tbuckley/cabot-search huggingface dataset:
Abstract LB-101: The expression of death receptor 4 is positively regulated by MEK/ERK signaling and suppressed upon MEK inhibition
Authors: You-Take Oh, Weilong Yao, Jiusheng Deng, Ping Yue, Shi-Yong Sun
Journal: Cancer Research (2016)

Abstract Death receptor 4 (DR4) is a cell surface receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and triggers apoptosis upon ligation with TRAIL or aggregation. MEK/ERK signaling is a well-known and the best-studied effector pathway downstream of Ras and Raf. This study focuses on determining the impact of pharmacological MEK inhibition on DR4 expression and elucidating the underlying mechanism.We found that several MEK inhibitors, including MEK162, AZD6244 and PD0325901, effectively decreased the levels of DR4 protein including cell surface DR4 in different cancer cell lines while suppressing ERK1/2 phosphorylation. Accordingly, pre-treatment of TRAIL-sensitive cancer cell lines with a MEK inhibitor attenuated TRAIL-induced apoptosis. These results indicate that MEK inhibition negatively regulates DR4 expression and cell response to TRAIL-induced apoptosis. MEK inhibitors did not alter DR4 protein stability, rather decreased its mRNA levels, suggesting a transcriptional regulation of DR4 expression. In contrast, enforced activation of MEK/ERK signaling by expressing ectopic B-Raf (V600E) or constitutively activated MEK1 (MEK1-CA) or MEK2 (MEK2-CA) activated ERK1/2 and increased DR4 expression; these effects were inhibited when a MEK inhibitor was present. Moreover, enforced expression of MEK1-CA enhanced DR4promoter activity; this effect could be abolished by the presence of a MEK inhibitor. Hence it is clear that activation of the MEK/ERK kinase cascade positively regulates DR4 transcription, resulting in increased DR4 expression. Detailed promoter analysis through deletion and mutation identified the AP-1 binding site as an essential response element for MEK enhancement of DR4 transactivation. In addition, inhibition of AP-1 by knocking down c-Jun abrogated the ability of MEK1-CA to increase DR4 promoter activity and DR4 expression. These results suggest an essential role of AP-1 in mediating MEK/ERK activation-induced DR4 expression. Our findings together highlight a previously undiscovered mechanism that positively regulates DR4 expression through activation of the MEK/ERK/AP-1 signaling pathway. (WY and YTO contribute equally to this work. This study was supported by Emory Winship Cancer Institute Robbins Scholar awards to YTO and to JD and Halpern Research Scholar award to SYS. SYS is a Georgia Research Alliance Distinguished Cancer Scientist and Halpern Research Scholar) Citation Format: You-Take Oh, Weilong Yao, Jiusheng Deng, Ping Yue, Shi-Yong Sun. The expression of death receptor 4 is positively regulated by MEK/ERK signaling and suppressed upon MEK inhibition. [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-101.
Abstract 4372: MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism
Authors: Lori Ramkissoon, Pratiti Bandopadhayay, Payal Jain, Guillaume Bergthold, Adam Resnick, Rameen Beroukhim, Keith Ligon
Journal: Cancer Research (2016)

Abstract Diffuse pediatric low-grade gliomas (PLGGs) are among the most common solid tumors in children. While BRAF mutations and MYBL1 rearrangements have recently been identified as diagnostic and treatment related oncogenic drivers in pediatric gangliogliomas and diffuse astrocytomas, respectively, for the majority of diffuse PLGGs the oncogenic driver(s) remain unknown. Recent efforts to identify new oncogenic drivers lack sufficient power to determine the true frequency of alterations in genes or to associate specific alterations with rare histological subtypes, such as Angiocentric gliomas (AGs). To address this issue, we performed genomic analysis of new and published data from 249 PLGGs including 19 AGs. We identified MYB-QKI fusions as a specific, recurrent, single candidate driver event in AGs. Although MYB is expressed during early brain development in a subset of progenitor cells, it is not known to play a role in normal cortical brain where AGs frequently occur. In vitro functional studies show MYB-QKI rearrangements promote tumorigenesis in mouse neural stem cells (mNSCs) through three mechanisms: MYB activation by truncation, enhancer translocation driving aberrant MYB-QKI expression, and hemizygous loss of the tumor suppressor QKI. Expression of the MYB-QKI fusion increases mNSC proliferation and activates known MYB target genes including KIT and CDK6. H3K27ac enhancer profiling of AG tumors demonstrate active enhancer elements are translocated proximally to the MYB promoter while in vitro promoter assays confirmed that QKI enhancer sequences activate the MYB promoter. Together with functional studies demonstrating that MYB-QKI can also bind and activate the MYB promoter, these data support a positive auto-regulatory feed-back loop model in which active MYB-QKI is able to drive its own expression through enhanced MYB-promoter-activation. Furthermore, when injected orthotopically into immunodeficient mice, expression of truncated MYB or MYB-QKI is sufficient to induce tumor formation that recapitulate histologic and immunophenotypic characteristics of AGs. Analysis of AG specific MYB-QKI fusion represents the first example of how a single driver rearrangement simultaneously transforms cells via three genetic and epigenetic mechanisms in a cancer. Citation Format: Lori Ramkissoon, Pratiti Bandopadhayay, Payal Jain, Guillaume Bergthold, Adam Resnick, Rameen Beroukhim, Keith Ligon. MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism. [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 4372.
Incorporating Indications into Medication Ordering — Time to Enter the Age of Reason
Authors: Gordon D. Schiff, Enrique Seoane-Vazquez, Adam Wright
Journal: New England Journal of Medicine (2016)

Beyond the five "rights" for safe medication ordering and use — the right patient, right drug, right dose, right time, and right route — a sixth element must be correct: the indication. Indications based prescribing can improve medication use in multiple ways.
Progression and impact of the first winter wave of the 2009 pandemic H1N1 influenza in New South Wales, Australia.
Authors: M. A. Cretikos, D. J. Muscatello, J. Patterson, S. Conaty, T. Churches, J. Fizzell, K. G. Chant, J. M. McAnulty, S. Thackway, M. G. Baker, H. Kelly, N. Wilson
Journal: Eurosurveillance (2009)
Abstract 935: Oral cancer cells may hijack stem cell altruism to survive during extreme hypoxia, and exposure to chemotherapeutic drugs
Authors: Rashmi Bhuyan, Hong Li, Sukanya Gayan, Bidisha Pal, Reza Bayat-Mokhtari, Jyotirmoy Phukan, Debabrata Baishya, Anupam Sarma, Joyeeta Talukdar, Manaf Muhammad Alkurdi, Wael Tasabehji, Seema Bhuyan, Gayatri Gogoi, Ista Pulu, Herman Yeger, Bikul Das
Journal: Cancer Research (2016)

Abstract The mechanism of tumor hypoxia induced reprogramming of cancer cells are not understood well. Hypoxia might activate evolutionary preserved cellular defense mechanism that could contribute to tumor progression and metastasis. We recently described that during hypoxia/oxidative stress, human embryonic stem cells (hES) exhibit an altruistic defense mechanism, where a few cells reprogram to a highly undifferentiated state, and secrete glutathione to protect rest of the community of cells from oxidative stress induced DNA damage (Das B et al, Stem Cells, 2012). The altruistic stem cells phenotype exhibited high HIF-2alpha and low p53 activity. After a few weeks, the reprogrammed cells, although highly fit to survives, underwent spontaneous apoptosis/differentiation by re-activating the p53/MDM2 oscillation. Thus, the reprogrammed cells sacrificed its own fitness to enhance the fitness of the rest of the community, an altruistic behavior (Das B et al. Stem Cells, 2012). Here, we investigated the potential hijacking of the altruistic defense mechanism by oral cancer cells during exposure to hypoxia. We exposed the four oral cancer cell lines SCC-25, SCC-15, SCC-9 and SCC-5 to extreme hypoxia followed by re-oxygenation for 72 hours. We found that while majority of cancer cells underwent apoptosis, a few cancer cell lines survived, exhibited side-population (SP) phenotype, high level of HIF-2alpha, Nanog, Sox-2 and MYC. The SP cells exhibited migratory activity, as well as high tumorigenic and metastatic activity in NOD/SCID mice. ChIP assay indicated that HIF-2alhpa interact with MYC and NOTCH1. The conditioned media of SP cells exhibited high level of glutathione, and ability to protect non-SP cells from cisplatin-induced toxicity. These results indicate that HIF-2alpha and MYC may cooperate to reprogram a few oral cancer cells to altruistic stemness phenotype. The altruistic phenotype that exhibited cytoprotective activity against cisplatin mediated toxicity. Thus, similar to bacteria, where altruistic biofilm exhibit novel drug resistance mechanism, stem cell altruism may serve as a novel drug resistance mechanism in oral cancer. Citation Format: Rashmi Bhuyan, Hong Li, Sukanya Gayan, Bidisha Pal, Reza Bayat-Mokhtari, Jyotirmoy Phukan, Debabrata Baishya, Anupam Sarma, Joyeeta Talukdar, Manaf Muhammad Alkurdi, Wael Tasabehji, Seema Bhuyan, Gayatri Gogoi, Ista Pulu, Herman Yeger, Bikul Das. Oral cancer cells may hijack stem cell altruism to survive during extreme hypoxia, and exposure to chemotherapeutic drugs. [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 935.
Investigating long noncoding RNAs using animal models
Authors: Michael Feyder, Loyal A. Goff
Journal: Journal of Clinical Investigation (2016)

The number of long noncoding RNAs (lncRNAs) has grown rapidly; however, our understanding of their function remains limited. Although cultured cells have facilitated investigations of lncRNA function at the molecular level, the use of animal models provides a rich context in which to investigate the phenotypic impact of these molecules. Promising initial studies using animal models demonstrated that lncRNAs influence a diverse number of phenotypes, ranging from subtle dysmorphia to viability. Here, we highlight the diversity of animal models and their unique advantages, discuss the use of animal models to profile lncRNA expression, evaluate experimental strategies to manipulate lncRNA function in vivo, and review the phenotypes attributable to lncRNAs. Despite a limited number of studies leveraging animal models, lncRNAs are already recognized as a notable class of molecules with important implications for health and disease.
Abstract 4404: NFAT-5/STAT-3 interaction mediates synergism of high salt with IL-17 towards induction of VEGF-A expression in breast cancer cells
Authors: Suneetha Amara, Dalal Alotaibi, Venkataswarup Tiriveedhi
Journal: Cancer Research (2016)

Abstract Chronic inflammation has been considered an important player in cancer proliferation and progression. High salt (sodium chloride) has been considered a potent inducer of chronic inflammation. In this study, we investigated the synergistic role of high salt with IL-17 towards induction of inflammatory and angiogenic stress factor VEGF. Stimulation of MCF-7 breast cancer cells with high salt (0.2 M NaCl) and sub-minimal IL-17 (1 ng/mL) enhanced the expression of VEGF-A (2.9 and 2.6 fold, respectively p&amp;lt;0.05) compared to untreated cells. Further, co-treatment with both high salt and sub-minimal IL-17 demonstrated a 5.9 fold increase in VEGF-A expression (p&amp;lt;0.01), thus suggesting a synergistic role of these both factors. VEGF-A promoter analysis and specific siRNA knock-down of transcription factors revealed that high salt induces VEGF-A through NFAT5, while IL-17 induced VEGF-A via STAT-3 signaling mechanisms. Treatment of the supernatant from activated MCF-7 cells on normalized human aortic endothelial cells induced enhanced cell migration and expression of migration specific factors VCAM, β1-integrin and CD31. Based on these data, we conclude that high salt synergizes with pro-inflammatory IL-17 to potentially induce cancer progression and metastasis through VEGF-A expression. Therefore, low salt diet, anti-NFAT5 and anti-STAT3 therapies might provide novel venues for enhanced efficiency of current cancer therapy. Citation Format: Suneetha Amara, Dalal Alotaibi, Venkataswarup Tiriveedhi. NFAT-5/STAT-3 interaction mediates synergism of high salt with IL-17 towards induction of VEGF-A expression in breast cancer 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 4404.
Efficacy of Dasatinib in Patients with Accelerated-Phase Chronic Myelogenous Leukemia with Resistance or Intolerance to Imatinib: 2-Year Follow-Up Data from START-A (CA180-005).
Authors: Francois Guilhot, Jane F. Apperley, Dong-Wook Kim, Gianantonio Rosti, Xiaobin Yuan, Jan M.A. Van Tornout, Felix T. Garzon, Jorge Cortes
Journal: Blood (2007)
Abstract 3247: Granulocytic MDSCs (CD11b+CD15+CD14-HLADR-) in peripheral blood of mesothelioma patients are elevated and suppress T cell proliferation and function via reactive oxygen species
Authors: Swati Khanna, Francis Mussai, Anish Thomas, Gary Middleton, Constance Yuan, Betsy Morrow, Jingli Zhang, Ira Pastan, Maryalice Stetler-Stevenson, Raffit Hassan
Journal: Cancer Research (2016)

Abstract The role of myeloid derived suppressor cells (MDSCs) in mediating tumor immunosuppression in patients with malignant mesothelioma has not been well characterized. The goal of our study was to analyze for the presence of both monocytic (Mo) and granulocytic (Gr) MDSCs in blood of mesothelioma patients, and characterize their mechanism of suppression of T cells responses. We evaluated the peripheral blood of patients (n = 23) for the presence of Gr-MDSC (CD11b+CD15+CD14-HLADR-) and Mo-MDSC (CD11b+CD14+HLADR-). Gr-MDSC (62.3±13.9% vs. 47.8±17.8%; p = 0.005) as well as monocytic MDSC (0.2±0.4% vs. 0.1±0.3%; p = 0.01) were significantly elevated in peripheral blood of mesothelioma patients as compared to healthy donors (n = 21). The frequency of Gr-MDSC was higher than Mo-MDSC. Thus, Gr-MDSCs appeared to be the main immunosuppressive population and were investigated further.Gr-MDSC from mesothelioma patients were found to inhibit the proliferation of both autologous CD4 and CD8 T cells (mean inhibition of proliferation of 61.9% for CD4 and 75.5% for CD8 at 1:2 T: Gr-MDSC ratio) and was accompanied by a decrease in IFN-γ released by T cells in the co-culture supernatants (92.4 pg/mL at 1:2 ratio). To determine the mechanism by which Gr-MDSC inhibit T cells, we tested the levels of reactive oxygen species (ROS), and nitrite oxide species and arginase activity in Gr-MDSC sorted from peripheral blood. Both arginase (0.3±0.3 vs. 0.2±0.3 μM) and nitrite levels (1.8±2.5 vs. 0 μM) in Gr-MDSC were below detection limit in both patients and donors and were marginally affected by the addition of their respective inhibitors (nor-NOHA and L-NMMA). However, the levels of ROS in Gr-MDSCs derived from mesothelioma patients were on average 3 folds higher than the Gr-myeloid cells from healthy donors (average MFI ∼15000 vs. ∼5000). In summary our results show that the major immunosuppressive cell population in mesothelioma patients are Gr-MDSCs and they suppress T cell proliferation and activation through release of reactive oxygen species. Citation Format: Swati Khanna, Francis Mussai, Anish Thomas, Gary Middleton, Constance Yuan, Betsy Morrow, Jingli Zhang, Ira Pastan, Maryalice Stetler-Stevenson, Raffit Hassan. Granulocytic MDSCs (CD11b+CD15+CD14-HLADR-) in peripheral blood of mesothelioma patients are elevated and suppress T cell proliferation and function via reactive oxygen species. [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 3247.
Development of a Multiplex PCR Assay for the Detection of Genomic Copy Number Changes in Myelodysplastic Syndromes
Authors: Aspasia Stamatoullas, Agathe Waultier, Fabrice Jardin, Marie Paule Callat, Francoise Parmentier, Dominique Penther, Herve Tilly, Christian Bastard
Journal: Blood (2008)
Abstract 1608: Resistin promotes cancer progression through induction of mesenchymal phenotypes and stem cell-like properties in breast cancer
Authors: Shyng-Shiou F. Yuan, Chie-Hong Wang
Journal: Cancer Research (2016)

Abstract Growing evidence indicates that resistin plays a role in insulin resistance, obesity, inflammation, coronary artery disease, atherosclerosis and malignancies. In this study, we have explored the effects and mechanisms of resistin in promoting breast cancer progression. High serum resistin levels were positively correlated with tumor stage, tumor size and lymph node metastasis in breast cancer patients. Resistin treatment modulated the expression of epithelial-mesenchymal transition (EMT) regulators and enhanced the migratory, invasive and anti-anoikis activities in breast cancer cells. Additionally, resistin treatment promoted the formation of mammospheres and the expression of pluripotency factors (sox2, nanog and oct4). STAT3 specific inhibitor, stattic, was able to abolish the resistin mediated enhancements of cell motilities and stem cell-like properties. Using in vivo model, we found that resistin markedly enhance metastasis and tumor growth. Taken together, our data clearly demonstrated that resistin promotes cancer progression through induction of EMT and stemness by activating TLR4/STAT3 signaling in breast cancer. Citation Format: Shyng-Shiou F. Yuan, Chie-Hong Wang. Resistin promotes cancer progression through induction of mesenchymal phenotypes and stem cell-like properties in breast 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 1608.
Farnesoid X receptor activation increases reverse cholesterol transport by modulating bile acid composition and cholesterol absorption in mice
Authors: Yang Xu, Fei Li, Munaf Zalzala, Jiesi Xu, Frank J. Gonzalez, Luciano Adorini, Yoon‐Kwang Lee, Liya Yin, Yanqiao Zhang
Journal: Hepatology (2016)

Activation of farnesoid X receptor (FXR) markedly attenuates development of atherosclerosis in animal models. However, the underlying mechanism is not well elucidated. Here, we show that the FXR agonist, obeticholic acid (OCA), increases fecal cholesterol excretion and macrophage reverse cholesterol transport (RCT) dependent on activation of hepatic FXR. OCA does not increase biliary cholesterol secretion, but inhibits intestinal cholesterol absorption. OCA markedly inhibits hepatic cholesterol 7α-hydroxylase (Cyp7a1) and sterol 12α-hydroxylase (Cyp8b1) partly through inducing small heterodimer partner, leading to reduced bile acid pool size and altered bile acid composition, with the α/β-muricholic acid proportion in bile increased by 2.6-fold and taurocholic acid (TCA) level reduced by 71%. Overexpression of Cyp8b1 or concurrent overexpression of Cyp7a1 and Cyp8b1 normalizes TCA level, bile acid composition, and intestinal cholesterol absorption.Activation of FXR inhibits intestinal cholesterol absorption by modulation of bile acid pool size and composition, thus leading to increased RCT. Targeting hepatic FXR and/or bile acids may be useful for boosting RCT and preventing the development of atherosclerosis. (Hepatology 2016;64:1072-1085).
Abstract 52: NF-kB promotes a Warburg metabolic profile in pediatric sarcomas
Authors: Yuichi Ijiri, Priya Londhe, Cheryl London, Peter J. Houghton, Denis C. Guttridge
Journal: Cancer Research (2016)

Abstract In contrast to normal cells that use mitochondrial oxidative phosphorylation for ATP production in aerobic conditions, many cancer cells depend on glycolysis even in the presence of sufficient oxygen. This process is known as aerobic glycolysis or the Warburg effect. Recent reports have shown that both the classical and alternative signaling pathways of NF-κB play important roles in controlling the metabolic profile of cancer and normal cells, respectively. However, how these signaling pathways affect the metabolism of pediatric sarcomas has not yet been explored. Here, we show NF-κB activity undergoes a shift in signaling from an alternative to a classical pathway in the genesis of sarcoma subtypes, rhabdomyosarcoma and osteosarcoma. Inhibition of classical NF-κB in sarcoma cells restores alternative signaling, as well as an oxidative metabolic phenotype in vitro and in vivo. In contrast, forced expression of the alternative pathway in rhabdomyosarcoma or in osteosarcoma cells is unable to reverse NF-κB classical activity, suggesting that the activation of the classical pathway in sarcomagenesis dominates over alternative signaling. Furthermore, we observed that inhibition of NF-κB in sarcoma cells reduced the expression of the glycolytic gene, hexokinase 2 (HK2). Through chromatin immunoprecipitation (ChIP) assays, we show that HK2 is a direct NF-κB target. Moreover, deletion of HK2 by using shRNA shifts the metabolic profile in sarcoma cells away from a warburg effect. These findings demonstrate a crucial role for classical NF-κB in sarcomagenesis and suggest that NF-κB metabolically reprograms sarcoma cells by regulating HK2. Citation Format: Yuichi Ijiri, Priya Londhe, Cheryl London, Peter J. Houghton, Denis C. Guttridge. NF-kB promotes a Warburg metabolic profile in pediatric sarcomas. [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 52.