tbuckley/cabot-search huggingface dataset:
Abstract 4880: A high-throughput siRNA screen identifies Nucleoside Diphosphate Kinase (NME3) as a novel host regulator of NF-êB signaling in response to <i>Salmonella</i>-induced activation of TLR-5
Authors: Caleb Gonzalez, Kelly Flentie, Brandon Kocher, Jayne Jayne Marasa, David Piwnica-Worms
Journal: Cancer Research (2016)

Abstract Bacterial flagellin is a potent activator of NF-êB signaling, inflammation and host innate immunity. In comparison to TNFá, perhaps the most studied NF-êB-inducing ligand, flagellin elicits an overlapping, yet unique downstream transcriptional response by host cells. In contrast to the pro-oncogenic functions of TNFá, recent data indicate that flagellin may represent a novel anti-tumor ligand that acts through TLR5 and the NF-êB pathway to induce host immunity and to aid in the clearance of tumor xenografts. To begin to characterize the molecular basis for the anti-tumor effect of flagellin and to identify downstream innate signaling components of NF-êB that are responsible for the pro-inflammatory program necessary for these anti-tumor effects, we employed a high throughput screen. Utilizing HCT116 colon carcinoma cells expressing a dynamic NF-êB bioluminescent reporter and Salmonella typhimurium expressing flagellin, we performed a live cell screen of a siRNA library targeting 691 known and predicted human kinases to identify novel modulators of flagellin-induced NF-êB activation. This screen uncovered nucleoside diphosphate kinase (NME3) as a previously unrecognized, positive regulator of NF-êB signaling in response to flagellin. Targeted knockdown and overexpression assays confirmed the regulatory contribution of NME3. Furthermore, Kaplan-Meier survival analysis for breast, lung and ovarian cancer patients showed that high level expression of NME3 correlated with increased overall survival. Together, these data identify a novel pro-inflammatory role for NME3 in NF-êB signaling that may potentially be exploited to optimize cancer immunotherapy. Citation Format: Caleb Gonzalez, Kelly Flentie, Brandon Kocher, Jayne Jayne Marasa, David Piwnica-Worms. A high-throughput siRNA screen identifies Nucleoside Diphosphate Kinase (NME3) as a novel host regulator of NF-êB signaling in response to Salmonella-induced activation of TLR-5. [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 4880.
Abstract 5064: CORO1B amplification and expression status identifies an aggressive subset of chromosome 11q13 amplified HNSCC
Authors: Jessica L. Allen, Elyse L. Walk, Kristen L. Rhodes, Colleen J. Beatty, Steven M. Markwell, Brenen W. Papenberg, Erik T. Interval, Hong Wu, Marileila Varella Garcia, James E. Bear, Scott A. Weed
Journal: Cancer Research (2016)

Abstract Head and neck squamous cell carcinoma (HNSCC) is highly invasive cancer type that occurs with greater incidence in West Virginia and the rest of Appalachia. The chromosome 11q13 region is amplified in approximately 30% of late stage HNSCC cases and is associated with a poor patient prognosis. The core 11q13 region encodes the well-studied tumor genes CCND1 (cyclin D1) and CTTN (cortactin). The CORO1B (coronin 1B) gene flanks the 11q13 core and is amplified in 9-14% of all HNSCC, but how CORO1B amplification contributes to HNSCC is unknown. Coronin 1B governs cell motility by negatively regulating F-actin stability through displacement of cortactin at actin related protein 2/3 (Arp 2/3) branch points, generating dynamic turnover of Arp2/3-F-actin networks required for productive cell movement. Kaplan-Meier analysis of two independent patient cohorts indicates that HNSCC cases with CORO1B amplification have significantly reduced overall survival. Cox hazard ratios also indicate the CORO1B amplification is strongly associated with increased mortality in both cohorts. Automated quantitative analysis (AQUA) of coronin 1B expression in HNSCC tissue microarrays indicates that coronin 1B overexpression decreases median survival of HNSCC patients from 81 to 29 months. Reduced expression of coronin 1B by RNAi-mediated knockdown in established HNSCC cell lines decreases several actin-mediated invasive processes, including invadopodia formation and extracelluar matrix degradation. Collectively these results suggest that elevated coronin 1B expression levels in HNSCC function to enhance tumor invasion, potentially through accelerated downregulation of cortactin stabilizing activity at Arp2/3-F-actin junctions. Importantly, CORO1B amplification and coronin 1B expression status may serve a role as a precision biomarker for identification of a subset of late-stage HNSCC patients that would benefit from more aggressive forms of initial clinical treatment. Citation Format: Jessica L. Allen, Elyse L. Walk, Kristen L. Rhodes, Colleen J. Beatty, Steven M. Markwell, Brenen W. Papenberg, Erik T. Interval, Hong Wu, Marileila Varella Garcia, James E. Bear, Scott A. Weed. CORO1B amplification and expression status identifies an aggressive subset of chromosome 11q13 amplified HNSCC. [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 5064.
Abstract 4448: Development of DNA methylation biomarkers for pancreatic cancer diagnosis
Authors: Keiko Shinjo, Keisuke Katsushima, Genta Nagae, Hiroyuki Aburatani, Kenji Yamao, Yutaka Kondo
Journal: Cancer Research (2016)

Abstract Pancreatic cancer is highly lethal malignancy despite the recent clinical advancement. Since pancreatic cancer is often difficult to diagnose, there is an urgent need to develop minimally invasive biomarkers for detection. Epigenetic alterations have emerged as a common hallmark of many types of human cancers as well as pancreatic cancer. The presence of cell-free DNA (cfDNA) in blood stream has been known and cfDNA possesses tumor-related genetic alterations as well as epigenetic alterations. Therefore, invention of blood-based DNA methylation biomarkers and their high-sensitive detection system might be a promising diagnostic tool for pancreatic cancer. In order to establish the diagnostic biomarkers, first, we performed genome-wide DNA methylation analysis of 38 EUS-FNA specimens of pancreatic cancer with clinical stage III-IV using Illumina Infinium HumanMethylation450 BeadChip. We further analyzed the DNA methylation profiles of other types of tumors in the public database, TCGA (The Cancer Genome Atlas), and identified five marker genes, which were specifically methylated in pancreatic cancers. In addition, analysis of DNA methylation status of pancreas cancers comparing 10 normal tissues in TCGA data set revealed that 99% of tumors were methylated at least one of the five markers (sensitivity, 98.9%; specificity, 44%). We validated these methylation markers in different FNA sample set (n = 19) by bisulfite pyrosequencing or quantitative methylation specific PCR and found that 18/19 (95%) cases were methylated in at least one marker (AUC = 0.95). Finally, we performed methylation analysis in cfDNA from pancreatic cancer patients. From our preliminary data, we could detect aberrant DNA methylation in cfDNA from pancreatic cancer patients. We identified potential DNA methylation biomarkers for the diagnosis of pancreatic cancers and these markers might be applicable for detecting cancer in cfDNA. Citation Format: Keiko Shinjo, Keisuke Katsushima, Genta Nagae, Hiroyuki Aburatani, Kenji Yamao, Yutaka Kondo. Development of DNA methylation biomarkers for pancreatic cancer diagnosis. [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 4448.
Environmental Isolation of Circulating Vaccine-Derived Poliovirus After Interruption of Wild Poliovirus Transmission — Nigeria, 2016
Authors: Andrew Etsano, Eunice Damisa, Faisal Shuaib, Gatei wa Nganda, Ogu Enemaku, Samuel Usman, Adekunle Adeniji, Jaume Jorba, Jane Iber, Chima Ohuabunwo, Chimeremma Nnadi, Eric Wiesen
Journal: MMWR Morbidity and Mortality Weekly Report (2016)

In September 2015, more than 1 year after reporting its last wild poliovirus (WPV) case in July 2014 (1), Nigeria was removed from the list of countries with endemic poliovirus transmission,* leaving Afghanistan and Pakistan as the only remaining countries with endemic WPV. However, on April 29, 2016, a laboratory-confirmed, circulating vaccine-derived poliovirus type 2 (cVDPV2) isolate was reported from an environmental sample collected in March from a sewage effluent site in Maiduguri Municipal Council, Borno State, a security-compromised area in northeastern Nigeria. VDPVs are genetic variants of the vaccine viruses with the potential to cause paralysis and can circulate in areas with low population immunity. The Nigeria National Polio Emergency Operations Center initiated emergency response activities, including administration of at least 2 doses of oral poliovirus vaccine (OPV) to all children aged <5 years through mass campaigns; retroactive searches for missed cases of acute flaccid paralysis (AFP), and enhanced environmental surveillance. Approximately 1 million children were vaccinated in the first OPV round. Thirteen previously unreported AFP cases were identified. Enhanced environmental surveillance has not resulted in detection of additional VDPV isolates. The detection of persistent circulation of VDPV2 in Borno State highlights the low population immunity, surveillance limitations, and risk for international spread of cVDPVs associated with insurgency-related insecurity. Increasing vaccination coverage with additional targeted supplemental immunization activities and reestablishment of effective routine immunization activities in newly secured and difficult-to-reach areas in Borno is urgently needed.
Abstract LB-147: Simultaneous profiling of mRNA and protein in single human induced pluripotent stem cells
Authors: Benjamin Liu, Gajalakshmi Dakshinamoorthy, Haibiao Gong, Aik Ooi, Nianzhen Li, Marc Unger, Ilona Holcomb, Ramesh Ramakrishnan
Journal: Cancer Research (2016)

Abstract The cancer stem cell theory proposes that a discrete, small number of “stem-cell-like” cancer cells are primarily responsible for driving cancer. Thus, future cancer treatments are likely to be developed by targeting these cancer stem cells. One approach to modeling cancer therapy utilizes induced pluripotent stem cell (iPSC) technology. While gene expression studies have measured differentiation propensities between different iPSC clones and compared protein coding gene profiles between iPSCs and embryonic stem cells (ESCs), relatively little is known about the expression characteristics of individual RNA transcripts and their corresponding protein within each single iPSC. In addition, studies of the dynamic interaction between RNA and protein during the cell differentiation stage remains rare. Here we present an integrated assay that simultaneously quantifies mRNAs and proteins of interest within single iPSCs. The C1™ system was utilized for individual cell capture, cell lysis, DNA template generation for protein detection and cDNA synthesis. Final products from each iPSC were quantified on the 96.96 Dynamic Array™ IFC on the Biomark™ HD system. PCR data were analyzed using the Singular™ Analysis Toolset. For each run, up to 5,000 data points for 52 protein targets and 2,880 data points for 30 RNA targets, in addition to control and reference assays, were simultaneously generated and analyzed in less than two days. Combined RNA and protein signatures of each iPSC were identified. By comparing these results to those obtained from non-induced fibroblast cells, we demonstrate that this method is capable of obtaining expression levels of both RNA and protein associated with pluripotency marker genes at a single-cell level. More interestingly, the profiling data also indicates changes of some key members (EGFR, TGFB1, EPCAM, etc.) of cancer related common signaling pathways. The current system significantly controls lab-specific differences in reprogramming processes, progenitor cells or cell culture and handling conditions. We believe this powerful method makes it a suitable approach of choice for providing new insights into cell differentiation, reprogramming and tumor progression, as well as cancer therapeutic targets research. Citation Format: Benjamin Liu, Gajalakshmi Dakshinamoorthy, Haibiao Gong, Aik Ooi, Nianzhen Li, Marc Unger, Ilona Holcomb, Ramesh Ramakrishnan. Simultaneous profiling of mRNA and protein in single human induced pluripotent stem cells. [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 LB-147.
Abstract 727: TSLP expression and high serum TSLP level indicate a poor prognosis in gastric cancer patients
Authors: Joji Watanabe, Hiroaki Saito, Kozo Miyatani, Masahide Ikeguchi, Yoshihisa Umekita, Shinji Otani, Shunichi Tsujitani
Journal: Cancer Research (2016)

Abstract Purpose: Thymic stromal lymphopoietin (TSLP) plays an important role in promoting tumor survival, by manipulating the immune response and angiogenesis. However, the clinical significance of TSLP in gastric cancer is unclear. Method: Immunohistochemistry was used to investigate TSLP expression in non-cancerous gastric mucosa and gastric cancer tissue from patients with gastric cancer. Serum TSLP levels were measured using an enzyme-linked immunosorbent assay. Results: Tumors with TSLP expression were significantly larger than those without TSLP expression. TSLP expression was observed more frequently in advanced (T2/T3/T4) than in early (T1) gastric cancer and in stage 3/4 than in stage 1/2. Lymph node metastasis, liver metastasis, positive peritoneal lavage cytology, lymphatic invasion, and vascular invasion occurred significantly more often in TSLP-expressing than in non-expressing tumors. The prognosis of patients with TSLP-positive tumors was significantly worse than that of patients with TSLP-negative tumors. Patients with high serum TSLP concentrations also had a significantly worse prognosis than those with low concentrations. Multivariate analysis identified serum TSLP level as an independent prognostic indicator. Conclusion: TSLP is closely related to the progression of gastric cancer and may predict survival in these patients. Citation Format: Joji Watanabe, Hiroaki Saito, Kozo Miyatani, Masahide Ikeguchi, Yoshihisa Umekita, Shinji Otani, Shunichi Tsujitani. TSLP expression and high serum TSLP level indicate a poor prognosis in gastric cancer patients. [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 727.
Frequency and Impact Of Allogeneic Hematopoetic Stem Cell Transplantation and Preparative Regimen In Patients With High and Intermediate Risk Acute Myeloid Leukemia: A Single Small Center Experience
Authors: Shatha Farhan, Catherine Carroll, Danielle Pelland, Jose Carlos Velasco, Edward Peres, Suseela M Janakiraman, Susan Wautelet, Kenneth Ruemenapp, Philip Kuriakose, Nalini Janakiraman
Journal: Blood (2013)
Effects of alteplase on survival after ischaemic stroke (IST-3): 3 year follow-up of a randomised, controlled, open-label trial
Authors: Eivind Berge, Geoffrey Cohen, Melinda B Roaldsen, Erik Lundström, Eva Isaksson, Ann-Sofie Rudberg, Karsten Bruins Slot, John Forbes, Joel Smith, Jonathan Drever, Joanna M Wardlaw, Richard I Lindley, Peter A G Sandercock, William N Whiteley
Journal: The Lancet Neurology (2016)
Abstract 665: Blocking IL-1-NF-kB axis inhibits Kras-induced pancreatic ductal adenocarcinoma
Authors: Jianhua Ling, Jie Fu, Min Wu, Yu Cao, Paul Chiao
Journal: Cancer Research (2016)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer mortality in the USA with approximately 50 000 new cases and 40 000 deaths in 2015.The 5-year survival rate has remained at 5% for the past three decades and the median survival duration is less than 6 months. The very high rate of mutant Kras occurs in pancreatic cancer (&amp;gt;90%) and pancreatic intraepithelial neoplasia (panIN) (&amp;gt;50%). However, the key signaling pathway of downstream Kras remains unidentified. We previously uncovered that the NF-êB signaling pathway was constitutively activated in most PDAC specimens and pancreatic cancer cell lines. More recently, our results showed that constitutive NF-êB activity in PDAC was induce by IL-1 autocrine mechanism. IL-1/p62 feedforward loops that initiated by the mutant Kras sustained NF-êB activity and were required for pancreatic cancer development. Therefore, we hypothesize that blocking IL-1 - NF-êB signaling pathway will inhibit Kras-induced pancreatic ductal adenocarcinoma. To identify the mechanistic role of mutant Kras-induced IL-1 expression in PDAC, we generated genetically engineered mice of Pdx1-cre/Kras LSL-G12D/p53 M/+IL-1á−/−. Our findings revealed that these mutant mice had developed significantly less PDAC number and a significantly delayed PDAC at old ages. Furthermore, we assess the effect of pharmacological IL-1R1 antagonist (anakinra) in human pancreatic cancer cell lines and orthotopic pancreatic cancer mouse. We found that IL-1R1 antagonist significantly decreased NF-êB activity and inhibited cell proliferation, migration and invasion. More interestingly, the combinational treatment IL-1R1 antagonist plus gemcitabine significantly reduced the tumor burden in orthotopic pancreatic cancer mouse. These results suggested that pharmacologically targeting IL-1á may provide a novel therapeutic approach for pancreatic cacner. Citation Format: Jianhua Ling, Jie Fu, Min Wu, Yu Cao, Paul Chiao. Blocking IL-1-NF-kB axis inhibits Kras-induced pancreatic ductal adenocarcinoma. [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 665.
Clinical Management of Opioid Use Disorder
Authors: Beth Dunlap, Adam S. Cifu
Journal: JAMA (2016)

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Abstract 3842: Design and engineering of TRAIL fusion proteins for cancer therapy
Authors: Eric M. Tam, Hannah Hudson, Tamara Dake, Sara Ghassemifar, Andreas Raue, Yasmin Hashambhoy-Ramsay, Stephen L. Sazinsky, Anahita Daruwalla, Neeraj Kohli, Lihui Xu, Charlotte F. Mc Donagh, Birgit Schoeberl, Diana H. Chai
Journal: Cancer Research (2016)

Abstract Protein-based agonists of apoptotic death receptors have shown remarkable preclinical efficacy but limited clinical response. The short circulating half-life of recombinant human TRAIL and the necessity of Fc-mediated clustering for potentiating agonistic antibodies against DR4 and DR5 have been proposed to be major impediments to the clinical success of this class. To address these limitations we have created Fc-scTRAIL, a single fusion polypeptide consisting of an IgG1 Fc region followed by three successive TRAIL monomers connected by two fifteen-amino acid linkers. While Fc-scTRAIL showed potent activity in vitro, we observed a low TM (48 °C) and rapid inactivation in serum indicating protein instability. Subsequently, we applied a directed evolution approach using yeast surface display to identify mutations that would stabilize the TRAIL trimer. When individual mutations were transferred to the Fc-scTRAIL format, we observed a dramatic increase in the TM (66-70 °C) while the combination of three mutations improved serum stability by ten-fold. Stabilized Fc-scTRAIL shows greater pro-apoptotic activity across a panel of cancer cell lines when compared to mapatumumab (anti-DR4) and drozitumab (anti-DR5), or the combination of antibodies even in the presence of anti-Fc cross-linking. Moreover, anti-Fc did not improve Fc-scTRAIL activity suggesting that the hexavalent design of the molecule maximizes death receptor activation. Currently, in vivo evaluation of Fc-scTRAIL for pharmacokinetic properties and activity is underway. We believe this format, when combined with an appropriate patient selection strategy, will result in improved clinical outcomes. Citation Format: Eric M. Tam, Hannah Hudson, Tamara Dake, Sara Ghassemifar, Andreas Raue, Yasmin Hashambhoy-Ramsay, Stephen L. Sazinsky, Anahita Daruwalla, Neeraj Kohli, Lihui Xu, Charlotte F. Mc Donagh, Birgit Schoeberl, Diana H. Chai. Design and engineering of TRAIL fusion proteins for cancer therapy. [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 3842.