bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5905: Sp1 acetylation associates with stemness characteristics in temozolomide-resistant glioblastoma
Authors: Chuang Jian-Ying , Hsu Che-Chia , Chang Kwang-Yu , Chang Wen-Chang 
Published: August 2018

Abstract
The prognosis of glioblastoma (GBM) is usually poor even following treatment with the first-line chemotherapeutic agent temozolomide (TMZ). One most known resistant mechanism is the presence of DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). However, compared with MGMT-mediated innate TMZ resistance, the development of acquired resistance is considered more complex with multi-factorial involvement such as the presence of cancer stem cells (CSCs). In this study, we treated the MGMT-negative GBM cells with TMZ to investigate the acquired resistance, and found that both histone deacetylases (HDACs) and Sp1 are key factors protecting GBM against TMZ. These results include the following: (1) Stemness markers were highly increased in TMZ-resistant GBMs; (2) The activity of HDACs affected the stem-like characteristics and cell survival of GBM stem cells (GSCs); (3) An HDAC1/2/6-selective inhibitor MPT0B291 increased TMZ-sensitivity and induced senescence in TMZ-resistant cells; (4) MPT0B291 suppressed anti-senescence genes (hTERT and BMI1) expression via inhibition Sp1 transactivation; (5) Both HDACs and Sp1 were elevated and interacted with each other in GSCs and resistant GBM cells; (6) TMZ treatment induced Sp1 deacetylation, but MPT0B291 attenuated that. In summary, we verified that HDACs increases Sp1 activation via protein deacetylation and causes Sp1-downstream target upregulation, which may enrich stemness properties and protect GBM against chemotherapeutic drugs.
Citation Format: Jian-Ying Chuang, Che-Chia Hsu, Kwang-Yu Chang, Wen-Chang Chang. Sp1 acetylation associates with stemness characteristics in temozolomide-resistant glioblastoma [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 5905.
Abstract 5911: A bicistronic adenoviral vector carrying cytosine deaminase and GM-CSF genes significantly improves antitumor immunity and overall survival in colon cancer
Authors: Akbulut Hakan , Coleri Arzu , Sahin Gunce , Tang Yucheng , Deisseroth Albert , Icli Fikri 
Published: August 2018

Abstract
Background: Combination of cytotoxic treatments with immunotherapeutic agents seem more efficacious than using either strategy alone. Oncolytic viral vectors carrying immunostimulatory genes like GM-CSF have emerged as treatment options in various tumors. Previously, we have shown that combination of suicide gene therapy either with GM-CSF or vector-induced dendritic cells has significant anti-tumor efficacy. In the current study, we aimed to combine the cytotoxic effect of the suicide gene cytosine deaminase and the immunostimulatory effect of granulocyte macrophage colony stimulating factor in a single vector construct. Methods: We have constructed a bicistronic adenoviral vector carrying cytosine deaminase (CD) and granulocyte macrophage-colony stimulating factor (GM-CSF) genes combined with an IRES element and driven by CMV promoter (Ad-CMV-CDiresGMCSF). We tested the in vitro efficacy of the vector in various tumor cell lines and in a mouse model of colon cancer. Results: Our bicistronic vector Ad-CMV-CDiresGMCSF showed significant in-vitro cytotoxic effects on tumor cell lines similar to the vector carrying CD gene alone when 5-FC added. Likewise, the GM-CSF producing efficacy of the bicistronic vector was comparable to the vector carrying GM-CSF gene alone. In the syngeneic colon cancer model, the bicistronic vector carrying CD and GM-CSF genes yielded significant tumor shrinkage and overall survival when compared to the control suicide vector carrying CD gene alone. Accordingly, anti-tumor immune response parameters including CTL assay and immune cell infiltration of tumor tissue were significantly improved in the Ad-CMV-CDiresGMCSF vector treated group (p&lt;0.01). Conclusions: The Ad-CMV-CDiresGMCSF vector construct suggests a potential for the treatment of established tumors by inducing significant tumor killing and tumor-specific immune response.
Citation Format: Hakan Akbulut, Arzu Coleri, Gunce Sahin, Yucheng Tang, Albert Deisseroth, Fikri Icli. A bicistronic adenoviral vector carrying cytosine deaminase and GM-CSF genes significantly improves antitumor immunity and overall survival in colon cancer [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 5911.
Abstract 5931: PDGFRα+ pericryptal stromal cells are the critical source of Wnts and RSPO3 for murine intestinal stem cells in vivo
Authors: Greicius Gediminas , Kabiri Zahra , Sigmundsson Kristmundur , Liang Chao , Bunte Ralph , Singh Manvendra K. , Virshup David M. 
Published: August 2018

Abstract
Wnts and R-spondins (RSPOs) support intestinal homeostasis by regulating crypt cell proliferation and differentiation. Ex vivo, Wnts secreted by Paneth cells in organoids can regulate the proliferation and differentiation of Lgr5-expressing intestinal stem cells. However, in vivo, Paneth cell and indeed, all epithelial Wnt production is completely dispensable, and the cellular source of Wnts and RSPOs that maintain the intestinal stem cell niche is not known. Here we investigated both the source and the functional role of stromal Wnts and RSPO3 in regulation of intestinal homeostasis. RSPO3 is highly expressed in pericryptal myofibroblasts in the lamina propria and is several orders of magnitude more potent than RSPO1 in stimulating both Wnt/β-catenin signaling and organoid growth. Stromal Rspo3 ablation ex vivo resulted in markedly decreased organoid growth that was rescued by exogenous RSPO3 protein. PdgfRα is known to be expressed in pericryptal myofibroblasts. We therefore evaluated if PdgfRα identified the key stromal niche cells. In vivo, Porcn excision in PdgfRα+ cells blocked intestinal crypt formation, demonstrating for the first time that Wnt production in the stroma is both necessary and sufficient to support the intestinal stem cell niche. Mice with Rspo3 excision in the PdgfRα+ cells had decreased intestinal crypt Wnt/β-catenin signaling and Paneth cell differentiation, and were hypersensitive when stressed with dextran sodium sulfate. The data support a model of the intestinal stem cell niche regulated by both Wnts and RSPO3 supplied predominantly by stromal pericryptal myofibroblasts marked by PdgfRα.
[G.G. and Z.K. contributed equally to this work.]
Citation Format: Gediminas Greicius, Zahra Kabiri, Kristmundur Sigmundsson, Chao Liang, Ralph Bunte, Manvendra K. Singh, David M. Virshup. PDGFRα+ pericryptal stromal cells are the critical source of Wnts and RSPO3 for murine intestinal stem cells in vivo [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 5931.
Abstract 609: Neutrophils play a critical role in mediating antitumor activity of a combination therapy of radiation and immunotherapy
Authors: Tao Mi-Hua , Wu Chia-Jen , Tsai Yi-Ting , Wu Ping-Yi 
Published: August 2018

Abstract
The goal of cancer immunotherapy is to elicit robust tumor-specific immune responses that can generate durable tumor regression and/or eradication. Recent clinical trials using immune checkpoint blockades specific to programmed cell death-1/ligand-1 (PD-1/PD-L1) have shown durable clinical responses in various cancer types but benefit only a small portion of patients. We previously demonstrated that combination of radiation and immunotherapy of interleukin 12 (IL-12) and granulocyte macrophage colony-stimulator factor (GM-CSF) greatly improved the therapeutic efficacy than either single therapy alone. In analysis of the tumor-infiltrating leukocytes post combination therapy, we found that the number of CD11b+F4/80-/Ly6G+ neutrophils were greatly increased. In this study, we characterized these tumor-associated neutrophils (TANs) before and after treatment and investigated their role in mediating the antitumor activity of the combination therapy. We isolated TANs from the regressing tumors and demonstrated that these TANs were impaired in their immunosuppressive activities. Flowcytometric analysis revealed that several co-stimulatory molecules, including class II major histocompatibility complex, CD40 and CD86, were increased on these TANs. Accordingly, these TANs gained the ability to stimulate T cell proliferation. Antibody-depletion experiments showed that TANs were required for tumor regression in RT/12GM combination therapy. Together, our data demonstrate that combination of radiotherapy and IL-12/GM-CSF improved antitumor immunity through enhancing antigen presentation activity and reduced immunosuppressive functions of TANs.
Citation Format: Mi-Hua Tao, Chia-Jen Wu, Yi-Ting Tsai, Ping-Yi Wu. Neutrophils play a critical role in mediating antitumor activity of a combination therapy of radiation and immunotherapy [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 609.
Abstract 610: Dynamic immune landscape of the peripheral blood mononuclear cells from recurrent hepatocellular carcinoma patients undergoing radiofrequency ablation treatment
Authors: Chen Dexi , Zhao Yang , Ouyang Yabo , Liu Kai , Rao Wei , Wei Feili , Liu Xiaoni , Shi Ying , Wang Shanshan , Pang Lijun , Qiao Luxin , Zang Yunjin , Yin Xiaoming 
Published: August 2018

Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignancies and the third most lethal malignancy worldwide. Radiofrequency ablation (RFA) is the most commonly used curative treatment for the patients not suitable for surgical resection or liver transplantation. It can cause regional and global anti-tumor immune response, but is insufficient to prevent HCC recurrence in many patients. Peripheral blood mononuclear cells (PBMC) are considered to be the best target for the study of the global immune status after RFA. Previous studies on PBMC were mainly based on traditional flow cytometry, which could not differentiate the complicated immune cell subtypes. In this study, we used mass cytometry to comprehensively characterize the phenotypic and functional alterations of the PBMC in recurrent HCC patients who had received RFA treatment. Fifty-four (54) blood samples from 13 patients were analyzed. Manual gating, SPADE analysis and viSNE analysis were used to interpret the mass cytometry data. The percentage of monocytes showed a fast increase after RFA, and reduced to the normal level before the HCC recurrence (P=0.026). A long-lasting reduction of B cells count were also found after the first RFA (P=0.021), and the B cell count remained at a low level before and after the secondary RFA. The percentage of CD4+ T cells in CD45+ cells was significantly reduced after the first RFA, then restored to the pretreatment level at the time of recurrence, and reduced again after the second RFA(P=0.024). CD8+ T cells showed the same alteration trend as CD4+ cells (P=0.03). We also examined the expression of functional markers in T cells and Tregs. Alterations of CD28 expression were most frequently found in T cells. The Treg population showed a large heterogeneity among the patients with TIM3, LAG3 or CTLA4 positive Tregs being the largest populations. These results suggest a more specific treating modality should be used in combination with the RFA treatment.
Citation Format: Dexi Chen, Yang Zhao, Yabo Ouyang, Kai Liu, Wei Rao, Feili Wei, Xiaoni Liu, Ying Shi, Shanshan Wang, Lijun Pang, Luxin Qiao, Yunjin Zang, Xiaoming Yin. Dynamic immune landscape of the peripheral blood mononuclear cells from recurrent hepatocellular carcinoma patients undergoing radiofrequency ablation treatment [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 610.
Abstract 62: Effect of cancer cell-derived exosome on energy metabolism associated with macrophage activation
Authors: Kam Yoonseok , Dranka Brian P. 
Published: August 2018

Abstract
Macrophage is a critical microenvironmental component which can control tumor progression, and dynamic changes in cellular metabolism accompany the polarization. As well as other immune cells, the activation of macrophages can be modulated by cancer cells. Cancer-derived exosome is a newly emerging microenvironmental factor enables cancer cells to communicate with macrophages. In this study, examined were the activation-associated bioenergetic changes and the effect of cancer cell-derived exosome on the changes by a) monitoring the early metabolic kinetics and b) profiling bioenergetic phenotype resulted. In vitro activation of RAW264.7 macrophage cell line by injecting lipopolysaccharide (LPS) and interferon γ (IFNγ) in a Seahorse XF analyzer induced an immediate early increase in glycolytic rate. It also showed a delayed down-regulation of mitochondrial respiration, which resulted in a secondary elevation of glycolytic rate. This secondary glycolytic response was only obtained by LPS-IFNγ co-stimulation and mediated by induced nitric oxide synthase (iNOS) signaling. In contrast to the dynamic changes in metabolic phenotype, the total ATP production rate appeared to be stably maintained according to the XF data normalized by cell number. However, macrophage activation significantly increased glycolysis-dependent portion of ATP production. ATPs were generated almost solely by glycolysis after the delayed mitochondrial down-regulation by iNOS. Co-injection of cancer cell-derived exosomes with LPS slightly but significantly accelerated the immediate early glycolytic response as well as the delayed mitochondrial down-regulation. Furthermore, exosomes induced the immediate early glycolytic response even in the absence of LPS. These results imply that presence of cancer cell-derived exosomes may promote macrophage activation and accelerate pro-inflammatory immune response in a tumor microenvironment.
Citation Format: Yoonseok Kam, Brian P. Dranka. Effect of cancer cell-derived exosome on energy metabolism associated with macrophage activation [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 62.
Abstract 628: Immunometabolic signature of papillary thyroid carcinoma
Authors: Weiss Vivian L. , Baregamian Naira 
Published: August 2018

Abstract
Introduction: Papillary thyroid carcinoma (PTC) is the most common subtype of thyroid cancer with rapidly rising incidence. The interface between PTC tumor metabolic reprogramming and metabolic immunomodulation remains poorly understood.
Experimental Procedures: We sought to investigate the immunometabolic interaction patterns of PTC tumors and to determine whether a correlative relationship exists between tumor-infiltrating immune cell phenotypes and the expression of tumor metabolic enzymes. We performed a computational immunogenomic analysis to calculate leukocyte fractions within 496 PTC tumors from The Cancer Genome Atlas (TCGA). Immunogenomic analysis was performed using CIBERSORT (Newman AM et al., Nature Methods2015), a deconvolution method to calculate leukocyte fractions using RNA gene expression signatures. The PTC immune cell fractions were then compared to the RNA expression of tumor metabolic enzymes within the TCGA data using regression analysis. Matching targeted metabolomic analysis (Metabolon, Inc.) of 20 human PTC tumors was performed to determine tumor metabolite profiles associated with perturbed tumor cellular metabolic pathways based on the TCGA data analysis.
Results: The immunogenomic and PTC metabolic pathway enzyme expression analysis demonstrated significant correlation between immune cell types and major metabolic pathway enzymes. Specifically, tumor glycolytic enzymes upstream of the TCA cycle correlated with CD8 (hexokinase-1, p&lt;0.0001) and T regulatory (enolase, p&lt;0.0001) cell infiltrates. Enhanced pyruvate cycling into the TCA cycle correlated with the presence of several immune cell types (malic enzyme 2 vs. follicular helper T cells, p&lt;0.0001; pyruvate carboxylase vs CD8 T cells, p&lt;0.0001). The expression of TCA cycle enzymes correlated with the fraction of macrophages (aconitase, p&lt;0.0001; IDH1, p&lt;0.05). Significant differences in PTC tumor and normal thyroid tissue metabolite profiles were observed in glycolysis and TCA cycle, further supporting our findings of immunometabolic plasticity it PTC. Together, these findings highlight the central role TCA cycle activity plays in PTC tumor immunometabolism.
Conclusion: We demonstrate, for the first time, a distinct immunometabolic tumor signature supported by tumor metabolic reprogramming in PTC tumors. This novel characterization approach provides an important foundation for future functional metabolic studies within the tumor and immunologic microenvironment. A mechanistic understanding of the complex integration of immune networks and cellular metabolism can be harnessed for future therapeutic immunometabolic modulation in PTC.
Citation Format: Vivian L. Weiss, Naira Baregamian. Immunometabolic signature of papillary thyroid carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 628.
Abstract 63: Microenvironment-derived mitochondria prime glioma chemoresistance by augmenting NAD+metabolism and PARP-dependent DNA repair
Authors: Liu Yang , Gilbert Mark , Yang Chunzhang 
Published: August 2018

Abstract
Background: Mitochondria, the major organelles of cellular metabolism, can be released into the microenvironment and affect adjacent cells, supporting recipient cell metabolism and protecting them from unfavorable conditions. While our knowledge of intercellular mitochondria transfer under normal physiological conditions is expanding, a key question remains unanswered: do microenvironment-derived mitochondria influence the survival and malignant transformation of cancer cells?
Methods: In this study, we have established in vitro and in vivo models to aid in the understanding of mitochondrial transfer between astrocytes and glioma cells.
Results: We demonstrate that mitochondria are released from normal astrocytes through extracellular vesicles, and are adopted by neighboring glioma cells. Mitochondrial transfer not only improves oxidative metabolism in recipient glioma cells, but also supports the detoxification of chemotherapeutic agents by fueling PARP-dependent DNA repair with ATP and NAD+. Targeting astrocyte mitochondria-releasing pathways increased the cytotoxic effects of chemotherapy, reduced xenograft progression, and prolonged overall survival. Our findings suggest that microenvironment-derived mitochondria confer both metabolic capability and chemoresistance to cancer cells.
Conclusion: Targeting microenvironment-derived mitochondria may be important in reducing the capacity for cancer cells to recover from cancer treatment, thereby enhancing treatment efficacy.
Citation Format: Yang Liu, Mark Gilbert, Chunzhang Yang. Microenvironment-derived mitochondria prime glioma chemoresistance by augmenting NAD+metabolism and PARP-dependent DNA repair [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 63.
Abstract 641: Cell free DNA in the supernatant of pleural effusion can detect driver and resistance mutations and can guide TKI treatment decisions
Authors: Hummelink Karlijn , Muller Mirte , Linders Dorothe , Noort Vincent van der , Nederlof Petra , Burgers Sjaak , Meijer Gerrit , Heuvel Michel van den , Broek Daan van den , Monkhorst Kim 
Published: August 2018

Abstract
Introduction:
Molecular profiling of tumors has become the mainstay of diagnostics for metastasized solid malignancies and guides personalized treatment, especially in non-small cell lung cancer (NSCLC). In current practice it is often challenging to obtain sufficient tumor material for reliable molecular analysis. Cell free (cf) DNA in blood or other bio-sources could present an alternative approach to obtain genetic information from the tumor. In a retrospective cohort we analyzed the added value of cfDNA analysis in pleural effusions for molecular profiling.
Methods:
We retrospectively analyzed both the supernatant and the cell pellet of 44 pleural effusions sampled from 39 patients with KRAS (23) or EGFR (16) positive tumors for the original driver gene mutation as well as for EGFR T790M resistance mutations. Patients were diagnosed with either NSCLC (32), colon carcinoma (4), appendiceal carcinoma (2) or adenocarcinoma of unknown primary (1). Samples collected in the context of routine clinical care were stored in the NKI-AVL biobank. We used Bio-Rad QX200 droplet digital PCR for analysis.
Results:
The original driver gene mutation could be detected in 37 of the 44 pleural effusions by analysis of both supernatant (35/44 positive) and cell pellet (29/44 positive). In 7 out of 20 pleural effusions from patients with EGFR mutation positive tumors, a T790M mutation was detected. All 7 supernatants were positive as were 5 of the 7 cell pellets. The EGFR T790M mutation was confirmed in all supernatants (4/4) and in 3 of the 4 cell pellets sampled from patients with T790M positive tumors (4).
Conclusions:
Cell free DNA in pleural effusion proved to be a valuable bio-source and can be used to detect driver gene mutations as well as resistance mechanisms like EGFR T790M in pleural effusion.
Citation Format: Karlijn Hummelink, Mirte Muller, Dorothe Linders, Vincent van der Noort, Petra Nederlof, Sjaak Burgers, Gerrit Meijer, Michel van den Heuvel, Daan van den Broek, Kim Monkhorst. Cell free DNA in the supernatant of pleural effusion can detect driver and resistance mutations and can guide TKI treatment decisions [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 641.