tbuckley/cabot-search huggingface dataset:
Abstract 5087: Precise characterization of macrophage secretory exosomes can lead to novel therapeutic approaches
Authors: Robert Bronislaw Bednarczyk, Yuki Kitadai, Neha Y. Tuli, Elyse K. Hanly, Ghada Benrahoma, Abraham Mittelman, Raj K. Tiwari
Journal: Cancer Research (2015)

Abstract Multiple cell types interact within the tumor microenvironment (TME) through crosstalk events that are mediated by many biomolecules including cytokines, mRNA, and miRNA-containing exosomes that can influence cancer progression as well as suppression. Inflammation within the TME is a major determinant in tumor progression. Since tumor associated macrophages (TAMs) are a major cellular factor in tumor inflammation, we hypothesized that crosstalk events initiated by macrophage secreted factors such as cytokines and exosomes will modulate breast cancer phenotype. We evaluated the cytokine profile of a human monocytic cell line, THP-1, following stimulation with a phorbol ester TPA (12-O-Tetradecanoylphorbol-13-acetate) in vitro. Activated THP-1 cells exhibited an M1 macrophage phenotype. In addition, we assessed the morphological and cellular growth changes of luminal (T47D, MCF-7) and basal-like (MDA-MB 231) breast cancer cell lines in vitro following treatment with activated THP-1 conditioned medium (CM). Each cell line displayed mesenchymal-like features and decreased cellular growth following activated THP-1 CM treatment. MCF-7 and MDA-MB 231 displayed increased MEK/ERK signaling, while all three cell lines showed increased p-AKT expression. Furthermore, epithelial-like T47D and MCF-7 cells exhibited an increase in EMT transcription factor expression. Moreover, although T47D and MCF-7 did not show drastic changes in E-cadherin expression via western blot analysis, immunofluorescence examination showed a decrease in E-cadherin following activated THP-1 CM treatments emphasizing a possible partial EMT event. Lastly, activated THP-1 exosomes were isolated and used to treat MDA-MB 231 to determine the effects on breast cancer cell proliferation and senescence. MDA-MB 231 exhibited significantly decreased cellular growth and increased senescence following incubation with activated THP-1 exosomes. The variety of secretory factors within the TME as a result of inflammation may contribute to tumor suppression as well as tumor progression via a secretion of cytokines and exosomes. Citation Format: Robert Bronislaw Bednarczyk, Yuki Kitadai, Neha Y. Tuli, Elyse K. Hanly, Ghada Benrahoma, Abraham Mittelman, Raj K. Tiwari. Precise characterization of macrophage secretory exosomes can lead to novel therapeutic approaches. [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 5087. doi:10.1158/1538-7445.AM2015-5087
A practical approach to nutritional screening and assessment in cirrhosis
Authors: Puneeta Tandon, Maitreyi Raman, Marina Mourtzakis, Manuela Merli
Journal: Hepatology (2016)

Malnutrition is one of the most common complications of cirrhosis, associated with an increased risk of morbidity and mortality. As a potentially modifiable condition, it is of particular importance to identify malnourished patients so that nutritional therapy can be instituted. Nutrition screening and assessment are infrequently performed in patients with cirrhosis. The reasons for this are multifactorial, including the absence of a validated “rapid” screening tool, multiple definitions of what constitutes malnutrition, and challenges with interpreting body composition and laboratory results in the setting of volume overload and liver dysfunction. This article summarizes the clinically relevant evidence and presents key issues, tools, and clinical options that are applicable to patients with cirrhosis. The definition, etiology, and clinically relevant outcomes associated with malnutrition are reviewed. Rapid nutritional screening is differentiated from more detailed nutritional assessment. Nutritional assessment in special populations, including women and the obese, and the role of inflammation are discussed. Multicenter studies using a common nutritional screening/assessment strategy are the next steps to fast‐track adoption and implementation of nutrition‐related evaluations into routine clinical practice. (H epatology 2017;65:1044‐1057).
The Effects of Glycoprotein IIb/IIIa Antagonists and Chloride Channel Blockers on Platelet Cytoplasmic Free Calcium.
Authors: Songmei Yin, Yiqing Li, Shuangfeng Xie, Danian Nie, Haiming Li, Liping Ma, Xiuju Wang, Yudan Wu, Jianghong Feng
Journal: Blood (2005)
Ofatumumab (OFA) Vs. Physician’s Choice (PC) of Therapy in Patients (pts) with Bulky Fludarabine Refractory (BFR) Chronic Lymphocytic Leukaemia (CLL): Results of the Phase III Study OMB114242
Authors: Anders Österborg, Miklós Udvardy, Andrey Zaritskey, Per-Ola Andersson, Sebastian Grosicki, Grzegorz Mazur, Polina Kaplan, Michael Steurer, Anna Schuh, Marco Montillo, Iryna Kryachok, Jan Moritz Middeke, Yaroslav Kulyaba, Grygoriy Rekhtman, Michele Gorczyca, Siobhan Daly, Chang Chai-Ni, Steen Lisby, Ira Gupta
Journal: Blood (2014)
Prognostic value of renal hemodynamic characteristics in patients with proliferative lupus nephritis
Authors: H. A. Martens, M. Bijl, C. G. M. Kallenberg
Journal: Annals of the Rheumatic Diseases (2007)

Background/Aim:  Previous studies showed that renal hemodynamic parameters, especially the filtration fraction (FF), are decreased in patients with active lupus nephritis (LN). In th
PWE-063 Epidermal growth factor receptor inhibitor reduces helicobacter-induced upregulation of gastric activation-induced cytidine deaminase in the murine INS-GAS cancer model
Authors: C Duval, M D Pritchard, A Abu Derman, A Varro, P A Robinson, J E Crabtree
Journal: Gut (2010)

<h3>Introduction</h3> Gastric infection with <i>Helicobacter</i> in transgenic hypergastrinaemic INS-GAS mice has been shown to accelerate the development of gastric cancer. Both <i>H pylori</i> and gastrin transactivate the EGF receptor (EGFR) in an autocrine or paracrine manner, respectively. The aims of the study were to examine the effects of treatment with an EGFR inhibitor in <i>H felis</i> infected INS-GAS mice. <h3>Methods</h3> Male INS-GAS mice were orally infected with <i>H felis</i>. Six weeks post-infection, infected and uninfected controls were fed either control, or EKB-569 (EGF inhibitor) supplemented food. Mice were sacrificed at 9 months post-infection. At post mortem gastric tissue was taken for pathology, analysis of RNA, proteins and DNA. Mucosal thickness and gastric epithelial cell proliferation (Mib1), apoptosis (active caspase 3), parietal cell density (H+K+ ATPase), B cell density (CD20) and Aicda (activation-induced cytidine deaminase, a DNA editing enzyme) were assessed immunohistologically. Gene expression was determined by quantitative RT-PCR. <h3>Results</h3> <i>H felis</i> infection resulted in significant increases in corpus mucosal thickness, Mib1 positive epithelial cells, active caspase 3 positive epithelial cells, and reduced number of parietal cells relative to uninfected controls. EKB-569 had no effect on epithelial proliferation, apoptosis, parietal cell number and mucosal thickness. Infection was associated with increased levels of transcripts for <i>Cox-2</i>, <i>Egfr</i>, <i>Hb-egf</i>, γ<i>-Ifn</i> (1.5–3.5-fold increase, p&lt;0.05), and a marked increase in transcripts of <i>CD20</i> and <i>Aicda</i> (17 and 18-fold increase, respectively, p&lt;0.001). Transcript levels of <i>Cox-2</i> and <i>Hb-egf</i> were not altered by EKB-569 treatment and <i>Egfr</i> transcripts were significantly increased (p&lt;0.05). In contrast, EKB-569 induced a marked reduction (p&lt;0.002) in <i>Aicd</i>a transcripts, but not in gastric <i>CD20</i> transcript levels. In EKB-569 treated infected mice there was a strong correlation between <i>Aicda</i> and <i>CD20</i> mRNA expression (r=0.73), which was absent in untreated infected mice (r=0.02), implying a non-B cell origin of Aicda in untreated mice. Immunohistology confirmed marked upregulation of Aicda in the hyperplastic epithelial cells of the corpus mucosa of infected untreated mice compared to controls. <h3>Conclusion</h3> In this study, EKB-569 did not affect gastric pathology, but markedly reduced <i>Helicobacter</i> induced aberrant expression of Aicda, a DNA editing enzyme, shown to induce TP53 mutations in human gastric epithelial cells in vitro.
P278 Does the six-minute walk test predict survival at one year and in the longer term in patients idiopathic pulmonary fibrosis (IPF)?
Authors: J Herridge, K Yuill, AH Kendrick
Journal: Thorax (2016)

Over 4000 new cases of IPF are diagnosed each year with a poor prognosis and median survival time of 3 to 5 years. Assessments of exercise performance using the 6-minute walk test (6MWT) have been shown to be useful in predicting survival in a variety of pulmonary conditions. <h3>Aim</h3> We wished to determine if indices of the six-minute walk test could predict survival in patients with IPF at one year and long-term survival. <h3>Methods</h3> We undertook a retrospective data analysis of patients with a confirmed diagnosis of IPF over the last 4 years. Data was obtained on 86 patients, who were divided into Group 1 – survivors (n = 56) and Group 2 – non-survivors (n = 30). Indices obtained from the 6MWT included SpO<sub>2</sub>, min, median SpO<sub>2</sub> rest, BORG scores, HR,rest and HR,max and distance walked. Spirometry, static lung volumes, and date of death were also recorded. Data are presented as median (IQR) in the format (Group 1 vs Group 2). Kaplan-Meier analysis was used to compared various indices and between groups. <h3>Results</h3> There was no significant differences between the two groups for FEV<sub>1</sub> (2.0 (0.58) vs 2.01 (0.55)), FVC (2.83 (1.16) vs 2.52 (0.88)) or TLC (4.19 (1.58) vs 4.09 (1.62)). From the 6 MWT, SpO<sub>2</sub>,rest was not significantly different (95 (2) vs 94 (5.5)), nor were HRrest, HRmax or BORG scores. There was a significant difference for SpO2, min (90 (8) vs 84 (13); p &lt; 0.01) and distance walked (380 (140) vs 340 (180); p &lt; 0.05). Kaplan-Meier analysis was used to assess outcomes for distance walked of &lt; or &gt;250 m and 350 m and SpO<sub>2</sub>, min &lt; or &gt;85% and 88%. For an SpO<sub>2</sub>, min cut-off of 85%, survival was 791 (&lt;85%) and 1181 (&gt;85%) days (p &lt; 0.05; hazard ratio 3.356). With a cut-off of 88%, survival was 757 (&lt;88%) and 1272 (&gt;88%) days (p = 0.0012; hazard ratio 3.161). Survival at one year as 84% (&lt;88%) and 91% (&gt;88%) (Figure). Distanced walked was not significantly different at cut-offs of 250 m or 350 m. <h3>Conclusions</h3> From this retrospective analysis, these results suggest that a cut-off for SpO<sub>2</sub>, min of 88% may be a useful predictor of survival at one year and in the longer term. Distance walked appears to contribute little to prediction of survival.
PWE-086 Ursodeoxycholic acid modulates the glucocorticoid receptor in oesophageal cells
Authors: D Prichard, R Sharma, A Byrne, D P Kelleher, J F Gilmer, A Long
Journal: Gut (2010)

Introduction Hydrophobic bile acids have been identified as aetiological agents in inflammatory oesophageal diseases. Ursodeoxycholic acid (UDCA) has been shown to attenuate the inflammatory effects of hydrophobic bile acids in numerous cell lines. This has been shown to be partly mediated by UDCA activation of the glucocorticoid receptor (GR). Here, we investigate the potential role of UDCA in modulating the GR in oesophageal cell lines. Methods Western blot analysis and RT-PCR were used to characterise GR expression in oesophageal cell lines (HET1A, SKGT-4). High Content Analysis (GE In-Cell analyser 1000) was used to investigate nuclear translocation of the GR in response to UDCA stimulation. Trans-activation of glucocorticoid response elements (GRE) was determined in a transient transfection assay using a construct of the human GRE promoter ligated to a firefly luciferase reporter gene Similarly trans-repression of NFKB was determined using a construct of the human NFKB promoter ligated to a luciferase reporter gene. Results GR was found to be present in the oesophageal cell lines used at the mRNA and protein levels. No GRβ was expressed at the mRNA level suggesting that the GR present is GRα. UDCA induced translocation of the GR in a time- and concentration-dependent manner (EC50 of 298.68 μM in SKGT-4 and 320 μM in HET1A cell lines, 54% and 36% efficacy of dexamethasone 100 nM, respectively, both p<0.05 relative to untreated control). UDCA activated the GRE at 300 μM (22% efficacy of dexamethasone 100 nM, p<0.05). UDCA was found to inhibit TNF-α stimulated NFKB activation in HEK-293 cells at 300 μM (100% efficacy of dexamethasone 100 nM, p<0.05). Conclusion Glucocorticoids are used as anti-inflammatory agents for treating a spectrum of diseases. Their chronic use is limited due to serious side effects, primarily thought to be due to GR-mediated transactivation. Here we show that UDCA can act as a GR modulator, with the ability to differentiate between transrepression and transactivation pathways. As a result UDCA may be of benefit in treating inflammatory conditions of the oesophagus.
3. Safety Assessment of SIN LVs Harboring Chromatin Insulators in the Sensitive Cdkn2a-/- In Vivo Genotoxicity Assay Show Enhancer-Blocking Activity of Specific Insulator Sequences
Authors: Monica Volpin, Andrea Calabria, Daniela Cesana, Erika Tenderini, Fabrizio Benedicenti, Koyel Mitra, Odile Cohen-Haguenauer, Luigi Naldini, Jack Lenz, George Stamatoyannopoulos, Eugenio Eugenio
Journal: Molecular Therapy (2015)

Chromatin insulators (CI) have been proposed as safety features to increase the safety of self-inactivating (SIN) lentiviral vectors (LV) for gene therapy applications. By taking advantage of an in vivo genotoxicity assay based on the systemic injection of LVs in newborn tumor-prone Cdkn2a-/- mice we were able to measure vector-induced genotoxicity as an accelerated tumor onset that was proportional to the genotoxic potential of the tested LV. Importantly, we took advantage of integration sites (IS) analysis to qualitatively characterize CI that were shown by other in vitro and ex vivo studies to function as insulators. Recently we showed for the first time that a CAAT-box binding Nuclear factor 1 (CTF/NF1)-based CI, when cloned in the LTRs of a SIN.LV with a strong SFFV enhancer-promoter in internal position, significantly reduced the frequency of tumors harboring integrations activating Map3k8 oncogene accompanied by a marked skewing towards tumors harboring inactivating insertions targeting Pten. Here by using this stringent in vivo genotoxicity assay and IS analysis in tumors we expanded our studies towards other CI sequences whose function is regulated by the binding of the CCCTC-binding factor (CTCF), the best characterized insulator protein in vertebrates. Each CTCF-based insulating cassette was cloned in the LTRs of a LV construct containing the SFFV promoter in internal position (CTCF.SIN.LVs) and injected in Cdkn2a-/- mice. Interestingly, mice treated with some of the CTCF.SIN.LVs tested displayed an increased median survival time (ranging from 193.5 to 214 days) compared to mice treated with the uninsulated parental SIN.LV (186 days). Importantly, our preliminary IS analysis in tumors (881 IS) showed that two CTCF.SIN.LVs did not target Map3k8 oncogene while Pten was often disrupted by exonic insertions, an escape genotoxicity mechanism on which CI cannot act. These data confirm that the inclusion of two novel CTCF-based CIs of human origin completely abrogated the formation of tumors caused by enhancer-mediated activation of an oncogene in vivo. The ability of these two new insulator elements to block the crosstalk between powerful vector enhancers and cellular regulatory elements increase the safety of SIN LVs and justify their prompt adoption in future gene therapy applications.
Using Nontraditional Risk Factors in Coronary Heart Disease Risk Assessment
Authors: Ned Calonge, Diana B. Petitti, Thomas G. DeWitt, Kimberly D. Gregory, Russell Harris, George Isham, Michael L. LeFevre, Carol Loveland-Cherry, Lucy N. Marion, Virginia A. Moyer, Judith K. Ockene, George F. Sawaya, Albert L. Siu, Steven M. Teutsch, Barbara P. Yawn, US Preventive Serv Task Force
Journal: Annals of Internal Medicine (2009)
Influence of potassium-competitive acid blocker on the gut microbiome of<i>Helicobacter pylori</i>-negative healthy individuals
Authors: Taketo Otsuka, Mitsushige Sugimoto, Ryo Inoue, Masashi Ohno, Hiromitsu Ban, Atsushi Nishida, Osamu Inatomi, Shunsuke Takahashi, Yuji Naito, Akira Andoh
Journal: Gut (2016)

We read with great interest two recent reports by Imhann et al 1 and Jackson et al .2 Through large population-cohort study, each group revealed that gastric acid inhibition by long-term use of proton pump inhibitors (PPIs) changes the gut microbiome to predispose to enteric infection including Clostridium difficile (CD) . Potassium-competitive acid blockers (P-CABs) have been reported to exert more potent gastric acid suppression than PPIs.3 ,4 The inhibitory effect of vonoprazan (TAK-438), a new P-CAB, on H+, K+-ATPase in vitro is approximately 400 times more potent than that of PPI (lansoprazole) (inhibitory concentration (IC)50 of vonoprazan 0.019 μM and lansoprazole 7.6 μM).5 We describe below that vonoprazan induces more complex alteration of the gut microbiome as compared with lansoprazole.

We enrolled serum Helicobacter pylori IgG-negative healthy individuals to eliminate the influence of H. pylori infection on gastric acid secretion (see online supplementary table S1). The PPI group (n=11) took 30 mg of lansoprazole daily for 4 weeks, and the P-CAB group …
Abstract 1123: Glutaminase inhibitors suppress pyrimidine synthesis and promote DNA replication stress in <i>VHL</i>-deficient human renal cancer cells
Authors: Arimichi Okazaki, Paulo Gameiro, Gregory Stephanopoulos, Othon Iliopoulos
Journal: Cancer Research (2015)

Abstract Hypoxic and VHL-deficient cells use glutamine to generate citrate and lipids through reductive carboxylation (RC) of a-ketoglutarate. To gain insights into the role of HIF and the molecular mechanisms underlying RC, we took advantage of a panel of disease associated Von Hippel-Lindau (VHL) mutants and showed that HIF2a expression is necessary and sufficient for the induction of RC in human renal cell carcinoma (RCC) cells. Reductive carboxylation can be detected in vivo. HIF2a-mediated glutamine metabolism is induced by low intracellular citrate levels, which promote the reductive flux by mass action to maintain lipogenesis. In addition to being a source of lipogenic acetyl-CoA, glutamine can be used in the Krebs cycle to generate aspartate - the carbon source for pyrimidine biosynthesis. We showed that VHL-deficient RCC cells rely on RC-derived aspartate to maintain de novo pyrimidine biosynthesis. Pharmacological inhibition of glutaminase (GLS) by the commercially available glutaminase inhibitor BPTES and a glutaminase inhibitor which is in Phase I clinical study (CB-839, Calithera Biosciences Inc) depleted the levels of pyrimidines in VHL-deficient cells but not in VHL-reconstituted cells, which utilized glucose oxidation to supply the aspartate pool. Nucleoside depletion activates an intra-S-phase checkpoint corresponding to DNA replication stress and suppressed S-phase transition in VHL-deficient RCC cells. DNA replication stress was rescued by administration of glutamate or dimethyl-alpha-ketoglutarate. Addition of nucleobases partially rescued the effect of glutaminase inhibitors on cell growth. Our data suggest that glutaminase inhibitors suppress de novo pyrimidine synthesis, leading to DNA replication stress in VHL-deficient RCC cells. We currently test the hypothesis that this mechanistic insight may allow the development of novel therapeutic strategies for RCC by combining glutaminase inhibitors with drugs promoting DNA replication stress. Citation Format: Arimichi Okazaki, Paulo Gameiro, Gregory Stephanopoulos, Othon Iliopoulos. Glutaminase inhibitors suppress pyrimidine synthesis and promote DNA replication stress in VHL-deficient human renal cancer cells. [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 1123. doi:10.1158/1538-7445.AM2015-1123
Depsipeptide in the Treatment of Relapsed and Refractory Multiple Myeloma (MM): A Prospective Evaluation of the Cell Cycle.
Authors: Zoe Goldberg*, Scott Ely, Selina Chen-Kiang, Martha Chesi, Peter L. Bergsagel, Karen Pekle*, Larry Lyons*, Udi Gelbshtein*, Roger Pearse, John Harpel, Hearn Cho, Morton Coleman, Ruben Niesvizky
Journal: Blood (2004)
Oral Acyclovir Is an Effective in Decreasing the Incidence of Bortezomib Associated Herpes Zoster in Patients with Multiple Myeloma.
Authors: Dawn DePaolo, Kena C. Miller, Amy Whitworth, Alice Mohr, Terry L. Mashtare, Gregory Wilding, Sikander Ailawadhi, Swaminathan Padmanabhan, Asher A. Chanan-Khan
Journal: Blood (2007)
Abstract 3030: De novo engineering of chromosomal amplifications in human cells
Authors: Josh Lauring
Journal: Cancer Research (2015)

Abstract Chromosomal amplifications are among the most common genetic alterations found in human cancers. However, experimental systems to study the processes that lead to recurrent amplification events are lacking. Moreover, some common amplification events, such as that at 8p11-12 in breast cancer, harbor multiple candidate driver oncogenes, which are poorly modeled by conventional overexpression approaches. We sought to develop an experimental system to model recurrent chromosomal amplification events in human cell lines. Our general strategy is to use homologous-recombination-mediated gene targeting to deliver a dominantly selectable, amplifiable marker to a specified chromosomal location. We chose regions recurrently amplified at high frequency in breast cancer, including 8p11-12, 17q12, and 11q13-14. After confirmation of successful gene targeting, the targeted cells are subjected to selective pressure directed at the amplifiable marker. Spontaneous DNA breakage events lead to varying degrees of co-amplification of linked loci near the targeting site. We used adeno-associated virus vectors to target human MCF-7 breast cancer cells at the ZNF703 locus, in the recurrent 8p11-12 amplicon, using either the E. coli inosine monophosphate dehydrogenase enzyme IMPDH or a mutant dihydrofolate reductase gene as a marker. We applied selective pressure using IMPDH inhibitors. Surviving clones were found to have increased copy number of ZNF703 (average 2.5-fold increase) by droplet digital PCR. Genome-wide array comparative genomic hybridization confirmed that amplification had occurred on the short arm of chromosome 8, without changes on 8q or other chromosomes. Patterns of amplification were variable and similar to those seen in primary human breast cancers, including “sawtooth” patterns, distal copy number loss suggesting a breakage-fusion-bridge mechanism, and large continuous regions of copy number gain. Amplification was confirmed by FISH. RT-PCR and immunoblotting demonstrated overexpression of selected amplified transcripts and proteins. In summary, we have used genome engineering techniques to create focal chromosomal amplification events de novo in human cell lines. These amplifications share many of the features of amplifications observed in primary human cancers. This system will allow study of the cis- and trans-acting factors that are permissive for chromosomal amplification and provide a system to model oncogene cooperativity in amplifications harboring multiple candidate driver genes. Citation Format: Josh Lauring. De novo engineering of chromosomal amplifications in human cells. [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 3030. doi:10.1158/1538-7445.AM2015-3030