bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1494: SOX18: A novel master regulator of high-grade serous ovarian tumorigenesis
Authors: Liu Annie Y. , Vavra Kevin C. , Corona Rosario I. , Abassi Forough , Fonseca Marcos , Segato Felipe , Freedman Matthew L. , Gayther Simon A. , Noushmehr Houtan , Lawrenson Kate 
Published: August 2018

Abstract
High-grade serous ovarian cancer (HGSOC) is the most common and lethal subtype of ovarian cancer. Recent data indicate that fallopian tube secretory epithelial cells (FTSECs) represent the cell of origin for HGSOC. While many studies have characterized molecular features associated with HGSOC biology, the master transcription factors (TFs) that drive disease development are not known. To identify master TFs for HGSOC, we first performed an integrative analysis of gene expression profiles from 73 FTSEC samples and 394 HGSOCs from The Cancer Genome Atlas (TCGA) project. We then integrated these data with chromatin immunoprecipitation sequencing (ChIP-seq) analyses performed on primary HGSOC samples to select active chromatin regions marked by H3k27ac and to identify super-enhancer (SE) regions. These analyses identified overexpressed TFs that coincide with tumor-specific SEs, a hallmark of master TFs. We identified multiple putative master TFs including SOX18, which was highly overexpressed in HGSOCs relative to normal FTSECs (log2 fold change in expression = 3.5, p = 2.5x10-19). SOX18 is a TF that regulates development of blood and lymphatic vessels, but its association with HGSOC development has not been reported before. We examined the expression of SOX18 in ~8,000 tumors representing 17 tumor types from TCGA. SOX18 expression was significantly elevated in HGSOC relative to any other tumor types, suggesting it is highly specific to this cancer. We found that SOX18 is highly expressed in the HGSOC cell lines UWB1.289, Kuramochi, and EFO21, and we then performed lentiviral-mediated shRNA knockdown of SOX18 in these cell lines to establish the effects of SOX18 depletion on neoplastic phenotypes. In ongoing experiments, we are performing gene expression profiling and H3k27ac ChIP-seq analysis after SOX18 knockdown to identify SOX18 target genes and characterize the landscape of SOX18 binding sites in HGSOC. These studies will likely identify novel molecular biomarkers that may represent much-needed therapeutic targets for HGSOC.
Citation Format: Annie Y. Liu, Kevin C. Vavra, Rosario I. Corona, Forough Abassi, Marcos Fonseca, Felipe Segato, Matthew L. Freedman, Simon A. Gayther, Houtan Noushmehr, Kate Lawrenson. SOX18: A novel master regulator of high-grade serous ovarian tumorigenesis [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 1494.
Abstract 1504: Opposing roles of FoxM1 and the hepatic specification genes FoxA1/A2 dictate differentiation state of liver cancer cells
Authors: Chand Vaibhav , Pandey Akshay , Kopanja Dragana , Guzman Grace , Raychaudhuri Pradip 
Published: August 2018

Abstract
The pro-proliferation transcription factor FoxM1 is over-expressed mainly in high-grade cancers. However, the significance of its over-expression in cancers, including poorly differentiated hepatocellular carcinoma (HCC), is not known. Here we provide evidence for a causal role of the over-expressed FoxM1 in driving high-grade progression of HCC. Immunohistochemical staining of human HCC specimens revealed opposite expression patterns of FoxM1 and the liver differentiation genes FoxA1/A2. Moreover, using a transgenic mouse model for oncogenic Ras-driven HCC as well as cell-based studies, we provide in vivo genetic evidence for a direct repression of FoxA1/A2 by FoxM1. Interestingly, FoxM1 represses these differentiation genes mainly in G1 phase, a phase in the cell cycle in which cells can undergo differentiation. Moreover, repression of FoxA1/A2 in G1 phase is important, as these genes are capable of inhibiting expression of the pluripotency genes that are mainly expressed in S/G2 phases. Also, we show that FoxA1/A2 inhibit expression of FoxM1 by inhibiting binding of FoxM1 to its own promoter and thus blocking its auto-activation. Our observations identify a significant new mechanism in which FoxM1 and the FoxA genes play opposing roles that determine the differentiation state of the HCC cells.
Citation Format: Vaibhav Chand, Akshay Pandey, Dragana Kopanja, Grace Guzman, Pradip Raychaudhuri. Opposing roles of FoxM1 and the hepatic specification genes FoxA1/A2 dictate differentiation state of liver 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 1504.
Abstract 1508: Cloning, expression and purification of Cionasavignyi polypeptide CS5931 and its antitumor activity
Authors: Zhang Yangyang , Lai Honglin , An Weixiao , Cao Shousong , Lin Xiukun 
Published: August 2018

Abstract
Previous study in our laboratory has shown that a novel polypeptide CS5931 (molecular weight 5931 Da) derived from Ciona savignyi possesses potent cytotoxicity against a variety of human cancer cells including cervical carcinoma Hela cells, colorectal carcinoma HCT-116 and RKO cells, lung carcinoma A549 cells, and leukemia HL60 cells ,with IC50 values of 4.17, 2.50, 5.54, 4.69 and 4.98uM,respectively. This result suggested that HCT116 cells are the most sensitive to the treatment of CS5931. We also found that CS5931 markedly induced apoptosis in a dose-dependent manner in HCT116 cells by Annexin V-FITC/PI double staining analysis. However, its content in Ciona savignyi is very low thus developing a novel method for increase of the production of the polypeptide is promising. GRN polypeptides typically consist of 56-58 amino acids with six disulfide bonds and four beta-sheets to make the GRN polypeptide structurally compact and complex so large-scale preparation of natural polypeptide CS5931 is very difficult. Therefore, recombinant expression of CS5931 by genetic engineering is one of the effective ways to solve this problem. In the present study, we cloned a full length cDNA of CS5931 precursor by rapid amplification of cDNA ends (RACE) and obtained the amino acid sequence of CS5931. We further made the polypeptide expression with high efficiency in E. coli. The expressed protein was purified through affinity chromatography. The gene fragment coding CS5931 was successfully cloned and then linked into prokaryotic expression carrier pET28a(+) and pPICZαa, respectively. Two expression vectors pET28a(+)-CS5931 and pPICZαa-CS5931 were transformed into E. coli and Pichia pastoris, respectively. Then recombinant polypeptide CS5931 were successfully induced with high expression . To investigate the expression and anticancer effect of polypeptide CS5931 in different vectors and strains, we purified the expressed product developed suitable methods for CS5931 great expression while maintaining its potent anticancer activity and identified the role of CS5931 target proteins. Moreover, the purified polypeptide native CS5931 and recombinant CS5931 equally display great antitumor activity against HT29 cells. Our studies indicate that we have successfully cloned, expressed and purified Ciona savignyi polypeptide CS5931 and demonstrated its potent antitumor activity against colorectal cancer cells. Therefore, CS5931 may be developed as a novel anticancer agent in the treatment of colorectal cancer clinically.
Citation Format: Yangyang Zhang, Honglin Lai, Weixiao An, Shousong Cao, Xiukun Lin. Cloning, expression and purification of Cionasavignyi polypeptide CS5931 and its antitumor activity [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 1508.
Abstract 1509: Cachexia: Leveraging transcriptomics to identify potential therapeutics
Authors: Ung Matthew , Fowler Kevin D. , Funt Jason M. , Escalante-Chong Renan , Koytiger Gregory , Kolitz Sarah , Kusko Rebecca L. , Zeskind Benjamin 
Published: August 2018

Abstract
Cachexia is a common cause of morbidity across multiple cancer types, yet remains largely under-studied especially in the realm of transcriptomics. An essential component of cancer cachexia is the induced transition of adipocytes from white to brown, which increases energetic inefficiency and contributes to systemic loss of adipose tissue. This is likely caused by the tumor secreting thermo-stimulatory factors into the extracellular space.
Here, we integrate publicly-available data to pinpoint actionable gene targets that enable cancer cells to induce fat “browning”. In particular, we identify genes differentially expressed between Lewis lung carcinoma subclones that can induce thermogenesis in primary adipocytes at high or low levels in vitro (GSE57797). We then evaluate whether the expression of these thermo-stimulatory genes predict patient survival in an independent gene expression dataset of primary tumors from advanced stage gastric cancer patients (GSE15459). Finally, we leverage drug gene expression data from CMAP and LINCS to identify molecules that reverse the thermo-stimulatory signature.
Our analysis reveals that the thermo-stimulatory signature predicts prognosis in patients with advanced gastric cancer (p=0.005), with the low thermo-stimulatory group exhibiting improved prognosis. The thermo-stimulatory signature is most strongly reversed by expression signatures from inhibitors of MEK (MAP2K1), including pd-0325901, AZD-8330 (ARRY-704), CI-1040, trametinib, and selumetinib. Interestingly, we observe a time-dependent effect of these MEK inhibitors, with shorter durations of exposure consistently reversing thermo-stimulatory signatures more effectively than longer durations of exposure.
Analysis of cachexia-related transcriptomic data reveals key marker genes and pathways which can be used to optimize MEK inhibitors for cachexia. Results from this study support the development of MEK inhibitors to treat cachexia, and suggest that careful optimization of pharmacokinetics will be important for success in the clinic.
Citation Format: Matthew Ung, Kevin D. Fowler, Jason M. Funt, Renan Escalante-Chong, Gregory Koytiger, Sarah Kolitz, Rebecca L. Kusko, Benjamin Zeskind. Cachexia: Leveraging transcriptomics to identify potential therapeutics [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 1509.
Abstract 1511: Differential expression analysis and biomarker identification in five salivary gland carcinoma types
Authors: Brayer Kathryn J. , Mitani Yoshitsugu , El-Naggar Adel , Ness Scott A. 
Published: August 2018

Abstract
Significant morphologic overlap can exist between distinct salivary gland neoplasms, making differential diagnosis challenging, even with the use of new immunohistochemistry stains and FISH probes (Griffith et al., Arch Pathol Lab Med 2017). RNA-sequencing (RNAseq) technology is increasingly being used as a tool for identify diagnostic molecular signatures in a wide variety of diseases (Byron et al., Nat Rev Genet 2016). Furthermore, transcriptomics data are being used to develop biomarkers that can be used in drug discovery assays. Using an unbiased RNAseq analysis pipeline (Brayer et al., Cancer Discov 2016; Brown et al., PLos One 2017), we developed molecular profiles for 126 salivary gland tumors with accompanying clinical data–68 adenoid cystic carcinoma (ACC), 23 acinic cell carcinoma (Acinic), 5 basal cell adenoma (BCA), 20 basal cell adenocarcinoma (BCAC), and 10 secretory carcinoma (SC)–and have identified distinct gene expression patterns for each neoplasm. Additionally, a detailed analysis within each cancer type has revealed heterogeneous gene expression patterns, with altered signaling pathways, suggesting molecular subtypes exist. In both ACC and Acinic samples we identified unique molecular signatures found in patients with poor overall survival. Transcripts within each molecular signature that are independent of gender, age, and cancer stage, but correlated with clinical outcome data, are being identified for use as diagnostic or prognostic biomarkers and for use in drug discovery assays. Preliminary results to identify biomarkers for these neoplasms will also be presented.
Citation Format: Kathryn J. Brayer, Yoshitsugu Mitani, Adel El-Naggar, Scott A. Ness. Differential expression analysis and biomarker identification in five salivary gland carcinoma types [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 1511.
Abstract 1518: Gene expression of trefoil proteins, gastrokines and mucins in Indian gastric cancer patients
Authors: Basak Dipjit , Mondal Pronoy Kanti , Mondal Brishti , Ghosh Ranajoy , Halder Aniket , Dhali Gopal Krishna , Chowdhury Abhijit , Mukhopadhyay Indranil , Datta Shalini 
Published: August 2018

Abstract
Background: Gastric cancer is the (GC) third most cause of cancer related mortality worldwide. Histopathologically, GC is sub classified into two major histopathological subtypes- diffuse and intestinal. The trefoil factor family - TFF1, TFF2 and TFF3 is known to play a pivotal role in gastrointestinal mucosal defence and repair. Gastrokines (GKN1, GKN2) are stomach specific secretary proteins which play fundamental roles in regulating gastric epithelial homeostasis. Similarly, secreted mucins are large O-glycosylated proteins that participate in the protection/defence of underlying mucosa in normal adults. The loss of expression of trefoil proteins, gastrokines and several mucins in retinoblastoma and colorectal cancer are reported in recent studies.
Aims: The molecular underpinnings and gene expression of Indian GC patients are largely unknown. In this study, we evaluated the gene expression of TFF1, TFF2, TFF3, GKN1, GKN2, MUC3A, MUC5AC, MUC13 in gastric cancer patients from India. Additionally, we wanted to see whether these gene expressions are different in two histopathological groups.
Materials and Methods: Endoscopic biopsy tissue from gastric tumour and adjacent normal regions were collected with ethical approval and informed consent from 42 patients . After histopathological confirmation by two pathologists, total RNA were isolated from tumour and corresponding normal tissue and gene expression was measured by qRT-PCR. Statistical analysis was performed by R package.
Result and Discussion: We identified that TFF1, TFF2, TFF3, GKN1, GKN2 are significantly differentially expressed in gastric tumour tissue with respect to adjacent normal tissue whereas mucins had no significant deregulation. TFF1, TFF2, GKN1 and GKN2 are found to be down regulated in most tumour tissues compared to adjacent normal. Only GKN2 expression is significantly different among diffuse and intestinal subtypes . Our statistical analysis also revealed that gene expression of TFF1, TFF2, GKN1 and GKN2 are highly correlated with the gene expression of MUC5AC. Further study with larger patient sample is required to fully understand the complex interplay of trefoil, gastrokines and mucins in GC.
Citation Format: Dipjit Basak, Pronoy Kanti Mondal, Brishti Mondal, Ranajoy Ghosh, Aniket Halder, Gopal Krishna Dhali, Abhijit Chowdhury, Indranil Mukhopadhyay, Shalini Datta. Gene expression of trefoil proteins, gastrokines and mucins in Indian gastric cancer patients [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 1518.
Abstract 1530: A multifunctional role for adjuvant anti-4-1BB therapy in augmenting antitumor responses by CAR T cells
Authors: Mardiana Sherly , John Liza B. , Kershaw Michael H. , Beavis Paul A. , Darcy Phillip K. 
Published: August 2018

Abstract
Adoptive immunotherapy utilising chimeric antigen receptor (CAR) T cells has demonstrated high success rates in hematological cancers, with up to 90% complete remission being reported in patients with acute lymphoblastic leukemia (ALL). However, this success is not currently transferrable to solid malignancies due in part to the immunosuppressive tumor microenvironment limiting CAR T cell responses. Given that activation of the 4-1BB (CD137) pathway using an agonistic α-4-1BB antibody is known to provide strong co-stimulatory signals for augmenting and diversifying T cell responses, we hypothesized that the combination of α-4-1BB and CAR T cell therapy would result in improved anti-tumor responses. Using a human-Her2 self-antigen mouse model, we found that α-4-1BB significantly enhanced CAR T cell efficacy directed against the Her2 antigen in two different established solid tumor settings. Investigation into the mechanism revealed increased expression of IFNγ and the proliferation marker Ki67 by tumor-infiltrating CAR T cells when combined with α-4-1BB. The importance of IFNγ was demonstrated in vivo where synergistic effects of the combination therapy were abrogated when IFNγ was depleted. Strikingly, we also found that α-4-1BB significantly reduced host immunosuppressive cells at the tumor site including regulatory T cells (Tregs) and myeloid derived suppressor cells (MDSCs), correlating with an increased therapeutic response. Investigation in immunocompromised RAG -/- mice showed reduced synergistic effects following the combination therapy, suggesting some contribution by host T cells. Furthermore, we found increased frequency of endogenous T cells and dendritic cells in the tumor-draining lymph nodes, supporting potential engagement of host immune cells. We therefore conclude α-4-1BB has a multifunctional role for enhancing CAR T cell responses including engagement of endogenous immune cells, and this combination approach has high translational potential given that CAR T cell therapy has recently been FDA approved for pediatric ALL, and that α-4-1BB is currently being tested in clinical trials against various types of cancer.
Citation Format: Sherly Mardiana, Liza B. John, Michael H. Kershaw, Paul A. Beavis, Phillip K. Darcy. A multifunctional role for adjuvant anti-4-1BB therapy in augmenting antitumor responses by CAR T 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 1530.
Abstract 1533: CD4+ T cells reprogram tumor metabolism and drive oxidative stress-induced tumor destruction
Authors: Zhou Gang , Habtetsion Tsadik , Ding Zhi-Chun 
Published: August 2018

Abstract
The inhibitory effects of cancer on T cell metabolism have been well established, but the metabolic impact of immunotherapy on tumor cells is poorly understood. Here, we developed a CD4+ T cell-based adoptive immunotherapy protocol that was curative for mice with implanted colorectal cancer. By conducting metabolic profiling on resected tumors, we show that adoptive immunotherapy profoundly altered tumor metabolism, resulting in glutathione depletion and accumulation of reactive oxygen species (ROS) along with increased oxidative DNA damages. We further demonstrate that T cell-derived TNFα can synergize with chemotherapy to drive heightened oxidative stress and tumor cell death. Reduction of oxidative stress, by neutralizing TNFα or scavenging ROS, antagonized the therapeutic effects of adoptive T-cell therapy. Conversely, provision of pro-oxidants after chemotherapy can partially recapitulate the antitumor effect of T-cell transfer. Furthermore, T cell-induced oxidative stress in tumor was observed in several different tumor models. These findings imply that tumor redox modulation represents an important mechanism underlying the efficacy of adoptive immunotherapy.
Citation Format: Gang Zhou, Tsadik Habtetsion, Zhi-Chun Ding. CD4+ T cells reprogram tumor metabolism and drive oxidative stress-induced tumor destruction [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 1533.
Abstract 1538: Analysis of the paired TCRα- and β-V(D)J full-length chains of single-cell sequence from human naïve and antigen-experienced T cells
Authors: Wang Fei , Zhou Qing , Chao Cheng-chi 
Published: August 2018

Abstract
The unbiased and paired characterization of T-cell receptor (TCR) alpha and beta chains is critical to understand the TCR repertoire and adaptive immunity. However, the direct cloning of the single human full-length TCRα- and TCRβ-chains has very few reports. We present a new methodology enabling capture of natively paired, full-length rearranged T-cell receptor (TCR) sequences at single-cell level of human T cells. More than 50% paired TCRα- and β- chains were captured in 100 single naïve human CD8+ T cells using 5'SMART and 3' TCRαβ constant region nested gene-specific primers (GSP). Furthermore, we sequenced the TCR of the specific T cells that were stimulated by representative tumor-associated antigens (TAA), virus-related antigens (VRA) and neoantigens. The highest proportion of TCR subtypes were extracted in the TCR abundance ranking by IMGT blast. Finally, we obtained the paired, full-length V(D)J TCR from melanoma antigen Melan A epitope 27-35 that was TRAV(12-2)J(47), TRBV(7-6)J(2-1), and the TCR from antigen EBV LMP2-FLY that was TRAV(26-1)J(7), TRBV(27)J(2-1). These results suggest that the method provides accurate identification of the paired, V(D)J rearrangements for each individual human naïve and antigen-experienced T cells. The information could be used in the construction of an engineered T-cell receptor for cancer immunotherapy and infectious diseases.
Citation Format: Fei Wang, Qing Zhou, Cheng-chi Chao. Analysis of the paired TCRα- and β-V(D)J full-length chains of single-cell sequence from human naïve and antigen-experienced T 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 1538.