tbuckley/cabot-search huggingface dataset:
Abstract 1182: Heparin-binding epidermal growth factor-like growth factor is a pro-differentiating factor in neuroblastoma
Authors: Angela L. Gaviglio, Gerard C. Blobe
Journal: Cancer Research (2016)

Abstract Neuroblastoma is the most common cancer in infancy. Current therapies are only modestly effective; patients with high-risk disease have less than a 50% chance of survival. High-risk neuroblastoma is characterized by undifferentiated neuroblasts and low Schwannian stroma content. The tumor stroma contributes to the suppression of tumor growth by releasing soluble proteins, including heparan sulfate proteoglycans (HSPGs), which act to promote neuroblast differentiation. Here we identify heparin-binding epidermal growth factor-like growth factor (HBEGF) as a potent pro-differentiating factor in neuroblastoma. Using microarray analysis, HBEGF mRNA expression is decreased in neuroblastoma compared to benign disease, correlating to an increase in mortality. HBEGF protein is expressed only in stromal compartments of tumor specimens, with tissue from high-stage disease having decreased stroma and HBEGF. Soluble HBEGF increased neuroblast differentiation and decreased proliferation, while HBEGF knockdown decreased neuroblast differentiation. In patient samples, HBEGF expression correlates with SOX10, a neural crest differentiation marker, and the cell cycle inhibitor, CDKN1A. Alternatively, HBEGF negatively correlates with ASCL1, a primitive neuroectodermal marker, and the cell cycle promoter CCND1. HSPGs, including TβRIII, GPC1, GPC3, and SDC3 further promote the differentiating effects of HBEGF treatment by forming a complex with the epidermal growth factor receptor (EGFR) via glycosaminoglycan modifications, leading to activation of the Erk1/2 pathway and upregulation of the inhibitor of DNA binding transcription factor, whose expression correlates with HBEGF in patient samples. Inhibition of EGFR with erlotinib, lapatinib, and gefitinib diminish HBEGF-induced differentiation. These data identify a novel member of the pro-differentiating secretome and support the use of heparan sulfate mimetics in neuroblastoma, while cautioning against the use of EGFR inhibitors for neuroblastoma treatment. Citation Format: Angela L. Gaviglio, Gerard C. Blobe. Heparin-binding epidermal growth factor-like growth factor is a pro-differentiating factor in neuroblastoma. [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 1182.
Abstract 3753: Improved oncolytic virotherapy by increasing adenovirus spread
Authors: Stephen L. Wechman, Xiao-Mei Rao, Kelly Marc McMasters, Heshan Sam Zhou
Journal: Cancer Research (2016)

Abstract Lung cancer is the leading cause of cancer-related death worldwide and kills more patients than the next four cancers combined (Colon, breast, prostate, and pancreas). Currently available lung cancer treatments have not been effective. Therefore the development of novel lung cancer therapeutics is of critical importance. One emerging treatment option is the use of E1b-deleted adenoviruses (Ads) which preferentially lyse cancer cells. Although E1b-deleted Ads have been applied in clinical trials, their efficacy remains low. We have developed a novel oncolytic vector, AdUV, via the bioselection of the cancer selective E1b-deleted Ad Adhz60. We have demonstrated that AdUV is much more potent against multiple cancer cell lines than the parental vector Adhz60 in vitro and suppressed tumor growth in vivo. We compared AdUV treated cells to cells treated with the wildtype Ad5 and the E1b-deleted Adhz60. AdUV lysed A549 lung cancer cells more efficiently than Adhz60, but neither AdUV nor Adhz60 killed MRC5 and HBEC normal lung cells. Possible mechanisms of action were then investigated to determine how AdUV lysed A549 cells more effectively. AdUV virions were shown to release from infected A549 cells and induce autophagy more effectively than both Adhz60 and Ad5. Autophagy induction is known to support Ad replication and spread through cancer cell monolayers. The plaque assay was used to verify if AdUV could spread more effectively than Ad5 and Adhz60 because viruses which efficiently replicate and release from cells are known to form larger plaques. The average size of plaques formed by AdUV is 340% and 214% larger than those plaques formed by Adhz60 and Ad5, respectively. In vivo, AdUV was non-lethal to athymic nude mice and strongly suppressed A549-xenograft tumor growth, prolonging murine survival. These results indicate that AdUV is a more effective, safe oncolytic Ad vector. Our findings also demonstrate the utility of bioselection of the generation of more effective cancer therapeutic vectors. Citation Format: Stephen L. Wechman, Xiao-Mei Rao, Kelly Marc McMasters, Heshan Sam Zhou. Improved oncolytic virotherapy by increasing adenovirus spread. [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 3753.
Effects Of Inhibition Of XPO1/CRM1-Dependent Nuclear Export By Selinexor (KPT-330), Alone and In Combination With Carfilzomib (CFZ), On Apoptosis and Autophagy In Multiple Myeloma (MM)
Authors: Shaun Rosebeck, Malathi Kandarpa, Mattina M. Alonge, Jagoda Jasielec, Dominik Dytfeld, Sean P Maxwell, Stephanie J Kraftson, Dilara McCauley, Sharon Shacham, Michael Kauffman, Andrzej J. Jakubowiak
Journal: Blood (2013)
Abstract 3210: An in vitro approach to study T cell exhaustion
Authors: William Hastings, Glenn Dranoff, Alexander Cao
Journal: Cancer Research (2016)

Abstract Immune checkpoint inhibition is now a validated modality in the treatment of multiple cancers. In vitro immune cell assays are a key tool in the study of pharmacological agents for immune modulation. Assays often involve isolating lymphocytes from human peripheral blood followed by a T cell stimulus such as anti-CD3, staph enterotoxin B, or allogeneic APCs. While this approach is useful to probe the events of immune stimulation, it likely reflects a primary or secondary immune activation, rather than a state of exhaustion. As intra-tumoral T cells are thought to be exhausted by chronic/repeated exposure to self-antigen, we sought to define experimental conditions that would reflect this state in vitro. We reasoned that repeated stimulation of T cells using anti-CD3/anti-CD28 coated microbeads would induce an exhausted phenotype. We found that, using PBMC from normal healthy donors, frequent and repeated stimuli resulted in a loss of T cells’ ability to produce IL-2, TNFa, and IFNg as measured by intracellular cytokine staining. Interestingly, only one restimulation was necessary to confer this phenotype, as repeated stimuli over a longer time course did not result in further suppression. We also found that repeat stimulation conferred a surface marker phenotype suggestive of exhausted cells. Finally, we used cell death inhibitors z-7AAD-cmk and EGTA and found no effect on cytokine loss, supporting the hypothesis that cells are exhausted and not deleted by activation induced cell death. Thus we have defined experimental conditions that possibly reflect an exhausted T cell phenotype in vitro. This may be useful for the pharmacological evaluation of different therapeutic agents for their immune modulatory activities in cancer. Citation Format: William Hastings, Glenn Dranoff, Alexander Cao. An in vitro approach to study T cell exhaustion. [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 3210.
Risk of Congenital Heart Defects after Ambient Heat Exposure Early in Pregnancy
Authors: Nathalie Auger, William D. Fraser, Reg Sauve, Marianne Bilodeau-Bertrand, Tom Kosatsky
Journal: Environmental Health Perspectives (2016)

Background:Congenital heart defects may be environmentally related, but the association with elevated ambient temperature has received little attention.Objectives:We studied the relationship between outdoor heat during the first trimester of pregnancy and risk of congenital heart defects.Methods:We carried out a retrospective cohort study of 704,209 fetuses between 2 and 8 weeks postconception from April to September in Quebec, Canada, 1988–2012. We calculated the prevalence of congenital heart defects at birth according to the number of days women were exposed to maximum temperature ≥ 30°C. In log-binomial regression models, we estimated prevalence ratios (PR) and 95% confidence intervals (CI) for the relationship of temperature with seven critical and eight noncritical heart defects, adjusted for pregnancy characteristics.Results:Prevalence of congenital heart defects was 979.5 per 100,000 for 10 days or more of temperature ≥ 30°C compared with 878.9 per 100,000 for 0 days of exposure. Temperature was more precisely associated with noncritical than critical defects, which had lower prevalence. Fetuses exposed to 15 days of temperature ≥ 30°C between 2 and 8 weeks postconception had 1.06 times the risk of critical defects (95% CI: 0.67, 1.67) and 1.12 times the risk of noncritical defects (95% CI: 0.98, 1.29) relative to 0 days. Associations were higher for atrial septal defects (PR 1.37, 95% CI: 1.10, 1.70) than for other noncritical defects. For atrial septal defects, associations with elevated temperatures began the 3rd week postconception.Conclusions:Extreme heat exposure during the first trimester may be associated with noncritical heart defects, especially of the atrial septum.Citation:Auger N, Fraser WD, Sauve R, Bilodeau-Bertrand M, Kosatsky T. 2017. Risk of congenital heart defects after ambient heat exposure early in pregnancy. Environ Health Perspect 125:8–14; http://dx.doi.org/10.1289/EHP171
Abstract 4066: The chemokine CXCL13 in lung cancers associated with environmental polycyclic aromatic hydrocarbons pollution
Authors: Gui-Zhen Wang, Xin Cheng, Guang-Biao Zhou
Journal: Cancer Research (2016)

Abstract More than 90% of lung cancers are caused by cigarette smoke and air pollution, with polycyclic aromatic hydrocarbons (PAHs) as key carcinogens. In Xuanwei City of Yunnan Province the lung cancer incidence is among the highest in China attributed to smoky coal combustion-generated PAH pollution. Here we screened for abnormal inflammatory factors in non-small cell lung cancers (NSCLCs) from Xuanwei and control regions (CR) where smoky coal was not used, and found that a chemokine CXCL13 was overexpressed in 63/70 (90%) of Xuanwei NSCLCs and 44/71 (62%) of smoker and 27/60 (45%) of non-smoker CR patients. CXCL13 overexpression was associated with the region Xuanwei and cigarette smoke. The key carcinogen bezo(a)pyrene (BaP) induced CXCL13 production in lung epithelial cells and in mice prior to development of detectable lung cancer. Deficiency in Cxcl13 or its receptor, Cxcr5, attenuated BaP-induced lung cancer in mice, demonstrating CXCL13's critical role in PAH-induced lung carcinogenesis. Citation Format: Gui-Zhen Wang, Xin Cheng, Guang-Biao Zhou. The chemokine CXCL13 in lung cancers associated with environmental polycyclic aromatic hydrocarbons pollution. [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 4066.
Salt-Inducible Kinase 2 Couples Ovarian Cancer Cell Metabolism with Survival at the Adipocyte-Rich Metastatic Niche
Authors: Fabrizio Miranda, David Mannion, Shujuan Liu, Yiyan Zheng, Lingegowda S. Mangala, Clara Redondo, Sandra Herrero-Gonzalez, Ruoyan Xu, Charlotte Taylor, Donatien Fotso Chedom, Eli M. Carrami, Ashwag Albukhari, Dahai Jiang, Sunila Pradeep, Cristian Rodriguez-Aguayo, Gabriel Lopez-Berestein, Eidarus Salah, Kamal R. Abdul Azeez, Jonathan M. Elkins, Leticia Campo, Kevin A. Myers, Daniel Klotz, Serena Bivona, Sunanda Dhar, Robert C. Bast, Hideyuki Saya, Hwan Geun Choi, Nathanael S. Gray, Roman Fischer, Benedikt M. Kessler, Christopher Yau, Anil K. Sood, Takeshi Motohara, Stefan Knapp, Ahmed Ashour Ahmed
Journal: Cancer Cell (2016)
Phosphatidyl Inositol (4,5)P2 Marks Megakaryocyte Internal Membranes and Is Associated with Megakaryocyte Maturation and Platelet Release.
Authors: Harald Schulze, Manav Korpal, Jonathan Hurov, Sang-We Kim, Jinghang Zhang, Lewis C. Cantley, Thomas Graf, Ramesh A. Shivdasani
Journal: Blood (2005)
Inducible MyD88/CD40 to allow rimiducid-dependent activation for control of proliferation and survival of chimeric antigen receptor (CAR) T cells targeting prostate stem cell antigen (PSCA).
Authors: Kevin Mark Slawin, Aruna Mahendravada, Nicholas Shinners, Peter Chang, An Lu, Jeannette Crisostomo, Eva Morschl, Joanne Shaw, Sunandan Saha, David M Spencer, Aaron E Foster
Journal: Journal of Clinical Oncology (2016)

206 Background: PSCA is a cell surface antigen that is overexpressed in a majority of metastatic prostate, transitional cell and pancreatic carcinomas. We describe a novel T cell costimulation switch, inducible MyD88/CD40 (iMC), activated by a small molecule, rimiducid, to enhance survival, proliferation and anti-tumor activity of CAR-T cells targeting PSCA. Methods: T cells were transduced with a retrovirus encoding tandem rimiducid-binding domains,cloned in-frame with MyD88 and CD40 signaling elements and first generation CARs (CAR.ζ) targeting PSCA (SFG-iMC-2A-PSCA.ζ). iMC activation was assessed with and without rimiducid treatment of T cells. Coactivation via iMC and CAR was tested in coculture assays with or without rimiducid using various PSCA + tumor cells, e.g. Capan-1 and HPAC pancreatic adenocarcinoma. Efficacy of iMC-modified CAR-T cells in vivo was assessed using an NSG mouse tumor model. Results: T cells transduced with iMC-PSCA.ζ produced cytokines (e.g., IFN-γ and IL-6) in response to rimiducid; however, IL-2 was only produced when both iMC and CAR were activated simultaneously by rimiducid and tumor antigen. Treatment of NSG mice bearing large (&gt; 200 mm 3 ) HPAC tumors with a single i.v. dose of 1x10 7 iMC-PSCA.ζ cells resulted in complete tumor elimination in 10/10 mice including both rimiducid-treated and untreated animals, compared to mice receiving non-transduced T cells (p = 0.0003). Weekly rimiducid administration dramatically increased CAR-T cell numbers, resulting in a 23-fold expansion of iMC-PSCA.ζ-modified T cells in the spleen compared to mice not receiving rimiducid four weeks after infusion (p = 0.02). In a dose-titration study, rimiducid administration was required for tumor control, and led to 565- and 948-fold T cell expansion at the tumor site, respectively, when lower numbers (1.25x10 6 or 6.25x10 5 , respectively) of iMC-PSCA.ζ-modified T cells were given. Conclusions: GoCAR-T cells targeting PSCA, which contain an inducible MyD88/CD40 activation switch, may be an effective adoptive cell therapy for patients with pancreatic, prostate, bladder, and other cancers that overexpress PSCA.
Outcomes based on prior VEGFR TKI and PD-1 checkpoint inhibitor therapy in METEOR, a randomized phase 3 trial of cabozantinib (C) vs everolimus (E) in advanced renal cell carcinoma (RCC).
Authors: Thomas Powles, Robert J. Motzer, Bernard J. Escudier, Sumanta K. Pal, Christian K. Kollmannsberger, Joanna Pikiel, Howard Gurney, Sun Young Rha, Se Hoon Park, Poul F. Geertsen, Marine Gross-Goupil, Enrique Grande, Cristina Suarez, Alan M Arroyo, Mark Dean, Daniel George, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2016)

4557 Background: Optimizing the sequence of systemic therapy to improve outcomes in patients (pts) with advanced RCC remains a clinical challenge. C, a tyrosine kinase inhibitor (TKI), was recently evaluated in pts with RCC and ≥ 1 prior VEGFR TKI in the Phase 3 METEOR trial (NCT01865747). The trial met its primary endpoint, significantly improving progression-free survival (PFS) compared with E (median [m] 7.4 vs 3.8 mo, HR = 0.58, 95% CI 0.45–0.75; P < 0.001; Choueiri NEJM 2015). Here clinical outcomes by prior sunitinib (S) and pazopanib (P) VEGFR TKI therapy and by prior anti-PD-1/PD-L1 therapy are evaluated. Methods: 658 pts were randomized (stratified by MSKCC risk groups and number of prior VEGFR TKIs) 1:1 to receive C (60 mg qd) or E (10 mg qd). Clinical outcome measures included PFS (primary endpoint), ORR, overall survival (OS), and safety. Results: Demographics and baseline characteristics of pts who received only S (n = 267) or only P (n = 171) as prior VEGFR TKI therapy were similar and were also balanced for C vs E. Efficacy outcomes by prior therapy were consistent with the primary PFS analysis. The number of prior VEGFR TKI therapies did not affect efficacy outcomes for C vs E. In pts with S as the only prior TKI, mPFS was 9.1 mo for C vs 3.7 mo for E (HR 0.43, 95% CI 0.32–0.59), while for pts with only prior P, mPFS was 7.4 mo for C vs 5.1 mo for E (HR 0.67, 94% CI 0.45–0.99). The ORR by independent radiology review with C was 16% for pts with only prior S and 19% for only prior P compared with 3% and 3.6% with E, respectively. In pts with prior anti-PD-1/PD-L1 therapy (n = 32; primarily nivolumab), the HR was 0.22 (95% CI 0.07–0.65) in favor of C. The mPFS for C could not be estimated, and was 4.1 mo for E; ORR was 22% for C and 0 % for E. The most common AEs reported for pts with only prior S, only prior P, and prior anti-PD-1/PD-L1 therapy were consistent with the overall safety profile in this population. Conclusions: Efficacy outcomes by prior VEGFR TKI therapy and prior anti-PD-1/PD-L1 therapy consistently favor C, as was seen in the primary analysis. C should be considered a new treatment option in previously treated pts with RCC regardless of prior systemic therapy. Clinical trial information: NCT01865747.
Abstract 1451: Analysis of expression MHC class I chain-related gene A and B (MICA/B) in normal and tumor tissue
Authors: Hormas Ghadially, Lee Brown, Arthur Lewis, Meggan Czapiga, Viia Valge-Archer, Robert W. Wilkinson
Journal: Cancer Research (2016)

Abstract MHC class I chain-related gene A and B (MICA and MICB) are highly polymorphic proteins that are induced upon stress, damage or transformation of cells which act as a “kill me” signal through the NKG2D receptor expressed on Natural Killer, CD8+ and γδ T cells. Experimentally, the MIC/NKG2D axis has been shown to be important for the recognition of tumour cells by cytotoxic cells of the immune system and many tumours have evolved strategies to evade the detection by NKG2D expressing cells, e.g. by shedding MIC from the cell surface. Expression of MIC has been reported for most tumour types and in normal gastrointestinal tract epithelium but the published data is often difficult to interpret. Additionally, it is not clear how much of the protein is expressed on the cell surface as MIC cell surface expression is known to be regulated tightly on multiple levels. A validated MICA/B IHC assay was developed using an in-house tool antibody to profile multiple frozen human normal and tumour tissue microarrays (TMA’s) by both standard and confocal microscopy techniques. Using a stringently characterised novel antibody that detects MICA as well as MICB this study describes the expression patterns in a wide range of tumours and normal tissues. With this method we generated data with unprecedented resolution, which enabled us to analyse the expression of MICA and MICB not only on the cellular but also on the sub-cellular level. Citation Format: Hormas Ghadially, Lee Brown, Arthur Lewis, Meggan Czapiga, Viia Valge-Archer, Robert W. Wilkinson. Analysis of expression MHC class I chain-related gene A and B (MICA/B) in normal and tumor tissue. [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 1451.
Abstract 762: The interleukin-1 inflammatory cytokine family modulates p62/SQSTM1 accumulation in breast cancer cell lines
Authors: Afshan Fathima Nawas, Janani Ramachandran, Shayna Thomas, Jananisree Ravichandran, Nikki Delk
Journal: Cancer Research (2016)

Abstract Tumors are likened to wounds that do not heal. Thus, not surprisingly, inflammatory cytokines are present in the primary and metastatic tumor microenvironments due, in part, to infiltrating bone-derived cells (e.g., macrophages). We previously discovered that a bone marrow stromal cell line that secretes the inflammatory cytokine, interleukin-1 beta (IL-1â), upregulates p62 mRNA and protein in prostate cancer cell lines and we showed that p62 can be cytoprotective for prostate cancer cells. p62/Sequestome-1 is a multifunctional scaffold protein that can be seen microscopically as subcellular “speckles” which serve as organizing centers for multiple different signaling cascades, ranging from autophagy-mediated degradation of ubiquitinated proteins to KEAP1-NRF2 antioxidant response. To determine if our previous discoveries might be cancer-type specific and to test our hypothesis that p62 promotes cancer cell survival in response to inflammatory cytokines, we expanded our studies to various breast cancer cell lines of varying receptor status, including ZR57-1, T47D, and MDA-MB-468 and determined cell response two interleukin-1 family members, alpha (á) and beta (â). We treated the breast cancer cells with IL-1á and/or IL-1â and analyzed p62 mRNA and protein levels, subcellular localization, and protein-protein interactions. IL-1á and IL-1â can induce p62 speckle accumulation that can be seen to co-localize with the autophagosome membrane protein, LC3B, suggesting an autophagy-dependent regulation and/or function for p62. In addition, p62 co-immunoprecipitates with KEAP1, suggesting a KEAP1-NRF2-dependent antioxidant function for p62. Taken together, our data implies that cancer cells usurp inflammatory cytokines, such as IL-1, present in the primary or metastatic tumor microenvironment to promote cell survival through proteins such as p62. Citation Format: Afshan Fathima Nawas, Janani Ramachandran, Shayna Thomas, Jananisree Ravichandran, Nikki Delk. The interleukin-1 inflammatory cytokine family modulates p62/SQSTM1 accumulation in breast cancer cell lines. [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 762.
Guanidinoacetate N-methyltransferase-knockout mice completely lacking myocardial phosphocreatine show normal in vivo cardiac function, but increased susceptibility to ischemia/reperfusion injury
Authors: C A Lygate, M ten Hove, J Wallis, A Fischer, J E Schneider, E Sang, D Dawson, K Hulbert, L Sebag-Montefiore, P J Cassidy, H Watkins, K Clarke, D Isbrandt, S Neubauer
Journal: Circulation (2004)