bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4332: Targeting MYC overexpressing leukemia with cardiac glycoside proscillaridin through downregulation of histone acetyltransferases
Authors: Costa Elodie Marie Da , Armaos Gregory , McInnes Gabrielle , Beaudry Annie , Moquin-Beaudry Gael , Bertrand-Lehouillier Virginie , Caron Maxime , St-Onge Pascal , Jonhson Jeffrey R. , Krogan Nevan , Sai Yuka , Downey Michale , Rafei Moutih , Boileau Meaghan , Eppert Kolja , Florez-Diaz Ema , Haman Andre , Hoang Trang , Sinnett Daniel , Beausejour Christian , McGraw Serge , Raynal Noel J. 
Published: August 2019

Abstract
Targeting MYC oncogene remains a major therapeutic goal in anticancer therapies. Here, we demonstrate that proscillaridin, a cardiac glycoside approved for heart failure treatment, causing Na+/K+ pump inhibition, targets efficiently MYC overexpressing cancer cells. At clinically relevant doses, proscillaridin induced rapid downregulation of MYC protein level, and produced growth inhibition preferentially against MYC overexpressing leukemic cell lines including lymphoid and myeloid stem cell populations. Whole transcriptome analysis with RNA sequencing of acute lymphoblastic leukemia cells showed a downregulation of gene sets involved in MYC pathways and cell replication, and an upregulation of genes involved in hematopoietic differentiation induced by proscillaridin treatment. Gene expression changes were associated with an epigenetic remodeling of chromatin active marks. Proscillaridin induced a significant loss of lysine acetylation in histone H3 (at lysine 9, 14, 18 and 27). In addition, mass spectrometry analysis revealed a loss of lysine acetylation in non-histone proteins such as MYC itself, MYC target proteins, and a series of histone acetylation regulators. Global loss of acetylation correlated with the rapid downregulation of histone acetyltransferase proteins (such as CBP, P300, TIP60 and GCN5) involved in histone and MYC acetylation. Overall, these results strongly support the repurposing of proscillaridin in MYC overexpressing leukemia and suggest a novel strategy to target MYC by inducing the downregulation of histone acetyltransferases involved in its stability.
Citation Format: Elodie Marie Da Costa, Gregory Armaos, Gabrielle McInnes, Annie Beaudry, Gael Moquin-Beaudry, Virginie Bertrand-Lehouillier, Maxime Caron, Pascal St-Onge, Jeffrey R. Jonhson, Nevan Krogan, Yuka Sai, Michale Downey, Moutih Rafei, Meaghan Boileau, Kolja Eppert, Ema Florez-Diaz, Andre Haman, Trang Hoang, Daniel Sinnett, Christian Beausejour, Serge McGraw, Noel J. Raynal. Targeting MYC overexpressing leukemia with cardiac glycoside proscillaridin through downregulation of histone acetyltransferases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4332.
Abstract 4340: A novel fluoride (ChlA-F) transcriptionally upregulates miR494 via a HuR/JunB axis to inhibit cell invasion in human bladder cancers
Authors: Tian Zhongxian , Hua Xiaohui , Xu Jiheng , Zhu Junlan , li Jingxia , Huang Chuanshu 
Published: August 2019

Abstract
Bladder cancer (BC) is a commonly occurring cancer and characterized by a low 5-year survival rate particularly in patients with invasive BCs. Here we investigated the chemotherapeutic activity of ChlA-F, a novel C8 fluoride derivative of cheliesisin A (ChelA) with potent anti-neoplastic properties. ChlA-F treatment upregulated miR494 expression and significantly suppressed cell invasion in human BC cell lines. Mechanistically, ChlA-F-induced upregulation of miR494 expression was due to a HuR-mediated increase in JunB mRNA stabilization and protein expression, which led to an increase in miR494 transcription via direct binding to the miR494 promoter region. After ChlA-F treatment, upregulated miR494 was found to bind to the 3’ UTR region of c-Myc mRNA, resulting in decreased c-Myc mRNA stability and protein expression. This, in turn, led to decreased transcription of a c-Myc downstream-regulated gene, MMP-2 and ultimately, inhibition of BC invasion. Here we provide the first evidence showing that our newly synthesized compound, ChlA-F, has a profound inhibitory effect on human BC invasion and elucidate the mechanisms underlying this anti-neoplastic activity. Our data suggest that ChlA-F may be a promising therapeutic alternative for treatment of invasive and metastatic human BC in patients.
Citation Format: Zhongxian Tian, Xiaohui Hua, Jiheng Xu, Junlan Zhu, Jingxia li, Chuanshu Huang. A novel fluoride (ChlA-F) transcriptionally upregulates miR494 via a HuR/JunB axis to inhibit cell invasion in human bladder cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4340.
Abstract 4347: Differentially expressed genes and molecular pathways in an autochthonous mouse prostate cancer model
Authors: Verma Shiv , Shukla Sanjeev , Pandey Mitali , MacLennan Gregory T. , Gupta Sanjay 
Published: August 2019

Abstract
Prostate cancer remains a major public health problem and second leading cause of cancer-related deaths in men in the United States. Despite widespread screening efforts and advancement in therapeutic regimens, incidence of prostate cancer remains steady in the past two decades. Although serum prostate-specific antigen (PSA) has been used as a screening test for prostate cancer for over two decades, the practice remains controversial. As a screening test for prostate cancer, PSA lacks sensitivity and specificity as early detection marker. Furthermore, screening may lead to unnecessary biopsies, over-detection, and overtreatment. There is a need for specific and sensitive biomarker(s) which can differentiate between cancer and non-cancer utilized for screening and early detection. The present study aims to comprehend the molecular pathways of prostate cancer which is essential for early detection and treatment. Dorso-lateral prostate from 20 week transgenic adenocarcinoma of the mouse prostate (TRAMP) mice, which spontaneously develops prostate cancer and recapitulates human disease and age-matched non-transgenic littermates were utilized for microarray analysis. Network and pathway analyses were mapped using the Ingenuity Pathway Analysis (IPA), and the database for annotation, visualization and integrated discovery. In total, 136 differentially expressed genes, including 32 downregulated genes and 104 upregulated genes were identified in the dorso-lateral prostate of TRAMP mice, compared to non-transgenic. A subset of differentially expressed genes were validated by QRT-PCR. Among these genes, 36% genes were connected to the nucleic acid binding especially ribosomal proteins which play important roles in protein synthesis, and is the most enriched pathway in the development of prostate cancer. Moreover, the results also suggest deregulation of the metabolic process and an imbalance between extracellular matrix components and adherens junction proteins could induce cancer progression. Taken together, the present study evaluated the underlying pathways and its connection to human cancer, which may further help to assess the risk of prostate cancer detection and its progression to identify potential targets of adjuvant treatment.
Citation Format: Shiv Verma, Sanjeev Shukla, Mitali Pandey, Gregory T. MacLennan, Sanjay Gupta. Differentially expressed genes and molecular pathways in an autochthonous mouse prostate cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4347.
Abstract 4348: DNA-based fusion detection using a pan-cancer tumor profiling 532-oncogene panel
Authors: Dilger Katharine , Sun Yongming , Lai Kevin , Chakravarty Ushati Das , Sponer Nicole , Giorda Kristina , Lau Patrick , Wang Yu 
Published: August 2019

Abstract
Large-scale cancer profiling using next generation sequencing (NGS) has become instrumental to the discovery and identification of new, targetable cancer alterations. A comprehensive set of 532 oncogene targets were combined to create the new xGen® Pan-Cancer Panel V2 for hybrid capture sequencing. This xGen panel covers 2.2 Mb of the human genome, and allows for the simultaneous detection of copy number variations (CNVs), insertions and deletions (indels), gene rearrangements, and microsatellite instability across a wide range of sample types, inputs, and quality. Using a new library prep workflow optimized for low quality samples and low input, panel performance was first evaluated with 30 ng of input DNA using libraries built from matched samples [formalin-fixed paraffin-embedded (FFPE) tumor gDNA, frozen adjacent normal tissue gDNA, and cell-free DNA (cfDNA)] from five lung cancer donors (n = 15). Sample quality ranged from a mean DIN of 4.4 ±1.1 to 8.3 ±0.9 for FFPE tumor gDNA and frozen normal gDNA, respectively. After subsampling to 200X mean target coverage, 96% of target bases had at least 40X coverage for all libraries. Comparative hierarchal clustering analysis was then used to identify lung cancer mutations shared in all tumor samples. NGS gDNA reference standards from Horizon Discovery (HD753, HD798, HD799, and HD803) with verified CNVs, single nucleotide variations (SNVs), amplifications, and fusions, and were used to evaluate detection rates at different library input masses down to 1 ng. cDNA libraries were also prepared from RNA extracted from FFPE 5-Fusion RNA Multiplex Reference Standards (HD796, HD783). We identified all possible gene fusion events in the positive control using the structural variant caller, LUMPY (https://github.com/arq5x/lumpy-sv). The xGen Pan-Cancer Panel V2 enables a cost-efficient and time-saving approach for the detection of multiple oncogene targets.
Citation Format: Katharine Dilger, Yongming Sun, Kevin Lai, Ushati Das Chakravarty, Nicole Sponer, Kristina Giorda, Patrick Lau, Yu Wang. DNA-based fusion detection using a pan-cancer tumor profiling 532-oncogene panel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4348.
Abstract 4353: Stroma drive metabolic reprogramming and induces stemness properties in pancreatic cancer cells
Authors: Kesh Kousik K. , Gupta Vineet K. , Sharma Nikita , Hadad Roey , Dudeja Vikas , Saluja Ashok , Banerjee Sulagna 
Published: August 2019

Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is one of the most devastating human malignancies with poor survival rate owing to chemoresistance and relapse. Small population of Tumor Initiating Cells (TIC) are considered major players driving these traits. Recent literature has demonstrated the importance of microenvironment “niche” in enrichment of these TIC populations. The desmoplastic stroma in pancreatic cancer comprising of stromal cells and immune cells are instrumental in pathogenesis and progression of PDAC. Among many cytokines, IL-6 a pro-inflammatory cytokine plays a major role in it. In this study, we show that stromal cell secreted IL6 altered metabolic reprogramming and increased cancer stemness in PDAC cells. PDAC cells cultured with pancreatic stellate cells condition media (PSC-CM) or recombinant IL6 and stem ness markers expression were investigated. Cytometry Bead Array (CBA) were used for cytokine profiling. Metabolic alteration along with TIC gene expression were measured using flow cytometry and Seahorse. PDAC cells when cultured with PSC-CM exhibited increase glucose uptake along with an enrichment of CD133+ population. An analysis of the conditioned media using CBA reveled that PSC-CM is enriched with cytokine IL-6 and TNF-α. Treatment of PDAC cells with recombinant IL-6 increased expression of self-renewal genes SOX2, OCT4, Nanog along with biochemical marker ALDH. In addition, TIC marker CD133 and invasion marker gene MMP7 expression also increased upon IL6 induction. Moreover, IL6 treatment increased glucose uptake and lactate secretion. Small molecule inhibitor Stattic (inhibitor of STAT3) inhibit glucose uptake and stemness gene expression.Our study shows that stromal IL6 altered metabolic reprogramming in cancer cells as well as increased cancer stemness and invasion. In future, the underlying mechanisms of IL-6 driven metabolic alteration and its impact on stemness and metastasis will be investigated.
Citation Format: Kousik K. Kesh, Vineet K. Gupta, Nikita Sharma, Roey Hadad, Vikas Dudeja, Ashok Saluja, Sulagna Banerjee. Stroma drive metabolic reprogramming and induces stemness properties in pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4353.
Abstract 4355: Altered acetate metabolism in cisplatin resistant bladder cancer
Authors: Kim Jayoung 
Published: August 2019

Abstract
Introduction and Objective: Cisplatin is an important chemotherapeutic agent against metastatic bladder cancer, but resistance often limits its usage. With the recent recognition of lipid metabolic alterations in bladder cancers, we studied the metabolic implications of cisplatin resistance using cisplatin-sensitive (T24S) and resistant (T24R) bladder cancer cells.
Methods: To test whether there should be differences in metabolism and metabolism-associated pathways between cisplatin-sensitive and resistant bladder cancer cells, we applied the live metabolomics approach that we recently developed to isogenic bladder cancer cell lines T24S (cisplatin sensitive) and T24R (cisplatin resistant). The metabolites generated from 13C-glucose tracer were monitored with 2D 1H-13C HSQC NMR in real time.
Results: Real-time live metabolomics revealed that T24R cells consume more glucose, leading to higher production of glucose-derived acetate and fatty acids. Along with the activation of general metabolic regulators, enzymes involved in acetate usage (ACSS2) and fatty acid synthesis (ACC) and a precursor for fatty acid synthesis (acetyl-CoA) were elevated in T24R cells. Consistently, metabolic analysis with 13C isotope revealed that T24R cells preferred glucose to acetate as the exogenous carbon source for the increased fatty acid synthesis, contrary to T24S cells. In addition, ACSS2, rather than the well-established ACLY, was the key enzyme that supplies acetyl-CoA in T24R cells through glucose-derived endogenous acetate. The relevance of ACSS2 in cisplatin resistance was further confirmed by the abrogation of resistance by an ACSS2 inhibitor and, finally, by the higher expression of ACSS2 in the patient tissues with cisplatin resistance.
Conclusions: Our results may help improve the treatment options for chemoresistant bladder cancer patients and provide possible vulnerability targets to overcome the resistance.
Citation Format: Jayoung Kim. Altered acetate metabolism in cisplatin resistant bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4355.
Abstract 4362: Glucose transporter 1 regulates cell glycolysis and proliferation in gastrointestinal stromal tumor and its clinicopathological significance
Authors: Iwatsuki Masaaki , Sawayama Hiroshi , Kuroda Daisuke , Koga Yuki , Yamashita Kohei , Harada Kazuto , Iwagami Shiro , Eto Kojiro , Ishimoto Takatsugu , Baba Yoshifumi , Yoshida Naoya , Ajani Jaffer A. , Baba Hideo 
Published: August 2019

Abstract
Background: The unique features that cancer cells prefer glycolysis rather than mitochondrial respiration despite of the presence of oxygen have been a potential target for cancer treatment. GIST is well-known as to demonstrate intense metabolic activity and avid glucose uptake on 18F-FDG PET scanning. In this study, we focused on glucose transporter 1 (GLUT 1), a key glycolytic enzyme which plays critical roles in several cancer type. The aim of this study was to examine the clinicopathological significance of GLUT1 expression in GIST and to characterize the molecular mechanism of cell glycolysis and proliferation by GIST cell.
Methods: We determined the expression level of GLUT1 in 65 GIST cases, correlated those values with clinicopathological features. Furthermore, we investigated that the alteration of GLUT1 can influence on glycolysis, cell proliferation, and cell cycle distribution by extracellular flux analyzer, CCK-8 assay and flow cytometry, respectively in GIST cell in vitro.
Results: Fifty-one (78.5%) cases were placed in the high GLUT1 expression group. In the high GLUT1 expression group, tumor size was significantly larger compared to the low GLUT1 expression group (P=0.02). There are significantly more high-risk cases by modified-Fletcher classification in GLUT1 expression group (P&lt; 0.01). The patients with high GLUT1 expression significantly exhibited a higher SUVmax value (P&lt; 0.01). Compared with the low GLUT1 expression group, the high expression group showed a significantly poorer prognosis in terms of recurrence-free survival. In vitro, GLUT1-specific siRNA suppressed cell proliferation and led to increase in G1 phase arrest. Also, knockdown of GLUT1 cells reduced glycolysis as a function of ECAR by extracellular flux analyzer.
Conclusion: We showed that GLUT1 plays a critical role in GIST by regulating glycolysis and proliferation. Our study suggests that glucose transporter can be a novel target of anticancer therapeutics mediating glucose metabolism in GIST.
Citation Format: Masaaki Iwatsuki, Hiroshi Sawayama, Daisuke Kuroda, Yuki Koga, Kohei Yamashita, Kazuto Harada, Shiro Iwagami, Kojiro Eto, Takatsugu Ishimoto, Yoshifumi Baba, Naoya Yoshida, Jaffer A. Ajani, Hideo Baba. Glucose transporter 1 regulates cell glycolysis and proliferation in gastrointestinal stromal tumor and its clinicopathological significance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4362.
Abstract 4371: To investigate the role of heme flux and function in growth and progression of NSCLC in vivo
Authors: Ashrafi Adnin , Ghosh Poorva , Sohoni Sagar , Zhang Li 
Published: August 2019

Abstract
Lung cancer is the leading cause of cancer-related mortality and about 85% of the cases are non-small cell lung cancer (NSCLC). Previous research from our lab has shown that the levels of rate limiting heme biosynthetic enzyme ALAS1, heme uptake proteins HCP1 and HRG1 and oxygen utilizing hemoproteins are strongly elevated in NSCLC cells. Furthermore, specific inhibition of heme synthesis using a well-known inhibitor suppresses NSCLC cell proliferation, colony formation and migration compared to normal cells. These results suggest that heme flux and function is important for NSCLC growth and progression.
Lentiviral particles overexpressing eGFP, Alas1, HRG1, and HCP1 were used to transfect NSCLC cell lines. Tumorigenic properties of these cells were analyzed in vitro using invasion, migration and colony formation assay. These cell lines were used to implant subcutaneous xenografts in NOD/SCID mice (n=6). Tumor growth was monitored using Bioluminescence imaging (BLI) and Vernier caliper measurements over a period of five weeks. Mice were sacrificed, tumor tissues were harvested and processed and embedded into FFPE blocks. The tissue sections were then used for histopathological analysis (Hematoxylin and Eosin staining) and immunohistochemistry experiments.
Our data show a significant increase in invasion, migration and colony formation properties of cells lines overexpressing Alas1, HRG1 and HCP1 compared to eGFP overexpressing cell lines (Control) in vitro. At week 5, BLI radiance (total photons/seconds), tumor volumes and masses of Alas1, HCP1 and HRG1 overexpression subcutaneous tumor xenografts were significantly higher compared to eGFP overexpression controls. This was further corroborated by H and E staining.
Our results demonstrate that overexpression of heme synthesis and uptake proteins causes an increase in tumorigenic properties of NSCLC cells in vivo. Thus, heme flux and function plays an important role in growth and progression of NSCLC. Further studies are underway to discern the molecular mechanisms underlying the role of heme in lung tumor growth.
Citation Format: Adnin Ashrafi, Poorva Ghosh, Sagar Sohoni, Li Zhang. To investigate the role of heme flux and function in growth and progression of NSCLC in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4371.
Abstract 4378: The association of enzymes related to cholesterol esters metabolism with hepatocellular carcinoma
Authors: Liu Zhirong , Shalaby Akram , Subramony Charu , Mao Jinghe , Zhou Xinchun 
Published: August 2019

Abstract
Objectives: The roles of cholesteryl esters (CE) in the pathogenesis of hepatocellular carcinoma (HCC) have not been completely elucidated. This study is aimed to investigate differences in the expression level of enzymes involving in synthesis and degradation of CEs between benign hapatic tissues (BHT) and HCC, and between male and female patients from African American (AA) and Caucasian American (CA).
Methods: TMAs were constructed with 97 BHT and 91 HCC samples from patients enrolled in the University of Mississippi Medical Center from 2010 to 2017. Immunochemistry (IHC) was performed on the TMAs for enzymes involved in CE synthesis (acyl CoA:cholesterol acyltransferase 1, ACAT1 and acyl CoA:cholesterol acyltransferase 2, ACAT2), and in CE degradation (lysosomal acid lipase, LAL and neutral cholesterol ester hydrolase 1, NCEH1) following the manufacturer’s instructions. The expression level for each enzyme was expressed as IHC score calculated with a scoring system. Two-tailed Student’s t-test was used to compare the difference in the expression level of each enzyme between two groups. Significant p value was set at p&lt;0.05.
Results: The IHC score of ACAT2 was significantly higher in HCC than in BHT in all population (6.21±2.42 vs (4.89.4±2.40, P=0.0006) and in stratified male population (6.15±2.33 vs 5.08±2.32, p=0.046), but not in stratified women, AA and CA populations. There was no significant difference in IHC score for ACAT1 between HCC and BHT in all population and populations stratified by race and gender. The IHC score of LAL was significantly higher in HCC as compared to BHT in all population (3.57±2.31 vs 2.40±1.30, P =0.0001) and in male population (3.33±2.01 vs 2.39±1.16, p=0.015), but not in stratified women, AA or CA population. The IHC score of NCEH1 was not significantly different between HCC and BHT in all studied population and population stratified by gender. However, it was disparate between AA and CA populations: The IHC score of NCEH1 was significantly lower in HCC than in BHT in AA population (5.59±2.04 vs 6.66±1.74, p=0.031) but it was higher in HCC than in BHT in CA population (6.84±1.96 vs 7.12±1.70, p&gt;0.05).
Conclusions: These results suggest that alterations in the expression levels of enzymes involving CE metabolism are associated with pathogenesis, progression and disparities in race and gender of HCC. This study also suggest that ACAT2 predominates CE synthesis as compared to ACAT1, and that LAL plays major role in CE degradation as compared to NCEH1 in association with HCC.
Citation Format: Zhirong Liu, Akram Shalaby, Charu Subramony, Jinghe Mao, Xinchun Zhou. The association of enzymes related to cholesterol esters metabolism with hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4378.