bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2871: Diosgenin inhibits the proliferation of MCF-7 breast cancer cells through the demethylation of miR-145 gene
Authors: Shi Fengqin , Lu Lingeng , Li Ya , Hou Li , Chen Xinyi , Rui Han , Wang Chong , Yue Ya 
Published: August 2018

Abstract
Background: Altered DNA methylation in microRNA (miRNA) host genes has been frequently associated with abnormal miRNA expression during the pathogenesis of cancer. miR-145 was identified as a tumor-suppressive miRNA that was down-regulated in several cancer types. Accumulating evidence has clearly demonstrated that a low expression of miR-145 in breast cancer was correlated with an aberrant hypermethylation in its host gene. Diosgenin is a steriod saponin, which is extracted from the tubers of Dioscorea wild yam. The anti-tumor mechanisms of diosgenin have been demonstrated via the modulation of multiple cell signaling pathways, which are associated with growth, differentiation, apoptosis and oncogenesis. However, there is little information regarding the epigenetic-based effects of Diosgenin in breast cancer. In our study, we hypothesize that Diosgenin has anti-proliferative effects on breast cancer cells through the demethylation of miR-145.
Material and Methods: MCF-10A breast epithelial cells and MCF-7 breast cancer cells were used to investigate the effects of Diosgenin on the expression and methylation of miR-145 using real time-PCR (RT-PCR) and methylation-specific PCR (MSP), respectively. An MTS proliferation assay was performed to assess the effect of Diosgenin on the proliferation of MCF-7 breast cancer cell.
Result: In comparison with MCF-10A breast epithelial cells, MCF-7 breast cancer cells showed the hypermethylation of miR-145, and significantly down-regulated miR-145 expression. Diosgenin treatment led to proliferation inhibition of MCF-7 breast cancer cells. In MCF-7 breast cancer cells, the Diosgenin treatment led to significantly up-regulated miR-145, whereas the methylation level of miR-145 significantly decreased.
Conclusion: Diosgenin, a natural compound, exhibits an anti-proliferative effect on breast cancer cells, and affects the methylation and expression of miR-145. These findings indicate that the demethylation of miR-145 may be a molecular mechanism underlying the anti-tumor of Diosgenin in breast cancer.
Citation Format: Fengqin Shi, Lingeng Lu, Ya Li, Li Hou, Xinyi Chen, Han Rui, Chong Wang, Ya Yue. Diosgenin inhibits the proliferation of MCF-7 breast cancer cells through the demethylation of miR-145 gene [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 2871.
Abstract 289: Probing the non-enhancing component of glioblastoma: Targeting what is left behind
Authors: Peng Sen , Halperin Rebecca , Dhruv Harshil , Byron Sara , Legendre Christophe , Phillips Joanna , Prados Michael , Berens Michael , Tran Nhan 
Published: August 2018

Abstract
While genomic profiling and therapeutic selection support individualized GBM treatment, such therapeutic decision-making is usually made with reference to tumor obtained from the enhancing core region. GBM is known to be heterogeneous and exhibits a high resistance to standard therapies. To address whether non-enhancing tumor (representing the majority of tumor left behind after surgery) shows distinct genomic characteristics and therapeutic targets compared to the enhancing tumor core, we performed genome-wide exome-sequencing and RNA-sequencing for 12 patients with matched enhancing region and at least one non-enhancing region. Non-enhancing biopsies show a surprisingly high level of tumor content, with a median of 28% tumor cells and 6 of the 22 samples having greater than 50% tumor cells. Cognate non-enhancing and enhancing specimens demonstrated overall concordance in therapeutically actionable alterations (single nucleotide variants) and copy number alterations. However, non-enhancing regions were not genetically identical and did reveal additional and distinct variants compared to enhancing cores. For example, the non-enhancing region of patient 1 showed two nonsense NF1 mutations (R1534X; R2517X) while the enhancing region showed an NF1 frameshift mutation (F1247fs). Clonality analysis by LumosVar also indicated that 7 out of 12 patients harbored dissimilar cellular prevalence patterns between enhancing and non-enhancing regions. In addition, comparison of alternative polyadenylation between enhancing and non-enhancing regions uncovered distinct 3' UTR usage: e.g. SGMS2 and TOB1 tended to have longer 3' UTR in enhancing regions whereas longer 3' UTR of SYNPO and NOS1AP were
prevalent in non-enhancing regions. We posit that the enhancing component of glioblastoma probably underrepresents the genomic alterations in patients' tumors. Given non-enhancing tumor is left behind after surgical debulking, genomic profiling of this region would potentially reveal more accurate tumor vulnerabilities and lead to more effective therapy.
Supported by a grant from the Ben & Catherine Ivy Foundation.
Citation Format: Sen Peng, Rebecca Halperin, Harshil Dhruv, Sara Byron, Christophe Legendre, Joanna Phillips, Michael Prados, Michael Berens, Nhan Tran. Probing the non-enhancing component of glioblastoma: Targeting what is left behind [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 289.
Abstract 2916: Targeting lysophospholipid metabolism inhibits pancreatic cancer cell proliferation under nutrient-limiting conditions
Authors: Jong Petrus R. de , Maruggi Marco , Campos Alejandro D. , Brand Morgan A. , Lemos Robert , Scott David A. , Litherland Sally A. , Arnoletti J. Pablo , James Brian P. , Powis Garth 
Published: August 2018

Abstract
Patients with pancreatic ductal adenocarcinoma (PDAC) have a poor prognosis, and more effective systemic treatments for patients with local progression or metastasis (85% of cases) are needed. The pancreatic tumor microenvironment provides a rich source for novel drug targets. We aimed to identify and validate novel metabolic drug targets that are unique to hypoxic PDAC cells. Using bulk RNA sequencing in combination with metabolomics analyses in vitro, we previously found that PDAC cells negate the loss of intracellular unsaturated fatty acids in hypoxia by orchestrating the release of lysophospholipids (lyso-PLs) by cancer-associated fibroblasts, which are then taken up and stored in intracellular lipid droplets in hypoxic cancer cells. To confirm the relevance of these findings in vivo, we performed 3' droplet based single-cell RNA sequencing (scRNA-seq) combined with metabolomics analyses of intracellular and extracellular (tumor interstitial fluid) metabolites of MIAPaCa2 and patient-derived xenografts (PDX). Identification of cell lineages and subpopulations with hypoxic gene signatures was performed to correlate changes in metabolite levels with metabolic gene expression in vivo. This approach confirmed differential expression of lipid droplet-associated enzymes in hypoxic areas of the tumor, including lyso-PL acyl transferases (LPCAT1, LPCAT3), and phospholipases (LYPLA1, PLA2G15). We found that resistance of PDAC cell lines to pharmacologic treatment with inhibitors of fatty acid desaturases (FADS), reminiscent of hypoxia and nutrient starvation in vivo, was mediated by uptake of lyso-PLs from the medium. Importantly, genetic knockdown of LPCAT and LYPLA isoforms reversed the resistance to FADS inhibitors in culture in vitro and in vivo. Clinical relevance was demonstrated by mRNA expression analysis of PDAC patients from The Cancer Genome Atlas (TCGA) database, which showed that the expression of lyso-PL metabolizing genes is correlated with a significant worse prognosis (log-rank test, P=0.008). We are currently developing pharmacologic approaches to target LPCAT and LYPLA enzymes in hypoxic cancer cells as a novel approach for PDAC patients with unresectable disease.
Citation Format: Petrus R. de Jong, Marco Maruggi, Alejandro D. Campos, Morgan A. Brand, Robert Lemos, David A. Scott, Sally A. Litherland, J. Pablo Arnoletti, Brian P. James, Garth Powis. Targeting lysophospholipid metabolism inhibits pancreatic cancer cell proliferation under nutrient-limiting conditions [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 2916.
Abstract 2931: MTX-211, a dual and selective inhibitor of EGFR and PI3 kinase, shows promising activity in combination with MEK inhibition in preclinical models of pancreatic cancer
Authors: Frankowski-McGregor Christy , Maust Joel , Ziemke Elizabeth , Mumby Rachel , Delaney Amy , Rehemtulla Alnawaz , Whitehead Christopher , Sebolt-Leopold Judith S. 
Published: August 2018

Abstract
Pancreatic cancer is one of the deadliest forms of cancer, with median 5-year survival rates less than 10%. This disease is recalcitrant to chemotherapeutic approaches and recently approved therapies afford only modest improvements in survival. KRAS is the most commonly mutated gene in pancreatic tumors with an incidence rate exceeding 90%. Despite intensive efforts, KRAS has remained undruggable. Kinases acting both upstream and downstream of RAS continue to be exploited for the development of novel agents to attenuate signaling through this critical oncogene. While EGFR and MEK inhibitor monotherapies have been evaluated in the clinic for the treatment of pancreatic cancer, efficacy has been modest despite their relevance to MAP kinase (MAPK) pathway-altered tumors. Novel therapies are urgently needed to address adaptive signaling mechanisms that diminish the effectiveness of kinase-targeted approaches. MTX-211 is a first-in-class dual inhibitor of PI3K and EGFR kinase with a promising pharmaceutical profile and proven ability to potentiate the effectiveness of MEK inhibitor therapy in KRAS mutant colorectal tumors. The present study was undertaken to extend our evaluation of MTX-211 to include pancreatic cancer model systems. We have found that MTX-211 exhibits low micromolar potency against an extensive panel of primary models of pancreatic cancer and is highly synergistic with the MEK inhibitor trametinib. Preliminary data suggest that this synergy is driven by the ability of MTX-211 to target compensatory transcriptional activation of HER3 that occurs in response to MEK inhibition. A genetically engineered KRAS and p53 mutant (KPC) mouse model was transduced with a lentiviral construct encoding a caspase reporter, which was used to show that the combination of MTX-211 and trametinib elicited a significant increase in apoptosis over single agent controls. Results from an animal study conducted with the KPC model further showed that the combination of MTX-211 and trametinib significantly slowed growth of these aggressive tumors. Employing both KPC and patient-derived xenograft models of pancreatic cancer, efforts are underway to optimize therapeutic outcome in response to MTX-211-based combination treatment regimens.
Citation Format: Christy Frankowski-McGregor, Joel Maust, Elizabeth Ziemke, Rachel Mumby, Amy Delaney, Alnawaz Rehemtulla, Christopher Whitehead, Judith S. Sebolt-Leopold. MTX-211, a dual and selective inhibitor of EGFR and PI3 kinase, shows promising activity in combination with MEK inhibition in preclinical models of pancreatic 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 2931.
Abstract 3064: Oral cancer stem cells modulate Fusobacterium nucleatum to acquire the capability to induce tumor stemness switch
Authors: Pal Bidisha , Bhuyan Seema , Baishya Debabrat , Das Bikul 
Published: August 2018

Abstract
Background: Fusobacterium nucleatum is an oral bacteria that contributes to oral carcinogenesis. Its potential role in oral cancer is not known. Fusobacterium nucleatum (henceforth FN) is a gram-negative anaerobe associated with periodontal diseases and also colon cancer. The bacteria modulates the host cell signaling mechanism including the activation of beta-catenin signaling and p38 pathway. The Fap2 is the outer membrane proteins of FN that inhibit lymphocytes and NK cells. The bacteria also directly binds to NKp46 receptor of NK cells. These properties of FN may be exploited by oral CSCs to defend their own niche as a part of niche-defense mechanism against immune system. Hence, it is not surprising that oral CSCs may hijack this specific oral bacterium to enhance tumor stemness. We speculate that oral CSCs may hijack specific bacteria type present in oral mucosa, and enhance their stemness-inducing mechanisms to switch non-CSCs to CSCs.
Methods: We have established an in vitro model of oral cancer cells/FN host/pathogen interaction model. Using this model, we wanted to study potential role of the bacteria in cancer stemness. We also used the saliva of subjects with oral cancer to infect oral cancer stem cells and non-stem cancer cells.
Results: When the SCC-25 oral cancer cell line was treated with the saliva of subjects with oral cancer, the EpCAM+/ABCG2+ oral CSCs population was increased and showed the presence of FN. The FN recovered from CSCs exhibited high expression of FadA and Fap2, two surface proteins present in FN that can modulate signaling pathways of host cells. Importantly, FN recovered from the infected CSCs induced stemness in the non-stem cancer cell population of SCC-25, suggesting that CSCs may modulate the pathogen. Indeed, our preliminary observation indicates that FN recovered from the FN strain ATCC 25586 infected SCC-25 ABCG2+ cells showed increased expression of FADA and Fap2 as compared to the parental strain ATCC 25586.
Conclusion: Our data suggests that CSCs have the capability to reprogram F. nucleatum genome in order to make the bacteria a potent inducer of tumor stemness in non-stem cancer cells.
Citation Format: Bidisha Pal, Seema Bhuyan, Debabrat Baishya, Bikul Das. Oral cancer stem cells modulate Fusobacterium nucleatum to acquire the capability to induce tumor stemness switch [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 3064.
Abstract 3208: Optimal array layouts for tumor treating fields therapy in glioblastoma: Oblique array layouts are superior to standard LR and AP positions
Authors: Mikic Nikola , Korshøj Anders 
Published: August 2018

Abstract
Introduction: Tumor treating fields (TTFields) is a new and effective treatment for glioblastoma. Two pairs of transducer arrays are placed on the scalp of the patient to deliver low intensity, alternating electric fields, which inhibit mitosis and cancer growth. In the present study, we investigated systematic variations in electrode array positions to identify optimal layouts, which induce the highest electric fields in the tumor tissue.
Method: The electric field distribution was calculated using finite element methods applied to a realistic computational head model. Array positions were rotated systematically in fifteen-degree intervals around a central cranio-caudal axis of the head to obtain thirteen different layouts in the same plane. Tumors were introduced in the computational mesh at nineteen different fronto-parietal positions in the same plane as defined by the electrode positions.
Results: Electrode array layout greatly affected the field distribution. For the vast majority of tumors, two optimal and oblique array orientations were identified. At these positions, field intensities were approximately 30-40% higher compared to the standard anterior/posterior and left/right positions. In addition, the two optimal layouts were oriented at ninety-degree interval to each other. Correspondingly, a single optimum layout was identified when analyzing the combination of two pairs of arrays. Each tumor position was associated with only one optimum (combined) layout, which was generally oblique relative to the sagittal plane (15-45 degrees). An oblique layout at forty-five degrees to the sagittal plane was effective for most tumor positions and in all cases it was superior to the default layout combination of anterior-posterior and left-right positions.
Conclusion: Our results provide guiding principles for optimal electrode placement, which will be helpful, especially in situations where the placement must be changed due to concurring clinical conditions such as shunts, scars, tissue rash etc. Patient specific models should be for more accurate TTF distributions. Additional research is needed to confirm these current results.
Citation Format: Nikola Mikic, Anders Korshøj. Optimal array layouts for tumor treating fields therapy in glioblastoma: Oblique array layouts are superior to standard LR and AP positions [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 3208.
Abstract 33: Calsequestrin 2 regulates proliferation, migration, and invasion in triple-negative breast cancer cells
Authors: Kim Ju Hee , Hong Bok sil , Heo Woohang , Han Jong Min , Han Wonsik , Noh Dong-Young , Moon Hyeong-Gon 
Published: August 2018

Abstract
Triple-negative breast cancer (TNBC) is the most heterogeneous and aggressive breast tumor subtype defined by absence of receptor for estrogen, progesterone, or HER2. However, the biologic mechanism for TNBC phenotype is still unclear. Here, we show that expression of Calsequestrin 2 (CASQ2), a Ca2+-binding protein, correlates with increase of proliferation, migration, and invasion, suggesting that intracellular Ca2+ may contribute to tumor growth and metastatic phenotype. CASQ2 is the main Ca2+-binding protein inside the sarcoplasmic reticulum of cardiomyocytes. CASQ2 forms a complex with ryodine receptor 2 (RyR2) luminal calcium release channel in cardiac muscle. Ca2+ is a sequestor and regulator of diverse cellular processes, and specific Ca2+ channels play important roles in cell proliferation and invasiveness of cancers. To know the role of CASQ2 TNBC cells, we established CASQ2-overexpressing stable cells in Hs578T (Hs578T-CASQ2) using retrovirus. Stimulation with caffeine triggered the remarkable increase of intracellular calcium in Hs578T-CASQ2 cells; in addition, the basal level of calcium in cells had much higher amount of Hs578T-CASQ2 than Hs578T. By contrast, calcium chelator BAPTM/AM blocked CASQ2-induced calcium release. Hs578T-CASQ2 cells showed higher level of proliferation, migration and invasion rate compared to Hs578T, which indicated that overexpression of CASQ2 related with cellular functions. We also found that CASQ2 overexpression elevates extracellular signal-related kinase (ERK) expression. In epidermal growth factor (EGF)-treated cells, Hs578T-CASQ2 cells had higher phosphorylated ERK compared to Hs578T, leading to the expression of epithelial-mesenchymal transition (EMT) marker, vimentin. These results indicate that CASQ2 overexpression increases the level of calcium and induces cell proliferation, migration and invasion through ERK signaling. Our findings from this study show a possible cause of migration and invasiveness in breast cancer cells. Taken together, these findings demonstrate that CASQ2 could be a new therapeutic target for breast cancer.
Citation Format: Ju Hee Kim, Bok sil Hong, Woohang Heo, Jong Min Han, Wonsik Han, Dong-Young Noh, Hyeong-Gon Moon. Calsequestrin 2 regulates proliferation, migration, and invasion in triple-negative breast cancer cells [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 33.
Abstract 3469: Dual inhibition of the EGFR and Aurora A pathways in Kras mutated non-small cell lung cancers
Authors: Bagnyukova Tetyana , Egleston Brian , Kramer Mackenzie , Astsaturov Igor , Golemis Erica , Borghaei Hossein 
Published: August 2018

Abstract
Lung cancer is the leading cause of cancer related death in the US. Patients with advanced disease generally have a poor prognosis with a median survival of around 10 to 12 months with standard chemotherapy. In patients with non-squamous non-small cell lung cancers (NSCLC) incidence of KRAS mutations reach ~22%. Specific treatments for Kras mutated NSCLC have not been developed although recent reports suggest an advantage for treatment with immunotherapy over chemotherapy in the second line setting. Published reports using a synthetic lethal screening method show that the combined inhibition of the EGFR and Aurora A kinase pathways could have synergistic effect on viability in head and neck and colon cancer cell lines suggesting a potential benefit of such combination therapy in these patients (Astsaturov and colleagues, 2010). Our study aims to examine the effects of combination of erlotinib (E), an EGFR small-molecule inhibitor, and Alisertib (MLN8237, A), an inhibitor of Aurora A kinase, in lung cancer models with different KRAS status. Human NSCLC cell lines with both wild type and mutated KRAS showed weak or moderate sensitivity to both drugs in vitro. Treatment with both E and A had synergistic activity in all examined cell lines, wild type KRAS (H2228, H1299) or mutated KRAS (A549, H1299, H358, H460, and H62). Western blot analysis confirmed that combination treatment enhanced apoptosis compared to single drug use as evidenced by cleaved PARP. In xenograft models, CB17 SCID mice were treated with single drug or E+A for three weeks. H322M xenograft tumors bearing wild type KRAS were moderately sensitive to growth inhibition by E (10 mg/kg/day) and A (20 mg/kg/twice daily) alone and the combination had an additive effect. A549 and H358 xenografts were insensitive to E because of the mutated KRAS and moderately sensitive to A. However, the combination of E+A had a synergistic effect and significantly inhibited tumor growth. Western blot analysis of signaling pathways downstream of the EGFR and Aurora A in tumor xenografts shows synergistic inhibition after two-drug treatment. Our results suggest that combined inhibition of both pathways might be an effective treatment strategy for lung cancers harboring KRAS mutations.
Citation Format: Tetyana Bagnyukova, Brian Egleston, Mackenzie Kramer, Igor Astsaturov, Erica Golemis, Hossein Borghaei. Dual inhibition of the EGFR and Aurora A pathways in Kras mutated non-small cell lung cancers [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 3469.