tbuckley/cabot-search huggingface dataset:
Abstract 1003: Targeting liver-tumor initiating cells via hampering the lipogenesis pathways through stearoyl - CoA desaturase
Authors: Kin Fai Ma, Jessica Lo, Eunice Yuen-Ting Lau, John A. Copland, Irene Oi-Lin Ng, Terence Kin-Wah Lee
Journal: Cancer Research (2016)

Abstract Hepatocellular carcinoma is one of the most lethal cancers in the world. Most of the patients are diagnosed at advanced stage, and they receive sorafenib as their treatment modality. However, sorafenib can only extend patients’ survival to a median of 3-4 months. Hence, there is an urgent need to identify a new therapeutic target for treatment of this disease. Increasing evidence showed that tumor-initiating cells (T-ICs) are intrinsically resistant to conventional treatments. Identification of the signalling pathways that maintain the functions of T-ICs provides potential targets for treatment of HCC. For this purpose, we cultured serial passages of hepatospheres combined with chemotherapeutic regimens as a strategy to enrich liver T-IC population. Using cDNA microarray, we found upregulation of several key enzymes in lipogenesis in enriched T-IC population, among which Stearoyl CoA desaturase-1 (SCD1), the enzyme involved in the conversion of saturated into monounsaturated fatty acids, was the most significant. In HCC clinical samples, 62% (36/58) was found to be overexpressed (&amp;gt; 2-fold) when compared with non-tumor counterparts and patients with SCD1 overexpression had shorter disease free survival. Using overexpression and knockdown approaches, SCD1 was found to regulate the traits of T-ICs, including tumorigenicity, self-renewal, drug resistance and expression of liver T-IC markers. SCD1 was found critical in survival of T-ICs, as enriched T-IC population are more sensitive to the inhibition of SCD1 compared to adherent lineages. Interestingly, SCD1 was found to be upregulated in sorafenib-resistant HCC cells. Pharmacological inhibition of SCD1 by A939572 not only suppressed self-renewal ability but also consistently enhanced the sensitivity towards sorafenib. Using a patient-derived xenograft model, we found that a new inhibitor against SCD1 demonstrated significant growth suppressive effect. By comparing the genetic profiles between SCD1 knockdown cells and control cells by RNA sequencing analysis, we found that upregulation of ER stress signature genes may be the potential downstream targets of SCD1 to maintain the properties of T-ICs. In conclusion, we demonstrated the crucial role of SCD1 in maintenance of liver T-ICs, and targeting SCD1 in combination with sorafenib might be a novel therapeutic regimen against HCC. Citation Format: Kin Fai Ma, Jessica Lo, Eunice Yuen-Ting Lau, John A. Copland, Irene Oi-Lin Ng, Terence Kin-Wah Lee. Targeting liver-tumor initiating cells via hampering the lipogenesis pathways through stearoyl - CoA desaturase. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1003.
High Efficacy of Combination Therapy with Pegylated Interferon and Ribavirin in Hemophiliacs with Chronic Hepatitis C.
Authors: Maria E. Mancuso, Elena Santagostino, Maria G. Rumi, Silvia Linari, Antonio Coppola, Angiola Rocino, Alfonso Iorio, Alfredo Dragani, Giovanni Barillari, Giuseppe Tagariello, Roberto Nicolin, Massimo Colombo, Pier M. Mannucci
Journal: Blood (2005)
Abstract 4431: Tandem profiling of 5-methyl and 5-hydroxymethylcytosine in glioblastoma identifies tumor-specific distribution of 5-hydroxymethylcytosine and associations with patient survival
Authors: Kevin C. Johnson, E. Andres Houseman, Jessica E. King, Camilo E. Fadul, Brock C. Christensen
Journal: Cancer Research (2016)

Abstract Glioblastomas exhibit widespread molecular alterations including a highly distorted epigenome. Genome-wide assessment of epigenetic alterations to cytosines in glioblastoma has largely been limited to 5-methylcytosine (5mC). 5-hydroxymethylcytosine (5hmC) is an additional cytosine modification that is deregulated in cancer, though the extent and context of these alterations at single cytosine resolution remain unclear. Through parallel processing of DNA with bisulfite and oxidative bisulfite treatments on Illumina 450K arrays we resolved both 5mC and 5hmC in 30 glioblastomas. We developed and applied a novel technique for estimating 5mC, 5hmC, and unmethylated proportions from array data to glioblastoma tissues and compare with normal brain tissue. Genomic distribution of 5hmC was associated with features of transcription despite the glioblastoma genome being relatively depleted of 5hmC. When integrating 5mC and 5hmC data using a Gaussian finite mixture model approach, we observed significant associations between 5hmC levels and gene-sets involved in immune and RNA regulatory processes while high 5mC classes were associated with receptor-mediated processes and cancer gene-sets. Significant differences in patient survival were observed among classes of 5hmC obtained from a recursively partitioned mixture model. Gene expression across epigenetic enzymes including methyltransferases and TETs was also investigated for relation with patterns and levels of 5hmC and 5mC. Analyses of elevated 5hmC with alternative splicing events that may promote disease progression are underway. Together, our results provide a genome-wide map of 5hmC in glioblastoma, indicate that transcription patterns as well as disrupted processes are associated with 5hmC patterns, and highlight the potential clinical prognostic utility of 5hmC in cancer. Citation Format: Kevin C. Johnson, E. Andres Houseman, Jessica E. King, Camilo E. Fadul, Brock C. Christensen. Tandem profiling of 5-methyl and 5-hydroxymethylcytosine in glioblastoma identifies tumor-specific distribution of 5-hydroxymethylcytosine and associations with patient survival. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4431.
Single centre analysis of 132 pulmonary resections: can we overcome VATS limits?
Authors: L. Rosso, C. Bareggi, M. Nosotti, A. Palleschi, D. Tosi, I. Righi, M. Montoli, B. Galassi, M. Tomirotti, L. Santambrogio
Journal: Annals of Oncology (2015)
Abstract 12521: Release Kinetics of Early Ischemic Biomarkers in Patients With Acute Myocardial Infarction
Authors: Christoph Liebetrau, Oliver Dorr, Luise Gaede, Sebastian Szardien, Matthias Willmer, Christian Troidl, Andreas Rolf, Christian Hamm, Holger Nef, Helge Mollmann
Journal: Circulation (2013)

Background:  Different biomarkers of myocardial ischemia have potential as novel early ischemic biomarkers in patients with acute coronary syndrome. The aim of this study was to determine the release kinetics of such biomarkers in patients with acute myocardial necrosis induced by transcoronary ablation of septal hypertrophy (TASH).   Methods:  We analysed the release kinetics of soluble fms-like tyrosine kinase (sFlt-1), ischemia-modified albumin (IMA), and heart-type fatty acid-binding protein (hFABP) in consecutive patients (n=21) undergoing TASH for hypertrophic obstructive cardiomyopathy, a procedure that mimics the conditions present during AMI. Blood samples were collected prior to TASH and 15, 30, 45, 60, 75, 90, and 105 minutes and 2, 4, 8, and 24 h after TASH. sFlt-1 and hFABP were quantified in serum, and IMA was quantified in plasma using immunoassays.   Results:  The values of sFLT-1 and hFABP increased significantly 15 min after induction of AMI vs. baseline as follows: sFlt-1, 3657.5 ng/L [IQR 2302.3-4475.0] vs. 76.0 ng/L [IQR 71.2-88.8] (P≤0.001); hFABP, 9.0 ng/mL [IQR 7.0-15.4] vs. 4.6 ng/mL [IQR 3.4-7.1] (P≤0.001). The IMA concentrations increased significantly 30 min after induction of AMI vs. baseline, with values of 26.0 U/mL [IQR 21.8-38.6] vs. 15.6 U/mL [IQR 10.1-24.7] (P=0.02).   Conclusions:  sFlt-1 and hFABP concentrations increased very early after induction of myocardial ischemia in patients undergoing TASH, while IMA provided no additional information.
Abstract 4879: Cancer cell-mediated signaling of TLR 2, 4, and 9 causes activation of PI3K/Akt/mTOR pathway and induces tumor cell proliferation in pancreatic cancer
Authors: Jennifer Kreckel, Tanja Grimmig, Romana Moench, Christoph T. Germer, Martin Gasser, Ana Maria Waaga-Gasser
Journal: Cancer Research (2016)

Abstract Background: Toll like receptor (TLR) ligands are in clinical use for the immunotherapy of different cancers. They are supposed to induce an inflammatory immune response against the tumor. Interestingly, several studies showed that TLRs were expressed by cancer cells in different tumor entities and that their activation can contribute to an inflammatory microenvironment. Yet, for pancreatic cancer, TLR expression and its impact in tumor cells is only poorly understood. Therefore this study analyzed the influence of TLR2, 4, and 9 expression and activation on tumor cell signaling and proliferation in pancreatic cancer. Methods: The expression of TLR 2, 4, and 9 was analyzed in vitro in several established as well as primary human pancreatic cancer cell lines by qRT-PCR and Western Blot. TLR stimulation was then performed in BxPC-3, MIA Paca2, and PacaDD135 cells using the TLR ligands oligodeoxyribonucleotide2006 (ODN2006), lipoteichonic acid of Staphylococcus aureus (LTA-SA) and High-Mobility Group Box 1 (HMGB1). Expression of MyD88 and pAkt was then analyzed by Western Blot. Functional analysis on proliferation (ATP assay) and cytokine expression (Luminex) was additionally performed. Results: Expression of TLR2, 4 and/or 9 was demonstrated in all investigated human pancreatic cancer cell lines. Receptor activation by single or combined use of TLR ligands resulted in increased MyD88 and pAkt (Ser473) expression. Additionally, up-regulated anti-apoptotic protein Bcl-2 expression was found in stimulated cells, but not in the unstimulated cells. Furthermore, TLR activation resulted in the production of the interleukin(IL)-6, IL-8 and tumor necrosis factor á (TNF-á). Interestingly, tumor cell proliferation was increased within 24 and 48 hours of stimulation. Conclusion: Our results demonstrate TLR2, 4 and/or 9 expression in all human pancreatic cancer cell lines. Additionally, our findings on TLR activation suggest chronic inflammation-mediated TLR signaling to negatively influence tumor cell apoptosis and to shift the cytokine release in pancreatic cancer towards an inflammatory microenvironment. These findings emphasize the particular role of TLR2, 4 and 9 and their activation in pancreatic cancer, outlining their relevance as potential targets for cancer therapy. Citation Format: Jennifer Kreckel, Tanja Grimmig, Romana Moench, Christoph T. Germer, Martin Gasser, Ana Maria Waaga-Gasser. Cancer cell-mediated signaling of TLR 2, 4, and 9 causes activation of PI3K/Akt/mTOR pathway and induces tumor cell proliferation in pancreatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4879.
Abstract 2523: Transcriptional profiling of glioblastoma stem-like cells reveals enrichment of ion channels with functional implications for malignancy
Authors: Julia Pollak, Karan G. Rai, Patrick J. Paddison, Robert C. Rostomily, Jan-Marino Ramirez
Journal: Cancer Research (2016)

Abstract Glioblastoma Multiforme (GBM) is the most prevalent and aggressive form of cancer in the adult central nervous system. Ion channels are increasingly being linked to cancer progression through the regulation of cell proliferation and migration. However, the role of ion channels in GBM tumor formation and progression is not well understood. Glioblastoma stem-like cells (GSCs) are a source of tumor formation and recurrence, suggesting that ion channel expression may be perturbed in this population. Here, we used RNA-sequencing to assess the expression patterns of ion channels and transporters and identify uniquely enriched ion channels in GSCs. Twenty-two patient-derived GSC samples were expression profiled along with human neural stem cell (NSC) and astrocyte control cell populations. Differential expression analysis revealed a set of ion channels highly enriched in GSCs compared with controls. Real-time PCR analysis confirmed the increased expression of ion channels of interest across selected GSC lines compared to NSCs. The expression pattern of ion channel candidates was also more likely to be associated with distinct GBM molecular subtypes. Next, an integrative approach was taken to further identify ion channels unique to GSCs; the abovementioned findings were compared to results from transcriptome analyses of GBM bulk tumor cells (The Cancer Genome Atlas) and region-specific GBM cells (Ivy Glioblastoma Atlas Project). Ion channels that were identified in these analyses were associated with altered clinical outcomes. The functional implications of these expression changes were further assessed with targeted drug screening of GSCs and NSCs. Pharmacological antagonists of GSC-enriched ion channels suppressed stem cell viability. These antagonists similarly hindered BrdU incorporation of dividing GSCs, suggesting that these channels play a role in stem cell proliferative capacity. Finally, calcium imaging was used to test the real-time functional responses of GSCs to channel blockers, and these outcomes will be discussed. Collectively, these findings suggest the presence of ion channels that uniquely identify GSCs from other neural cell types and influence GSC proliferation, a hallmark of GBM tumor recurrence. Citation Format: Julia Pollak, Karan G. Rai, Patrick J. Paddison, Robert C. Rostomily, Jan-Marino Ramirez. Transcriptional profiling of glioblastoma stem-like cells reveals enrichment of ion channels with functional implications for malignancy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2523.
191P Comparison of neoadjuvant chemotherapy followed by surgery (NAC) with adjuvant chemotherapy following surgery (ADJ), and NAC with definitive chemoradiotherapy for locally advanced esophageal cancer patients
Authors: Y. Tsubosa, M. Niihara, K. Takebayashi, A. Shimada, H. Yasui, T. Tsushima, T. Yokota
Journal: Annals of Oncology (2015)
Metastatic Progression of Prostate Cancer Is Mediated by Autonomous Binding of Galectin-4-<i>O</i>-Glycan to Cancer Cells
Authors: Chin-Hsien Tsai, Sheue-Fen Tzeng, Tai-Kuang Chao, Chia-Yun Tsai, Yu-Chih Yang, Ming-Ting Lee, Jiuan-Jiuan Hwang, Yu-Ching Chou, Mong-Hsun Tsai, Tai-Lung Cha, Pei-Wen Hsiao
Journal: Cancer Research (2016)

Abstract Metastatic prostate cancer continues to pose a difficult therapeutic challenge. Prostate cancer progression is associated with aberrant O-glycosylation of cancer cell surface receptors, but the functional impact of such events is uncertain. Here we report spontaneous metastasis of human prostate cancer xenografts that express high levels of galectin-4 along with genetic signatures of EGFR-HER2 signaling and O-glycosylation. Galectin-4 expression in clinical specimens of prostate cancer correlated with poor patient survival. Galectin-4 binding to multiple receptor tyrosine kinases stimulated their autophosphorylation, activated expression of pERK, pAkt, fibronectin, and Twist1, and lowered expression of E-cadherin, thereby facilitating epithelial–mesenchymal transition, invasion, and metastasis. In vivo investigations established that galectin-4 expression enabled prostate cancer cells to repopulate tumors in orthotopic and heterotopic tissues. Notably, these effects of galectin-4 relied upon O-glycosylation mediated by C1GALT1, a galactosyltransferase implicated in other cancers. Parallel changes in galectin-4 and O-glycosylation triggered aberrant receptor signaling and more aggressive invasive character in prostate cancer cells, which through better survival in the circulation also contributed to the bulk cell progeny of distal tumors. Our findings establish galectin-4 and C1GALT1-mediated glycosylation in a signaling axis that is activated during prostate cancer progression, with implications for therapeutic targeting of advanced metastatic disease. Cancer Res; 76(19); 5756–67. ©2016 AACR.
Abstract 180: Identification and characterization of ATM substrates in mitosis
Authors: Rebecca J. Boohaker, Qinghua Zeng, Bo Xu
Journal: Cancer Research (2016)

Abstract The Ataxia-Telangiectasia Mutated (ATM) Kinase, mutation of which is responsible for the autosomal recessive disorder Ataxia-Telangiectasia, is an essential element for cells to deal with DNA double-strand breaks. In the absence of DNA damage, it has also been recognized that ATM has a role in optimizing the spindle assembly checkpoint during mitosis. In the process, ATM is activated at a lower level (compared to the DNA damage response) which requires phosphorylation by the Aurora-B kinase. Known ATM targets in mitosis include kinetochore proteins Bub1 and Mad1. However, it has become clear that ATM-mediated phosphorylation in mitosis is distinct from that in the DNA damage response. Therefore, we performed an unbiased assay to identify ATM substrates in mitosis in order to study the functional significance of mitotic ATM activation. To achieve our goal, we utilized a stable isotope labeling by amino acid (SILAC) /Peptide IP with phosphor-specific SQ/TQ antibodies and mass spectrometry (MS). About 18 proteins were identified as substrates of mitotically activated ATM in the assay. We then conducted bioinformatic analyses for the identified proteins using PANTHER and Ingenuity programs. With many proteins having their known functions in mitosis, we found a much smaller number, but highly interconnected, pool of proteins in the ATM substrate list as compared to that of the DNA damage response. Among them, we validated several phosphorylation events using an in vitro kinase assay. Furthermore we present data to demonstrate the functional significance of ATM-mediated phosphorylation. Taken together, our data provide a comprehensive picture of how mitotically activated ATM signals to downstream targets to fine-tune the mitotic checkpoint. Citation Format: Rebecca J. Boohaker, Qinghua Zeng, Bo Xu. Identification and characterization of ATM substrates in mitosis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 180.
Detection of Zika virus RNA in whole blood of imported Zika virus disease cases up to 2 months after symptom onset, Israel, December 2015 to April 2016
Authors: Yaniv Lustig, Ella Mendelson, Nir Paran, Sharon Melamed, Eli Schwartz
Journal: Eurosurveillance (2016)

Zika virus RNA presence in serum, whole-blood and urine samples from six Israeli travellers symptomatic for Zika virus disease was examined. Whole-blood samples were positive for as late as 2 months (58 days) post-symptom onset, longer than for urine (26 days) and serum (3 days). These findings suggest the utility of whole blood in Zika infection diagnosis.
Unsuspected cervical osteophytes and complex endoscopy: there is cause for concern!
Authors: Fabio Sbaraglia, Giorgia Spinazzola, Guido Costamagna, Maria Sammartino
Journal: Endoscopy (2016)

Cervical osteophytes are a common disorder in elderly people [1]. The most common warning sign that cervical osteophytes may be present is dysphagia [2] [3]; however, the condition is often asymptomatic. During complex endoscopic procedures they can cause major difficulties in both airway management and the insertion and positioning of large endoscopes.
Abstract 3059: Discovery of BET family proteins as cancer targets using phenotypic-based profiling and affinity capture mass spectrometry
Authors: Scott E. Warder, Shaun M. McLoughlin, T. Matthew Hansen, Paul L. Richardson, Denise M. Wilcox, Sadiya N. Addo, Hua Tang, Chaohong Sun, Andrew M. Petros, Sanjay C. Panchal, Chang H. Park, M. Shannon Duggan, Melanie J. Patterson, F. Greg Buchanan, Dong Cheng, Heather M. Davis, David J. Calderwood, Steven W. Elmore, Yu Shen
Journal: Cancer Research (2016)

Abstract As part of a multi-year technology integration strategy to identify unprecedented targets, AbbVie has committed to building broad-endpoint profiling assays to enable phenotypic screening campaigns and compound prioritization. Early on, phenotypic cell-based screening employing a panel of protein-fragment complementation assays (PCAs) identified A-1107604 as a hit with potent activity against a subset of endpoints. While its activity profile had some commonalities with known anti-cancer agents, the overall profile of PCAs that were significantly and concomitantly modulated represented a unique signature. Further analysis revealed A-1107604 to have potent and selective activity in a panel of human tumor cell lines. Inhibitor affinity capture from cellular lysates coupled with mass spectrometry identified the BET family of proteins as the putative cellular targets of A-1107604. Binding was localized to the bromodomain of the target proteins using affinity capture-protease digestion and was confirmed by thermal shift assay, solution binding and X-ray crystallography. This binding was found to be highly selective when A-1107604 was counter-screened against a 150-member kinase panel and an 80-member receptor panel. To correlate target affinity with cellular efficacy, a series of analogs were prepared with affinities spanning 3 orders magnitude. Affinity for BRD4, a BET family member, strongly correlated with efficacy in human tumor cell lines. Finally, A-1107604 was evaluated in human tumor xenograft models where it demonstrated significant tumor growth inhibition. This discovery effort laid the foundation for our BET inhibitor program. Disclosures: All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. Citation Format: Scott E. Warder, Shaun M. McLoughlin, T. Matthew Hansen, Paul L. Richardson, Denise M. Wilcox, Sadiya N. Addo, Hua Tang, Chaohong Sun, Andrew M. Petros, Sanjay C. Panchal, Chang H. Park, M. Shannon Duggan, Melanie J. Patterson, F. Greg Buchanan, Dong Cheng, Heather M. Davis, David J. Calderwood, Steven W. Elmore, Yu Shen. Discovery of BET family proteins as cancer targets using phenotypic-based profiling and affinity capture mass spectrometry. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3059.