tbuckley/cabot-search huggingface dataset:
Abstract 3289: Cutaneous melanocytic nevi and risk of melanoma deaths in women and men: a prospective study
Authors: Wen-Qing Li, Hao Geng, Eunyoung Cho, Abrar Qureshi
Journal: Cancer Research (2017)

Abstract Background: Increased number of common acquired melanocytic nevi (moles) has been associated with an increased risk of melanoma. It is unclear whether melanocytic nevi may predict melanoma deaths. We prospectively examined the association between number of melanocytic nevi and risk of melanoma deaths based on 77316 women from the Nurses’ Health Study (NHS) and 32454 men from the Health Professionals Follow-up Study (HPFS). Methods: In both cohorts, diagnosis of melanoma was reported biennially and pathologically confirmed. Deaths were confirmed by next of kin or the National Death Index. Information on the number of moles with ≥3 mm diameter on the upper extremity was collected in 1986. We used Cox regression models to evaluate the associations between number of melanocytic nevi and risk of melanoma deaths in the overall cohorts as well as only among melanoma cases. Results: A total of 2450 cases of melanoma were documented (1545 in NHS and 905 in HPFS), out of which we identified 192 incident deaths due to melanoma (87 in NHS and 105 in HPFS) during the follow-up (1986-2012). Increased number of melanocytic nevi was associated with melanoma deaths; the multivariate-adjusted hazard ratio (HR) for 3 or more melanocytic nevi compared with no nevi on the upper extremity was 2.55 (95% confidence interval (CI): 1.52-4.28) for women and 3.97 (95% CI: 2.54-6.22) for men. A secondary analysis further found that increased number of melanocytic nevi was associated with both lethal melanoma (melanoma cases that died of melanoma) and non-lethal melanoma. Among melanoma cases, increased number of melanocytic nevi was independently associated with risk of melanoma deaths in men, with a HR of 1.89 (95% CI: 1.17-3.05) for 3 or more melanocytic nevi. The association persisted even after adjusting for Breslow thickness of melanoma and appeared particularly stronger among those with lower Breslow thickness (P for interaction=0.03). However, number of melanocytic nevi was not significantly associated with risk of melanoma deaths among melanoma cases in women (HR=1.03, 95% CI: 0.61-1.76 for 3 or more nevi). Conclusion: Increased number of melanocytic nevi was significantly associated with risk of melanoma deaths in our cohorts of women and men. A high number of melanocytic nevi may independently predict the risk of melanoma deaths among men with melanoma. Citation Format: Wen-Qing Li, Hao Geng, Eunyoung Cho, Abrar Qureshi. Cutaneous melanocytic nevi and risk of melanoma deaths in women and men: a prospective study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3289. doi:10.1158/1538-7445.AM2017-3289
Abstract 866: The epithelial-to-mesenchymal transition regulates E-selectin ligand activities of breast cancer cells
Authors: Grady E. Carlson, Alexander O. Ostermann, Venktesh S. Shirure, Fabian Benencia, Monica M. Burdick
Journal: Cancer Research (2017)

Abstract The epithelial-to-mesenchymal transition (EMT) leads to specific stem-like and invasive properties in breast cancer cells. However, it remains unclear whether the EMT modifies sialofucosylated ligands that circulating tumor cells use to attach and adhere to vascular endothelial E-selectin during metastasis. To address this issue, immunohistochemistry and E-selectin microsphere dynamic adhesion assays were initially used to assay 110 cases of breast cancer for EMT biomarkers and E-selectin ligand activity. The expression of E-cadherin, but not N-cadherin or vimentin, directly correlated with E-selectin ligand activity. Thus, it was hypothesized that the EMT, and in turn the mesenchymal-to-epithelial transition (MET), regulate expression of functional E-selectin ligands in breast cancer cells. The ectopic expression or shRNA knockdown of transcription factors (i.e., Snail and Twist) in target cell lines were used to induce EMT or MET, respectively. Shear flow adhesion assays and flow cytometry demonstrated that cells with epithelial phenotypes had greater E-selectin ligand activities and greater expression of sialofucosylated carbohydrates compared to cells with mesenchymal phenotypes. Moreover, glycoprotein E-selectin ligand activities of breast cancer cells were more affected by the EMT compared to glycolipid E-selectin ligand activities. Assessing expression of α1,3- and α1,4- fucosyltransferases (FUT) at the RNA level using qRT-PCR revealed that FUT3 and FUT6 gene expression were decreased via the EMT, corresponding to the lowered E-selectin ligand activities observed in mesenchymal phenotype cells. Altogether, the results of this investigation demonstrate that the EMT, as well as the MET, mechanistically regulate the expression of functional E-selectin ligands expressed by breast cancer cells. Citation Format: Grady E. Carlson, Alexander O. Ostermann, Venktesh S. Shirure, Fabian Benencia, Monica M. Burdick. The epithelial-to-mesenchymal transition regulates E-selectin ligand activities of breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 866. doi:10.1158/1538-7445.AM2017-866
Abstract 1491: Mitochondrial dysfunction from defective Cytochrome oxidase complex induces tumorigenic phenotype
Authors: Satish Srinivasan, Manti Guha, Gordon Ruthel, Hiroshi Nakagawa, Narayan Avadhani
Journal: Cancer Research (2017)

Abstract Mitochondrial defects that affect activity of the electron transport chain (ETC) complexes are associated with several diseases including cancer. Dysfunctional mitochondria resulting from mitochondrial DNA (mtDNA) alterations or exposure to xenobiotics have been shown to initiate retrograde signaling pathway characterized by disrupted membrane potential, elevated cytosolic calcium and activation of Calcineurin, a calcium dependent phosphatase. In some cell types these events form the basis for triggering transcriptional reprogramming that converts non tumorigenic cells to tumorigenic phenotype. Cytochrome oxidase (CcO) is the terminal enzyme of the ETC that catalyzes the transfer of electrons from reduced cytochrome C to oxygen. All the mutations of CcO subunits identified as prevalent in various cancers like prostrate, pancreatic, colon and ovarian cancers have been found in mtDNA encoded subunits. Effect of loss of nuclear subunits leading to reduced Cytochrome oxidase activity on tumor progression are not well studied. Nuclear subunits IVi1 and Vb of CcO are susceptible to various stress conditions like exposure to long term hypoxia, ischemia-reperfusion and treatment with ethanol resulting in selective degradation and loss of activity. Here we report the activation of retrograde signaling by loss of these subunits. Genetic silencing of the subunits IVi1 and Vb, and loss of activity resulted in metabolic shift to glycolysis and was accompanied by increased glucose utilization. Disruption of the CcO complex activated many of the hallmark factors of Ca2+/Calcineurin mediated retrograde signaling. Importantly, rescue of the CcO deficiency by overexpressing CcO subunits or by inhibitors of retrograde signaling pathway attenuated the phenotypic changes such as anchorage independent growth and increased invasive potential. Further, esophageal tumor sections from human patients revealed reduced CcO subunits IVi1 and Vb in the center of the tumor mass suggesting a pathological significance of these findings. Our results show that mitochondrial ETC defect initiates a retrograde signaling and induces genes with major roles in tumor development. (Supported by NIH grants CA-22762 and GM-34883) Note: This abstract was not presented at the meeting. Citation Format: Satish Srinivasan, Manti Guha, Gordon Ruthel, Hiroshi Nakagawa, Narayan Avadhani. Mitochondrial dysfunction from defective Cytochrome oxidase complex induces tumorigenic phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1491. doi:10.1158/1538-7445.AM2017-1491
Abstract 3137: Breast cancer anti-estrogen resistance 4 (BCAR4) is a novel oncogene in lung cancer
Authors: Kieun Bae, Minkyong Lee, Daseul Yoon, Yun-Hee Kim, Kyong-Ah Yoon
Journal: Cancer Research (2017)

Abstract BCAR4 was identified as tamoxifen resistance related gene in breast cancer due to its function to activate estrogen-independent cell growth. Instead of estrogen receptor, ERBB2 and ERBB3 genes were activated by BCAR4 in tamoxifen resistant cells. Recently, the function of BCAR4 as a long non-coding RNA (lncRNA) was reported to regulate a non-canonical Hedgehog/GLI2 pathway in breast cancer. However, the association of BCAR4 and lung cancer has not been identified. Here, we describe the oncogenic effect of BCAR4 in human lung cancer. Expression pattern of BCAR4 was examined in lung cancer cell lines, primary tumor tissues, and adjacent normal tissues. BCAR4 was highly expressed in 71% of lung cancer cell lines and especially in 43% of cancer tissues of lung adenocarcinoma patients who did not harbor the activational mutations of EGFR nor KRAS. Exogenous expression of BCAR4 protein promoted cell growth of non-tumorigenic bronchial epithelial cell line, BEAS-2B, and lung cancer cell line, NCI-H1299. We also confirmed the oncogenic feature of BCAR4 by colony forming assay using stably expressing cells. These effects were notably reduced after knockdown of BCAR4 by small interfering RNA. BCAR4 encoded a functional protein and its overexpression resulted in the enhanced migration than controls cells. This result proposed a similar role of BCAR4 in lung cancer considering its previously reported role in breast cancer metastasis. We also detected a fusion gene of BCAR4 in a lung cancer tissue by analyzing RNA-sequencing data. BCAR4 protein as well as its fusion form showed the improved tumorigenic feature in the mouse xenograft model with lung cancer cells. We compared the gene expression pattern in BCAR4 overexpressed cells to identify the possible mechanism of the oncogenic effect of BCAR4. Cyclin D1, Cyclin E, and MMP1 mRNA and protein levels were significantly increased after BCAR4 overexpression. However, downstream genes of GLI2 signaling were not altered by protein expression of BCAR4 arguing an alternative role for lncRNA BCAR4. Our results suggest a novel oncogenic role of BCAR4 protein in lung cancer. Citation Format: Kieun Bae, Minkyong Lee, Daseul Yoon, Yun-Hee Kim, Kyong-Ah Yoon. Breast cancer anti-estrogen resistance 4 (BCAR4) is a novel oncogene in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3137. doi:10.1158/1538-7445.AM2017-3137
Abstract 5440: miRNAs as novel therapeutic adjuvants for improving the efficacy of vincristine and radiation therapy in treating medulloblastoma
Authors: Nourhan Abdelfattah, Subapriya Rajamanickam, Panneerdoss Subbarayalu, Santosh Timilsina, Benjamin Onyeagucha, Yidong Chen, Manjeet Rao
Journal: Cancer Research (2017)

Abstract Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Despite recent improvements in the overall survival, only a modest percentage of patients survive Myc-driven high-risk MB. The quality of life for surviving patients is substantially reduced due to the devastating and often irreversible side effects of radiation and chemotherapy. Recently, in a large unbiased genomic screen, we uncovered a group of microRNAs (miRNAs) capable of meditating drug sensitivity in c-myc amplified high-risk MB. Our functional screen of ~1900 miRNAs identified miR-584-5p as a potent candidate that uniquely sensitizes high-risk MB to radiation as well as vincristine (VCR) (20 to 25-fold dose reduction), an anti-mitotic agent routinely administered alongside radiation and in combination with other chemotherapeutic drugs to treat medulloblastoma patients. Our studies revealed that miR-584 might act as a potent tumor suppressor as it inhibited MB growth in vivo as well as migration and invasion of c-myc amplified MB. We show that miR-584 overexpression results in defective mitosis leading to mitotic catastrophe, apoptosis, DNA damage and G2-M cell-cycle arrest in high-risk MB cells without affecting normal neural stem cell growth. Notably, we discovered that miR-584 directly regulates the expression and activity of genes including histone deacetylase 1 (HDAC1), and eukaryotic translation initiation factor 4e family member 3 (EIF4E3) that are known to play important roles in microtubule dynamics, metaphase-anaphase transition and radio-resistance. Moreover, silencing either of these two target genes resulted in significant inhibition of MB growth and enhanced sensitivity to VCR and ionizing radiation. Overexpressing miR-584 or silencing either HDAC1 or EIF4E3 also inhibited the MB stem cell proliferation and self-renewal. We report that while miR-584-5p is predominantly expressed in normal brain and cerebellum, its expression is significantly reduced in MB patient derived xenografts (PDXs). In contrast to miR-584, EIF4E3 and HDAC1 were found to be overexpressed in medulloblastoma patients. These findings are highly significant, unexpected and innovative as this miRNA and its target genes are the first to be shown to affect the therapeutic efficacy of VCR and radiation in c-myc amplified high-risk medulloblastoma. Citation Format: Nourhan Abdelfattah, Subapriya Rajamanickam, Panneerdoss Subbarayalu, Santosh Timilsina, Benjamin Onyeagucha, Yidong Chen, Manjeet Rao. miRNAs as novel therapeutic adjuvants for improving the efficacy of vincristine and radiation therapy in treating medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5440. doi:10.1158/1538-7445.AM2017-5440
Abstract 2693: Inflammatory signalling in the colon tumour microenvironment enhances stromal cell mediated suppression of anti-tumour immune responses
Authors: Grace O'Malley, Kevin Lynch, Serika Naicker, Paul Lohan, Athina Rigalou, Thomas Ritter, Laurence J. Egan, Aideen E. Ryan
Journal: Cancer Research (2017)

Abstract The colon tumour microenvironment (TME) comprises many cell types including endothelial cells, stromal cells and immune cells. Recent evidence suggests that high tumour stromal cell density correlates with a poor prognosis for colon cancer patients. The majority of these stromal cells are of mesenchymal origin (MSCs) and are known contributors to tumour angiogenesis and invasiveness. Little is known about the role of their immunosuppressive potential in the colon TME. We investigated the molecular regulation of the induced immunosuppressive, tumour-promoting phenotype of tumour-associated MSCs, and the effect of inflammation on this process. Balb/c bone marrow derived MSCs were treated with conditioned medium from untreated CT26 tumour cells (MSCTCM) or TNF-α treated CT26 cells (MSCTNF-TCM). Cell surface analysis of MSCs after 72h revealed an increased expression of TCR ligands MHC-I, MHC-II and PD-L1 compared to MSCControl. This was further potentiated by TNF-α induced tumour cell inflammation. MSCTCM co-cultured with syngeneic activated T cells displayed an enhanced ability to suppress CD8+ T cell proliferation, which was further potentiated by inflammatory activation of CT26 (MSCTNF-TCM). This effect was dependent on induced PD-L1 expression on MSCs as PD-1 blockade restored CD8+ T cell proliferation, activation and granzyme B secretion. In an immunocompetent Balb/c syngeneic model, we assessed tumour growth and anti-tumour immune responses following sub-cutaneous injection of CT26 cells alone or co-injection with MSCControl/MSCTNF-TCM. Co-injection of MSCControl significantly promoted tumour growth, and this was further potentiated by the co-injection of MSCTNF-TCM. This effect was associated with significantly reduced tumour infiltration of CD8 Granzyme B secreting T cells. We showed that this stromal cell mediated tumour promotion could be reversed by administration of a PD-1 blocking antibody, via restoration of granzyme B secreting CD8+ T cells. We show for the first time that stromal cells in the inflammatory TME directly modulate anti-tumour immune responses via PD-L1. This data could lead to better stratification of patients for immunotherapeutic regimens resulting in more targeted and durable responses to overcome stromal mediated tumour immunosuppression in colon cancer. Citation Format: Grace O'Malley, Kevin Lynch, Serika Naicker, Paul Lohan, Athina Rigalou, Thomas Ritter, Laurence J. Egan, Aideen E. Ryan. Inflammatory signalling in the colon tumour microenvironment enhances stromal cell mediated suppression of anti-tumour immune responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2693. doi:10.1158/1538-7445.AM2017-2693
Abstract 4022: Validation of label-free impedance analysis as a versatile tool for cancer molecular therapeutics screening
Authors: Fabio Cerignoli, Biao Xi, Brandon Lamarche, Leyna Zhao, Yama Abassi
Journal: Cancer Research (2017)

Abstract In vitro monitoring cancer cells response to treatment often involves laborious sample processing and collects single data points that are against the dynamic nature of cancer cells. Here we present the adaptation of an impedance-based methodology to dynamically monitor cancer cell behavior and therapeutic response. The technology detects cell death, proliferation or migration by measuring changes in conductance of microelectrodes embedded in 96 and 384-wells cell culture plates. It avoids sample labeling and processing and allows continuous monitoring of cell response. Our data shows validation with cancer cell lines and primary cells monitored for cell invasion/migration, anticancer drug response and receptor signaling activation, with similar results over end point assays. Easy experiment set up and minimal sample processing make the technology ideal for applications in large screening campaigns, while label-free technology allows further analysis on the same samples through orthogonal assays. Citation Format: Fabio Cerignoli, Biao Xi, Brandon Lamarche, Leyna Zhao, Yama Abassi. Validation of label-free impedance analysis as a versatile tool for cancer molecular therapeutics screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4022. doi:10.1158/1538-7445.AM2017-4022
Abstract 584: From code to cure: Computational discovery of novel immune checkpoints
Authors: Yair Benita, Amit Novik, Gady Cojocaru, Itamar Borukhov, Assaf Wool, Yossef Kliger, Tomer Zekharya, Zurit Levine, Sergey Nemzer, Ofer Levy, Amir Toporik
Journal: Cancer Research (2017)

Abstract Antibody blockade of CTLA4 and PD-1 immune checkpoints emerged as an effective treatment modality for cancer. However, the majority of patients do not achieve sustained long term benefit, suggesting a need for targeting of additional immune checkpoints. To identify additional B7/CD28 immune checkpoint targets, we developed a unique compendium of computational algorithms that identified multiple novel targets including TIGIT in 2008, which was an unknown protein at the time of discovery [Proc Natl Acad Sci U S A. 2009 Oct 20;106(42):17858-63], and PVRIG which we recently disclosed. Since their initial discovery, these targets have been functionally validated and anti-tumor activity was demonstrated with antibodies that target them. In this presentation, we will describe the computational algorithms that led to the discovery of these novel immune checkpoints. These algorithms combine two complementary aspects: (i) endogenous immune checkpoint function prediction and (ii) prediction of immuno-modulatory activity in cancer. Immune checkpoint function was predicted based on gene structure similarity to B7/CD28 family members that is reminiscent of ancient common evolutionary origins. A gene structure alignment tool was developed to identify functional homologs of B7/CD28 genes even in the absence of sequence similarity. Next, the expression profile of these candidates was modeled and compared to profiles of known immune checkpoints in normal and cancer tissues. We will review the details of TIGIT and PVRIG discovery, which were among the immune checkpoints predicted in this process. Our approach demonstrates the powerful ability of computational biology to translate genomic knowledge into rational and reliable drug target discovery. Citation Format: Yair Benita, Amit Novik, Gady Cojocaru, Itamar Borukhov, Assaf Wool, Yossef Kliger, Tomer Zekharya, Zurit Levine, Sergey Nemzer, Ofer Levy, Amir Toporik. From code to cure: Computational discovery of novel immune checkpoints [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 584. doi:10.1158/1538-7445.AM2017-584