bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 21: Survival prognostic significance of TNFRII, TGFa, TIMP1 & CRP in high-risk melanoma patients.
Authors: Tarhini Ahmad A. , Lin Yan , LaFramboise William A. , Lee Sandra , Kirkwood John 
Published: August 2014

Abstract
Background:
The E1694 trial tested the GM2-KLH-QS21 (GMK) vaccine versus high dose interferon-alpha2b as adjuvant therapy for patients with operable high-risk stage IIB/III melanoma in relation to relapse-free survival (RFS) and overall survival (OS). Multiplex analysis of candidate serum analytes utilizing banked specimens from patients participating in this trial was evaluated to develop biomarkers of prognostic or therapeutic predictive value.
Methods:
The Aushon Multiplex Platform was used to simultaneously quantitate the serum levels of 115 candidate analytes selected based on previous data. Univariate proportional hazard (PH) model was used to assess the association between each marker and OS or RFS. The Benjamini and Hochberg's method was used to adjust for multiple testing. Baseline serum samples from 40 patients treated with the GMK vaccine were analyzed. The least absolute shrinkage and selection operator proportional hazard regression (LASSOPH) was used to select markers that are most informative for RFS and OS. We then fit the regular PH models using the markers selected by the LASSOPH. The survival ROC analysis was used to evaluate the ability of the models to predict 1 year RFS and 5 year OS. Leave-one-out cross validations (LOOCVs) were used to avoid over fitting.
Results:
A panel of four markers, Tumor Necrosis Factor alpha Receptor II (TNFRII), Transforming Growth Factor alpha (TGFa), Tissue Inhibitor of Metalloproteinases 1 (TIMP1), and C-reactive protein (CRP), at baseline was found to be most informative to OS after GMK vaccine treatment (high serum levels correlate with worse prognosis). The dichotomized risk score based on the four markers can separate the OS curves well (log rank test p-value=0.0005). When using the 4 marker PH model to predict the 5 year OS, we achieved an AUC of 89% (cross validated AUC=72%). High baseline TNFRII was also identified as the most informative marker of worse RFS after GMK vaccine. The RFS of patients with high (above median) baseline TNFRII was significantly lower than that of patients with low (below median) baseline TNFRII (log rank test p-value=0.01).
Conclusions:
Our modeling analysis yielded a panel of four serum biomarkers that is significantly prognostic of survival in patients with high-risk melanoma and warrants further investigation.
Citation Format: Ahmad A. Tarhini, Yan Lin, William A. LaFramboise, Sandra Lee, John Kirkwood. Survival prognostic significance of TNFRII, TGFa, TIMP1 & CRP in high-risk melanoma patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 21. doi:10.1158/1538-7445.AM2013-21
Abstract 210: GPR56 regulates the turnover of tissue transglutaminase and tumor growth in melanoma.
Authors: Yang Liquan , Mohanty Sonali , Corson Nancy , Xu Lei 
Published: August 2014

Abstract
Biochemical and biophysical properties of extracellular matrix (ECM) regulate multiple aspects of cancer cell behavior during tumor progression. The mechanisms of these regulations are not well defined. We previously reported that an atypical G protein-coupled receptor (GPCR), GPR56, inhibited melanoma growth and metastasis and its N-terminus binds to tissue transglutaminase, TG2, a major cross-linking enzyme in ECM. We thus postulated that GPR56 might suppress melanoma progression by influencing ECM properties through its interaction with TG2. To test this, we examined the effects of GPR56 on melanoma growth in the presence or absence of TG2, using the immunodeficient Tg2+/+ or Tg2−/− mice. Our results showed that the crosslinking enzyme, TG2, promoted melanoma growth, but this tumor-promoting effect was antagonized by GPR56. The mechanisms of this antagonism were revealed through a series of immunohistochemical and biochemical analyses. In GPR56-expressing cells, the extracellular TG2 was internalized by GPR56 and subsequently degraded in a lysome-dependent manner, resulting in a down-regulation of TG2 in ECM. This down-regulation of TG2 by GPR56 led to changes in the deposition of TG2 and other matrix proteins in melanomas and a reduction in melanoma growth. Taken together, we present evidence that a surface receptor on melanoma cells, GPR56, regulates the turnover of the crosslinking enzyme, TG2, in the tumor microenvironment, leading to changes in ECM deposition and melanoma progression.
Citation Format: Liquan Yang, Sonali Mohanty, Nancy Corson, Lei Xu. GPR56 regulates the turnover of tissue transglutaminase and tumor growth in melanoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 210. doi:10.1158/1538-7445.AM2013-210
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 2100: Preclinical evaluation of PF-04691502 in nasopharyngeal carcinoma.
Authors: Loong Herbert H. , Wong Eric C H , Hui Connie W C , Lau Cecilia P Y , Hui Edwin P. , Ma Brigette B Y , Chan Anthony T C 
Published: August 2014

Abstract
Nasopharyngeal carcinoma (NPC) is common in Southeast Asia. PF-04691502 (PF) is a novel potent dual inhibitor of PI3K/mTOR capable of inhibiting downstream effectors Akt, S6 and 4E-BP1, resulting in suppression of protein synthesis and cell survival. Five NPC cell lines include two well differentiated cell lines CNE-1 and HK1, two poorly differentiated NPC cell lines CNE-2 and HONE-1, and an undifferentiated NPC cell line C666-1 were selected for this preclinical study. All cell lines expressed basal level of Akt and p70S6K in both phosphorylated and total forms. The cytotoxicity of PF on NPC was evaluated by MTT assay. Cells were incubated in PF with increasing concentration (0.1nM, 50nM, 100nM, 200nM, 500nM, 1μM and 10μM) in culture medium for either 48 hours or 72 hours. Maximum growth inhibition was achieved in over 80% in 72 hours of PF incubation. The IC50 of all cell lines were in hundred nanomolar range (CNE-1 = 276nM, CNE-2 = 84nM, HK1 = 121nM, HONE-1 = 157nM and C666-1 = 395nM). Two most sensitive cell lines (CNE-2 and HK1) together with the least sensitive one (HONE-1) were selected to further evaluate the effect of PF on cell cycle, apoptosis and Akt signaling. Cells treated with either 100nM or 500nM PF for 6 hours and 24 hours were evaluated by cell cycle analysis and G0/G1 arrest was observed at 24 hour time point. Apoptotic effect was indicated by increasing cleaved PARP expression in which 500nM PF treatment for 24 hours induced apoptosis in CNE-2 and HK1 but not in HONE-1. At 48 hours, a lower dose of PF at 100nM could induce apoptosis in all NPC cell lines. The expression of pi-mTOR, pi-p70S6K, pi-Akt(S473), pi-Akt(T308), pi-S6 and pi-4EBP1 was inhibited in by PF, suggesting its effectiveness in anti-proliferation and inhibition of protein synthesis. Antitumor activity was observed in NPC xenograft model after 2 weeks of 10mg/kg PF administration to tumor bearing female athymic nude mice. Both tumor volume and tumor weight in the treatment group were significantly smaller and lighter than that in vehicle group (3.17cm3 vs. 5.58cm3 at 18 days, p=0.005 and 146mg vs. 284mg, p=0.001 respectively) while the body weight between groups were comparable, suggesting this working dose was well-tolerated. The beneficial effects of PF-09641502 in both in vitro and in vivo studies for NPC warrant a further investigation.
Acknowledgement: This work is supported by an independent research grant from Pfizer.
*Co-authorship
Citation Format: Herbert H. Loong, Eric C H Wong, Connie W C Hui, Cecilia P Y Lau, Edwin P. Hui, Brigette B Y Ma, Anthony T C Chan. Preclinical evaluation of PF-04691502 in nasopharyngeal carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2100. doi:10.1158/1538-7445.AM2013-2100
Abstract 2102: Investigational agent 5F 203 modulates apoptotic regulatory gene expression and induces lysosomal membrane permeabilization in breast cancer cells.
Authors: Brantley Eileen J. , Thorne Gabriell , Daly Devin , Zylstra Dain , McLean Lancelot 
Published: August 2014

Abstract
Despite advances in targeted therapeutic agents for women with breast cancer that either express estrogen receptor (ER) alpha or over-expresses human epidermal growth factor receptor 2 (Her2), nearly 40,000 women die each year due to this malignancy. An investigational anticancer agent 2-(4-amino-3-methylphenyl)-5-benzothiazole (5F 203) potently inhibits the growth of breast cancer cells irrespective of either ER or Her2 status. In our current studies we used the Annexin V/PI assay to determine that 5F 203 induced a dose-dependent increase in the percentage of ER/Her2-positive T47D cells and ER/Her2-negative MDA-MB-468 breast cancer cells in early apoptosis. Cell death was not entirely caspase-dependent as pretreatment with pan-caspase inhibitor z-VAD-fmk only partially suppressed apoptosis. A pathway specific PCR-array revealed the ability for 5F 203 to increase the mRNA expression of pro-apoptotic genes bcl-2-antagonist/killer 1 (BAK1) and lymphotoxin alpha (LTA). Using the Acridine Orange assay, we found that 5F 203-mediated cell death was associated with lysosomal membrane permeabilization in both T47D and MDA-MB-468 cells. Additionally, we determined using the Cathepsin B assay that 5F 203 promoted the release of cathepsin B from the lysosomes in both breast cancer cell types. These data indicate 5F 203 upregulates BAK1 and LTA expression and promotes lysosomal cell death triggering the release of cathepsin B in breast cancer cells to confer its anticancer action.
Citation Format: Eileen J. Brantley, Gabriell Thorne, Devin Daly, Dain Zylstra, Lancelot McLean. Investigational agent 5F 203 modulates apoptotic regulatory gene expression and induces lysosomal membrane permeabilization in breast cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2102. doi:10.1158/1538-7445.AM2013-2102
Abstract 2105: Advanced glycation end products of type I collagen promote cell proliferation and resistance against doxorubicin in HT-1080 cancer cells.
Authors: Saby Charles , EL Btaouri Hassan , Van Gulick Laurence , Guilbert Marie , Jeannesson Pierre , Morjani Hamid 
Published: August 2014

Abstract
Resistance to apoptosis and chemotherapy is a critical factor in cancer recurrence and patient relapse. Extracellular matrix via its receptors, the integrins, has emerged as a major pathway contributing to cancer cell survival and resistance to chemotherapy (Aoudjit and Vuori, Chemother Res Pract. 2012;2012:283181). However, the effects of extracellular matrix advanced glycation end products (AGE) on cell proliferation and sensitivity to chemotherapy is not well established. In this study, we investigated whether type I collagen and particularly its AGE are involved in cell proliferation and resistance to doxorubicin in human fibrosarcoma HT-1080 cancer cells.
Type I collagen was extracted from rats tail tendons (10 days, 8 and 96 weeks-old) and prepared as already described (Millerot-Serrurot et al., 2010, Cancer Cell Int, 13: 10-26). First, we characterized the glycation pattern of the different collagens using SDS-PAGE electrophoresis and fluorescence spectroscopy. A significant increase in AGE level has been observed in collagen extracted from 8 and 96 weeks-old rats. AGE level was significantly higher in collagen extracted from 96 weeks-old rats when compared to 8 weeks-old ones. Only collagen extracted from 96 weeks-old rats was able to induce 3-fold increase in proliferation of HT-1080 cells. Western-blot analysis showed that activation of MAPK/ERK, but not PI3K/AKT, was required for collagen AGE mediated cell proliferation. The MAPK/ERK inhibitor U0126 abolished this effect. Both collagens were able to inhibit doxorubicin-induced apoptosis in HT-1080 cells. Moreover, protection against apoptosis was significantly higher in the presence of collagen extracted from 96 weeks-old rats.
Our data suggest extracellular matrix AGE signalling as an important promoter of cancer cell proliferation and that this pathway may contribute to a new mechanism of drug resistance.
Citation Format: Charles Saby, Hassan EL Btaouri, Laurence Van Gulick, Marie Guilbert, Pierre Jeannesson, Hamid Morjani. Advanced glycation end products of type I collagen promote cell proliferation and resistance against doxorubicin in HT-1080 cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2105. doi:10.1158/1538-7445.AM2013-2105
Abstract 2109: Activation of multiple cellular stresses by the NO generating antineoplastic agent JS-K.
Authors: Kaur Imit , Terrazas Moises , Kosak Ken M. , Shami Paul J. 
Published: August 2014

Abstract
The NO prodrug O2-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate or JS-K is active against acute myeloid leukemia (AML), multiple myeloma, hepatocellular carcinoma, prostate cancer, glioma and non-small lung cancer. We have developed a nanoscale micelle formulation for JS-K (P123/JS-K) using Pluronic® P123 polymers to stabilize and solubilize the drug. In the present study, the mechanism of action of JS-K was investigated. We speculated that, being a NO-releasing drug, JS-K causes nitrosative/oxidative stress. We therefore hypothesized that JS-K causes multiple stress responses that ultimately trigger apoptosis in the cell. We also hypothesized that JS-K affects the “intrinsic component” (defined as cell cycle, survival and stress pathways in the cell) of leukemic cells.
In this work, using human myeloid leukemia HL-60 cells, we studied the effect of JS-K on two major cellular stresses, namely ER stress and nitrosative/oxidative stress. On treating HL-60 cells with 5μM JS-K formulated in DMSO (JS-K) or P123/JS-K for 4-8 hours, activation of both GRP-78 and CHOP (markers of ER stress) was observed using western blot analysis. ER stress could also be triggered by phosphorylation of JNK protein. Again, using western blot analysis, JNK phosphorylation was observed when HL60 cells were treated with JS-K or P123/JS-K for 4-6 hours. Oxidative stress was studied by quantifying intracellular levels of reactive oxygen/reactive nitrogen species (ROS/RNS) using the ROS/RNS sensitive fluorophore 5-(and-6)-chloromethyl-2’-7’-dichlorodihydrofluorescein diacetate. Treatment of HL-60 cells with 5μM of JS-K or P123/JS-K for 30, 60 or 120 minutes lead to increased levels of ROS/RNS.
These experiments show that JS-K activates the intrinsic component of cell death by producing ER stress and oxidative stress. JS-K is at an advanced stage of pre-clinical development. Its novel and multiple mechanisms of action make it an attractive therapy for the treatment of AML and other malignancies.
Citation Format: Imit Kaur, Moises Terrazas, Ken M. Kosak, Paul J. Shami. Activation of multiple cellular stresses by the NO generating antineoplastic agent JS-K. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2109. doi:10.1158/1538-7445.AM2013-2109
Abstract 2117: Lasonolide A-induced premature chromosome condensation is mediated by the proto-oncogene c-Raf (Raf1).
Authors: Zhang Yong-Wei , Josse Rozenn , Ghosh Arun , Luo Ji , Pommier Yves 
Published: August 2014

Abstract
Lasonolide A (LSA) was originally identified in a screen for novel antitumor compounds from marine organisms with high and selective cytotoxicity against mesenchymal cancer cells. We recently demonstrated that LSA induces rapid and reversible premature chromosome condensation (PCC) associated with profound epigenetic alterations in different cell types, independently of cyclin-dependent kinases activation. In order to identify cellular targets involved in LSA sensitivity, we used a pool of kinases and phosphatases shRNAs in the human colon carcinoma HCT-116 cell line. Among the genes whose inactivation promotes the survival of LSA-treated cells, we observed an enrichment of genes involved in mitotic functions including Raf1, a well-known serine-threonine kinase regulating cell proliferation and survival. LSA induces the rapid and reversible phosphorylation of Raf1 on Ser338 in a time- and a dose-dependent manner. To establish a causal relationship between LSA-induced PCC and Raf1, we first used siRNA targeting Raf1. Knocking-down Raf1 decreased LSA-induced PCC. Furthermore, mouse embryonic fibroblasts depleted in Raf1 were found resistant to LSA-induced PCC. Our results suggest a novel role of Raf1 in chromatin condensation. They also demonstrate that the target of LSA affects the c-Raf pathway and a novel mechanism of action of LSA as an effective inducer of PCC and potential novel anticancer agent.
Citation Format: Yong-Wei Zhang, Rozenn Josse, Arun Ghosh, Ji Luo, Yves Pommier. Lasonolide A-induced premature chromosome condensation is mediated by the proto-oncogene c-Raf (Raf1). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2117. doi:10.1158/1538-7445.AM2013-2117
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 2122: The role of Rho GTPase in cell stiffness and cisplatin resistance in ovarian cancer cells.
Authors: Santiskulvong Chintda , Sharma Shivani , Bentolila Laurent , Rao Jian Y. , Gimzewski James , Dorigo Oliver 
Published: August 2014

Abstract
Introduction: Cell stiffness (Young's E modulus), as measured via Atomic Force Microscopy (AFM) is a newly recognized characteristic of cancer cells. We previously demonstrated that cisplatin-resistant ovarian cancer cells have a stiffer cell membrane as compared to their syngeneic cisplatin-sensitive counterpart, and that cisplatin increases cell stiffness in cisplatin-sensitive cells. Here we examine the role of Rho GTPase in cell stiffness and cisplatin resistance.
Experimental Procedures: Prior to AFM analysis, cells were stained with Annexin V-FLUOS and only non-apoptotic cells were chosen for measurements. Cell stiffness was measured via AFM on live cells in physiological buffer. The actin cytoskeleton was visualized using phalliodin-ATTO 647N. Cells were imaged with a Leica TCS SP5 STED confocal system or a Nikon Eclispe 90i. Cisplatin sensitivity was determined via the XTT [2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide inner salt] cell viability assay. A nonlinear regression curve fit (one phase exponential decay) was used to analyze cisplatin dose response experiments and determine the IC50 (GraphPad Prism). Rho inhibition and activation were accomplished using Rho Inhibitor I and Rho Activator II, respectively (Cytoskeleton, Inc.).
Results: The cisplatin IC50 of cisplatin-sensitive (A2780, OVCAR5, SKOV3) and cisplatin-resistant (CP70, OVCAR5-CisR, SKOV3-CisR, RMG-1) cells correlated with Young's E modulus, with increasing IC50 corresponding to a stiffer cell phenotype. Cells that are resistant to cisplatin displayed an actin cytoskeleton that consisted of long stress fibers that spanned the width of the cell. Rho inhibition in CP70 and OVCAR5-CisR cells abolished this network of actin stress fibers, decreased cell stiffness, and increased cisplatin sensitivity. In contrast, Rho activation in A2780 and OVCAR5 cells induced the reorganization of the actin cytoskeleton into long stress fibers, increased cell stiffness, and decreased cisplatin sensitivity. We demonstrated previously that cisplatin increases cell stiffness in cisplatin-sensitive OVCAR5 cells, and here we show that cisplatin induces actin stress fiber formation in these cells.
Conclusions: Rho-mediated actin stress fiber formation increases cell stiffness and mediates cisplatin resistance in ovarian cancer cells.
Citation Format: Chintda Santiskulvong, Shivani Sharma, Laurent Bentolila, Jian Y. Rao, James Gimzewski, Oliver Dorigo. The role of Rho GTPase in cell stiffness and cisplatin resistance in ovarian cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2122. doi:10.1158/1538-7445.AM2013-2122
Abstract 2130: Small molecule activation of diaphanous-related formins as a novel anti-cancer strategy.
Authors: Lash Leanne L. , Alberts Arthur S. 
Published: August 2014

Abstract
Formin-based cytoskeletal remodeling contributes to structural rearrangements that support an array of cellular demands, including chemotaxis and cell division. The Diaphanous formin family is managed in cells by Rho small GTP-binding proteins. Rho-GTP binding to the formin interferes with the intramolecular interaction between the Dia-inhibitory and -autoregulatory (DID & DAD) domains that flank the critical formin homology-2 (FH2) domain. The FH2 domain can then interact with microtubules to stabilize microtubule dynamics and loosely associate with barbed ends of polymeric actin filaments to add actin monomers. As a consequence of monomer consumption into filaments, formins also activate the MAL/MRTF-SRF transcription factor axis.
DAD-derived peptides can activate formins in cells by interrupting the DID-DAD autoregulatory mechanism. We screened for drug-like small molecules with in vitro, cellular, and in vivo activities that could mimic the impact of DAD peptides. Two chemically similar molecules, called the Intramimics (IMMs) were identified. Both molecules (IMM-01 and -02) blocked DID-DAD binding in vitro, induced actin/microtubule stabilization in cells, activated SRF, and impaired cell-cycle progression. The IMMs each reduced xenograft tumor growth in mice. Due to their novel activity on formins, the IMMs represent an innovative therapeutic strategy for the study and treatment of diseases impacted by defects in cell structure, including autism, neurodegenerative disease, and cancer.
Citation Format: Leanne L. Lash, Arthur S. Alberts. Small molecule activation of diaphanous-related formins as a novel anti-cancer strategy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2130. doi:10.1158/1538-7445.AM2013-2130