tbuckley/cabot-search huggingface dataset:
Abstract 3965: Novel biomimetic, interfacing 3D hydrogels to investigate roles of glioblastoma (GBM) niche on GBM progression
Authors: Alireza Sohrabi, Jesse Liang, Gevick Safarians, Elnaz Guivatchian, Itay Solomon, Stephanie Seidlits
Journal: Cancer Research (2020)

Abstract Glioblastoma (GBM) is the most common and lethal form of brain tumors with survival rate of 5% after 5 years. In the tumor microenvironment, invading GBM cells experience various ECM transitions at the tumor margin, such as alterations in matrix stiffness. Although conventional three-dimensional (3D) hydrogels have improved upon existing in vitro tumor models, these biomaterial platforms are not capable of separating the migratory GBM population from the bulk of the tumor. In addition, conventional hydrogels can only mimic a single microenvironment property (i.e. stiffness and protein presentation). In this study, we fabricated interfacing hyaluronic acid (HA)-based hydrogels using thiol-ene photochemistry to mimic the distinct stiffness conditions of tumor and surrounding tissue as well as the stiffness transition. The novel interfacing model enabled us to isolate invading GBM cells for further in vitro analysis. Atomic Force Microscopy (AFM) analysis of our xenograft GBM tumors in mice brain demonstrated that GBM tumor is stiffer than surrounding brain tissue. Therefore, mechanical properties of each hydrogel condition were characterized via AFM to confirm similarity of hydrogel stiffness to GBM xenografts and patient-derived, primary GBM cell migration in the HA-hydrogels was investigated. Immunohistochemistry staining showed that invading GBM cells, passing the interface have higher expression of RHAMM and CD44. Our findings suggest that invading GBM cells might have different expression profile and therefore require more thorough analyses using single cell RNA-seq. Citation Format: Alireza Sohrabi, Jesse Liang, Gevick Safarians, Elnaz Guivatchian, Itay Solomon, Stephanie Seidlits. Novel biomimetic, interfacing 3D hydrogels to investigate roles of glioblastoma (GBM) niche on GBM progression [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 3965.
Nonculprit Lesion Severity and Outcome of Revascularization in Patients With STEMI and Multivessel Coronary Disease
Authors: Tej Sheth, Natalia Pinilla-Echeverri, Raul Moreno, Jia Wang, David A. Wood, Robert F. Storey, Roxana Mehran, Kevin R. Bainey, Matthias Bossard, Sripal Bangalore, Jon-David Schwalm, James L. Velianou, Nicholas Valettas, Matthew Sibbald, Josep Rodés-Cabau, John Ducas, Eric A. Cohen, Akshay Bagai, Stephane Rinfret, David E. Newby, Laurent Feldman, Steven B. Laster, Irene M. Lang, Joseph D. Mills, John A. Cairns, Shamir R. Mehta
Journal: Journal of the American College of Cardiology (2020)
Abstract LB-018: Chemotherapeutic stress influences epithelial-mesenchymal transition and stemness in cancer stem cells of triple-negative breast cancer
Authors: Xiao Li, Juliane Strietz, Andreas Bleilevens, Elmar Stickeler, Jochen Maurer
Journal: Cancer Research (2020)

Abstract Triple-negative breast cancer (TNBC) is a subtype of breast cancer characterized by the absence of estrogen and progesterone receptors (ER, PR) and lacking an overexpression of human epidermal growth factor receptor 2 (HER2). Apart from this lack of therapeutic targets, TNBC also shows an increased capacity for early metastasis and therapy resistance. Currently, many TNBC patients receive neoadjuvant chemotherapy (NACT) upon detection of the disease. With TNBC likely being driven at least in part by a cancer stem-like cell type, we wanted to evaluate the response of primary cancer stem cells (CSCs) to standard chemotherapeutics. Therefore, we set up a survival model using primary CSCs to mimic tumor cells in patients under chemotherapy. Breast cancer stem cells (BCSCs) were exposed to chemotherapeutics with a sublethal dose for six days. Surviving cells were allowed to recover in culture medium without chemotherapeutics. Surviving and recovered cells were examined in regard to proliferation, migratory capacity, sphere forming capacity, epithelial-mesenchymal transition (EMT) factor expression at the mRNA level, and cancer-related microRNA (miRNA) profile. Our results indicate that chemotherapeutic stress enhanced sphere forming capacity of BCSCs, and changed cell morphology and EMT-related gene expression at the mRNA level, whereas the migratory capacity was unaffected. Six miRNAs were identified as potential regulators in this process. Citation Format: Xiao Li, Juliane Strietz, Andreas Bleilevens, Elmar Stickeler, Jochen Maurer. Chemotherapeutic stress influences epithelial-mesenchymal transition and stemness in cancer stem cells of triple-negative breast 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 LB-018.
Abstract 5778: Hernia and Ewing sarcoma
Authors: Di He, Johnni Hansen, Noah Federman, Jorn Olsen, Beate Ritz, Julia E. Heck
Journal: Cancer Research (2020)

Abstract Introduction: Ewing sarcoma (ES) is a rare cancer with an incidence that peaks in adolescence and young adulthood. The tumor occurs in bone and soft tissue and the etiology is unclear. Several studies have observed increased ES risk in children and young adults with hernia, including umbilical and inguinal hernia, suggesting a mechanism for a common causal pathway. A meta-analysis of 3 case-control studies reported a threefold increased risk of ES among hernia patients. The purpose of this study is to examine the association between hernia and ES in a population-based study. Methods: We ascertained Ewing sarcoma cases (age &amp;lt;20 years) from the Danish Cancer Registry (diagnoses 1977-2016; births 1977-2013), then randomly selected controls free of cancer at the date of corresponding cases diagnosis and matched (25:1) by sex and year of birth from the Central Population Register (N=4,160). Ewing sarcoma cases (N=122) were identified with the International Classification of Diseases for Oncology (ICD-O-1 and ICD-O-3 code 9260). Information on birth outcomes and gestational factors were taken from the Medical Birth Registry (1973+) and information on mother's and child's health was taken from the National Patient Register (1977+). We also searched this Register for diagnoses of hernia in the child based on procedure codes (a Nordic coding system from 1977-1995, and an extended version of ICD-10 thereafter). We used conditional logistic regression to determine associations for hernia and ES. Results: 122 ES cases were identified, among whom 6 cases had a diagnosis of hernia (1 of them had hernia diagnosed within the first 3 years of life). Among controls, 203 (6.7%) had a diagnosis of hernia. Of all children diagnosed with hernia, 27 (12.9%) presented hernia during the first year of life and 74 (35.4%) presented during the first 3 years of life. In ES cases there was no increase in risk of hernia (OR= 0.53, 0.17-1.72). Adjustment for presence of other congenital malformations did not change the results for hernia (OR=0.65). Restriction to younger cases (diagnosed ≤15 years) showed similar results for hernia. Conclusions: Previous studies have raised the possibility that inherited genes causing both developmental anomalies and cancer might be involved with the etiology of ES. However, based on registry and hospitalization data, we were not able to confirm previous associations with hernia. Either this study or earlier studies may have been influenced by small sample size. There is also a possibility that previous reports of positive associations are due to recall or publication biases. Citation Format: Di He, Johnni Hansen, Noah Federman, Jorn Olsen, Beate Ritz, Julia E. Heck. Hernia and Ewing sarcoma [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 5778.
Education and treatment adherence during the COVID-19 pandemic. Response to: ‘Adherence to medication in patients with rheumatic diseases during COVID-19 pandemic’ by Khabbazi<i>et al</i>
Authors: Rita Angélica Pineda-Sic, Griselda Serna-Peña, Jesus Alberto Cardenas-de la Garza, Sergio A Torres-Castillo, Dionicio Angel Galarza-Delgado, Diana Elsa Flores-Alvarado
Journal: Annals of the Rheumatic Diseases (2020)

With great interest, we read the study of Dr Khabbazi et al 1 regarding treatment adherence in patients with inflammatory rheumatic diseases during the COVID-19 pandemic in the East Azarbaijan province of Iran. They conducted telephone interviews to 1324 patients and inquired about treatment adherence behaviours during 2 weeks from July 2020. Of the 858 patients included in the final analysis, non-adherence was reported by 6.5% of the patients (defined by the group as ≥20% change in the dose or frequency of medications). In accordance to previous studies,2 …
Abstract 747: Pak1, TGFα, Ki 67 and survival in human gastric and gastroesophageal junction adenocarcinomas
Authors: Larry E. Douglass, Michael Parritt, Adam Neltner, Mariah Dooley, Michelle Robillard, Molly Frydl, Leah Focke, Kyle Damen, James A. Deddens, Julia H. Carter
Journal: Cancer Research (2020)

Abstract Stomach cancer is the third most common cause of cancer mortality worldwide. Most are adenocarcinomas. Adenocarcinomas of the stomach fall into two obvious groups based on site of origin; those arising in the area of the gastroesophageal junction (GEJ) and those arising from a more distal location, which we term gastric in this study. Adenocarcinomas of the stomach fall into four obvious groups based on a combination of genomic, molecular biologic, clinical and histopathologic characteristics (Nagara A, Kikuchi O, Bass AJ, Cancer Discovery 2019; DOI: 10.1158/2159-8290.CD-19-0487). We are reporting herein a study of 99 patients with adenocarcinoma of the stomach. This study evaluates the location of the tumor, the histopathologic features of the tumor, the immunohistochemically determined nuclear and cytoplasmic expression of P21 activated kinase (Pak 1), Transforming Growth Factor α (TGFα), and Ki67, a marker of cell proliferation. This study correlates these findings with patient survival. The study reveals: 1. significantly lower survival in patients with diffuse type adenocarcinoma compared to intestinal type, in both GEJ and gastric locations. 2. both GEJ and gastric adenocarcinomas had a poor prognosis. 3. increased expression of both TGFα and Pak1 in GEJ adenocarcinomas. 4. Ki67 expression is significantly less in diffuse type than the intestinal type (p=0.01 for GEJ and 0.03 for gastric). 5. cytoplasmic Pak1 and cytoplasmic TGFα were highly positively correlated (p=0.0001). 6. Ki67 expression was significantly inversely correlated with both nuclear Pak1 (p=0.04) and nuclear TGFα (p=0.02). 7. significantly increased expression of nuclear Pak1 in gastric diffuse type compared with gastric intestinal (p=0.0002) and GEJ intestinal (p=0.0001). These data suggest that Pak1 and TGFα might serve as diagnostic biomarkers of subtypes of adenocarcinomas of the stomach and gastroesophogeal junction. Citation Format: Larry E. Douglass, Michael Parritt, Adam Neltner, Mariah Dooley, Michelle Robillard, Molly Frydl, Leah Focke, Kyle Damen, James A. Deddens, Julia H. Carter. Pak1, TGFα, Ki 67 and survival in human gastric and gastroesophageal junction adenocarcinomas [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 747.
Adenylate Kinase 4 Modulates the Resistance of Breast Cancer Cells to Tamoxifen through an m6A-Based Epitranscriptomic Mechanism
Authors: Xiaochuan Liu, Gwendolyn Gonzalez, Xiaoxia Dai, Weili Miao, Jun Yuan, Ming Huang, David Bade, Lin Li, Yuxiang Sun, Yinsheng Wang
Journal: Molecular Therapy (2020)

N6-methyladenosine (m6A) is the most abundant internal modification in mRNA and this methylation constitutes an important regulatory mechanism for the stability and translational efficiency of mRNA. In this study, we found that the protein levels of adenylate kinase 4 (AK4) and m6A writer METTL3 are significantly higher in tamoxifen-resistant (TamR) MCF-7 cells than in parental cells. The TamR MCF-7 cells also exhibit increased methylation at multiple m6A consensus motif sites in the 5' untranslated region (5' UTR) of AK4 mRNA, and genetic depletion of METTL3 in TamR MCF-7 cells led to a diminished AK4 protein level and attenuated resistance to tamoxifen. In addition, we observed augmented levels of reactive oxygen species (ROS) and p38 activity in TamR MCF-7 cells, and both are diminished upon genetic depletion of AK4. Reciprocally, overexpression of AK4 in MCF-7 cells stimulates ROS and p38 phosphorylation levels, and it suppresses mitochondrial apoptosis. Moreover, scavenging of intracellular ROS leads to reduced p38 activity and re-sensitizes TamR MCF-7 cells to tamoxifen. Thus, our results uncover a novel m6A-mediated epitranscriptomic mechanism for the regulation of AK4, illustrate the cellular pathways through which increased AK4 expression contributes to tamoxifen resistance, and reveal AK4 as a potential therapeutic target for overcoming tamoxifen resistance.
Micro RNA signature predicts survival and relapase in lung cancer
Authors: S. L. Yu, H. Y. Chen, G. C. Chang, C. Y. Chen, H. W. Chen, S. Singh, C. L. Cheng, C. J. Yu, Y. C. Lee, H. S. Chen, T. J. Su, C. C. Chiang, H. N. Li, Q. S. Hong, H. Y. Su, C. C. Chen, W. J. Chen, C. C. Liu, W. K. Chang, K. C. Li, J. J. W. Chen, P. C. Yang
Journal: Cancer Cell (2008)
Abstract 6622: The identification of extranodal NK/T cell lymphoma-associated antigen for helper T cell-based immunotherapy
Authors: Takumi Kumai, Ryusuke Hayashi, Tatsuya Hayashi, Hiroya Kobayashi, Yasuaki Harabuchi
Journal: Cancer Research (2020)

Abstract Extranodal natural killer/T-cell lymphoma, nasal type (NKTL) is a fatal destructive tumor that develops around the nasopharyngeal and nasal/paranasal areas. Although this disease was originally considered to be endemic to East Asia, Central and South America and was extremely rare in Europe and the United States, the incidence of NKTL has increased during the last several decades in countries where it was previously not epidemic. The combination of irradiation and chemotherapies such as SMILE and MPVIC-P are effective. However, these therapies cause severe and sometimes fatal adverse effects indicating that a novel strategy to treat NKTL is required. The positive results of clinical trials using immune checkpoint inhibitors in solid tumors proved that immune cells are capable of eliminating tumor. However, autoimmune diseases are inevitable adverse events in this type of therapy, which non-specifically activates T cells. Thus, the identification of epitope peptides in tumor has re-emerged as an attractive concept. I will describe our study to identify NKTL-derived T cell epitopes as a basis of cancer vaccine. The expression of c-Met and its ligand HGF plays a critical role in cell proliferation and is involved in numerous malignancies. Because c-Met expression and its role in NKTL remain unclear, we first studied the expression and function of c-Met in NKTL cells. As a result, we found that HGF and c-Met were expressed and contributed to the proliferation of cells in NK/T-cell lymphoma. Next, the helper epitopes were identified from c-Met protein using computer-based algorism. The identified epitope peptides could elicit peptide-specific helper CD4 T cells (HTLs), which showed antitumor responses in vitro. The addition of c-Met inhibitor suppressed TGF-β production from tumor followed by the augmentation of HTL responses. In summary, we identified novel c-Met HTL epitopes that can elicit effective antitumor responses against tumors expressing c-Met. Our results provide the rationale of combining c-Met targeting therapy and immunotherapy for NKTCLs and epithelial tumors. Citation Format: Takumi Kumai, Ryusuke Hayashi, Tatsuya Hayashi, Hiroya Kobayashi, Yasuaki Harabuchi. The identification of extranodal NK/T cell lymphoma-associated antigen for helper T cell-based immunotherapy [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 6622.
A novel mechanism of inhibiting in-stent restenosis with arsenic trioxide drug-eluting stent: Enhancing contractile phenotype of vascular smooth muscle cells via YAP pathway
Authors: Yinping Zhao, Guangchao Zang, Tieying Yin, Xiaoyi Ma, Lifeng Zhou, Lingjuan Wu, Richard Daniel, Yunbing Wang, Juhui Qiu, Guixue Wang
Journal: Bioactive Materials (2020)

Arsenic trioxide (ATO or As2O3) has beneficial effects on suppressing neointimal hyperplasia and restenosis, but the mechanism is still unclear. The goal of this study is to further understand the mechanism of ATO's inhibitory effect on vascular smooth muscle cells (VSMCs). Through in vitro cell culture and in vivo stent implanting into the carotid arteries of rabbit, a synthetic-to-contractile phenotypic transition was induced and the proliferation of VSMCs was inhibited by ATO. F-actin filaments were clustered and the elasticity modulus was increased within the phenotypic modulation of VSMCs induced by ATO in vitro. Meanwhile, Yes-associated protein (YAP) nuclear translocation was inhibited by ATO both in vivo and in vitro. It was found that ROCK inhibitor or YAP inactivator could partially mask the phenotype modulation of ATO on VSMCs. The interaction of YAP with the ROCK pathway through ATO seems to mediate the contractile phenotype of VSMCs. This provides an indication of the clinical therapeutic mechanism for the beneficial bioactive effect of ATO-drug eluting stent (AES) on in-stent restenosis (ISR).
Abstract 2466: A novel role for the transcription factor SNAIL in alternative splicing
Authors: Atrayee Ray, Smruthi Rudraraju, Shawn Krueger, Janani kumar, Danielle Perley, Adam Scheidegger, Archana Dhasarathy
Journal: Cancer Research (2020)

Abstract The transcription factor SNAIL is a master regulator of the Epithelial to Mesenchymal Transition (EMT), a hallmark event during cancer metastasis. SNAIL repressed transcription of several epithelial cell-specific genes such as E-cadherin, leading to a mesenchymal phenotype that is less attached and more migratory. As a DNA-binding transcription factor, SNAIL binds consensus E-box motifs in gene promoters, and recruits epigenetic modifiers to repress or activate gene expression. Previous studies from our lab and others have indicated that SNAIL and its family member SLUG have several gene targets in common but also bind to unique gene targets. Whether SNAIL or SLUG share protein-interacting partners is unknown. To identify interactome partners of SNAIL and SLUG, we performed co-immunoprecipitation followed by iTRAQ mass spectrometry. The protein interactome of SNAIL, but not SLUG, was highly enriched for splicing proteins, of which the top hit was the Serine-Arginine Rich-Splicing Factor, SRSF1. SRSF1 participates in regulation of alternative splicing, a mechanism through which a cell can generate multiple proteins from the same gene. Alternative splicing events play a central role in EMT progression, and SRSF1 is overexpressed in many cancers. We explored the role of SNAIL and SRSF1 in driving alternative splicing events during EMT. First, we confirmed the association of SNAIL and SRSF1 by co-immunofluorescence, PLA assay and co-immunoprecipitation experiments during TGF-beta induction of EMT. RNA-IP (RIP) experiments demonstrated association of SNAIL with mesenchymal specific but not epithelial-specific splice isoforms, further suggesting an RNA binding role for SNAIL. Lastly, RNA-EMSA experiments suggest specificity for some but not all four Zinc fingers of SNAIL in binding to RNA. Based on these observations, we hypothesize that SNAIL regulates alternative splicing events during EMT at least in part through association with SRSF1 on RNA. As transcription and splicing are closely coupled, we predict that the regulation of splicing by transcription factors through RNA binding is universally utilized by other biological systems to alter phenotype in response to external stimuli. We are currently working on identifying the genome-wide changes in alternative splicing regulated by SNAIL, and the mechanism by which SNAIL interacts with the spliceosome to regulate alternative splicing. Citation Format: Atrayee Ray, Smruthi Rudraraju, Shawn Krueger, Janani kumar, Danielle Perley, Adam Scheidegger, Archana Dhasarathy. A novel role for the transcription factor SNAIL in alternative splicing [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 2466.
Abstract 4800: Pyruvate dehydrogenase inhibition leads to decreased glycolysis and increased reliance on asparagine in acute myeloid leukemia
Authors: Rebecca Anderson, Kristin M. Pladna, Timothy S. Pardee
Journal: Cancer Research (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.