tbuckley/cabot-search huggingface dataset:
Abstract 1763: A novel RNAin situhybridization approach highly sensitive for detection of Merkel cell polyomavirus
Authors: Lisha Wang, Paul W. Harms, Nallasivam Palanisamy, Shannon Carskadon, Xuhong Cao, Javed Siddiqui, Rajiv M. Patel, Sylvia Zelenka-Wang, Timothy M. Johnson, Alison Durham, Fengyun Su, Sudhanshu Shukla, Rohit Mehra, Arul M. Chinnaiyan
Journal: Cancer Research (2017)

Abstract Background: Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine tumor of the skin. Merkel cell polyomavirus (MCPyV) plays an oncogenic role in the majority of MCC tumors. Detection of MCPyV in MCC tumors has diagnostic utility, and potentially prognostic and therapeutic implications. We investigated whether RNAscope, a novel RNA in situ hybridization (ISH) method for detection of RNA transcripts in tissues at the single-cell/single-molecule level, is useful for MCPyV detection. Methods: We applied an RNAscope probe targeting MCPyV T antigen transcripts on tissue microarrays (TMAs) and full tissue sections encompassing 91 MCC tumors from 75 patients, 14 carcinomas of other types, and various normal tissues. qPCR and immunohistochemistry (IHC) for MCPyV were performed on 58 and 88 cases, respectively. qPCR was also performed on 18 cases of normal skin to establish background levels of MCPyV in non-tumor tissues. Results: RNA-ISH demonstrated the presence of MCPyV in 46.2% (42/91) of cases. A total of 58 samples had data from all the three detection modalities (qPCR, RNA-ISH and IHC). RNA-ISH demonstrated 100% concordance with qPCR results, whereas IHC had a slightly lower concordance (96.6%). RNA-ISH demonstrated higher agreement than IHC among TMA cores from the same case, and between TMA cores and matched full tissue sections. Of samples with background inflammatory cells, 5 of 37 (15.6%) showed moderate nonspecific staining of lymphocytes by IHC, whereas RNA-ISH lacked background. Conclusions: RNA-ISH is comparably sensitive to qPCR for detection of MCPyV, and allows for correlation with tissue morphology. Our findings support RNA-ISH as a highly effective method for MCPyV detection in tumors. Citation Format: Lisha Wang, Paul W. Harms, Nallasivam Palanisamy, Shannon Carskadon, Xuhong Cao, Javed Siddiqui, Rajiv M. Patel, Sylvia Zelenka-Wang, Timothy M. Johnson, Alison Durham, Fengyun Su, Sudhanshu Shukla, Rohit Mehra, Arul M. Chinnaiyan. A novel RNA in situ hybridization approach highly sensitive for detection of Merkel cell polyomavirus [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 1763. doi:10.1158/1538-7445.AM2017-1763
Impact of the SCARE guideline on the reporting of surgical case reports: A before and after study
Authors: R.A. Agha, R. Farwana, M.R. Borrelli, T. Tickunas, T. Kusu-Orkar, M.C. Millip, R. Thavayogan, J. Garner, D.P. Orgill
Journal: International Journal of Surgery (2017)
Abstract 1399: <i>In vitro</i> characterization of several enzymes of the Fe(II)/2-oxoglutarate-dependent dioxygenase superfamily using a universal succinate detection assay
Authors: Juliano Alves, Said Goueli, Hicham Zegzouti
Journal: Cancer Research (2017)

Abstract The covalent modification of histone proteins, DNA and RNA by Fe(II)/2-oxoglutarate-dependent dioxygenases are key to the modulation of biological processes such as epigenetics, hypoxic signaling and DNA/RNA repair. Of these, JumonjiC domain-containing histone lysine demethylases (JMJCs), the ten-eleven-translocation (TET) DNA dioxygenases, the ALKB DNA/RNA hydroxylases and the prolyl hydroxylases EGLN1-3 have generated increased interest as potential drug targets for the treatment of a number of pathological conditions, including cancer. Since succinate is a common product to all Fe(II)/2-oxoglutarate-dependent dioxygenases, we determined the substrate specificities, the apparent kinetic constants for several JMJCs and members of the dioxygenase superfamily (i.e.: TET1, EGLN1, ALKBH3 and FTO), as well as inhibition profiles of reported inhibitors using a novel bioluminescent and homogenous succinate detection assay. Our results demonstrate that succinate detection is a useful strategy for the characterization of multiple Fe(II)/2-oxoglutarate-dependent dioxygenases with distinct substrate requirements, enabling the investigation of a large number of enzymes that cannot be evaluated in a miniaturized or high-throughput manner with the methods currently available. Citation Format: Juliano Alves, Said Goueli, Hicham Zegzouti. In vitro characterization of several enzymes of the Fe(II)/2-oxoglutarate-dependent dioxygenase superfamily using a universal succinate detection assay [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 1399. doi:10.1158/1538-7445.AM2017-1399
Abstract 4626: Macrophages alter heparan sulfate-modifying enzyme levels, growth factor activity and cancer cell growth in 3D hydrogels
Authors: Fabio Henrique Brasil da Costa, Nora M. Navone, Mary C. Farach-Carson, Daniel D. Carson
Journal: Cancer Research (2017)

Abstract Tumor progression in both primary and metastatic niches often involves the activation of associated or “reactive” stroma similar to that seen in a wound healing response. The stromal participants include fibroblasts, endothelial and immune cells, including macrophages. Cancer-associated fibroblasts (CAFs) and tumor-associated macrophages communicate with local cells including cancer cells and the surrounding stroma to induce epithelial-to-mesenchymal transition, immunosuppression and increased production of extracellular matrix (ECM) components, growth factors, and ECM-remodeling enzymes. Heparan sulfate (HS)-modifying enzymes produced by tumor-associated stroma play key roles in the delivery of heparin-binding growth factors (HBGFs) and cytokines, serving to enhance tumorigenesis, foster growth and recruit other bystander cells to sites of metastasis. Through the use of a novel, biomimetic, 3D collagen/hyaluronic acid hydrogel system developed in our labs, this study focused on interactions between primary human macrophages and cancer cells, specifically on how this dialogue impacts the production of the secreted HS-modifying enzymes, heparanase (HPSE) and endosulfatase 1 (SULF1). We studied the impact of co-cultures containing macrophages and endometrial or prostate cancer cell lines, as well as patient-derived xenografts, on the levels of HPSE and SULF1. We also assessed cancer growth characteristics in the presence of macrophages. Taken together, our observations indicate cancer cell responses to macrophages are cell type specific, and we demonstrated significant functional consequences of interactions between macrophages and HS-mediated signaling. We are currently determining if macrophage polarization to classically activated (M1) or alternatively activated (M2) phenotypes alters cancer cell responses in 3D. This system is being used to determine novel approaches to intervene in HBGF delivery to limit cancer growth in a more physiologically relevant in vitro system. Citation Format: Fabio Henrique Brasil da Costa, Nora M. Navone, Mary C. Farach-Carson, Daniel D. Carson. Macrophages alter heparan sulfate-modifying enzyme levels, growth factor activity and cancer cell growth in 3D hydrogels [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 4626. doi:10.1158/1538-7445.AM2017-4626
Abstract 2149A: CRISPR/Cas9 mutagenesis invalidates a genetic target of clinical trials in cancer
Authors: Ann Lin, Christopher Giuliano, Nicole Sayles, Joan Smith, Jason Sheltzer
Journal: Cancer Research (2017)

Abstract The Maternal Embryonic Leucine Zipper Kinase MELK has been described as a genetic dependency in several cancer types, most notably in the highly-aggressive basal subtype of breast cancer; MELK inhibition through the use of both RNAi and small-molecule approaches appears to block the growth of cancer types with such dependency. Based on these results, the MELK inhibitor OTS167 is currently being tested as a novel chemotherapy agent in multiple clinical trials. Here, however, we report that mutagenizing MELK with CRISPR/Cas9 has no effect on the fitness of basal breast cancer cell lines or cell lines from other cancer types. Through seven guide RNAs targeting the kinase and kinase-associated domains of MELK, we demonstrate that mutagenesis of MELK causes no defect in proliferative ability or anchorage independent growth in these cancer types. Additionally, cells with mutagenized MELK remain sensitive to OTS167, suggesting that this drug blocks proliferation through an off-target mechanism. Finally, the patient tumor gene expression data that initially identified MELK as being significantly upregulated in patients with poor survival was reexamined. As MELK is thought to play a role in mitosis, we compared MELK expression to a set of well-known cell proliferation markers and show significant correlations of MELK with the proliferation genes; this suggests a role of MELK in representing the mitotic activity of a tumor, rather than possessing a transformative role in itself. In total, our results undermine the rationale for a series of current clinical trials based on MELK inhibition and provide an experimental approach for the use of CRISPR/Cas9 in preclinical target validation that can be broadly applied. Citation Format: Ann Lin, Christopher Giuliano, Nicole Sayles, Joan Smith, Jason Sheltzer. CRISPR/Cas9 mutagenesis invalidates a genetic target of clinical trials in 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 2149A. doi:10.1158/1538-7445.AM2017-2149A
Abstract 4012: Visualization of EPR effect and active targeting by using microscopic mass spectrometry
Authors: Masahiro Yasunaga, Masaru Furuta, Koretsugu Ogata, Yuki Fujiwara, Yoshikatsu Koga, Yasuhiro Matsumura
Journal: Cancer Research (2017)

Abstract Microscopic mass spectrometry (MMS), in which a microscope is coupled with an atmospheric pressure matrix-assisted laser desorption/ionization (MALDI) and quadruple ion trap time-of-flight (TOF) analyzer has been developed for the investigation of the distribution of various molecules including drugs. The matrix-coated drug sample is ionized and then separated on the basis of its mass-to-charge ratio (m/z). Images were acquired from imaging mass spectrometry (IMS) or tandem mass spectrometry (MS/MS) data. Recently, pharmacokinetic (PK) and pharmacodynamic (PD) studies have become important to evaluate the efficacy and toxicity of the drugs. In these analyses, tissue homogenates are generally used for the quantification by high-performance liquid chromatography (HPLC) or liquid chromatography mass spectrometry (LC-MS). However, they lack the information regarding the drug distribution in a specific anatomical area. The information of the drug distribution would allow us to optimize the drug design enabling more efficient drug delivery. (1) We studied the tissue distribution of paclitaxel (PTX) and its micellar formulation (NK105) using a MMS. NK105 showed much stronger antitumor effects on a human pancreatic cancer BxPC3 xenograft than PTX. In the drug imaging, we demonstrated that NK105 delivered more PTX to the whole tumor tissue. In the mouse model, PTX caused the peripheral neurotoxicity but NK105 did not. Multiple high drug-signal areas surrounding and inside the caudal nerve were observed in the case of PTX, whereas the signals after NK105 administration were quite low. (2) The tissue distribution and controlled drug release of ADC (antibody-drug conjugate) consisting of a tissue factor specific antibody (TF) linked to the anticancer agent monomethyl auristatin E (MMAE) was evaluated in comparison with control-ADC (control antibody-MMAE conjugation). TF-ADC showed stronger antitumor effect on BxPC3 xenograft than control-ADC. We then established the selective detection method of MMAE for distinguishing free MMAE and its conjugated form. The released MMAE signal detected following the accumulation of TF-ADC was greatest 24 h after the administration, compared with the control-ADC at the same time (P&amp;lt;0.01). In summary, we succeeded in visualizing (1) the EPR (Enhanced permeability and retention) effect and (2) active targeting using MMS. The data obtained will facilitate more efficient drug development in the preclinical setting. Citation Format: Masahiro Yasunaga, Masaru Furuta, Koretsugu Ogata, Yuki Fujiwara, Yoshikatsu Koga, Yasuhiro Matsumura. Visualization of EPR effect and active targeting by using microscopic mass spectrometry [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 4012. doi:10.1158/1538-7445.AM2017-4012
RBFOX3 Promotes Tumor Growth and Progression via hTERT Signaling and Predicts a Poor Prognosis in Hepatocellular Carcinoma
Authors: Tianze Liu, Wenbin Li, Wenjing Lu, Miao Chen, Meihua Luo, Changlin Zhang, Yixin Li, Ge Qin, Dingbo Shi, Binyi Xiao, Huijuan Qiu, Wendan Yu, Lan Kang, Tiebang Kang, Wenlin Huang, Xinfa Yu, Xiaojun Wu, Wuguo Deng
Journal: Theranostics (2017)

Activation of the telomere maintenance mechanism is a key hallmark of cancer. Human telomerase reverse transcriptase (hTERT) is the catalytic subunit of telomerase, which is highly expressed in more than 80% of tumors, including hepatocellular carcinoma (HCC). However, the exact mechanisms by which hTERT is up-regulated in HCCs and promotes tumor growth and progression is not fully understood. The aim of this study was to discover the novel molecular targets that modulate hTERT signaling and HCC growth. In this study, we pulled down and identified RBFOX3 (RNA binding protein fox-1 homolog 3) as a novel hTERT promoter-binding protein in HCC cells using biotin-streptavidin-agarose pull-down and proteomics approach, and validated it as a regulatory factor for hTERT signaling and tumor growth in HCCs. Knockdown of RBFOX3 suppressed the promoter activity and expression of hTERT and consequently inhibited the growth and progression of HCC cells in vitro and in vivo. The suppression of HCC growth mediated by RBFOX3 knockdown could be rescued by hTERT overexpression. Conversely, exogenous overexpression of RBFOX3 activated the promoter activity and expression of hTERT and promoted the growth and progression of HCC cells. Moreover, we found that RBFOX3 interacted with AP-2β to regulate the expression of hTERT. Furthermore, we demonstrated that RBFOX3 expression was higher in the tumor tissues of HCC patients compared to the corresponding paracancer tissues, and was positively correlated with hTERT expression. Kaplan-Meier analysis showed that the HCC patients with high levels of RBFOX3 and hTERT had poor prognosis. Collectively, our data indicate that RBFOX3 promotes HCC growth and progression and predicts a poor prognosis by activating the hTERT signaling, and suggest that the RBFOX3/hTERT pathway may be a potential therapeutic target for HCC patients.
Abstract 5478: The TRPA1 Ca2+-permeable channel mediates a non-canonical redox adaptation in cancer cells
Authors: Nobuaki Takahashi, Hsing-Yu Chen, Isaac Harris, Daniel Stover, Roderick Bronson, Thomas Deraedt, Karen Cichowski, Alana Welm, Gordon Mills, Joan Brugge
Journal: Cancer Research (2017)

Abstract Generation of reactive oxygen species (ROS), a natural byproduct of oxygen metabolism, occurs in all aerobic organisms at a controlled rate. Cancer cells are subjected to numerous cellular insults, including dysregulated oncogenes and dissociation from their natural extracellular matrix (ECM) niches, leading to the generation of high levels of ROS. Although cancer cells possess enhanced canonical antioxidant programs that neutralize ROS, they nevertheless exhibit prominent ROS levels in response to these insults, suggesting the existence of additional programs that allow cancer cells to tolerate elevated ROS. In this study, we provide evidence for an unconventional mechanism for redox adaptation involving the ROS-activated, Ca2+-permeable TRPA1 channel, which normally functions as an irritant receptor in sensory neurons but is highly upregulated in breast, lung, malignant neural sheath, and other tumors. We found that TRPA1 overexpression enhances survival and proliferation of MCF-10A cells under conditions of matrix-detachment and this effect was dependent on TRPA1 activation by ROS generated as loss of matrix anchorage. In MCF-10A acini, TRPA1 expression induced Ca2+ entry in ECM-deprived cells in the luminal space and promoted their survival and proliferation. Conversely, TRPA1 knockdown inhibited Ca2+ responses to ROS generated through ECM detachment and induced clearance of cells from the luminal space in breast cancer spheroids. TRPA1 was also activated by ROS-inducing chemotherapies and drove chemoresistance in breast, lung and malignant peripheral nerve sheath tumor cells, and its downregulation suppressed breast xenograft tumor growth and enhanced chemosensitivity. TRPA1 mediated these effects independent of antioxidant responses, but through activation of cellular survival and anti-apoptotic programs involving the RAS-ERK/AKT/mTOR pathways. Together, our findings describe an unexpected mechanism whereby cancer cells co-opt the neuronal TRPA1 channel in order to adapt to oxidative environments. This TRPA1-induced response is distinct from canonical redox adaptation mechanisms that rely on antioxidant program. As TRPA1 inhibitors are currently in clinical trials for pain and respiratory therapies, these studies raise the possibility of using these inhibitors as therapeutic chemosensitizers in TRPA1-enriched tumors. Citation Format: Nobuaki Takahashi, Hsing-Yu Chen, Isaac Harris, Daniel Stover, Roderick Bronson, Thomas Deraedt, Karen Cichowski, Alana Welm, Gordon Mills, Joan Brugge. The TRPA1 Ca2+-permeable channel mediates a non-canonical redox adaptation in 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 5478. doi:10.1158/1538-7445.AM2017-5478
Reprocessing of single-use endoscopic variceal band ligation devices: a pilot study
Authors: Kavel Visrodia, Abdul Haseeb, Yuri Hanada, Kelly Pennington, Magdalen Clemens, Paul Pearce, Pritish Tosh, Bret Petersen, Mark Topazian
Journal: Endoscopy (2017)

Background and study aims The preferred management of bleeding esophageal varices includes endoscopic band ligation. Endoscopic ligation devices (ELDs) are expensive and designed for single use, limiting their uptake in developing countries. We aimed to assess the efficacy of reprocessing ELDs using terminal microbial cultures and adenosine triphosphate (ATP) testing. Materials and methods ELDs were recovered after clinical use and their components (cap, handle, and cord) were subjected to reprocessing. This included manual cleaning, automated high-level disinfection (HLD), and drying with forced air. Using sterile technique, ELD components were sampled for ATP at three stages: before manual cleaning, after manual cleaning, and after HLD. Components were sent to an external laboratory for culturing. Cultures were interpreted as positive upon identification of Gram-negative bacilli. Results A total of 14 clinically used ELDs were studied, and 189 ATP tests and 41 cultures were evaluated. Overall, 95 % (39/41) of components and 86 % (12/14) of ELDs were culture-negative or did not yield Gram-negative bacilli. Two components (5 %; one handle and one cord) harbored Gram-negative bacilli in quantities of 1 CFU per component. There was no apparent correlation between ATP at any juncture of reprocessing and terminal cultures. Conclusions Reprocessing of ELDs is effective, resulting in infrequent and minimal microbial contamination. Microbial culturing can be used to ensure adequacy of ELD reprocessing if pursued. Until reusable ELDs are commercially available, continued efforts to better define the adequacy and long-term effects of reprocessing ELDs are needed.
Abstract 3349: A regulatory circuit HP1 gamma/miR-451a/c-Myc promotes prostate cancer progression
Authors: Ruimin Huang, Cunjie Chang, Jiakuan Liu, Xiaojing Huang, Lan Shen, Dianzheng Zhang, Jun Yan
Journal: Cancer Research (2017)

Abstract Heterochromatin protein 1 gamma (HP1 gamma), as a reader of the histone codes, is involved in the determination of higher order of chromatin structure. It has also been implicated in carcinogenesis of various cancer types. However, the role of HP1 gamma in prostate cancer (PCa) progression and the underlying molecular mechanisms remain largely unknown. Using the public microarray data from GEO and TCGA database, we found that HP1 gamma was upregulated in PCa, comparing with benign prostate tissues. PCa patients with higher level of HP1 gamma had shorter disease-free survival, indicating that HP1 gamma level can serve as prognostic marker in PCa patients (p = 0.016). In addition, depletion of HP1 gamma by shRNA in PCa cells not only repressed proliferation and induced apoptosis, but also impaired tumorigenicity in vitro and in vivo. We also found that c-Myc was capable of upregulating HP1 gamma by directly binding to the E-box element in the first exon of HP1 gamma gene, and the upregulated HP1 gamma, in turn, repressed the expression of miR-451a by enhancing H3K9 methylation at the promoter region of miR-451a. Furthermore, reduction of miR-451a significantly reversed HP1 gamma loss-induced PCa cell apoptosis, whereas miR-451a overexpression repressed cell survival by targeting and downregulating c-Myc. The association among mRNA and protein expression levels of c-Myc, HP1 gamma and miR-451a were further confirmed in human clinical samples using Spearman correlation analysis. Therefore, we propose that an HP1 gamma/miR-451a/c-Myc regulatory circuit exists in PCa cells and this circuit plays a crucial role in PCa progression. Citation Format: Ruimin Huang, Cunjie Chang, Jiakuan Liu, Xiaojing Huang, Lan Shen, Dianzheng Zhang, Jun Yan. A regulatory circuit HP1 gamma/miR-451a/c-Myc promotes prostate cancer progression [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 3349. doi:10.1158/1538-7445.AM2017-3349