tbuckley/cabot-search huggingface dataset:
Molecular dynamics investigation of radiation-induced activation of NF-κB by selective nitration of Tyr181 IκBα
Authors: Igor J. Barani, Vasily A. Yakovlev, Ross B. Mikkelsen
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

4420 

NF-κB is an important transcription factor of cytoprotective signal transduction pathways activated by cellular stress. It was recently shown that clinically relevant doses of ionizing radiation (IR) stimulate NF-κB activity by nitration of Tyr181 of Iκ-Bα and leading to dissociation of NF-κB/Iκ-Bα complex (submitted). We performed femto-second (10–12 s) scale molecular dynamics (MD) simulations to test if Tyr181 nitration is alone sufficient to activate NF-κB. Crystallographic studies show that fingers 3/4, 4/5, and 5/6 of Iκ-Bα contact the p50 subunit of NF-κB. Tyr181 and Asn182 extend from finger 3/4 in multiple contacts with side chains arising from multiple strands of p50. Tyr181 forms hydrogen bonds with p50 Lys252 and Arg258, π-stacks with Tyr351 and makes multiple van der Waals (vdW) contacts with Ala261, Pro327, and Leu349 of p50. Our experimental results with site-directed mutagenesis confirm the importance of this residue in stabilizing the NF-κB/Iκ-Bα complex. We performed quantum mechanical simulations using HF 6–31G basis set to determine physical parameters for nitrated Tyr and validated the calculated parameters by NMR, UV/Vis, and infrared spectroscopies. MD simulations of fully hydrated NF-κB/Iκ-Bα complex over 10 ns time scale were carried out demonstrating that IR-induced Tyr181 nitration leads to dissociation of NF-κB/Iκ-Bα complex and therefore activation of NF-κB. Nitro-Tyr181 disrupts local vdW and H-bonding interactions early (within 500 ps) that translate into backbone displacements after 2 ns. NO2 group of Tyr181 of Iκ-Bα forces Tyr351 of p50 to shift laterally exposing Tyr351 to the solvent, further disrupting the interaction surface between p50 and Iκ-Bα which normally contributes most to the complex stability. Iκ-Bα then shears off the p50 subunit and consequently off p65 as the number of stabilizing interactions decreases with increasing exposure to solvent. The dramatic displacement of N-terminal region of p50 due to interaction of nitro-Tyr181 and Tyr351 appears to be the initiating event in IR-induced activation of NF-κB. These simulations provide a mechanistic view of how an IR-induced oxidative stress activates NF-κB signaling.
Abstract 16877: Correlation of Antibody Binding Strength to Complement Fixation
Authors: Vishal Y Parikh, Nancy Reinsmoen, Jignesh Patel, Zhe Yu, Frank Liou, Jamie Yabuno, Michelle Kittleson, Babak Azarbal, David H Chang, Lawrence Czer, Jon Kobashigawa
Journal: Circulation (2014)

Background: In patients (pts) who are highly sensitized, desensitization therapy is commonly applied to reduce antibody (Abs) load and to reduce potential morbidity and mortality following heart transplant (HTx). It is not known as to what level of antibody binding is needed to initiate desensitization therapy. It is believed that high binding Abs may have the ability to fix complement and lead to cytotoxicity. Methods: Between 2011 and 2012 we assessed 13 highly sensitized pts who were noted to have standardized fluorescence intensity (SFI) &gt;100,000 pretransplant. A complement binding assay (C1q binding assay) was then applied to these Abs to assess for a correlation of binding to cytotoxicity. Correlation statistics were used to derive significance between higher antibody binding and capacity to bind complement. Results: There seems to be no correlation between the different binding strength and C1q positivity. However, when evaluating Luminex 1:8 test, there seems to be correlation between class I binding strength with C1q positivity. There was C1q positive rate of 10.8% in SFI 200,000 range. Conclusions: Undiluted antibodies do not correlate to C1q binding ability. However the 1:8 dilution test seems to provide an better prediction of complement binding. 1:8 dilutions should be performed to accurately assess the ability for antibodies to bind complement.
Gene expression profiles identify an aggressive phenotype in endometrial carcinoma
Authors: Helga B. Salvesen, Trond H. Bo, Ingunn M. Stefansson, Monica Mannelqvist, Geir Bredholt, Ingeborg B. Engelsen, Anne M. Oyan, Inge Jonassen, Karl Henning Kalland, Lars A. Akslen
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

4514 

Background: Endometrial cancer is the most common gynecologic malignancy of western women. The disease generally has a favourable prognosis with a 75% 5-year survival. There is still a need for reliable tumor markers for identification of high-risk patients. This would provide an improved basis for individualized treatment and potentially reduce morbidity in low-risk groups. Aim: The aim of this study was to identify signatures of differentially expressed genes in aggressive endometrial carcinomas. Materials and Methods: Carefully dissected fresh endometrial cancer tissues were prospectively collected from 57 patients treated for primary endometrial cancer. Microarray analysis was performed using Agilent DNA oligonucleotide microarrays (21K). Tissue microarrays from a separate population based validation series of 316 endometrial carcinomas with long and complete follow-up were included. Results: Unsupervised analysis revealed 2 distinct patient clusters being significantly associated with FIGO stage, histologic type and grade (p=0.001), presence of vessel infiltration, necrosis, number of mitoses and prognosis (recurrence free survival, log-rank test, p=0.03). We are in the process of validating differentially expressed genes by using low-density arrays and a separate patient series with follow-up information. Conclusions: Gene expression data provided tumor clusters which were significantly associated with clinico-pathologic features and patient prognosis, and novel markers of potential relevance for molecular classification, prognosis and therapy of endometrial cancer were found.



View this table:
Abstract 14462: Elective Arterio-Venous Fistula Creation in Chronic Kidney Disease is Associated With Maladaptive Cardiovascular Adaptation: A Cardiovascular MRI Study
Authors: Benjamin K Dundon, Matthew I Worthley, Adam J Nelson, David K Torpey, Rae F Duncan, Dennis T Wong, Kym M Bannister, Randall J Faull, Stephen G Worthley
Journal: Circulation (2011)

Introduction: Chronic kidney disease (CKD) is associated with a marked increase in cardiovascular risk. We sought to evaluate the independent impact of arterio-venous fistula creation on cardiovasc...
Herpetic Eye Disease Study
Authors: Kirk R. Wilhelmus, Lauren Gee, Walter W. Hauck, Natalie Kurinij, Chandler R Dawson, Dan B. Jones, Bruce A. Barron, Herbert E. Kaufman, Joel Sugar, Robert A. Hyndiuk, Peter R. Laibson, R. Doyle Stulting, Penny A. Asbell
Journal: Ophthalmology (1994)
The Chromosome 21 Kinase DYRK1A Controls Cell Cycle Exit and Survival During Lymphoid Development and Is a Novel Therapeutic Target In Acute Lymphoblastic Leukemia
Authors: Benjamin J. Thompson, Lauren Diebold, Sebastien Malinge, Bertrand Leblond, Anne-Sophie Casagrande, Laurent Désiré, Alicia Foucourt, Thierry Besson, Nobuko Hijiya, John D. Crispino
Journal: Blood (2013)
Abstract #5129: Bortezomib sensitizes human renal cancer cells to TRAIL-mediated apoptosis
Authors: Alan Brooks, Kristen Jacobsen, Anil Shanker, Thomas Sayers
Journal: Cancer Research (2009)

Bortezomib (Velcade/PS-341), a specific and reversible proteasome inhibitor, sensitized certain human renal carcinoma (RCC) lines to apoptosis induced by both the TNF family member TRAIL, and an agonist antibody to the TRAIL receptor DR5. Analysis of 7 human RCC demonstrated a clear increase in the sensitivity of 4 renal lines to TRAIL following bortezomib (5-20nM) treatment, while the remaining 3 renal lines remained resistant. The enhanced antitumor activity of the bortezomib and TRAIL combination was confirmed in long-term tumor outgrowth assays. No difference in levels of proteasome inhibition by bortezomib in sensitized and resistant RCC was observed. No major differences were noted between sensitized and resistant cells in the levels of a variety of apoptosis proteins including cFLIPL, IAP-1, XIAP, Bcl-2, Bax or Bid following bortezomib treatment. Also, bortezomib-induced changes in Mcl-1, Bik and survivin in human RCC did not correlate with sensitization or resistance to TRAIL. Furthermore changes in surface expression of TRAIL receptors (DR4, DR5, DcR1, DcR2) following bortezomib treatment did not correlate well with sensitization or resistance. However, enhanced procaspase 8 activation following bortezomib pretreatment and TRAIL exposure was only observed in the sensitized RCC. This increase in procaspase 8 activation in cell extracts of sensitized RCC was observed using both enzyme assays as well as western blotting for activated (cleaved) procaspase 8. In addition, immunoprecipitation of the death-inducing signaling complex (DISC) demonstrated higher levels of active caspase 8 in the DISC of sensitized but not resistant RCC. This data suggests that the molecular basis for bortezomib sensitization of RCC to TRAIL primarily involves very proximal events in the extrinsic apoptotic signaling pathway, that result in an amplification of caspase 8 activity. Funded in part by DHSS #NO1-CO-12400   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5129.
Abstract 9: Hydrogen Sulfide Improves Outcome after Cardiac Arrest and Cardiopulmonary Resuscitation in Mouse
Authors: Shizuka Minamishima, Jia De Yu, Masahiko Bougaki, Christophe Adrie, Yoji A Minamishima, David J Lefer, Fumito Ichinose
Journal: Circulation (2008)

Introduction: Administration of hydrogen sulfide (H2S) donor has been shown to attenuate ischemia-reperfusion injury. The aim of this study was to evaluate the effect of an H2S donor sodium sulfide...
Abstract 2707: Survival of Octogenarians Undergoing Concomitant Mitral Valve Surgery and Coronary Artery Bypass in Northern New England
Authors: Bruce J Leavitt, Cathy S Ross, Elaine M Olmstead, Robert A Clough, Felix Hernandez, John H Braxton, David C Charlesworth, Mitchell C Norotsky, Gerald T O'Connor
Journal: Circulation (2006)

Background: As life expectancy increases, surgeons are performing more valve replacements with coronary artery bypass graft (CABG) surgery on patients 80 years and over. We examined the in-hospital...
Abstract #2304: Effects of reirradiation on human glioblastoma cells previously treated with low dose fractionated radiotherapy
Authors: Ravesanker Ezhilarasan, Indra Mohanam, Jasti Rao, Sanjeeva Mohanam
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

Glioblastoma multiforme is the most common primary brain tumor in adults and radiotherapy is an important adjuvant treatment in the management of glioblastoma. The radiosensitivities of glioblastomas vary widely with respect to clinically relevant radiation doses. Reirradiation is applied to relapsing primary malignant brain tumors. We treated human glioblastoma cells U87 and SNB19 with low dose fractionated irradiation (FIR) and established sublines. This study aims to focus on biological responses of irradiation on parental and established sublines of FIR. Cells of parental and FIR were exposed to different doses of radiation and cell survival was assessed by the colony formation assay. Induction of apoptosis was measured by cell cycle analysis and Hoechst 33258 staining. MMP-9 activity was evaluated by zymography and tumor cell invasion by in vitro Matrigel assay. We also assessed how reirradiation modulates in vitro angiogenesis. Human microvascular endothelial cells were exposed to conditioned medium from irradiated parental and FIR sublines and endothelial migration and capillary-like structure formation were studied. Reirradiation caused an increase in clonogenic cell survival. A decrease in induction of apoptosis was observed in FIR sublines compared with parental cells and this was found to be associated with an increase in survivin, a member of the inhibitor of apoptosis family and downregulation in the activation of Caspase-9, Caspase-3 and PARP. Increase in MMP-9 activity and invasiveness was found in FIR sublines exposed to irradiation. Reirradiation results in increased activation of ERK and PI3K/Akt signaling pathways in FIR sublines compared with parental cells. The results suggest that glioblastoma tumor cells surviving low dose fractionated radiation therapy, afterwards exhibit enhanced angiogenic potential and increased resistance to induction of apoptosis to a new radiation exposure.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2304.
Abstract LB-274: Transcriptional factor Snail and MMP-9 signaling axis amplifies Neu1-MMP-9 crosstalk on EGF receptor to regulate tumor neovascularization, growth and metastasis in mouse model of human ovarian carcinoma
Authors: Myron R. Szewczuk, Samar Abdulkhalek, Olivia Geen, Lacey Brodhagen, Fiona Haxho, Farah Alghamdi, Stephanie Allison, Duncan Simmons, Leah O'Shea, Ronald Neufeld
Journal: Cancer Research (2015)

Abstract Snail is a transcriptional factor and repressor of E-cadherin. It is well known for its role in cellular invasion, epithelial to mesenchymal transition (EMT), tumor progression and metastases. shRNA lentiviral knockdown (KD) of Snail and its associated member Slug in human A2780 ovarian epithelial carcinoma cell line was investigated to identify its role in tumor neovascularization. Live cell sialidase, WST-1 and immunohistochemistry assays were used to evaluate sialidase activity, cell proliferation and the expression levels of tumor E-, N- and VE-cadherins, and host endothelial CD31+(PECAM-1) cells in A2780, A2780 Snail KD and A2780 Slug KD tumors grown in RAGxCγ double mutant mice. Oseltamivir phosphate (OP), anti-Neu1and MMP-9 specific inhibitor blocked Neu1 activity associated with epidermal growth factor (EGF) stimulated A2780 cells. Silencing Snail and Slug in A2780 cells abrogated the Neu1 activity following EGF stimulation of the cells compared to parental cells. OP treatment of A2780 and cisplatin-resistant A2780cis cells reproducibly and dose-dependently abated the cell viability with a LD50 of 7 and 4μM, respectively. Heterotopic xenografts of A2780 tumors developed abnormal bloody tumor vasculature in these mice. Anti-tumor activity of OP treatment at 50 mg/kg daily I.P. did not significantly impede A2780 tumor growth rate in a time-to-progression, but significantly cause a reduction of lung metastases compared with the untreated and OP 30 mg/kg cohorts. Silencing Snail in A2780 cells, but not the Slug KD member completely abrogated the tumor vascularization, growth and spread to the lungs in these mice. A2780 and A2780 Slug KD tumors expressed high levels of human N- and VE-cadherins, and host CD31+ endothelial cells. These findings uncover a novel organizational signaling platform connecting the Snail-MMP-9 signaling axis in amplifying the Neu1-MMP-9 cross-talk in regulating EGF receptors, tumor neovascularization, growth and invasiveness. Citation Format: Myron R. Szewczuk, Samar Abdulkhalek, Olivia Geen, Lacey Brodhagen, Fiona Haxho, Farah Alghamdi, Stephanie Allison, Duncan Simmons, Leah O'Shea, Ronald Neufeld. Transcriptional factor Snail and MMP-9 signaling axis amplifies Neu1-MMP-9 crosstalk on EGF receptor to regulate tumor neovascularization, growth and metastasis in mouse model of human ovarian carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-274. doi:10.1158/1538-7445.AM2015-LB-274
Notch1 targeting siRNA delivery nanoparticles for rheumatoid arthritis therapy
Authors: Min Ju Kim, Jong-Sung Park, So Jin Lee, Jiyeon Jang, Jin Su Park, Seung Hyun Back, Gahee Bahn, Jae Hyung Park, Young Mo Kang, Sun Hwa Kim, Ick Chan Kwon, Dong-Gyu Jo, Kwangmeyung Kim
Journal: Journal of Controlled Release (2015)
Evaluation of anti-solid tumor activity using multicellular layer of DLD-1 cells.
Authors: Hyo-Jeong Kuh, Jung-Won Lee, Jin-Hyoung Kang
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

2042 

For efficient selection of anticancer agents with promising activity against human solid tumors, an in vitro system that maintains important characteristics of solid tumors in vivo, i.e., multicellular resistance (MCR), should be utilized. Tissue penetration and cellular degradation are of a major part of MCR in solid tumors. In this study we evaluated cytotoxicity of agents after penetration through layers of human cancer cells using multicellular layer (MCL) of cancer cells in conjunction with SRB cytotoxicity assay, in order to test the feasibility of this methodology for the evaluation of anti-solid tumor activity of anticancer agents. DLD-1 human colorectal carcinoma cells were grown in Transwell® insert to form MCL and the agents tested were oxaliplatin (LOHP), cisplatin (CDDP), heptaplatin (HTP, SKI-3063R), irinotecan, SN-38 and 5-FU. Drugs were applied to top chamber (TC) of Transwell® with or without MCL. The amount of drug penetrated into bottom chamber (BC) was monitored by LSC and its activity was determined using SRB assay in DLD-1 monolayers exposed for 72 hr to the BC media. Paclitaxel was used as a model drug of which poor penetration without significant deactivation attributed to its limited activity in some solid tumors. MCL of DLD-1 reached 45 μm thickness in 8 day and the penetration of [14C]mannitol was 79% in 24 hr. [14C]paclitaxel showed limited penetration of 59% and 27% at 10 μM and 1 μM, respectively, in 24 hr, indicating that its penetration is not via paracellular pathway but via transcellular pathway that can be facilitated by higher drug concentrations. The cytotoxicity of 1 μM paclitaxel after 24 hr penetration through the MCL was decreased by 61% compared to that of cell free insert, which is consistent with the amount of drug penetrated. On the other hand, the activity of 5-FU was increased by 30% (P<0.05) and the same tendency was observed although not statistically significant, for irinotecan and SN-38, suggesting these agents may be activated when penetrating thru cell layers to the degree which can compensate incomplete their penetration. The cytotoxicity of platinum agents after 24 hr penetration through MCL was significantly lower than the expected by 31% (HTP) and 82 % (CDDP, LOHP). The lower activity of CDDP and LOHP could not be fully attributed to poor penetration (up to 50%), instead, the instability observed for these two agents observed in cell culture condition as well as possible deactivation in cell layers seemed to contribute. These data indicate that the changes in cytotoxicity after penetration thru MCL may be caused by poor penetration and degradation/activation in cell culture medium and cancer cell layers. Cytotoxicity assay combined with MCL penetration may have a potential as an efficient screening system in vitro for the selection of promising agents against human solid tumors.
Abstract 2514: Ivabradine is an Effective and Safe Treatment for Inappropriate Sinus Tachycardia
Authors: Antonella Sette, Annamaria Martino, Giuseppe Giunta, Tamara Coppi, Antonio Cciccaglioni, Ermenegildo de Ruvo, Lucia de Luca, Luigi Sciarra, Francesco Fedele, Ernesto Lioy, Leonardo Calo
Journal: Circulation (2009)

Introduction Inappropriate sinus tachycardia (IST) is characterized by an exaggerated increase in heart rate with sinual P wave, in the absence of predisposing conditions. Beta blockers, calcium ch...
Abstract 17341: The Impact of Intravenous Ferric Carboxymaltose on Renal Function: An Analysis of the FAIR-HF Study
Authors: Piotr Ponikowski, Iain Macdougall, Josep Comin Colet, Kenneth Dickstein, Gerasimos Filippatos, Thomas Luscher, Ronnie Willenheimer, Claudio Mori, John Norrie, Ian Ford, Stefan D Anker
Journal: Circulation (2010)

Background: Renal dysfunction commonly complicates the natural course of chronic heart failure (CHF) and predicts poor outcome. Currently applied CHF therapies have either no effect on, or even wor...
Modulation of P16INK4A activity by Hsp90, Cdc37 and CRM1 influences the progression of preneoplastic lesions in rats with different predisposition to liver cancer and the prognosis of human hepatocellular carcinoma
Authors: Diego F. Calvisi, Rosa M. Pascale, Maria M. Simile, Maddalena Frau, Maria R. Muroni, Maria A. Seddaiu, Lucia Daino, Maria D. Muntoni, Maria R. De Miglio, Snorri S. Thorgeirsson, Francesco Feo
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

357 

Current evidence indicates that neoplastic nodules induced in liver of BN rats genetically resistant to hepatocarcinogenesis are not prone to evolve to hepatocellular carcinoma (HCC). Previous research showed cell cycle deregulation in neoplastic liver nodules and HCCs of susceptible F344 rats. Lower or no changes were found in BN rats, where overexpression of p16INK4a occurs. Here we show that BN rats subjected to diethylnitrosamine/2-acetylaminofluorene/partial hepatectomy treatment of “resistant-hepatocyte” protocol display higher number of glutathione-S-transferase 7-7(+) hepatocytes when compared to F344 rats, both during and at the end of 2-acetylaminofluorene treatment. However, DNA synthesis declines in BN but not in F344 rats after completion of promoting stimulus represented by reparative growth. Cell cycle inhibition by p16INK4A can be modulated by Cdc37-Hsp90 complex and Crm1 protein. The Cdc37- Hsp-90 complex protects Cdk4/6 from forming a complex with p16INK4A. Crm1 operates the cytoplasmic redistribution of E2f4, a transcription repressor acting as a downstream mediator of p16INK4A. We observed up-regulation of p16INK4A , Hsp90 , and Cdc37 genes, an increase in Cdc37-Cdk4 complexes, and a decrease in p16INK4A-Cdk4 complexes in preneoplastic liver, nodules and hepatocellular carcinomas of F344 rats. These parameters do not change significantly in BN rats. E2f4 is equally expressed in the lesions of both strains, but Crm1 expression and levels of E2f4-Crm1 complex are higher in F344 rats. Marked up-regulation of P16INK4A is associated with moderate overexpression of HSP90, CDC37, E2F4, and CRM1 in human HCCs with a better prognosis. In contrast, strong induction of HSP90, CDC37, and E2F4 is paralleled by P16INK4A down-regulation and high levels of HSP90-CDK4 and CDC37-CDK4 complexes in human HCCs with poorer prognosis. CDC37 down-regulation by small interfering RNA inhibits in vitro growth of HepG2 cells. In conclusion, our results underline the role of Hsp90/Cdc37 and E2f4/Crm1 systems in the acquisition of a susceptible or resistant phenotype. The results also suggest that protection by Cdc37 and Crm1 against growth restraint by P16INK4A influences the prognosis of human hepatocellular carcinoma.