tbuckley/cabot-search huggingface dataset:
Abstract 444: Hyaluronan-mediated motility receptor (RHAMM) in ovarian cancer
Authors: Stephanie Buttermore, Patricia Kruk
Journal: Cancer Research (2016)

Abstract This study focuses on Hyaluronan Mediated Motility Receptor (RHAMM) protein expression in ovarian carcinoma (OC). RHAMM protein increases migration, invasion and is associated with poor prognosis when overexpressed. It is a dualistic oncogenic protein located within and on the cell surface acting as a receptor for Hyaluronan (HA). RHAMM is not generally overexpressed in normal tissues, but is upregulated in a number of cancers and is associated with poor clinical outcome. However, the role of RHAMM in OC progression is unknown. Hypothesis: Elevated RHAMM levels promote OC progression and represent a novel urinary biomarker for OC. Procedures: Measuring RHAMM expression in OC cell protein lysate and conditioned media (CM) was done by western blot (WB) and densitometry. With institution approval, patient cohort urine from male and female healthy controls and patients with cancer of the ovary, lung, breast, prostate, cervix, colorectum, skin, endometrium, head and neck, and brain were acquired from the H. Lee Moffit Cancer Center at the University of South Florida. Enzyme-linked immunosorbent assay (ELISA) designed for RHAMM detection, was used to measure patient urine expression levels. Results: Cultured OC cells overexpress and secrete RHAMM. Using OC, SV-40 large T-antigen transfected human ovarian surface epithelial (IOSE) cells (HIO118, IOSE-121) and human dermal fibroblasts (HDF), we found &amp;gt;2x the expression of RHAMM protein in BC (MCF7) and OC (OVCAR5, OV2008, C13) cells by WB. WB of CM indicated &amp;gt;3x RHAMM levels secreted by OC compared to IOSE cells. Urinary levels of RHAMM are elevated in OC patients. Since RHAMM is not an integral membrane protein, but rather loosely tethered to the plasma membrane, we determined whether RHAMM could be detected in bodily fluids of OC patients. ELISA showed detection of urinary RHAMM protein levels averaged 0.140 ng/ml (n = 26) in healthy patient controls whereas OC patients averaged 0.411 ng/ml (n = 132). Conclusions: Prior to this study, overexpression and secretion of RHAMM by OC cells had not been reported. This has expanded our knowledge of OC etiology by delineating a functional role for RHAMM-driven OC progression. Validating elevated urinary levels of RHAMM suggests it is a potential diagnostic marker alone or in combination with other markers for OC detection. Further, the ability to monitor OC through the course of disease using urinary RHAMM levels could indicate recurrent disease or therapeutic efficacy. Understanding RHAMM expression in OC may lead to a possible diagnostic/prognostic indicator or therapeutic target for OC. Citation Format: Stephanie Buttermore, Patricia Kruk. Hyaluronan-mediated motility receptor (RHAMM) 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 444.
Abstract 1186: Inhibition of topoisomerase 2β sensitizes acute myeloid leukemia cells to ATRA induced apoptosis independent of the MAPK/ERK pathway
Authors: Eric J. Norris, Amy Dorszynski, Aaron Lucander, Darla Destephanis, Ram Ganapathi, Mahrukh Ganapathi
Journal: Cancer Research (2016)

Abstract Pharmacologic inhibition or molecular down-regulation of topoisomerase 2β (TOP2β) potentiates all trans retinoic acid (ATRA)-induced differentiation and apoptosis in acute myeloid leukemia (AML) cells. Since ATRA-induced myeloid differentiation involves activation of the MAPK/ERK signaling pathway and aberrant activation of MAPK/ERK is frequently observed in AML we tested the role of this pathway in modulating the cellular effects of ATRA when TOP2β is inhibited with the bisdioxopiperazines, ICRF 187 (dexrazoxane, Zinecard™) or ICRF193. Treatment of HL-60 AML (M2) cells with ATRA increased the percentage of differentiated cells, as assessed by the nitroblue tetrazolium reduction assay, and enhanced levels of phosphorylated ERK. Paradoxically, while combination treatment with ATRA/ICRF187 enhanced differentiation (P&amp;lt;0.05), ERK phosphorylation was attenuated compared to treatment with ATRA alone. Moreover, pretreatment with the MEK inhibitor PD98059, which completely blocks ATRA-induced differentiation and ERK phosphorylation, only partially blocked (46% reduction) differentiation induced by ATRA/ICRF187 (P&amp;lt;0.01) and had no effect on ATRA/ICRF187-induced apoptosis. In agreement with this observation, combination treatment with ATRA/ICRF187 induced apoptosis (P&amp;lt;0.05) in KG-1 (M1) AML cells and primary AML cells from patients, that do not phosphorylate ERK or differentiate in response to ATRA treatment. In summary, our data suggest that inhibition of TOP2β sensitizes AML cells to ATRA induced differentiation and apoptosis primarily via an ERK-independent mechanism. Further, combination treatment ATRA and ICRF187 may be clinically relevant to overcome ATRA resistance in AML patients with a deregulated MAPK/ERK signaling pathway. Citation Format: Eric J. Norris, Amy Dorszynski, Aaron Lucander, Darla Destephanis, Ram Ganapathi, Mahrukh Ganapathi. Inhibition of topoisomerase 2β sensitizes acute myeloid leukemia cells to ATRA induced apoptosis independent of the MAPK/ERK pathway. [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 1186.
Chimeric Antigen Receptor Transgenic, T Cell Receptor/CD3 Negative Monospecific T Cells Generated from Cord Blood CD34 Positive Cells
Authors: Yasmine van Caeneghem, Glenn Goetgeluk, Karin Weening, Greet Verstichel, Sarah Bonte, Tom Taghon, Georges Leclercq, Fritz Offner, Hinrich Abken, Tessa Kerre, Bart Vandekerkhove
Journal: Blood (2015)
Abstract 2738: Establishing an <i>in vitro</i> cell culture model for studying the function of FAM190A deletions
Authors: Eric S. Calhoun
Journal: Cancer Research (2016)

Abstract A growing number of studies have reported a variety of genetic alterations to FAM190A (CCSER1) in cancer. Interestingly, a large percentage of these are focused on deleting downstream exons producing in-frame arrangements for this protein. An analysis of coding sequences reveals that regions of FAM190A are highly conserved throughout the N-terminus, however, with no recognizable protein domains. Published immunofluorescence and shRNA knockdown studies have since suggested that FAM190A is localized to the midbody during cytokinesis and may function in maintaining genome stability. Unfortunately, attempts to overexpress FAM190A were not successful by these authors. The aim of our current study was to try to generate an in vitro model that would allow us to examine the effect of a C-terminal deletion on cellular division and FAM190A's ability to associate with the spindle and/or midbody structures. To accomplish this, full length FAM190A and a deletion mutant construct lacking exons 8-11 were separately cloned into mammalian expression vectors that include a N-terminal HaloTag Fusion marker and a modified CMV promoter. Current studies are focused on introducing these constructs into the pancreatic cancer cell line, PL-5, to generate FAM190A stably expressing cell lines. Citation Format: Eric S. Calhoun. Establishing an in vitro cell culture model for studying the function of FAM190A deletions. [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 2738.
Rasip1-Mediated Rho GTPase Signaling Regulates Blood Vessel Tubulogenesis via Nonmuscle Myosin II
Authors: David M. Barry, Yeon Koo, Pieter R. Norden, Lyndsay A. Wylie, Ke Xu, Chonlarat Wichaidit, D. Berfin Azizoglu, Yi Zheng, Melanie H. Cobb, George E. Davis, Ondine Cleaver
Journal: Circulation Research (2016)

Vascular tubulogenesis is essential to cardiovascular development. Within initial vascular cords of endothelial cells, apical membranes are established and become cleared of cell-cell junctions, thereby allowing continuous central lumens to open. Rasip1 (Ras-interacting protein 1) is required for apical junction clearance, as well as for regulation of Rho GTPase (enzyme that hydrolyzes GTP) activity. However, it remains unknown how activities of different Rho GTPases are coordinated by Rasip1 to direct tubulogenesis.The aim of this study is to determine the mechanisms downstream of Rasip1 that drive vascular tubulogenesis.Using conditional mouse mutant models and pharmacological approaches, we dissect GTPase pathways downstream of Rasip1. We show that clearance of endothelial cell apical junctions during vascular tubulogenesis depends on Rasip1, as well as the GTPase Cdc42 (cell division control protein 42 homolog) and the kinase Pak4 (serine/threonine-protein kinase 4). Genetic deletion of Rasip1 or Cdc42, or inhibition of Pak4, all blocks endothelial cell tubulogenesis. By contrast, inactivation of RhoA (Ras homologue gene family member A) signaling leads to vessel overexpansion, implicating actomyosin contractility in control of lumen diameter. Interestingly, blocking activity of NMII (nonmuscle myosin II) either before, or after, lumen morphogenesis results in dramatically different tubulogenesis phenotypes, suggesting time-dependent roles.Rasip1 controls different pools of GTPases, which in turn regulate different pools of NMII to coordinate junction clearance (remodeling) and actomyosin contractility during vascular tubulogenesis. Rasip1 promotes activity of Cdc42 to activate Pak4, which in turn activates NMII, clearing apical junctions. Once lumens open, Rasip1 suppresses actomyosin contractility via inhibition of RhoA by Arhgap29, allowing controlled expansion of vessel lumens during embryonic growth. These findings elucidate the stepwise processes regulated by Rasip1 through downstream Rho GTPases and NMII.
CMV-Specific Cytokine-Induced Killer Cells Comprise Concomitant Cytotoxicity Against Leukemia and Cytomegalovirus
Authors: Verena Pfirrmann, Sarah Oelsner, Eva Rettinger, Sabine Huenecke, Jindrich Cinatl, Winfried Wels, Thomas Klingebiel, Peter Bader
Journal: Blood (2014)
Abstract LB-003: Androgen-regulated proteome reveals a therapeutically relevant androgen receptor coactivator target in prostate cancer
Authors: Mohammad Asim, Charlie Massie, Anne Warren, Katarina Luko, Brinder Chohan, Suraj Menon, Ajoeb Baridi, Folake Orafidiya, Wanfeng Zhao, Carlos Escriu, Hisham Mohammed, Clive D’Santos, Xiaoping Yang, Chris Taylor, Arham Qureshi, Kate Watt, Vincent Zecchini, Luke Selth, Scott Dehm, Ian Mills, Jason Carroll, Wayne Tilley, Iain McEwan, Aria Baniahmad, David Neal
Journal: Cancer Research (2016)

Abstract Resistance to androgen deprivation therapy (ADT) and the development of castration resistant prostate cancer (CRPC) remains a major challenge in the treatment of advanced prostate cancer (PCa). Elucidation of resistance mechanisms leading to CRPC is essential to develop novel therapeutic interventions. Using a systems biology approach, we interrogated the androgen-regulated proteome and identified a mitotic Kinase as a novel androgen regulated kinase in PCa. The kinase was shown to be androgen-regulated in PCa and its nuclear localisation significantly increased in CRPC and was associated with biochemical relapse. Interestingly, the Kinase interacted directly with the amino terminus transactivation and carboxy terminus ligand binding domain of androgen receptor (AR), resulting in stabilisation of AR protein and its activity. The AR-driven global transcriptional program was regulated by this coactivator kinase including pathways involved in tumour invasion and metastasis. The inhibition of the kinase function decreased AR levels and activity, and slowed growth of PCa cell lines and human PCa explants. Thus the mitotic kinase is a novel AR-Stablised kinase with potential for clinical applications as both a candidate biomarker of PCa progression and a therapeutic target in advanced disease. Citation Format: Mohammad Asim, Charlie Massie, Anne Warren, Katarina Luko, Brinder Chohan, Suraj Menon, Ajoeb Baridi, Folake Orafidiya, Wanfeng Zhao, Carlos Escriu, Hisham Mohammed, Clive D’Santos, Xiaoping Yang, Chris Taylor, Arham Qureshi, Kate Watt, Vincent Zecchini, Luke Selth, Scott Dehm, Ian Mills, Jason Carroll, Wayne Tilley, Iain McEwan, Aria Baniahmad, David Neal. Androgen-regulated proteome reveals a therapeutically relevant androgen receptor coactivator target in prostate 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 LB-003.
International Scale (IS)-Standardized BCR-ABL1 Digital Polymerase Chain Reaction (dPCR) Assays Using ABL1, BCR, and GUS Control Genes for Measuring Deep Molecular Response (MR) in Chronic Myeloid Leukemia (CML)
Authors: Alice Huang, Jennifer Salcius, Connie Wong, Stephane Wong, Sha-Sha Wang
Journal: Blood (2015)
Abstract 1736: Physical activity, sitting time and prostate cancer specific mortality: The Cancer Prevention Study II Nutrition Cohort
Authors: Ying Wang, Eric J. Jacobs, Ted Gansler, Marjorie L. McCullough, Victoria L. Stevens, Susan M. Gapstur, Alpa V. Patel
Journal: Cancer Research (2016)

Abstract Objective: To investigate the associations of pre- and post-diagnostic recreational physical activity, and sitting time with prostate cancer specific mortality (PCSM) among men diagnosed with non-metastatic prostate cancer in the Cancer Prevention Study II Nutrition Cohort. Methods: 10,067 men were diagnosed with non-metastatic prostate cancer between enrollment in 1992 or 1993 and June 2011, of whom 600 died of prostate cancer during follow-up through 2012. Multivariable-adjusted Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of self-reported pre-diagnostic and post-diagnostic physical activity and sitting time with PCSM. Results: Compared with engaging in fewer than 3.5 metabolic equivalent (MET) hours per week of recreational physical activity, 17.5 or more MET hours (equivalent to 5 hours of walking) per week was associated with 30% lower risk of PCSM (HR: 0.70, 95% CI: 0.54-0.92) for pre-diagnostic, and with 34% lower risk (HR: 0.66, 95% CI: 0.46-0.93) for post-diagnostic recreational physical activity. Among men with walking as the only form of leisure time physical activity, walking 4 hours or more per week before diagnosis was associated with lower risk of PCSM (for 4-6 hours, HR: 0.65, 95% CI: 0.46-0.91; for 7+ hours, HR: 0.60, 95% CI: 0.41-0.88), while no statistically significant association was observed with walking after diagnosis. Sitting time was not associated with PCSM. Conclusion: Higher recreational physical activity levels before and after diagnosis may improve prognosis in men diagnosed with non-metastatic prostate cancer. These results additional support that prostate cancer survivors should adhere to physical activity guidelines and that physicians should promote adopting a physically active lifestyle to prostate cancer survivors. Citation Format: Ying Wang, Eric J. Jacobs, Ted Gansler, Marjorie L. McCullough, Victoria L. Stevens, Susan M. Gapstur, Alpa V. Patel. Physical activity, sitting time and prostate cancer specific mortality: The Cancer Prevention Study II Nutrition Cohort. [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 1736.
Abstract 15582: Cardiovascular Risk Factors in Breast Cancer Survivors: Analysis of NHANES 1999-2012
Authors: Ahmed Hassoon, Lawrence Appel, Nisa Maruthur, Hsin-Chieh Yeh
Journal: Circulation (2015)

Introduction: There are 2.8 million breast cancer survivors in the U.S. With improved survival from breast cancer, cardiovascular disease has emerged as one of the leading causes of morbidity and mortality. However, few studies have assessed CVD risk factors among breast cancer survivors. Methods: We analyzed the National Health and Nutrition Examination Survey (NHANES) 1999-2012 to assess CVD risk factors, as defined by AHA/ACC, in adult women with and without a history of breast cancer. Results: A total of 537 women, age 20 and older, with breast cancer history and 17,902 women without cancer history were included in the analysis. Among women with breast cancer, the mean (SE) age at diagnosis was 56y (0.81). 32.8% had the diagnosis &lt; 5 years; 39.9% survived more than 10 years after diagnosis. Compared to women without cancer, the breast cancer survivors were older (mean age 65 (0.80) vs 46 (0.23)), and more likely to be white (84.2% vs. 67.6%) (both p&lt;0.0001), but with similar education level. In stratified analyses, after adjustment for age, black women with breast cancer compared to black women without cancer history had significantly higher SBP (128.9 vs 124.5, p=0.003), and were more likely to be obese, have hypertension and diabetes (Table). In contrast, there were no significant differences in CVD risk factors in non-black women. There were no differences in lipids profiles between women with and without breast cancer. Conclusion: CVD risk factors are very prevalent in breast cancer survivors. Improving cardiovascular health through lifestyle change and preventive strategies, particularly in black women with breast cancer, is a public health priority.
P0804 : Efficacy of sofosbuvir-based treatment regimens in HIV/HCV co-infected patients after liver transplantation: The ANRS CO23 CUPILT study
Authors: T.M. Antonini, A. Coilly, S. Radenne, A. Veislinger, D. Botta-Fridlund, F. Durand, P. Houssel-Debry, N. Kamar, V. Canva, P. Perre, I. Bertucci, J. Dumortier, V. Leroy, D. Samuel, G.-P. Pageaux, J.-C. Duclos-Vallee
Journal: Journal of Hepatology (2015)
Abstract 204: Disruption of the RACK1/PP2A complex results in a decrease in the adhesion, proliferation, migration and invasion capabilities of breast cancer cells
Authors: Maeve Kiely, Rosemary O’Connor, David Adams, George S. Baillie, Patrick A. Kiely
Journal: Cancer Research (2016)

Abstract Conflicting reports implicate the scaffolding protein RACK1 in the progression of breast cancer. PP2A has a well-established role as a tumour suppressor within signalling pathways but is also known to play a pro-carcinogenic role in certain circumstances [1]. RACK1 has been identified as a direct binding partner of PP2A to regulate cell migration and stabilize PP2A activity [2]. Our objective was to further characterise the interaction between PP2A and RACK1 in breast cancer cells. The PP2A holoenzyme is assembled in MCF-7 cells and we found that both the C subunit and A subunit of PP2A are assembled on the RACK1 scaffold. We used immobilized peptide arrays representing the entire PP2A-Catalytic protein to identify amino acids on the C subunit of PP2A that are required for the binding of RACK1. Once identified, these sites were mutated and expressed in the context of the full length PP2A C subunit protein and stable cell lines were generated. When the RACK1/PP2A interaction was disrupted, cells exhibited reduced PP2A phosphatase activity, confirming the role for RACK1 in stabilizing PP2A activity. We used the stable cell lines to determine that disruption of the RACK1/PP2A complex also reduces the adhesion, proliferation, migration and invasion of this breast cancer cell model. The work has significantly advanced our understanding of the RACK1/PP2A complex and indicates a pro-carcinogenic role for the RACK1/PP2A complex. This work has highlighted a novel mechanism to target PP2A activity and may provide a potential therapeutic target in the treatment of breast cancer. 1. Kiely, M. and P.A. Kiely, PP2A: The Wolf in Sheep's Clothing? Cancers, 2015. 7(2): p. 648-669. 2. Kiely, P.A., et al., Tyrosine 302 in RACK1 is essential for insulin-like growth factor-I-mediated competitive binding of PP2A and β1 integrin and for tumor cell proliferation and migration. Journal of Biological Chemistry, 2008. 283(34): p. 22952-22961. Citation Format: Maeve Kiely, Rosemary O’Connor, David Adams, George S. Baillie, Patrick A. Kiely. Disruption of the RACK1/PP2A complex results in a decrease in the adhesion, proliferation, migration and invasion capabilities of 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 204.
Abstract 4854: Bazedoxifene inhibits ESR1 somatic mutants with improved potency compared to tamoxifene and raloxifene
Authors: Sean W. Fanning, Venkat Dharmarajan, Christopher G. Mayne, Weiyi Toy, Kathryn E. Carlson, Teresa A. Martin, Jason Nowak, Jerome Nwachukwu, David J. Hosfield, Emad Tajkhorshid, Sarat Chandarlapaty, Patrick Griffin, Yang Shen, John A. Katzenellenbogen, Geoffrey L. Greene
Journal: Cancer Research (2016)

Abstract Despite continued administration of antiestrogen therapies, approximately 50% of all estrogen receptor alpha (ERalpha) positive breast cancers will present new metastatic lesions. The acquisition of secondary hormone-resistant metastatic breast cancers represents a significant clinical barrier towards life-long disease free survival for the patient. Somatic mutations to the ERalpha gene (ESR1) Y537S and D538G represent a novel mechanism of acquired antiestrogen resistance because they confer hormone-free transcriptional activity and reduced selective estrogen receptor modulator (SERM) and selective estrogen receptor degrader (SERD) potency. Fulvestrant, a SERD, was the only molecule that could completely ablate mutant ERalpha activity. Unfortunately, fulvestrant possesses poor pharmacologic profiles that limit its therapeutic utility. Bazedoxifene (BZA) is a potent mixed SERM/SERD and has improved pharmacokinetics and oral bioavailability compared to fulvestrant. We show that BZA inhibits Y537S and D538G ESR1 somatic mutation transcriptional activity with a greater potency than the SERMs 4-hydroxytamoxifen (TOT) and raloxifene (RAL). Further investigations into the biophysical and structural basis for BZA action suggest that BZA increases the conformational dynamics of helix 12, a key molecular switch that governs ERalpha action resulting in SERD-like properties and improved potency against the somatic mutations compared to TOT and RAL. Citation Format: Sean W. Fanning, Venkat Dharmarajan, Christopher G. Mayne, Weiyi Toy, Kathryn E. Carlson, Teresa A. Martin, Jason Nowak, Jerome Nwachukwu, David J. Hosfield, Emad Tajkhorshid, Sarat Chandarlapaty, Patrick Griffin, Yang Shen, John A. Katzenellenbogen, Geoffrey L. Greene. Bazedoxifene inhibits ESR1 somatic mutants with improved potency compared to tamoxifene and raloxifene. [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 4854.