark field microscopy and inductively-coupled plasma mass spectrometry (ICP-MS). DNA damage due to radiation was evaluated through γH2AX and 53BP1 foci staining. Clonogenic cell survival assay was performed to evaluate the radiosensitization effect after irradiation with 250-kVp X-rays, Cs-137, Co-60, 6 MV and 100 MeV protons (LET 2.5 and 7.7 keV/µm).
Results
Nuclear-targeted particles (nAuNS) and non-targeted particles (PEGylated, pAuNS) demonstrated similar cellular internalization. However, enhanced uptake of nuclear-targeted particles was observed in the nucleus when compared to non-targeted particles. This was confirmed using dark field microscopy, WB and ICP-MS analysis. DNA double strand breaks through γH2AX and 53BP1 foci staining revealed significantly higher numbers of foci at early (1 hour) and late (24 hour) time points following radiation and nAuNS compared to radiation and pAuNS treatment. Clonogenic cell survival assay revealed significantly higher radiosensitization enhancement factor (REF) at 10% survival fraction for nAuNS compared to pAuNS for all beams assessed. Protons with higher LETs resulted in greater clonogenic cell death and nAuNS further increased radiosensitization whereas pAuNS did not.
Conclusion
Our data demonstrates that, across a spectrum of radiation energies and LETs, nuclear-targeted gold nanoparticles enhance radiosensitization beyond that achievable with strictly intracytoplasmic gold nanoparticles.
Citation Format: Sunil Krishnan, Maureen Aliru. Nuclear-targeted gold nanoparticles as radiosensitizers [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 3212.
Abstract 3219: Sensitizing hypoxic small cell lung cancer cells to radiation and hydrogen peroxide-producing agents using CuATSM
Authors: Sciegienka Sebastian , Rodman Samuel , Tomanek-Chalkley Ann , Falls Kelly C. , Spitz Douglas R. , Fath Melissa A. 
Published: August 2018

Abstract
Cancer cells have increased steady state levels of reactive oxygen species (ROS; O2•- and H2O2) compared to normal cells. It has been proposed that using redox active agents that further increase ROS levels will result is selective cancer cell death. This metabolic frailty can be targeted using drugs deemed safe for human use, ascorbate (ASC) and disulfiram (DSF), via a mechanism of H2O2 production. CuATSM is a drug being used in clinical trials to treat ALS disease. Imaging studies have shown that CuATSM preferentially concentrates in hypoxic tissues, releasing its Cu after entering cells. Copper (Cu) can participate in oxidation reactions that result in highly toxic hydroxyl radicals. Tumors often have areas of hypoxic tissue that exhibit resistance to ionizing radiation (IR). Our hypothesis is that CuATSM can be used to sensitize hypoxic regions of tumors to IR, ASC and/or DSF.
Method: H2O2 flux after addition of ASC or DSF was measured in small cell lung cancer (SCLC) cells DMS53 using the 3-aminotriazole method. The Cu uptake of these cells was measured in normoxia and hypoxia after treatment with CuATSM. DMS53 and DMS273 (SCLC lines) were treated with ASC, CuATSM, and/or DSF+CuSO4 at varying oxygen tensions with and without IR and clonogenic assays were performed.
Results: Pharmacologically relevant dosing of DSF and ASC resulted in significantly higher fluxes of H2O2 compared to control. Both DSF and ASC enhanced IR clonogenic cell death in SCLC lines. Treatment with CuATSM resulted in increased intracellular Cu and enhanced cell death from ASC and IR in hypoxic conditions.
Conclusion: These observations support the hypothesis that the differences in steady-state level of ROS in small cell lung cancer cells can be exploited to develop effective therapies using ASC and DSF. Furthermore CuATSM can enhance responses in hypoxic tumor tissues to both IR and ASC. (Supported by P50 CA174521, T32 CA078586, P30 CA086862 and Carver Research Program of Excellence in Redox Biology and Medicine.)
Citation Format: Sebastian Sciegienka, Samuel Rodman, Ann Tomanek-Chalkley, Kelly C. Falls, Douglas R. Spitz, Melissa A. Fath. Sensitizing hypoxic small cell lung cancer cells to radiation and hydrogen peroxide-producing agents using CuATSM [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 3219.
Abstract 3222: Evaluation of associations between circulating proteins and breast cancer risk using genetic variants
Authors: Shu Xiang , Bao Jiandong , Wu Lang , Long Jirong , Guo Xingyi , Michailidou Kyriaki , Bolla Manjeet K. , Wang Qin , Dennis Joe , Simard Jacques , Easton Douglas F. 
Published: August 2018

Abstract
Breast cancer is the most commonly diagnosed cancer in women in many countries. Several circulating protein biomarkers have been identified in relation to breast cancer risk. However, previous studies either had small sample sizes or employed low-throughput techniques. To search for novel biomarkers, we utilized genetic variants as instruments and evaluated over 1,400 proteins in relation to breast cancer risk using data from the Breast Cancer Association Consortium (BCAC).
We extracted beta coefficients from reported protein quantitative trait loci (pQTL) derived from genome-wide association studies of circulating proteins. Summary statistics of these pQTL variants associated with breast cancer risk were obtained from 122,977 cases and 105,974 controls of European descent in the BCAC. Associations of genetically predicted protein levels with breast cancer risk were evaluated using the inverse-variance weighted method. For proteins with a significant association, expression levels of the corresponding gene were predicted using genotyping and transcriptomic data from the Genotype-Tissue Expression project and then evaluated for their associations with breast cancer risk.
We identified 56 protein biomarkers showing a significant association with breast cancer risk after accounting for multiple comparisons (false discovery rate &lt; 0.05). Among them, levels of 32 proteins were influenced by variants close to a newly reported breast cancer susceptibility locus (9q34.2, ABO). Inverse associations of breast cancer risk were found with membrane proteins such as insulin receptor, insulin-like growth factor receptor 1, hepatocyte growth factor receptor, neurogenic locus notch homolog protein 1, and vascular endothelial growth factor receptor 2, with odds ratios ranging from 0.82 to 0.97 per unit increase in genetic risk scores (p-values ranging from 6.53x10-4 to 3.28x10-8). Genetically predicted expression of five genes, CPNE1, CTSF, TFPI, SCG3, and QSOX2, was found to be associated with breast cancer risk at p &lt;0.05 in the same direction as the associations observed for the corresponding proteins. Results from our study suggest that multiple membrane proteins related to insulin resistance may be linked to breast cancer risk through genetic variants at 9q34.2.
Citation Format: Xiang Shu, Jiandong Bao, Lang Wu, Jirong Long, Xingyi Guo, Kyriaki Michailidou, Manjeet K. Bolla, Qin Wang, Joe Dennis, Jacques Simard, Douglas F. Easton. Evaluation of associations between circulating proteins and breast cancer risk using genetic variants [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 3222.