tbuckley/cabot-search huggingface dataset:
Abstract 1492: Development of a CD123xCD3 bispecific antibody to treat acute myeloid leukemia (AML)
Authors: Francois Gaudet, Jennifer F. Nemeth, Ronan McDaid, Yingzhe Li, Benjamin Harman, Hillary Millar, Alexey Teplyakov, John Wheeler, Jinquan Luo, Susan Tam, Sheng-Jiun Wu, Emily Chen, Alexander Babich, Yusri Elsayed, Ricardo Attar
Journal: Cancer Research (2016)

Abstract AML is a heterogeneous disease characterized by uncontrolled clonal expansion of leukemic stem cells (LSCs). Current therapies for AML are not curative, in part due to their inability to eradicate LSCs from the bone marrow. T cell redirection has been shown to be effective in heme malignancies and represents a promising approach to treat AML by targeting markers differentially expressed on the cell surface of cancer cells. One marker, CD123 (α-chain of the interleukin-3 receptor) is often present on AML LSCs and blasts. We developed a human bispecific antibody (CD123xCD3; Ab-178) capable of binding to the extracellular domain of CD123 and the ϵ chain of CD3 on T cells to induce T cell–mediated tumor cell killing. This bispecific IgG4 antibody can recruit T cells to CD123+ AML cells (MOLM-13, KG-1 and OCI-AML5) and induce T cell activation as evidenced by CD69 and CD25 up-regulation on T cells. Ab-178 potently killed these CD123+ AML cell lines in vitro (EC50 = 0.51-0.91 nM) but not a CD123− cell line (JIM3). Ab-178 was also able to induce tumor inhibition (MOLM-13 cells) and regression (KG-1 cells) in murine xenograft CD123+ AML models in the presence of human PBMCs. Furthermore, this antibody was able to kill AML blasts in primary AML blood samples ex vivo in the absence of exogenous T cells (autologous setting; EC50 = 0.83 nM). Related bispecific antibodies directed against a viral epitope (nullxCD3 or CD123xnull) did not activate T cells or cause tumor cell killing in the various assays tested. Ab-178 had no impact on T cell activation when incubated with T cells alone. These results indicate that Ab-178 can potently and specifically activate T cells in the presence of CD123+ AML cells and induce their killing. Furthermore, because of the antibody format, this molecule is expected to have a longer half-life compared to smaller bispecific biologic scaffolds. Ab-178 is currently being evaluated pre-clinically for its potential to treat patients with AML. Citation Format: Francois Gaudet, Jennifer F. Nemeth, Ronan McDaid, Yingzhe Li, Benjamin Harman, Hillary Millar, Alexey Teplyakov, John Wheeler, Jinquan Luo, Susan Tam, Sheng-Jiun Wu, Emily Chen, Alexander Babich, Yusri Elsayed, Ricardo Attar. Development of a CD123xCD3 bispecific antibody to treat acute myeloid leukemia (AML). [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 1492.
Smoothed Bootstrap Aggregation for Assessing Selection Pressure at Amino Acid Sites
Authors: Joseph Mingrone, Edward Susko, Joseph Bielawski
Journal: Molecular Biology and Evolution (2016)

To detect positive selection at individual amino acid sites, most methods use an empirical Bayes approach. After parameters of a Markov process of codon evolution are estimated via maximum likelihood, they are passed to Bayes formula to compute the posterior probability that a site evolved under positive selection. A difficulty with this approach is that parameter estimates with large errors can negatively impact Bayesian classification. By assigning priors to some parameters, Bayes Empirical Bayes (BEB) mitigates this problem. However, as implemented, it imposes uniform priors, which causes it to be overly conservative in some cases. When standard regularity conditions are not met and parameter estimates are unstable, inference, even under BEB, can be negatively impacted. We present an alternative to BEB called smoothed bootstrap aggregation (SBA), which bootstraps site patterns from an alignment of protein coding DNA sequences to accommodate the uncertainty in the parameter estimates. We show that deriving the correction for parameter uncertainty from the data in hand, in combination with kernel smoothing techniques, improves site specific inference of positive selection. We compare BEB to SBA by simulation and real data analysis. Simulation results show that SBA balances accuracy and power at least as well as BEB, and when parameter estimates are unstable, the performance gap between BEB and SBA can widen in favor of SBA. SBA is applicable to a wide variety of other inference problems in molecular evolution.
Results of Imatinib Therapy In Patients with Early and Late Chronic-Phase Chronic Myeloid Leukemia In a South Brazilian Cohort.
Authors: Marcelo Capra, Mariza Shaan, Katia Fassina, Mario Sérgio Fernandes, Marco Antônio Schilling, Denise Almeida, Moema Nene, Tânia Hellwig, Gilca Nachtigal, Adriana Zardo, Andréia Dias Almeida, Tito Vanelli Costa, Erica Lammerhirt Ottoni, Mayde Seadi Torriani, Christina G S Fraga, Liane Esteves Daudt, Lucia Silla, Laura Fogliatto
Journal: Blood (2010)
Abstract 31: Metabolic reprogramming in ovarian cancer
Authors: JI HEE HA, Rangasudhagar Radhakrishnan, Jeremy D. Ward, Muralidharan Jayaraman, Danny N. Dhanasekaran
Journal: Cancer Research (2016)

Abstract Ovarian cancer is currently the most lethal gynecologic malignancy, with no new significant changes in treatment options for these patients in the last 30 years. Importantly, ovarian cancer patients have increased levels of lysophosphatidic acid (LPA), a bioactive phospholipid in ascites and serum that has been linked to driving oncogenesis and progression of ovarian cancer. Accumulating evidence has implicated Hypoxia-inducible factor-1α (HIF-1α) as a critical mediator of the glycolytic shift observed in cancer cells. However, the precise biological role of LPA in regulating HIF-1α-mediated glycolytic shift is largely unknown. Therefore, we were interested in examining the potential role of LPA in promoting metabolic reprogramming in ovarian cancer via HIF-1α signaling. In this study, we identified a novel mechanism by which LPA upregulates HIF-1α expression via Gαi2 (the gip2 oncogene) in human ovarian cancer cells. This study demonstrates that LPA induces a glycolytic shift via LPA-mediated activation of Gαi2, which causes a subsequent upregulation of HIF-1α in ovarian cancer cells. Additionally, we show that LPA-signaling via Gαi2 induces an increase in the expression of Hexokinase-2 (HK2) and Glucose transporter 1 (GLUT1), which are known targets of HIF-1α. We also demonstrate that LPA induces an increase in extracellular acidification rate (ECAR) in a dose dependent manner in both ovarian cancer cell lines and in patient-derived cells taken from the ascites fluid of ovarian cancer patients using an XFe96 analyzer. Furthermore, we found that inhibition of Rac signaling caused a reduction in LPA-induced ECAR, identifying Rac as a critical downstream component of Gαi2-medidated increase of ECAR. Moreover, using NAC, an inhibitor of redox signaling, we found that this caused a decrease in LPA-induced ECAR in SKOV3-ip cells, indicating that inhibition of redox signaling abolishes LPA-induced ECAR in ovarian cancer cells. Similarly, the use of EUK-134, a scavenger of superoxide and H2O2, also decreased LPA-induced increase in ECAR. Altogether, these results indicate that LPA regulates glycolysis through redox signaling via a Gαi2-Rac-HIF1α-dependent signaling pathway. Most importantly, the Gαi2-Rac-dependent pathway identified in this study more than likely serves as a potential driver of HIF-1α-mediated metabolic changes in ovarian cancer cells and represents a potential target for therapy in these patients. Citation Format: JI HEE HA, Rangasudhagar Radhakrishnan, Jeremy D. Ward, Muralidharan Jayaraman, Danny N. Dhanasekaran. Metabolic reprogramming in ovarian 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 31.
Abstract 1000: The long non-coding RNA HIF1A-AS2 regulates mesenchymal glioma stem cell tumorigenicity
Authors: Marco Mineo, Franz Ricklefs, Arun Rooj, Shawn M. Lyons, Pavel Ivanov, Ennio A. Chiocca, Jakub Godlewski, Agnieszka Bronisz
Journal: Cancer Research (2016)

Abstract Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in adults, which initiation and progression is driven by a subset of self-renewing GBM stem-like cells (GSCs). Long-non coding RNAs (lncRNAs) have been recently shown to play important roles in regulating numerous biological processes both in physiologic and pathologic condition. Identification of functional lncRNAs important for GBM initiation and progression may shed new light on understanding pathophysiology of the disease. We used a custom made lncRNA Nanostring platform to profile the expression of lncRNAs in subtype-characterized collection of patient-derived GSCs. We demonstrated that lncRNA signature may distinguish between GSC subtypes. Out of 73 lncRNAs we found 7 that were overexpressed specifically in the most aggressive mesenchymal (M) GSC subtype. Among them, HIF1A-AS2 was the most differentially expressed lncRNA. HIF1A-AS2 was reported to be overexpressed in many types of cancers; however its biological function and its role in GBM progression are unknown. Knockdown of HIF1A-AS2 in M GSCs resulted in reduced growth, increased cytotoxicity, and it strongly inhibited their neurosphere formation capability. Using more global approach we found out that knockdown of HIF1A-AS2 in M GSCs caused deregulation of several out of 730 cancer-related genes. Functional bioinformatic analysis revealed that these differentially expressed mRNAs are closely related to proliferation, transcriptional regulation and cell division. RNA pull-down assay showed that HIF1A-AS2 may exert its effects through specific binding of RNA helicase DHX9, a multifunctional protein with important roles in transcription, pre-mRNA processing and translation. We also demonstrated that HMGA1, a gene known to be regulated by DHX9, was specifically down-regulated in HIF1A-AS2 knockdown cells both at mRNA and protein level. Finally, we showed that silencing of HIF1A-AS2 blocked M GSC tumor growth in vivo resulting in significant survival benefits. Taken together, our results suggest HIF1A-AS2 as an important lncRNA in pathophysiology of GBM. Citation Format: Marco Mineo, Franz Ricklefs, Arun Rooj, Shawn M. Lyons, Pavel Ivanov, Ennio A. Chiocca, Jakub Godlewski, Agnieszka Bronisz. The long non-coding RNA HIF1A-AS2 regulates mesenchymal glioma stem cell tumorigenicity. [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 1000.
Abstract 1343: P32-targeting TT1 peptide delivers nanoparticles to intracranial glioblastomas
Authors: Pille Säälik, Hedi Hunt, Allan Tobi, Anne-Mari Anton Willmore, Kadri Toome, Shweta Sharma, Ramana Kotamraju, Gabriele Bergers, Rolf Bjerkvig, Erkki Ruoslahti, Tambet Teesalu, Tambet Teesalu
Journal: Cancer Research (2016)

Abstract Targeted delivery of cancer therapeutics using affinity ligands can dramatically improve antitumor efficacy. Over the years a number of homing peptides that upon systemic injection accumulate in solid tumors have been identified by in vivo peptide phage display. In a quest to find homing peptides optimally suited for drug delivery to high-grade gliomas, our laboratories are using advanced mouse models of glioblastoma (GBM) to systematically audit known tumor-homing peptides and to perform new in vivo screens using peptide phage libraries. P32 is a mitochondrial chaperone that is aberrantly expressed on the cell surface in activated malignant and stromal cells in tumors. P32 is a receptor for widely used LypP-1 peptide and for recently identified TT1 peptide. Here we show that iron oxide nanoworms (IONW) functionalized with linear TT1 peptide (CKRGARST) strongly home to intracranial GBMs grafted in immune deficient mice. IONW are paramagnetic nanoparticles that are PEGylated to extend blood half-life, and have, because of their elongated shape, more effective targeting properties than spherical nanoparticles. Five hours after intravenous injection of IONW (7.5 mg/kg), macroscopic fluorescence imaging demonstrated robust homing of TT1-IONW in GBMs of murine origin (WT GBM and VEGF KO GBM from the G. Berger lab) and in a patient-derived glioma model (P13 model from the Bjerkvig lab). Confocal microscopy confirmed the presence of TT1 but not control IONW in gliomas, with TT1-IONW signal showing partial overlap with blood- and lymphatic vessel markers (CD31 and LYVE-1) in WT GBM and P13 gliomas, whereas lower level of colocalization with these markers was detected for mouse GBM not expressing VEGF. In addition, moderate colocalization between TT1-IONW and the macrophage marker CD11b was detected in the P13 tumors. Detailed phenotyping and functional characterization of TT1-positive macrophages is ongoing. Our data suggest that TT1 peptide has potential applications as a glioma-targeting vehicle. Currently, we are evaluating TT1-targeted IONWs as a contrast agent for glioma MRI and as carriers for cytotoxic compounds. Citation Format: Pille Säälik, Hedi Hunt, Allan Tobi, Anne-Mari Anton Willmore, Kadri Toome, Shweta Sharma, Ramana Kotamraju, Gabriele Bergers, Rolf Bjerkvig, Erkki Ruoslahti, Tambet Teesalu, Tambet Teesalu. P32-targeting TT1 peptide delivers nanoparticles to intracranial glioblastomas. [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 1343.
Pembrolizumab Outperforms Docetaxel for NSCLC
Authors: Mitch Leslie
Journal: Cancer Discovery (2016)

Abstract Pembrolizumab improves survival in patients with advanced non–small cell lung cancer (NSCLC). Compared with docetaxel, the drug more than doubles survival in patients whose tumor cells express high levels of PD-L1. Although the drug had a beneficial effect in patients with nonsquamous NSCLC, it didn't significantly increase survival in patients with squamous NSCLC.
Human circulating group 2 innate lymphoid cells can express CD154 and promote IgE production
Authors: Laura Maggi, Gianni Montaini, Alessio Mazzoni, Beatrice Rossettini, Manuela Capone, Maria Caterina Rossi, Veronica Santarlasci, Francesco Liotta, Oliviero Rossi, Oreste Gallo, Raffaele De Palma, Enrico Maggi, Lorenzo Cosmi, Sergio Romagnani, Francesco Annunziato
Journal: Journal of Allergy and Clinical Immunology (2016)
Xalia, a Non-Interventional Study Comparing Rivaroxaban with Standard Anticoagulation for Initial and Long-Term Therapy in Deep Vein Thrombosis
Authors: Alexander G G Turpie, Lorenzo G Mantovani, Sylvia Haas, Reinhold Kreutz, Danja Monje, Jonas Schneider, Martin van Eickels, Martin Gebel, Walter Ageno
Journal: Blood (2015)
Abstract 4060: The role of p62-dependent regulation of COX-2 in UVA response and skin tumor progression
Authors: Ashley Sample, Lei Qiang, Baozhong Zhao, Yu-Ying He
Journal: Cancer Research (2016)

Abstract Skin cancer is the most common type of cancer in the US, with an estimated 3.5 million cases diagnosed each year. Exposure to ultraviolet (UV) radiation, namely UVA (320-400 nm) and UVB (290-320 nm), is the major risk factor for the development of skin cancer. UVA is 20-fold more abundant in sunlight than UVB and is the major component of tanning beds. However, the mechanism of UVA's contribution to skin cancer remains unclear. One putative effector of UVA in skin cancer is p62, a selective autophagy cargo protein and substrate. We have found that UVA upregulates p62 expression, independent of autophagy, by inducing transcription of p62. p62 is upregulated in many types of cancer, including squamous cell carcinoma (SCC) and melanoma, and can facilitate the activation of a number of pathways to promote cell proliferation, invasion, inflammation, and survival. We have previously shown that p62 stabilizes Twist1 to promote invasion and proliferation, indicating p62 can function independent of autophagy to promote tumor progression. However, the function of p62 in UVA-induced tumor progression is unknown. Using a candidate gene approach, we identified a novel interaction between p62 and cyclooxygenase-2 (COX-2), which suggests a putative function for p62 in UVA-induced skin cancer. COX-2 is a prostaglandin synthase often overexpressed in cancer, where it correlates with poor prognosis. COX-2 promotes cell proliferation and survival, and inhibition of COX-2 prevents skin cancer development. COX-2 protein expression is induced concomitantly with p62 in response to UVA and knockdown of p62 prevents induction of COX-2 by UVA. As COX-2 transcription is not induced by UVA in skin cancer cells along with p62, we assessed a possible protein-level regulatory mechanism. Co-immunoprecipitation of endogenous p62 and COX-2 in skin cancer cells reveals a novel physical interaction between these proteins. Therefore, we hypothesize that p62 transcription is induced by UVA to promote stability of cyclooxygenase-2 (COX-2) and consequently, tumor progression. This project aims to further understand how UVA regulates p62 and thus COX-2 availability, and the functional significance for skin tumor progression. As both p62 and COX-2 are critical for skin tumor progression, understanding the link between these proteins will unravel a signaling axis central to skin cancer progression. Citation Format: Ashley Sample, Lei Qiang, Baozhong Zhao, Yu-Ying He. The role of p62-dependent regulation of COX-2 in UVA response and skin tumor progression. [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 4060.
1′-Acetoxychavicol Acetate (ACA) Is a Novel NF-κB Inhibitor with Significant Activity Against Multiple Myeloma in Vitro and in Vivo.
Authors: Keisuke Ito, Tomonori Nakazato, Yoshitaka Miyakawa, Ming Ji Xian, Taketo Yamada, Hajime Ohigashi, Yasuo Ikeda, Masahiro Kizaki
Journal: Blood (2004)
Outcome After Admission at Veterans Affairs vs Non–Veterans Affairs Hospitals
Authors: Thomas R. Radomski, Michael J. Fine, Walid F. Gellad
Journal: JAMA (2016)

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Abstract 1022: The ketone body β-hydroxybutyrate down regulates c-Myc signaling in a malignant glioma model
Authors: Alex P. Rossi, Helena B. Silva-Nichols, Eric C. Woolf, Adrienne C. Scheck
Journal: Cancer Research (2016)

Abstract Glioblastoma (GB) is the most common primary malignant brain tumor with a dismal median survival of 1.5 years. To address the need for novel therapeutics for the treatment of GB, investigations into high fat, low carbohydrate ketogenic diets (KD) have been explored as potential adjuvant therapeutic modalities. Preclinical studies of the KD in a mouse model of malignant glioma demonstrated that the KD extended median survival when used alone and substantially potentiated both radiotherapy and chemotherapy. However, the underlying mechanisms by which the KD exerts its therapeutic benefits remain poorly understood. A key result of the KD is the production of the ketone bodies β-hydroxybutyrate (βHB), acetoacetate, and acetone. Of these, BHB is the most prevalent ketone body produced. In order to elucidate the underlying molecular mechanisms of the KD, we have examined the interactions between BHB and the mouse glioma cell line GL261-Luc2. Previously, we demonstrated the ability of βHB to recapitulate the in vivo effects of the KD in tumor cells in an in vitro model. In the present study, we demonstrate that the ketone βHB is able to significantly down regulate the master transcription factor c-Myc, which is intimately involved in cell cycle progression, apoptosis, proliferation, DNA damage and repair, and metabolism. Overexpression of c-Myc is tied to a variety of human malignancies. In GB, upregulation of c-Myc signaling has been connected to an increase in tumor glucose metabolism. Furthermore, downregulating c-Myc expression has been demonstrated to confer sensitivity to tumors. We show that doses of both 5mM and 10mM βHB significantly reduced the expression of c-Myc in the GL261-Luc2 cell line when evaluated by both immunocytochemistry and western blot. Downregulation of c-Myc may, in part, be a mechanism by which βHB and thus the KD exert their radiosensitizing and antiproliferative effects on tumors. We intend to further investigate the role of c-Myc in the KD by investigating downstream targets of c-Myc as well as potential regulators of c-Myc transcription that are affected by BHB. Citation Format: Alex P. Rossi, Helena B. Silva-Nichols, Eric C. Woolf, Adrienne C. Scheck. The ketone body β-hydroxybutyrate down regulates c-Myc signaling in a malignant glioma model. [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 1022.