bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4358: The immunomodulatory anticancer agent RRx-001 induces a vaccine-like interferon response through epigenetic induction of viral mimicry
Authors: Zhao Hongjuan , Ning Shoucheng , Nolley Rosalie , Scicinski Jan , Oronsky Bryan , Knox Susan J. , Peehl Donna M. 
Published: July 2017

Abstract
RRx-001, sourced from the aerospace industry and currently in phase II clinical trials, is a novel anti-cancer agent that mediates immunomodulatory effects, either directly through polarization of tumor associated macrophages or indirectly through vascular normalization and increased T-lymphocyte infiltration. With multiple additional mechanisms of action including upregulation of oxidative stress, depletion of GSH and NADPH, anti-angiogenesis and epigenetic modulation, RRx-001 is being studied as a single chemotherapeutic agent to resensitize tumors to prior therapy and to prime tumors to respond to radiation, chemotherapy and immunotherapy in combination therapy studies. In this study, we identified another mechanism, viral mimicry, which refers to the ‘unsilencing’ of epigenetically repressed viral genes present in the tumor that provokes an immune response and may contribute to the anti-cancer activity of RRx-001. Specifically, RRx-001 inhibited the growth of human colon cancer cells (HCT 116) and decreased levels of the DNA methyltransferases Dnmt1 and Dnmt3a in a time and dose-dependent manner. Treatment of HCT 116 cells with 0.5 μM RRx-001 for 24 hours significantly increased transcripts of interferon (IFN)-responsive genes and this induction was sustained for up to 4 weeks after transient exposure to RRx-001. ELISA assays showed that RRx-001 increased secretion of type I and III IFNs by HCT 116 cells, and these IFNs were confirmed to be bioactive. Transcription of endogenous retroviruses was induced by RRx-001 through demethylation of the promoter of endogenous retrovirus genes as determined by methylation-specific polymerase chain reaction and combined bisulfite restriction analysis. Immunofluorescence staining with J2 antibody confirmed induction of double-stranded RNA. In conclusion, transient exposure of HCT 116 cells to low-dose RRx-001 induced transcription of silenced retroviral genes present in the cancer cell DNA with subsequent synthesis of IFN in response to this “pseudo-pathogenic” stimulus, mimicking an antiviral defense. RRx-001-mediated IFN induction may have the potential to improve the efficacy of immunotherapies as well as radiotherapy, standard chemotherapies and molecularly targeted agents when used in combination.
Citation Format: Hongjuan Zhao, Shoucheng Ning, Rosalie Nolley, Jan Scicinski, Bryan Oronsky, Susan J. Knox, Donna M. Peehl. The immunomodulatory anticancer agent RRx-001 induces a vaccine-like interferon response through epigenetic induction of viral mimicry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4358. doi:10.1158/1538-7445.AM2017-4358
Abstract 4359: Systematic approach to methylation biomarker development in chronic lymphocytic leukemia, breast and lung cancers
Authors: Wojdacz Tomasz K. , Daugaard Iben , Kjeldsen Tina , Hager Henrik , Kristensen Thomasz , Kristensen Louise , Møller Michael B. , Hansen Lise Lotte 
Published: July 2017

Abstract
There is no doubt that testing for disease specific methylation changes can guide disease risk assessment, facilitate detection of the disease, support prognostication and personalization of treatment as well as guide post treatment patient care (1). Nevertheless, the use of methylation biomarkers in standard patient care is still marginal. Difficulties in implementation of methylation biomarker testing in standard in-vitro diagnostics are mainly attributed to challenges in establishment of the systematic approach allowing for efficient discovery and subsequent validation of clinical utility of potential disease specific methylation biomarkers. We have combined state-of-the-art genome wide methylation screening technologies (including: newest Illumina MethylationEPIC 850k BeadChip) enabling methylation biomarker discovery with the cost and time efficient locus specific technologies to streamline the development, validation and implementation of methylation biomarkers for clinical disease management. With the use of technologies that in an affordable fashion enable screening for genome wide methylation changes in a substantial number of clinical samples, we were able to discover clinically relevant disease specific methylation signatures e.g. in CLL. The high technical complexity of the genome wide screen technologies prevents them for being straightforward applicable in diagnostic settings. Thus we used techniques such as Methylation-Sensitive High Resolution Melting (MS-HRM) (2) to develop assays fulfilling the requirements for diagnostic applications. Subsequently, we evaluated the clinical relevance of the most promising biomarker candidates in chronic lymphocytic leukaemia, breast and lung cancers, using these assays (3, 4). Overall, our workflow allows fast and efficient validation of not only already existing biomarker candidates but also discovery of new disease specific methylation changes that show promise for clinical implementation.
References:
(1) Wojdacz TK. Expert Rev Mol Diagn. 2012 Jan;12(1):39-47 (2) for BLUEPRINT consortium, Nature Biotechnology, Vol. 34, Nr. 7, s. 726-737. (3) Daugaard I et al., Sci Rep. 2016 Oct 26;6:35807. (4) Wojdacz TK et al.. Breast Cancer Res. 2014 Feb 3;16(1):R17
Note: This abstract was not presented at the meeting.
Citation Format: Tomasz K. Wojdacz, Iben Daugaard, Tina Kjeldsen, Henrik Hager, Thomasz Kristensen, Louise Kristensen, Michael B. Møller, Lise Lotte Hansen. Systematic approach to methylation biomarker development in chronic lymphocytic leukemia, breast and lung cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4359. doi:10.1158/1538-7445.AM2017-4359
Abstract 4360: Epigenetic alteration at HBV integrants is associated with methylation at flanking human genome
Authors: Watanabe Yoshiyuki , Oikawa Ritsuko , Yamamoto Hiroyuki , Itoh Fumio 
Published: July 2017

Abstract
Integration of DNA viruses into the human genome plays an important role in various types of tumors, including hepatitis B virus (HBV)-related hepatocellular carcinoma. However, the molecular details and clinical impact of HBV integration on either human or HBV epigenomes are unknown. Here, we show that methylation of the integrated HBV DNA is related to the methylation status of the flanking human genome. We developed a next-generation sequencing-based method for structural methylation analysis of integrated viral genomes (denoted G-NaVI). This method is a novel approach that enables enrichment of viral fragments for sequencing using unique baits based on the sequence of the HBV genome. We detected integrated HBV sequences in the genome of the PLC/PRF/5 cell line and found variable levels of methylation within the integrated HBV genomes. Allele-specific methylation analysis revealed that the HBV genome often became significantly methylated when integrated into highly methylated host sites. After integration into unmethylated human genome regions such as promoters, however, the HBV DNA remains unmethylated and may eventually play an important role in tumorigenesis. The observed dynamic changes in DNA methylation of the host and viral genomes may functionally affect the biological behavior of HBV. These findings may impact public health given that millions of people worldwide are carriers of HBV. We also believe our assay will be a powerful tool to increase our understanding of the various types of DNA virus-associated tumorigenesis.
Citation Format: Yoshiyuki Watanabe, Ritsuko Oikawa, Hiroyuki Yamamoto, Fumio Itoh. Epigenetic alteration at HBV integrants is associated with methylation at flanking human genome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4360. doi:10.1158/1538-7445.AM2017-4360
Abstract 4378: Gastric cancer organoid culture shows preserved genomic stability in long-term passage
Authors: Yue Sarah Siu Kuen , Yan Helen Hoi Ning , Siu Hoi Cheong , Ho Siu Lun , Tsui Wai Yin , Chan Dessy , Chan Annie Shuk Yee , Lee Bernard Chi Hang , Chan Anthony Kin Wang , Leung Suet Yi 
Published: July 2017

Abstract
With recent advances in 3D organoid culture techniques, normal epithelial and tumor cells can be directly cultured from clinical specimens in vitro and expanded long-term with a very high success rate. Thus, this constitutes a good platform for various mechanistic functional studies and clinical applications. A previous karyotyping and gene expression profiling study has indicated that organoid culture of normal epithelial cells can be propagated for long periods of time without genomic alterations. However, data on the genomic stability of tumor organoids in long-term culture are not yet available. We have successfully established organoid cultures derived from either primary tumor or lymph node metastasis from 4 gastric cancer patients. For each sample, we performed long-term culture for at least 6 months. DNA was extracted from blood, as well as the early and late passages of these organoids, and submitted for whole-exome sequencing (WES), achieving a mean coverage approaching 50X. Somatic mutations detected in early versus late passage gastric cancer organoids were compared. Furthermore, we examined the organoids for copy number variations based on the coverage and loss of heterozygosity (LOH) information derived from exome sequencing.
We detected between 80 to 228 somatic mutations in the 4 early passage organoids, in which over 84-99% of them were retained during long-term culture. We detected 16, 20, 31 and 98 new mutations in the 4 long-term cultures, respectively. The one case with a substantially large number of new mutations (n=98) appeared to have emerged from a subclone of TP53 wild-type cells in a TP53 mutant tumor. Notably, the C&gt;T mutation was the most dominant mutation spectrum in this case, constituting 48%. Despite the presence of frequent long segment LOH and chromosomal aberrations in early passage organoids, indicating the presence of chromosomal instability, these patterns of aberrations were stably maintained in long-term passage.
Overall, with the current organoid culture protocol, tumor genomes are mostly stably maintained with the accumulation of only a small number of new mutations. Our results indicate that this is a reliable and stable in vitro cell culture model for various cancer-related and clinical studies.
Citation Format: Sarah Siu Kuen Yue, Helen Hoi Ning Yan, Hoi Cheong Siu, Siu Lun Ho, Wai Yin Tsui, Dessy Chan, Annie Shuk Yee Chan, Bernard Chi Hang Lee, Anthony Kin Wang Chan, Suet Yi Leung. Gastric cancer organoid culture shows preserved genomic stability in long-term passage [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4378. doi:10.1158/1538-7445.AM2017-4378
Abstract 4398: Identification of bile duct cancer specific fusion genes in patient tissues
Authors: Kim Kahee , Jung Dawoon Esther , Seo Mi-kyoung , Kim Sang Woo , Song Si Young 
Published: July 2017

Abstract
Gene fusion occurs when a part of one gene fuses with or attaches to a part of another gene by genome rearrangement and the result in gene fusion may possess oncogenic properties; fused gene may be translated into a unique protein that may promotes cancer properties. Bile duct cancer are one of the most lethal cancer types with low 5-year survival rates, but lack of proper diagnostic or prognostic markers. Our aim was to investigate bile duct cancer specific fusion genes found in patient’s specimens. We extracted total RNA from five bile duct cancer tissues and normal tissues from the same patients. We performed RNA sequencing and the result data was analyzed using ChimeraScan, Jaffa or Fusionchacher softwares to detect gene fusion. To identify the cancer somatic fusion gene, the fusion occurred in normal tissues and previously reported fusion genes found in normal tissues were excluded and the fusion occurred in coding region was included. As a result, we found 52 bile duct cancer tissue specific- fusion genes. We analyzed the expression of selected fusion genes in 30 bile duct cancer patients and cancer cell lines by qRT-PCR. As a result we observed two novel bile duct cancer specific fusion genes. We cloned one of the fusion genes and transfected into the bile duct cancer cell lines SNU-1196 to assess, and increase in cell motility was observed in vitro. These findings indicate the presence of novel fusion genes as well as its possible application for the early diagnosis or prognosis of bile duct cancer.
Citation Format: Kahee Kim, Dawoon Esther Jung, Mi-kyoung Seo, Sang Woo Kim, Si Young Song. Identification of bile duct cancer specific fusion genes in patient tissues [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4398. doi:10.1158/1538-7445.AM2017-4398
Abstract 4405: A new energy restriction mimetic decreases survival and FOXM1 expression in pancreatic cancer cells
Authors: Scolaro Laura , Lanza-Jacoby Susan 
Published: July 2017

Abstract
Pancreatic cancer is a deadly disease with only 6% of the patients living longer than 5 years. Even if the disease is diagnosed when it is localized, the 5-year survival rate is approximately 19%. A characteristic of cancer cell metabolism is a shift from oxidative phosphorylation to aerobic glycolysis known as the Warburg effect. It is well known that calorie restriction (CR) is a powerful intervention that suppresses tumorigenesis in animal models by targeting glycolysis and oncogenic signaling pathways. Recent studies have shown that the metabolic responses characteristic of CR can be obtained with the use of energy restriction mimetics (ERM). The purpose of this study is to evaluate a new ERM, OSU-CG5 in altering growth of pancreatic cancer cells and nutrient-sensitive signaling pathways.
Tumors including those of the pancreas have uncontrolled proliferation necessitating increased fuel demands by increasing glucose availability and altering metabolic signaling pathways. Since ERM have been reported to target glucose transport, we evaluated whether OSU-CG5 alters glucose transport (Glut) proteins and glucose uptake.
Glut1, but not Glut2, 3, 4, and 6, were overexpressed in Panc-1 cells with a 6-fold higher expression compared to HPNE cells. Glut proteins were not altered in MiaPaca cells. OSU-CG5 did not alter Glut1 protein expression in either cell line. Silencing Glut1 also had no effect on the cytoxicity of OSU-CG5. OSU-CG5 did not alter glucose uptake when measured in different concentrations of glucose in the media. Cell survival, as measured with Pico green, was decreased after OSU-CG5 treatment with an IC 50 of 3uM when cultured in physiological concentration of 5 and 10mM of glucose.
FOXM1 is unregulated in pancreatic cancer and a promoter of the Warburg effect. We found that OSU-CG5 significantly decreased expression of FOXM1 in Panc1 and MiaPaca cells. Our findings indicate that OSU-CG5 does not inhibit the growth of Panc1 and MiaPaca pancreatic cancer cells by decreasing glucose uptake but may target the FOXM1 signaling pathways.
Citation Format: Laura Scolaro, Susan Lanza-Jacoby. A new energy restriction mimetic decreases survival and FOXM1 expression in pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4405. doi:10.1158/1538-7445.AM2017-4405
Abstract 4418: Enhanced endocytosis as a metabolic detour for cancer cells
Authors: Liu Yang , Lu Yanxin , Li Aiguo , Celiku Orieta , Gilbert Mark R. , Yang Chunzhang 
Published: July 2017

Abstract
INTRODUCTION: Metabolic defects impair physiology and life cycle of every somatic cell. However, emerging evidence showed abnormalities in metabolic pathways paradoxically serve as initial steps in many types of human cancers. Little is known about the molecular mechanisms that confer metabolic adaptation and oncogenic predisposition for a transforming cell with intrinsic metabolic defect. In the present study, we explore the molecular mechanism that assists cellular adaptation when confronting metabolic deficiency, and its correlation acquisition of aggressive phenotypes.
METHOD: We took advantage of clinical cases and in vitro cellular models with neomorphic IDH1 mutations, as a paradigm of metabolic deficiency-associated cancer. We investigated whole transcriptomic profiling based on RNA sequencing on IDH1-mutated cells and seek for selective activated canonical pathways. As a validation, we investigated the signature pathways in IDH1-mutated cells, with a focus on cytoskeleton assembly, cellular migration and endocytosis. Moreover, we investigated mTORC pathway and identified its pivotal role in the metabolic adaptation and cellular motility changes in IDH1-mutated cells.
RESULTS: Transcriptomic profiling suggested profound activation in molecular pathways that govern cell movement, endocytosis, chemotaxis and invasion in IDH1-mutated cells. Hierarchical clustering analysis suggested that acquisition of R132C or R132H IDH1 mutant leads to consistent activation pattern for cellular movement. In addition, we confirmed that IDH1-mutated cells exhibit stronger capacity in cellular migration, endocytosis and cytoskeleton re-organization. Importantly, we demonstrated remarkable enhancement in endocytosis pathways in IDH1-mutated cells, suggesting cellular transformation eases metabolite uptake for metabolic deficient cell. Finally, we demonstrated that Rictor/mTORC2/Rac1 pathway is selectively activated in IDH1-mutated glioma cells, which is essential to enable cytoskeleton mobilization, endocytosis and acquisition of aggressive phenotype in transforming cells.
CONCLUSION: Our findings demonstrate that metabolic deficiency leads to enhancement in food seeking behavior in cellular level, highlighted with enhanced cell motility, chemotaxis, and endocytosis; suggesting that this is an important molecular mechanism in cellular transformation during oncogenesis. This phenotypic transformation provides additional carbon sources, compensating for IDH mutation related alterations and may help explain the enhanced cell migration and invasion characteristic of these cancers.
Citation Format: Yang Liu, Yanxin Lu, Aiguo Li, Orieta Celiku, Mark R. Gilbert, Chunzhang Yang. Enhanced endocytosis as a metabolic detour for cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4418. doi:10.1158/1538-7445.AM2017-4418
Abstract 4419: HER2 expression and 17β-estradiol induce ACSL4 expression in estrogen receptor positive mammary carcinoma cells
Authors: Mbarik Maroua , Belkaid Anissa , Surette Marc E. 
Published: July 2017

Abstract
Breast cancer is a multifactorial disease involving several molecular changes and a high proliferation rate often under the activation of hormonal receptors. Therefore, cancer cells require the metabolic machinery for membrane synthesis and to promote signaling pathways. Amongst biomolecules required for efficient cell growth are polyunsaturated fatty acids, like arachidonic acid, that are essential nutrients whose cellular uptake is partly governed by long chain acyl-CoA synthetases (ACSL). In this study, we investigated the impact of 17β-estradiol and Human Epidermal growth factor Receptor 2 (HER2) on cellular uptake of polyunsaturated fatty acids and on the expression of ACSLs. The administration of 17β-estradiol in steroid-starved MCF-7 and T47D mammary carcinoma cells induced a significant increase in cellular uptake of arachidonic acid (AA) and eicosapentaenoic acid (EPA), and in ACSL4 protein content (p&lt;0.05). There was no change in the expression of the ACSL1, ACSL3 and ACSL6 isoforms. Increased ACSL4 protein expression was not accompanied by changes in ACSL4 mRNA expression, but was associated with a significant increase in the protein half-life (T1/2=26±2h) compared to untreated cells (T1/2=8±0.5h). Silencing of ERα reversed the impact of 17β-estradiol on ACSL4 protein expression and half-life. Silencing of ACSL4 eliminated the 17β-estradiol-induced increase in cellular polyunsaturated fatty acid uptake, cell migration and invasion capacities. ACSL4 silencing also prevented the 17β-estradiol-induced increases in p-Akt and p-GSK3β, as well as the 17β-estradiol-induced decrease in E-cadherin expression, important events in epithelial to mesenchymal transition. In addition, the forced expression of HER2 in MCF7 cells induced an increase in cellular uptake of AA and in the expression of ACSL4 measured by both qPCR and western blots. This suggests that HER2-induces ACSL4 expression by a mechanism that differs from that of 17β-estradiol. Further investigations are planned to study the implication of ACSL4 on cellular functions induced by HER2. Overall, these results demonstrate that an induction of ACSL4 protein expression in ERα positive MCF-7 and T47D cells is implicated in 17β-estradiol-induced cellular migration and invasion capacities.
Citation Format: Maroua Mbarik, Anissa Belkaid, Marc E. Surette. HER2 expression and 17β-estradiol induce ACSL4 expression in estrogen receptor positive mammary carcinoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4419. doi:10.1158/1538-7445.AM2017-4419