tbuckley/cabot-search huggingface dataset:
Abstract 1979: Role of Akt1 on the viability, migration and cytoskeleton organization of murine mammary tumor cells reexpresing glypican-3 (GPC3)
Authors: Silvina A. Romero, María A. Lago Huvelle, Guillermo Peluffo, Elisa Bal de Kier Joffé, María Giselle Peters
Journal: Cancer Research (2011)

Abstract Previously, we have demonstrated that the restatement of GPC3 in the murine mammary adenocarcinoma LM3 cell line induces the inhibition of its metastatic ability in vivo, event associated with a partial reversion of the epithelial-mesenchymal transition. We also found that LM3-GPC3 cells present a constitutive lower activity of the Akt pathway. The Akt kinases 1, 2 and 3 have a critical role in regulating survival, metabolism and other cellular activities. Their role on migration and metastasis is less clear. The aim of this study was to analyze the function of Akt1 on the viability, migration and cytoskeleton organization of LM3-GPC3 cells. Experiments were done employing two clones reexpressing GPC3 (LM3-GPC3) and two control clones transfected with the empty vector (LM3-vector). By means of WB we determined that all the clones express similar levels of total Akt (1, 2 and 3). However, while LM3-vector cells presented a higher proportion of Akt2 (Akt1/Akt2=0.75), GPC3 reexpression reversed this relationship (Akt1/Akt2=1.45). To study the role of Akt1, we introduced by viral infection a constitutively active variant of this isoform (CA Akt1) into LM3-GPC3 cells. We corroborated previous findings that GPC3 reexpression increases LM3 cell line susceptibility to death under serum deprivation (ANOVA-Bonferroni p&amp;lt;0.001). However, CA Akt1 did not affect the viability of LM3-GPC3 cells (ANOVA, ns). While no changes were detected in the actin cytoskeleton organization, we found by wound healing assays that LM3-GPC3 cells expressing CA Akt1 were more motile than their controls (Wound coverage: LM3-GPC3 control=45% vs LM3-GPC3 CA Akt1=90%, ANOVA-Bonferroni p&amp;lt;0.001). These results suggest that the Akt family would have isoform-specific mechanisms to regulate the studied cellular parameters. Since the migration of LM3-GPC3 cells expressing CA Akt1 reached similar levels to those of LM3-vector clones, we conclude that GPC3 reduces the migratory ability of LM3 cells by inhibiting Akt1. On the other hand, CA Akt1 did not affect either viability or the organization of the actin cytoskeleton of LM3-GPC3 cells. Thus, we deduce that other isoforms of Akt and/or other signaling pathways are involved in the modulation of these cellular properties. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1979. doi:10.1158/1538-7445.AM2011-1979
Abstract ES6-2: Cell to Cell Variability in the Responses of Tumor Cells to Death Ligands and Other Anti-Cancer Drugs
Authors: PK Sorger, S Spencer, S Gaudet, B Aldridge, Flusberg D
Journal: Cancer Research (2010)

Abstract Cell to cell variability in phenotype and fate is important for tissue homeostasis, the emergence of drug resistance and the evolution of tumors. I will discuss cell to cell variability in the responses of clonal populations of human cells to TRAIL, a prototypical inducer of receptor-mediated (extrinsic) apoptosis and an investigational therapeutic, as well as to other pro-apoptotic drugs. Some TRAIL-treated human cells die within ∼40 min, others only after 12 hr and some live indefinitely. During this variable delay initiator caspases (ICs) are active in processing substrates such as Bid and downstream effector caspases (ECs) but mitochondrial membrane permeablization (MOMP) does not occur and (ECs are catalytically inactive. We have explored three explanations for cell to cell differences among members of a clonal and notionally uniform population: (i) genetic or epigenetic variation (ii) the involvement of one or more biochemical processes subject to stochastic fluctuation (iii) difference in cell state such as position in the cell cycle or protein concentrations. To distinguish these three possibilities we compared the fates of sister cells exposed to TRAIL and other drugs using live-cell microscopy. Genetic and epigenetic factors are transmitted with near-perfect fidelity; reaction rates dominated by stochastic fluctuations are no more similar in sisters than in any two cells chosen at random and variability arising from differences in mRNA or protein levels should be transiently heritable (because division is a binomial process in which sister cells inherit roughly equal numbers of abundant cytosolic and nuclear factors but drift towards the population average over time). The later explanation is correct — natural fluctuations in protein levels dominate phenotypic heterogeneity in extrinsic apoptosis and cause transient phenotypic heritablility. Variability can be manipulated by protein over-expression and drugs and I will describe analytic methods for modeling these perturbations mathematically. A key conclusion from this work is that variability in the responses of cells to drugs is inherent to the stochastic operation of the biochemical pathways that anti-cancer drugs target. Fractional killing is one inevitable consequence. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr ES6-2.
Abstract P3-10-04: Regulation of inflammatory breast cancer cell invasion through Akt1/PKBα phosphorylation of RhoC GTPase
Authors: HL Lehman, SJ Van Laere, CM van Golen, PB Vermeulen, LY Dirix, KL van Golen
Journal: Cancer Research (2012)

Abstract With a 42% and 18% 5- and 10-year respective disease-free survival rate, inflammatory breast cancer (IBC) is arguably the deadliest form of breast cancer. IBC invades the dermal lymphatic vessels of the skin overlying the breast and as a consequence nearly all women have lymph node involvement and ∼1/3 have gross distant metastases at the time of diagnosis. One year after diagnosis ∼90% of patients have detectable metastases, making IBC a paradigm for lymphovascular invasion. Understanding the underlying mechanisms of the IBC metastatic phenotype is essential for new therapies. Work from our laboratory and others show distinct molecular differences between IBC and non-inflammatory breast cancers. Previously we demonstrated that RhoC GTPase is a metastatic switch responsible for the invasive phenotype of IBC. In the current study we integrate observations made in IBC patients with in vitro analysis. We demonstrate that the PI3K/Akt signaling pathway is crucial in IBC invasion. Key molecules involved in cytoskeletal control and cell motility are specifically upregulated in IBC patients compared with stage and cell-type-of-origin matched non-inflammatory breast cancer patients. Distinctively, RhoC GTPase is a substrate for Akt1 and its phosphorylation is absolutely essential for IBC cell invasion. Further our data show that Akt3, not Akt1 has a role in IBC cell survival. Together our data demonstrate a unique and targetable pathway for IBC invasion and survival. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-10-04.
Development and external validation of two nomograms to predict overall survival and occurrence of distant metastases in adults after surgical resection of localised soft-tissue sarcomas of the extremities: a retrospective analysis
Authors: Dario Callegaro, Rosalba Miceli, Sylvie Bonvalot, Peter Ferguson, Dirk C Strauss, Antonin Levy, Anthony Griffin, Andrew J Hayes, Silvia Stacchiotti, Cecile Le Pechoux, Myles J Smith, Marco Fiore, Angelo P Dei Tos, Henry G Smith, Luigi Mariani, Jay S Wunder, Raphael E Pollock, Paolo G Casali, Alessandro Gronchi
Journal: The Lancet Oncology (2016)
THU0092 CD4+CD25+FoxP3+ T Regulatory Cells in Rheumatoid Arthritis: Decreased or Increased but not Able to Fight Back Inflammation? is it a Question of Number or Balance with their Counteracting FoxP3- Population?
Authors: N. Abaza, R. H. El-kabarity, R. A. Abo-Shady
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Despite the presence of an increase in immunoregulatory cells in rheumatoid arthritis (RA), chronic inflammation persists and activity recurs. This finding has been intriguing rheumatologists and immunologists trying to justify the presence of activity daring this quarterback of cells usually aiming to fight inflammatory process. Namely the forkhead box P3 (FoxP3) transcription factor, essential for T regulatory cells (T regs) development and function is now considered their most specific marker denoting FoxP3<sup>+</sup> cells as suppressors whereas FoxP3<sup>-</sup> effectors. <h3>Objectives</h3> To clarify the subsets distribution of peripheral blood (PB) CD4<sup>+</sup>CD25<sup>+</sup> T regulatory cells (T regs) according to FoxP3 expression in RA (both in remission &amp; activity) for a better understanding of RA pathogenesis highlighting future therapeutic targets. <h3>Methods</h3> In our observational cross-sectional study PB T regs from 40 RA patients &amp; 20 age and sex matched healthy controls (HC) were characterized and quantified by flow cytometry. Disease activity was evaluated by DAS28. Patients were divided into 2 equal groups: active RA group (ARA) &amp; remission RA group (RRA). All patients were on methotrexate MTX and folic acid. <h3>Results</h3> A significantly higher T regs subsets numbers were found on comparing RRA, ARA patients &amp; HC as shown in table 1 <h3>Conclusions</h3> CD4<sup>+</sup>CD25<sup>+</sup>FoxP3<sup>+</sup> &amp; CD4<sup>+</sup>CD25<sup>+</sup>FoxP3<sup>-</sup> are both increased in RA but it is their balance that is more important; the abundance of Foxp3<sup>-</sup> cells gave the effector function the upper hand over the suppressive function represented in Foxp3<sup>+</sup> cells. This imbalance is related to the presence of RA &amp; to its activity. Restoring this imbalance by future targeting therapeutics might be of great benefit in RA patients. <h3>References</h3> Beyer M &amp; Schultze JL: Regulatory T cells in cancer. Blood. 2006; 108:804–811. Wan YY &amp; Flavell RA: Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression. Nature. 2007;445:766–770. Han GM, O'Neil-Andersen NJ, Zurier RB &amp; Lawrence DA:CD4+CD25high T cell numbers are enriched in the peripheral blood of patients with rheumatoid arthritis. CellImmunol. 2008; 253(1-2):92-101. <h3>Disclosure of Interest</h3> None Declared
Left Ventricular Thrombi and Cerebral Embolism
Authors: Valentin Fruster, Jonathan L. Halperin
Journal: New England Journal of Medicine (1989)

Cerebral embolism of cardiac origin is responsible for close to 15 percent of all cases of acute ischemic stroke — far fewer than the number attributed to thrombotic complications of cerebrovascular disease but still the source of catastrophic stroke in more than 75,000 North Americans per year.1 The destructive thrombi of cerebral embolism derive from a diverse array of cardiac diseases, about half of which involve atrial fibrillation and half, valvular heart disease or left ventricular mural thrombi.1 , 2 The cause of 60 percent of the emboli of left ventricular origin is acute myocardial infarction; the rest involve chronic ventricular dysfunction . . .
Abstract 3487: Molecular basis for induction of IL-8 expression by thymidine phosphorylase
Authors: Shin-ichi Akiyama
Journal: Cancer Research (2011)

Abstract Thymidine phosphorylase (TP) is identical to platelet-derived endothelial cell growth factor (PD-ECGF) and has an angiogenic activity. 2-Deoxy-D-ribose, one of the degradation products of thymidine, is a down stream mediator of the TP function. We investigated the molecular basis for the induction of an angiogenic factor, interleukin-8 (IL-8) by TP. First we confirmed that the enzymatic activity of TP is needed for the induction of IL-8 by TP in KB cells, and 2-deoxy-D-ribose increased the expression level of IL-8. ROS generated by TP augmented the expression of heme oxygenase-1 (HO-1) and increased the expression of IL-8. Two inhibitors of NADPH oxidase, apocynin and diphenyleneiodonium, suppressed the expression of HO-1 and IL-8 in TP-overexpressing KB/TP cells. Knock down of the component of NADPH oxidase, Nox2 or p22phox, also suppressed the enhanced expression of IL-8 in KB/TP cells. ROS generated by TP activated NFκB, which subsequently enhanced the promoter activity of IL-8. Our findings suggest that NADPH oxidase is involved in the ROS generation by TP, and the ROS caused the activation of NF-κB, which subsequently enhanced the expression of IL-8. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3487. doi:10.1158/1538-7445.AM2011-3487
AB1317 The effect of biological agents on participation in paid work in patients with chronic inflammatory arthritides: A meta-analysis of randomized controlled trials
Authors: S. Fendri, C. Gaujoux-Viala, B. Fautrel
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> The addition of biological agents in treatment strategies in chronic inflammatory arthritides have improved the possibility of controlling disease activity and slowing the progression of joint damage. However their impact on work participation is unclear. <h3>Objectives</h3> To assess the effect of biological agents on participation in paid work among patients with chronic inflammatory arthritides. <h3>Methods</h3> A systematic review of the literature using PUBMED, EMBASE and the Cochrane library was performed until November 2010. All randomized controlled trials (RCTs) reporting the effect of biological agents (TNF inhibitors, antiCD20 monoclonal antibody, CTLA4Ig, antiIL6, antiIL1) on work participation among patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) or psoriatic arthritis (PsA) were selected. Data extraction: Data were collected using a predetermined form. The outcomes were missed workdays (for a period of 100 days at work), productivity (on a visual analogue scale) and job loss. Statistical analysis determined in each RCT effect size (ES), standardized response mean (SRM) or odds-ratios (OR) as appropriate to assess the magnitude of treatment effect. Pooled ES, SRM and OR were computed by meta-analysis. A random effect model was used in case of heterogeneity. <h3>Results</h3> 7 RCTs were analyzed i.e. 1115 patients treated by biological agents (adalimumab, etanercept, infliximab) and 779 controls.Among those 1894 patients, 1658 suffered from RA, 122 from AS, and 144 from PsA. Pooled analyses indicated that biological agents significantly reduced missed workdays (yes/no; 2 trials): OR=0.49 (95%CI 0.33 to 0.72), (continuous; 3 trials): SRM= -0.90 (95%CI -2.09 to 0.29) and improved work productivity (2 trials): ES=0.29 (95%CI 0.12 to 0.46). The positive effect on job loss was not significant (2 trials):OR=0.54 (95%CI 0.26 to 1.14). Figure: the efficacy on missed work days (yes/no) of biological agents versus control <h3>Conclusions</h3> Despite the scarcity and the heterogeneity of the data, this meta-analysis showed the beneficial effect of biologics agents on both absenteeism and presenteeism in chronic inflammatory rheumatism. Thus the high cost of biologic agents could be partly balanced with savings in indirect costs. <h3>Disclosure of Interest</h3> None Declared
P455Different patterns of coronary microvascular function induced by type 1 diabetes and intermittent hypoxia in rats
Authors: S Ogura, T Shimosawa, H Nagai, A Nara, I Kuwahira, K Yoshida, M Shirai
Journal: Cardiovascular Research (2014)

Background: Patient with Obstructive sleep apnea (OSA) exposed to chronic intermittent hypoxia (IH), which is thought to be the underlying mechanism that links OSA with cardiovascular disease. However, it remains unclear whether chronic intermittent hypoxia (IH) is associated with in vivo functional impairment in the coronary microvasculature.
Abstract 5289: Identification of basal-like subtype-specific MicroRNAs in lymph node negative breast cancer .
Authors: Wei Shi, Jeff Bruce, Rui Yan, Fei-Fei Liu
Journal: Cancer Research (2013)

Abstract Background: Breast cancer is a heterogeneous disease both clinically and biologically. With the recent recognition of the many different molecular subtypes, a desire to more specifically categorize tumors to allow tailoring of treatment to individual patients has developed. One particularly aggressive and treatment-resistant group is the “basal-like” subtype. However, the molecular events driving this subtype of breast cancer are largely unknown. Here, we propose to examine whether MicroRNAs specifically expressed in basal-like breast cancers contribute to their development and progression. Materials and Methods: Fifty-four formalin fixed paraffin embedded primary tumour samples from lymph-node negative breast cancer patients who were participants in a phase III randomized trial of tamoxifen (Tam) +/- whole breast radiation were collected. Intrinsic molecular subtyping was determined using semi-quantitative analysis of ER, PR, Ki-67, HER2, EGFR and cytokeratin (CK) 5/6 on tissue microarrays (TMAs) constructed from the tumor blocks. Patients were classified into the following categories: luminal A, luminal B, luminal-HER2, HER2 enriched or basal-like phenotypes. The median follow-up for this cohort was 10 years. The expression of 365 miRNAs was measured in these samples using the qRT-PCR based Taqman low density array human miRNA panel (Applied Biosystems). Data were validated in cell line models and further analyzed using level 3 TCGA breast cancer data. Results: Twenty-three miRNAs were identified at a significantly different expressed level in basal-like breast cancers (n = 6) compared with other subtypes (n = 48). This differential expression was validated in publically available RNA-Seq data generated by the TCGA for 20 of the 23 miRNAs. Eight of these twenty miRNAs were found to correlate with corresponding copy-number alterations at their genomic loci using the data generated by TCGA. Further analysis is currently underway to determine the potential contribution of methylation to the expression differences observed. The putative target genes and pathways involved will also be analyzed. Conclusions: MiRNAs are known to play numerous roles in cancer development and progression. In the current study we report several miRNAs with distinct expression patterns in basal-like breast cancers. Further characterization of the phenotypic impact of this deregulation may lead to a better understanding of this aggressive subtype and provide valuable insight needed to develop novel targeted therapies to treat these tumours. Citation Format: Wei Shi, Jeff Bruce, Rui Yan, Fei-Fei Liu. Identification of basal-like subtype-specific MicroRNAs in lymph node negative breast cancer . [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 5289. doi:10.1158/1538-7445.AM2013-5289
Hypocalcemia — An Unusual Metabolic Complication of Breast Cancer
Authors: Thomas C. Hall, C. Thomas Griffiths, J. Robert Petranek
Journal: New England Journal of Medicine (1966)

HYPOCALCEMIA as a complication of metastatic cancer is rare. It has been reported as occurring spontaneously in lung cancer,1 in response to successful treatment of carcinoma of the prostate2 , 3 and in chronic leukemia,4 but has seldom been noted in breast cancer.5 Hypercalcemia, however, is common in breast cancer6 , 7 and appears to be variable in etiology, pathogenesis and prognostic significance.8 , 9 Recent reports of hypercalcemia that occurred in the absence of metastatic bony involvement suggest the secretion of a parathormone-like substance by the tumor.10 The secretion of a thyrocalcitonin-like11 substance by tumors is an intriguing alternate possibility but has not been described . . .
Response in Two Groups of Anergic Patients to the Transfer of Leukocytes from Sensitive Donors
Authors: Eduardo Rodriguez Paradisi, Yolanda P. de Bonaparte, Marcos Carlos Morgenfeld
Journal: New England Journal of Medicine (1969)

Leukocytes from sensitive donors (between 18,000,000 and 20,000,000 viable cells) were injected subcutaneously into six patients with malignant lymphomas and 13 with lepromatous leprosy. In three of the patients with malignant lymphomas previously negative tuberculin reactions (old tuberculin, 1:10 dilution), became positive and remained so for at least eight months. In patients with lepromatous leprosy, who had previously had negative cutaneous tuberculin, lepromin and histoplasmin reactions, the response became positive in four to lepromin (Fernandez reaction, interpreted at 48 hours), in three to tuberculin and in one to both antigens. In two the reactivity persisted for approximately one year. Thus, it is possible to obtain partial reversal of the altered immunologic mechanisms in lepromatous patients by means of leukocyte transfer.
Interferon Alfa-2a Therapy in Cryoglobulinemia Associated with Hepatitis C Virus
Authors: Rocco Misiani, Piermario Bellavita, Domenico Fenili, Omar Vicari, Donatella Marchesi, Pier Luigi Sironi, Pio Zilio, Arialdo Vernocchi, Margherita Massazza, Giovanni Vendramin, Elisabetta Tanzi, Alessandro Zanetti
Journal: New England Journal of Medicine (1994)

Essential mixed cryoglobulinemia is frequently associated with hepatitis C virus (HCV) infection. A beneficial effect of interferon alfa therapy has been reported, but we do not know whether the antiviral activity of the drug affects the clinical and biochemical manifestations of disease.
Abstract 5698: Concurrent delivery of paclitaxel and 17-AAG via micellar nanocarriers
Authors: Usha Katragadda, Wei Fan, Chalet Tan
Journal: Cancer Research (2012)

Abstract Combination therapy of paclitaxel and 17-allylamino-17-demethoxygeldanamycin (17-AAG) had previously been tested in patients with advanced solid malignancies. Owing to the very low aqueous solubility of both drugs, large volumes of organic solvents were employed in the intravenous formulations, which contributed to serious toxicities in cancer patients and consequently restricted the optimal use of these drugs in the clinical setting. The aim of the present study was to develop micellar nanocarriers for concomitant delivery of paclitaxel and 17-AAG without the inclusion of any organic solvent. At clinically relevant concentrations, paclitaxel and 17-AAG were simultaneously loaded into polyethylene glycol-distearoylphosphatidylethanolamine (PEG-DSPE) micelles by a dry film method. The physicochemical and biological characteristics of the dual drug-loaded micelles were evaluated in vitro and in vivo. The simultaneous incorporation of paclitaxel and 17-AAG into PEG-DSPE micelles was confirmed by 1H NMR analysis. The drug-loaded micelles had an average diameter of 11 nm with a surface charge at −22 mV. In the presence of 90% serum, the release half-lives of paclitaxel and 17-AAG from PEG-DSPE micelles were 7.1 h and 4.8 h, respectively. Paclitaxel/17-AAG-loaded micelles were as effective in blocking the proliferation of human ovarian cancer SKOV-3 cells as the combined free drugs. When administered intravenously to nude mice bearing SKOV-3 tumor xenografts, paclitaxel/17-AAG-loaded PEG-DSPE micelles resulted in significantly elevated drug concentrations in the blood circulation and tumor tissues, compared to the free drug counterparts. These results suggest that paclitaxel/17-AAG-loaded micelles preferentially accumulate in the tumor tissue via the enhanced permeability and retention (EPR) effect. PEG-DSPE micellar nanocarriers may provide a novel and advantageous delivery approach for paclitaxel/17-AAG combination therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5698. doi:1538-7445.AM2012-5698