bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4762: Metabolome in 5-FU resistant gastric cancer organoids
Authors: Sakamoto Naoya , Naka Kazuhito , Ukai Shoichi , Honma Ririno , Taniyama Daiki , Takashima Tsuyoshi , Maruyama Ryota , Tanabe Kazuaki , Ohdan Hideki , Yasui Wataru 
Published: September 2020

Abstract
Recent advances in metabolomics have deepened our understandings of the roles that specific modes of metabolism play in the maintenance of stem cells. Several pieces of evidence have demonstrated that cancer stem cells (CSCs) play a key role in the acquisition of drug resistance. Organoid is a novel 3D cell culture system through using the specific niche factors in a dish and is believed to harbor abundant stem cells; cancer organoid could possibly be useful for scrutinizing CSC biology. In this study, we successfully established 5-FU resistant gastric cancer organoids (GCOs) from patient-derived specimens, which were further confirmed by significant changes in the expression of molecules related to 5-FU metabolism. We then performed metabolome analysis using 3 pairs of 5-FU resistant/ parental GCOs and 10 pairs of non-neoplastic gastric organoid/ GCOs generated from the same patients. PCA plotting revealed that 5-FU resistant GCOs showed a distinct signature compared to those of their parental GCOs and 10 pairs of non-neoplastic gastric organoid/ GCOs. Among various significant changes in the metabolic pathways, we focused on the excessive reliance on the energy from TAC cycle in 5-FU resistant GCO because the difference was specifically seen in the comparison between 5-FU resistant and parental GCOs: not found in the comparison between 10 pairs of non-neoplastic gastric organoid and GCOs. We examined IC50 value for Tigecyclin and VLX600, both of which have an inhibitory effect on TCA cycle, by MTT assay using 5-FU resistant GCO and 2 gastric cancer cell lines (MKN-45 and MKN-74). Although there was almost no difference in IC50 values for Tigecyclin and VLX600 between 2 gastric cell lines and their 5-FU resistant cells, IC50 for both of TCA cycle inhibitors in 5-FU resistant GCO was significantly lower compared to that in parental GCO. Further studies are ongoing in order to verify the significance of dependency on TCA cycle, which could potentially lead to the development of new therapy for 5-FU resistant gastric cancer.
Citation Format: Naoya Sakamoto, Kazuhito Naka, Shoichi Ukai, Ririno Honma, Daiki Taniyama, Tsuyoshi Takashima, Ryota Maruyama, Kazuaki Tanabe, Hideki Ohdan, Wataru Yasui. Metabolome in 5-FU resistant gastric cancer organoids [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4762.
Abstract 4800: Pyruvate dehydrogenase inhibition leads to decreased glycolysis and increased reliance on asparagine in acute myeloid leukemia
Authors: Anderson Rebecca , Pladna Kristin M. , Pardee Timothy S. 
Published: September 2020

Abstract
Acute myeloid leukemia (AML) is an aggressive disease characterized by poor outcomes and chemotherapy resistance. Devimistat (CPI-613 ®) is a novel agent that inhibits two key tricarboxylic acid (TCA) cycle enzymes, pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase complexes (KGDH). Our lab has shown that genetic and pharmacologic inhibition of PDH sensitizes cells to chemotherapy and recent clinical trials of chemotherapy plus devimistat have been promising. However, the means by which AML cells adapt to PDH loss during devimistat treatment is unknown. AML cells with PDH deleted by CRISPR-Cas9 (PDH KO) show decreased mitochondrial oxygen consumption, membrane potential and altered mitochondrial morphology. Surprisingly, PDH KO cells also showed decreased glycolytic rates. In order to explore this mechanism we assessed glucose uptake and found PDH KO cells had significantly less glucose uptake. We next assessed expression of hexokinase II, a key enzyme that commits glucose retention in the cell, in PDH KO and devimistat treated cells. Strikingly, we found that hexokinase II expression was decreased in PDH KO cells, which was rescued with proteasomal inhibition. Consistent with disruption of the protective interaction between mitochondrial membrane channel VDAC1 and HKII. However, PDH KO and devimistat treated cells are more sensitive to the glycolytic inhibitor 2-deoxy-D-glucose. This indicates that even though TCA cycle inhibition decreases glycolysis through loss of HKII, the cells are still reliant on the activity that remains. Cells can supplement TCA cycle intermediates through amino acid metabolism. Two key amino acids, asparagine and glutamate, were reintroduced to devimistat treated, amino acid starved, AML cells and asparagine significantly rescued the cells. Asparaginase, which converts asparagine into aspartic acid and ammonia, significantly increased sensitivity to genetic and pharmacological inhibition of PDH in AML cells. This indicates that glycolysis inhibition and amino acid deprivation in combination with devimistat-mediated PDH inhibition should be further explored in clinical trials.
Citation Format: Rebecca Anderson, Kristin M. Pladna, Timothy S. Pardee. Pyruvate dehydrogenase inhibition leads to decreased glycolysis and increased reliance on asparagine in acute myeloid leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4800.
Abstract 4809: Monoethanolamine stimulates calcium-induced metabolic stress leading to autophagic cell death in prostate cancer
Authors: Garlapati Chakravarthy 
Published: September 2020

Abstract
Mitochondrial activity and metabolism are crucial to meet the energy demands of cancer cells. We have recently shown the efficacy of monoethanolamine (Etn), an orally deliverable lipid formulation, in reducing tumor growth in various xenograft models including prostate cancer (PCa). Etn increased the metabolic stress of PCa cells by depleting cellular glucose and glutamine levels. However, the precise mechanism of Etn-mediated metabolic stress in cancer cells remains elusive. Herein, we examined how Etn alters the activity and structure of the mitochondria to induce cell death. Etn treatment modulated phosphatidylethanolamine (PE) lipid and glycerophosphoethanolamine (GPE) levels in PCa cells. Altered PE lipids correlated with disruption of mitochondrial cristae and led to a concomitant accumulation of autophagosomes. Deregulated functional activity of mitochondria, as evidenced by reduced oxygen consumption rate (OCR), extracellular acidification rate (ECAR), were associated with structural distortions of the mitochondria and a transient increase in the intracellular calcium concentration. Etn treatment reduced the amount of cytosolic lipid droplets (LD) and caused a reduction in PE/GPE ratio. Further, we observed an increase in lipolysis and death-inducing autophagy activation in Etn-treated PCa cells. These data suggest that Etn is a promising anticancer agent for PCa and further studies to determine its efficacy in other cancer types are warranted.
Citation Format: Chakravarthy Garlapati. Monoethanolamine stimulates calcium-induced metabolic stress leading to autophagic cell death in prostate cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4809.
Abstract 4820: Novel protein AX-295aa encoded by circAX promotes gastric carcinogenesis by activating Wnt pathway
Authors: Peng Yin , Zhang Xiaojing , Deng Shiqi , He Jieqiong , Chen Wangchun , Zhu Xiaohui , Yuan Yuan , Feng Xianling , Fan Xinmin , Jin Zhe 
Published: September 2020

Abstract
Recently, traditionally non-encoding circRNA has been shown to encode a new protein to play an important role in oncogenesis. Based on the sequencing data and bioinformatics analysis, circAX was screened as an oncogenic circRNA encoding AX-295aa in gastric cancer. CircAX is highly expressed in gastric cancer and associated with lymph node metastasis. We found that circAX promotes GC cell proliferation and migration and it encodes a novel protein AX-295aa. AX-295aa interacts with APC and competitively inhibits AXIN1 binding to APC. It enhances β-catenin nuclear translocation and activates Wnt signaling pathway to promote the carcinogenesis and development of gastric cancer. The study reveals a new regulatory mechanism of circAX and clarify the mechanism by which circAX promotes gastric carcinogenesis. It will ultimately provide novel circRNA molecular markers for early diagnosis and targets for more effective treatment of gastric cancer.
Citation Format: Yin Peng, Xiaojing Zhang, Shiqi Deng, Jieqiong He, Wangchun Chen, Xiaohui Zhu, Yuan Yuan, Xianling Feng, Xinmin Fan, Zhe Jin. Novel protein AX-295aa encoded by circAX promotes gastric carcinogenesis by activating Wnt pathway [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4820.
Abstract 4836: Diagnostic and prognostic significance of microRNA modulation in oral cancer
Authors: Falzone Luca , Vivarelli Silvia , Crimi Salvatore , Bianchi Alberto , Candido Saverio , Libra Massimo 
Published: September 2020

Abstract
Oral cancer is one of the leading causes of cancer death worldwide. Despite the availability of screening programs, oral cancer is often not correctly diagnosed resulting in a significant fraction of late diagnosis.Currently, there are not effective biomarkers for the early diagnosis of oral cancer and for the definition of patients' prognosis. Therefore, the identification of new effective diagnostic and prognostic biomarkers is one of the main challenges for the management of this tumor. Our preliminary analyses of GEO DataSets and TCGA miRNA profiling datasets identified a set of microRNAs (miRNAs) significantly de-regulated in oral cancer. In addition, through the use of different bioinformatics tools (miRCancerdb, GO PANTHER, STRING and DIANA-mirPath), the diagnostic and prognostic significance of selected miRNAs, as well as the modulated molecular pathways and genes were predicted.Starting from these preliminary bioinformatics results, the aim of the present study was to validate the sensitivity and specificity of selected miRNAs in oral cancer patients and healthy controls. For this purpose, the expression levels of selected miRNAs were determined in plasma and matched saliva samples from a subset of oral cancer patients and healthy controls by using specific miRNA TaqMan probes and droplet digital PCR (ddPCR).The ddPCR results showed that the selected miRNAs can be easily detected in both plasma and saliva samples with concordant expression levels and that the expression levels of miRNAs were significantly different in oral cancer patients compared to healthy controls as predicted in the bioinformatics analyses. Furthermore, the comparison of the molecular data with the clinical-pathological features of patients allowed us to establish the prognostic significance of selected miRNAs.
Citation Format: Luca Falzone, Silvia Vivarelli, Salvatore Crimi, Alberto Bianchi, Saverio Candido, Massimo Libra. Diagnostic and prognostic significance of microRNA modulation in oral cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4836.
Abstract 4873: Molecular mechanism of neddylation-dependent suppression of cancer cell migration
Authors: Chun Yang-Sook , Seo Jieun , Park Jun Bum 
Published: September 2020

Abstract
Neddylation is a process by which NEDD8 is covalently conjugated to target proteins by sequential enzymatic reaction. Its role in cancer cell migration has only been recently acknowledged. Previously in cancer cell migration, the epithelial to mesenchymal transition (EMT) process has been well-known to play an important role in both invasion and metastasis by promoting mesenchymal phenotype in epithelial cells. However, the role of neddylation in the EMT process and its mechanistic details are yet to be elucidated. We recently reported that neddylation plays a crucial role in cancer cell migration through the PI3K-Akt pathway. Here, we report that inhibiting neddylation activates the hypoxia-inducible factor-1α through the PI3K-Akt pathway, which eventually regulates the EMT-activator zinc finger E-box binding homeobox 1 in various cancer cell lines. As induction of hypoxia-inducible factor-1α is known to deteriorate the state of cancer and EMT process is one of the hallmarks of metastasis in cancer, our findings uncover the novel association of hypoxia-inducible factor-1α and zinc finger E-box binding homeobox 1 through the process of neddylation.
Citation Format: Yang-Sook Chun, Jieun Seo, Jun Bum Park. Molecular mechanism of neddylation-dependent suppression of cancer cell migration [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4873.
Abstract 4879: Identification of degron motifs and mutations by analyzing a deep neural network
Authors: Chen Cynthia , Tokheim Collin , Liu Shirley 
Published: September 2020

Abstract
Degrons, short amino acid sequences on protein substrates, play a critical role in the ubiquitin-proteasome system (UPS), which regulates over 80 percent of protein degradation in cells. When recognized by E3 ubiquitin ligases, degrons signal the destruction of its substrate protein, determining the regulatory specificity of the UPS. While a few degrons have been reported to be affected by mutations driving cancer growth, the effect of specific mutations on degrons remains largely unidentified. In this study, we analyze a deep neural network model that predicts the likelihood of an input protein sequence to contain a degron. To characterize the important C-terminal degron motifs learned by the model, we ran computational methods including sequence ranking and selection, enrichment analyses, and sequence logo visualization. This revealed the discovery of 101 significant degron motifs across lengths 2, 3, and 4. While previous studies suggested that di-amino acid motifs might be the primary source of c-end degron, the new motifs suggest that additional complexity might exist with a longer extended degron. Using these putative motifs as targets for mutations, we performed in silico mutagenesis to identify high-impact amino acid mutations that cause degron loss or gain. Our discovery of degron motif-mutation pairs could inform the development of targeted small-molecule drugs for cancer treatments and identification mutational biomarkers used for early detection of cancers.
Citation Format: Cynthia Chen, Collin Tokheim, Shirley Liu. Identification of degron motifs and mutations by analyzing a deep neural network [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4879.
Abstract 4903: Minimal mutational determinants of human squamous cell carcinoma
Authors: Planells-Palop Vicente , Koo Angie , Malave Heydi , Lee Katharine , Tward Aaron 
Published: September 2020

Abstract
Dozens of driver mutations and copy number changes have been implicated in human squamous cell carcinomas (SCCs), and each tumor harbors multiple putative driver mutations. However, the minimal set of mutations sufficient to transform a normal keratinocyte into squamous cell carcinoma is unknown. By analyzing TCGA data and previously published datasets, we have identified common combinations of driver mutations in SCCs. Among the most common driver events are mutations in TP53, CDKN2A, and NOTCH1. Using CRISPR editing at endogenous loci in primary human keratinocytes, we demonstrate that no single driver mutation is sufficient to transform keratinocytes, and in fact many single gene mutations appear toxic to keratinocytes. The combination of loss of function mutations in TP53 and CDKN2A are sufficient to immortalize both skin and oral primary human keratinocytes in 2D culture, and confer a selective advantage in competition assays. Simultaneous mutation of TP53, CDKN2A, and NOTCH1 demonstrates a very similar phenotype in 2D culture as mutation of TP53 and CDKN2A alone. However, using 3D organotypic squamous epithelial cultures consisting of genome-edited keratinocytes grown on decellularized dermis impregnated with fibroblasts and grown at an air-liquid interface demonstrates that keratinocytes with TP53 and CDKN2A mutation alone are sufficient to induce dysplasia, whereas keratinocytes harboring TP53, CDKN2A, and NOTCH1 mutation exhibit an SCC like phenotype including invasion through the basement membrane. RNAseq analysis demonstrates that the transition to SCC by NOTCH1 loss involves a partial-EMT like program. Targeted hybrid capture sequencing of edited keratinocytes revealed no other driver mutations or copy number changes other than the experimentally induced ones, consistent with the notion that TP53, CDKN2A, and NOTCH1 mutations alone are sufficient to reprogram normal keratinocyte into their malignant counterparts. Thus, despite a high mutation burden and frequent chromosomal instability, as few as three mutational events appear to be sufficient to induce SCC.
Citation Format: Vicente Planells-Palop, Angie Koo, Heydi Malave, Katharine Lee, Aaron Tward. Minimal mutational determinants of human squamous cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4903.
Abstract 4973: Comparison of tumor immune microenvironment in triple negative breast cancer (TNBC) of African American versus that of white patients
Authors: Yaghoobi Vesal , Pelekanou Vasiliki , O'Meara Tess , Silber Andrea , Pusztai Lajos , Rimm David , Blenman Kim 
Published: September 2020

Abstract
Introduction: Although there are many possible causes, it has been observed that Triple Negative Breast Cancer (TNBC) has a worse overall outcome in African American (AA) than white patients. Recently, there is also evidence that the patients response to the tumor, or the biological response expressed as the tumor immune microenvironment, impacts outcome. The goal of this study was to compare the Tumor Microenvironment (TME) of TNBC in the two mentioned groups in order to seek molecular parameters that are different in TNBC in AA patients as compared to whites.
Methods: We selected N=50 AA and N=50 white TNBC samples from the Yale Pathology archives that were matched by diagnosis date. We measured CD45, CD3, CD8, CD20, CD14, CD68, PD-L1, THY1, aSMA and Fibroblast Activation Protein (FAP) expression in both the tumor and stromal compartments in whole slides from formalin fixed paraffin embedded (FFPE) tissues using multiplexed quantitative immunofluorescence (QIF). We also assessed the activation status of CD3-positive cells using Ki67 and Granzyme B markers. Median of each marker expression was calculated for each case by using quantitation from all Fields of View (FOV) that contained at least 10% tumor area.
Results: AA tumors contained a significantly higher CD45-positive cells in overall, within tumor and stromal compartments (p = 0.0102, 0.0007 and 0.0280 respectively). Being more specific about CD45 marker, AA also showed to have a significantly higher level of overall lymphocyte population, measured by quantitating CD45+ CD14- cells (p =0.0081). AA tumors also had a significantly higher level of CD8 expression (p &lt;0.0001). Even though we could not find any differences in CD3 expressions between the two groups, AA tumors contained a significantly higher level of activated T-cells (p =0.0432), where activation is defined as CD3 cells with high Ki67 or Granzyme B. AA tumors contained a significantly higher level of CD68 positive cells (p &lt; 0.0001) and PD-L1 expression in CD68+ cells (p =0.0101). All other markers showed no difference between the two groups.
Conclusion: Significant differences are seen in the TME of AA vs. white TNBCs. Further characterization of macrophages, fibroblasts, regulatory T-cells and Extracellular Matrix are underway to more specifically define TME and determine the relationship between TME features and outcome.
Citation Format: Vesal Yaghoobi, Vasiliki Pelekanou, Tess O'Meara, Andrea Silber, Lajos Pusztai, David Rimm, Kim Blenman. Comparison of tumor immune microenvironment in triple negative breast cancer (TNBC) of African American versus that of white patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4973.
Abstract 4984: Where do the T lymphocytes go in prostate cancer: Correlation with CD103, CD39 expression and clinical pathological parameters
Authors: Walter Beatriz , Gasmi Billel , Naizen Xu , Valera Vladimir , Pinto Peter , Merino Maria J. 
Published: September 2020

Abstract
Introduction: Many solid tumors such as prostate cancer have shown limited response to immunotherapy treatment. Whether this is due to absence of tumor specific antigens or poor immune infiltrate, the exact mechanism is not well understood. Our study evaluates the presence and spatial distribution in benign versus malignant tissue of CD4+ and CD8+ cells in whole mounted radical prostatectomies samples and characterized the subset of intraepithelial CD103+ and CD39+ cells, which have been previously shown to harbor more cancer specific T-cells.
Materials and Methods: Sixteen cases of whole mounted radical prostatectomy samples were used to asses CD4, CD8, CD103 (all abcam) and CD39 (Sigma) expression by IHC. Location of positive cells within epithelium and stroma in tumor and benign prostatic tissue was evaluated. The results were confirmed using QuPath Software, for positive detection of immune cells by color deconvolution and threshold adjustments.
Results: The CD4 and CD8 staining demonstrated that most of the immune cells were present in the stroma but not within the malignant glands. The whole prostate sections (mean size 51.4 × 44mm) generated around 1650 ROI's per/case. All the ROI's were included in the analysis. CD4+ and CD8+ were evaluated in whole gland vs tumor area. No significant difference = of CD4+ and CD8+ cell density was seen between whole prostate area and tumor areas (CD4+ 2.9 vs 1.9%) and (CD8+ 1.3 vs 1.2%). The density of CD4+ and CD8+ cells in tumors vs benign gland was approximately the same (means 0.93 for both). For the CD103+ analysis, the positive cells were rarely found in the tumor epithelium in comparison with the benign glands (mean 1.09 vs 5.41; representing 2 vs 9.3% of the total lymphocytes). The CD39 stain showed positive cells mostly at the benign epithelium. No correlation was found between our results and Gleason grade, stage or prognosis.
Conclusion: Our study suggests the possibility that in solid cancers such as prostate cancer, immune cells may not be able to reach appropriately the malignant epithelium with only a small subset of T cells reaching their target. This may have important clinical implication for the success of the immune therapy in this group of patients. Further studies are being performed to deeply characterized the tumor infiltrating cell population.
Citation Format: Beatriz Walter, Billel Gasmi, Xu Naizen, Vladimir Valera, Peter Pinto, Maria J. Merino. Where do the T lymphocytes go in prostate cancer: Correlation with CD103, CD39 expression and clinical pathological parameters [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4984.