tbuckley/cabot-search huggingface dataset:
Abstract 113: Defining the metabolic regulation of epigenetics using chemical proteomics
Authors: Jordan L. Meier, David C. Montgomery, Alexander W. Sorum, Rhushikesh A. Kulkarni
Journal: Cancer Research (2015)

Abstract Substantial evidence indicates that chromatin modifiers are sensitive to changes in the cellular concentration of metabolites and cofactors. These findings potentially connect metabolism and gene expression, and have major implications for the regulation of cell signaling in cancer. However, missing from many of these studies has been the direct identification of the specific chromatin modifiers that sense change in metabolic state. Their identification is critical to our basic understanding of how metabolism regulates epigenetically-driven phenotypes, and may inform novel strategies to restore balance in metabolically-perturbed cancers. Towards this goal, here we report a strategy to directly define the metabolic regulation of epigenetic signaling using chemical proteomics. Our initial efforts have focused on understanding the metabolic regulation of lysine acetyltransferases (KATs), a major class of chromatin modifiers responsible for protein acetylation. We demonstrate that chemoproteomic probes can report on the interaction of acyl-CoA metabolites with KAT active sites, and when combined with affinity purification and LC-MS/MS analysis, highlight an expanded landscape of acetyltransferases present in the human genome. Next-generation chemoproteomic methods highlight the interactions of metabolic acyl-CoAs with megadalton lysine acetyltransferase protein complexes, which have implications for the regulation of KAT activity by cellular acyl-CoA pools. By defining the molecular links connecting metabolism and gene expression,these approaches will illuminate our understanding of cancer biology and inspire new therapeutic strategies to combat cancer. Citation Format: Jordan L. Meier, David C. Montgomery, Alexander W. Sorum, Rhushikesh A. Kulkarni. Defining the metabolic regulation of epigenetics using chemical proteomics. [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 113. doi:10.1158/1538-7445.AM2015-113
Complementary Tolls in the periodontium: how periodontal bacteria modify complement and Toll-like receptor responses to prevail in the host
Authors: Jennifer L. Krauss, Jan Potempa, John D. Lambris, George Hajishengallis
Journal: Periodontology 2000 (2009)

The complement and the Toll-like receptors are rapidly activatable systems which, in concert, provide first-line innate defense against infection and act as mediators between the innate and the adaptive immune response.The ability of periodontal bacteria to persist and establish chronic infections in the periodontium suggests that they may have evolved strategies to evade, disarm, or subvert these defense systems to their own advantage.Indeed, accumulating evidence indicates that at least some of the major periodontal pathogens utilize ingenious mechanisms to not only undermine each system separately, but also exploit crosstalk points between the complement and the Toll-like receptor pathways.It is conceivable that immune subversive activities by certain keynote periodontal pathogens, such as those comprising the so-called "red complex", may be critical for the persistence of the entire mixed-species biofilm community in the diseased periodontium.This review summarizes and synthesizes recent discoveries in this field, which offers important insights into the pathology associated with the complex periodontal host-microbe interplay.
Brief Report: Inadequate Description and Discussion of Enrolled Patient Characteristics and Potential Inter-Study Site Differences in Reports of Randomized Controlled Trials: A Systematic Survey in Six Rheumatology Journals
Authors: Sebahattin Yurdakul, Bediha Nezhdi Mustafa, Izzet Fresko, Emire Seyahi, Hasan Yazici
Journal: Arthritis & Rheumatology (2014)

Detailed information on patient recruitment and study settings is an important component of reports of randomized controlled trials (RCTs). We had the impression that many RCTs published in rheumatology journals lacked this information. This study was undertaken to systemically survey this matter in 6 leading journals.A hand search was conducted for RCTs published in 2011 and 2012 in Arthritis & Rheumatism, Annals of the Rheumatic Diseases, Rheumatology (Oxford), Arthritis Care & Research, The Journal of Rheumatology, and Clinical and Experimental Rheumatology. Using the Consolidated Standards of Reporting Trials (CONSORT) guidelines, 2 observers evaluated the articles for the inclusion of patient eligibility criteria, including method of recruitment; study health care settings; geographic location; and, among multicenter studies, a discussion of possible effects of intercenter differences on outcomes.Among 118 articles, an informative account of the method of recruitment was available in 36 (30.5%). Information about the study health care setting was found in 56 (47.5%). Patient socioeconomic profile was available in 11 (9.3%), patient education level in 10 (8.4%), and patient race in 48 (40.7%). Among 76 multicenter studies, the potential effects of possible intercenter differences on outcome were discussed in 13 (17.1%). There were no important differences between the 3 journals that emphasized the use of CONSORT in their author guidelines and the remaining 3 journals.Adequate information on patient recruitment, the trial setting, and a discussion of possible multicenter design effects on outcomes are lacking in the majority of RCT reports in rheumatology. This affects the validity of these reports and calls for closer attention of authors, journals, and reviewers.
CHEMICAL AND HISTOCHEMICAL STUDY OF THE EFFECT OF TRANSPLANTED TUMOR UPON ACTIVITY OF ADRENAL NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE DIAPHORASE IN RATS.
Authors: Kihyoe Ichinoe, Jeffrey P. Chang, Clarmon A. Sumrall
Journal: Cancer Research (1965)

Chemical and histochemical studies were conducted to determine the effect of progressive tumor growth upon the activity of the diaphorase of reduced nicotinamide adenine dinucleotide phosphate (NADPH) in the adrenal glands of the host. Walker carcinosarcoma 256, Novikoff hepatoma, and a new hepatoma induced in our laboratory were transplanted into male Sprague-Dawley rats. As the tumors grew, the activity of the enzyme in the cortices became elevated in conjunction with adrenal hypertrophy and thymic involution. Similar results, other than in the zona glomerulosa, were obtained in studies of the adrenal glands of tumor-free rats receiving injections of adrenocorticotropic hormone (ACTH). Adrenal hypertrophy and thymic involution, as well as the high enzymatic activity in the inner cortical zones, caused by the tumor growth, were inhibited by hypophysectomy. Interestingly, the high activity of the enzyme in the glomerulosa was observed not only in tumor-bearing intact rats, but also in tumor-bearing hypophysectomized rats. In addition, this increased activity appeared in a much earlier stage of tumor growth than that observed in the inner cortices of tumor-bearing intact animals. The activity in the glomerulosa of tumor-free intact and of tumor-free hypophysectomized rats, however, was increased only slightly by injections of ACTH.

From these enzymatic patterns, it appears that tumor growth affects the activity of the NADPH diaphorase in the glomerulosa of the adrenal cortex by an unknown pathway; in the fascicular and reticular zones the effect appears to be mediated through the pituitary-adrenal axis.
Abstract 73: Ewing's sarcoma Ewsa protein regulates Sox9 during skeletogenesis in zebrafish
Authors: Chris Merkes, Timothy K. Turkalo, Nicole Wilder, Hyewon Park, Mizuki Azuma
Journal: Cancer Research (2014)

Abstract Ewing's sarcoma is the second most common bone cancer in adolescents and is characterized by the aberrant chimeric fusion gene EWS/FLI1. Wild-type EWS has been proposed to play a role in splicing and transcription, but how these functions affect early development is unknown. To elucidate the function of EWS in early development, we analyzed a mutant ewsa zebrafish line. We generated a maternal zygotic (MZ) ewsa/ewsa line because the ewsa/wt and ewsa/ewsa zebrafish appear to be normal and fertile. The adult MZ ewsa/ewsa mutants display defects in the craniofacial bones (dentary and basihyal). Compared to wt/wt, the MZ ewsa/ewsa mutants have a higher number of craniofacial prehypertrophic chondrocytes, and they fail to mature into hypertrophic chondrocytes possibly due to impaired intercalation at 4 days post-fertilization (dpf). The adult MZ ewsa/ewsa mutants also display curved spines due aberrant differentiation of the nucleus pulposus cells in the intervertebral discs (IVD). These altered differentiation is preceded by increased Collagen type II in the IVD, and Ctgf in the craniofacial chondrocytes in MZ ewsa/ewsa mutants compared to wt/wt at 36 hpf. We further discovered that both Ewsa and Ewsb interact with the master transcriptional factor for chondrogenesis, Sox9, in zebrafish. Consistently, qPCR analysis consistently demonstrated that Sox9 target genes are either upregulated (ctgfa, ctgfb, col2a1a, col2a1b) or downregulated (sox5, nog1, nog2, bmp4) in MZ ewsa/ewsa mutants compared to the wt/wt zebrafish embryos. This study is the first demonstration of Ewsa-dependent regulation of skeletogenesis through modulation of Sox9 target gene expression. Citation Format: Chris Merkes, Timothy K. Turkalo, Nicole Wilder, Hyewon Park, Mizuki Azuma. Ewing's sarcoma Ewsa protein regulates Sox9 during skeletogenesis in zebrafish. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 73. doi:10.1158/1538-7445.AM2014-73
Abstract 1942: Lgl1 loss promotes stemness and invasion in EGFRvIII-driven gliomas
Authors: Sandra Gomez-Lopez, Robin G. Lerner, Claudia Petritsch
Journal: Cancer Research (2014)

Abstract Stem and progenitor cells may divide asymmetrically to self-renew and produce differentiating progeny in a single division. Usually, during an asymmetric cell division (ACD), determinants of self-renewal and differentiation segregate to opposite daughter cells during mitosis and thereby specify distinct cell fates. Disruption of ACD is seen in many cancers with a stem or progenitor cell component, including malignant gliomas (Sugiarto et al., 2011, Cancer Cell 20:328-40). Yet, it is not clear whether this is a contributing factor or a consequence of neoplastic transformation. Lethal giant larvae 1 (Lgl1), a gene that was initially identified as a tumor suppressor in Drosophila, has been implicated in the asymmetric localization of cell fate determinants in neural progenitor cells (Klezovitch et al., 2004, Genes Dev 18:559-571). Here, we investigated the effects of Lgl1 depletion on distinct hallmarks of glioma. In murine neural progenitor cells carrying conditional null alleles of Lgl1 (Klezovitch et al., 2004, Genes Dev 18:559-571), depletion of Lgl1 resulted in reduced rates of ACD, increased expression of progenitor markers and impaired differentiation. In an orthotopic model of glioma, driven by expression of EGFRvIII, a frequent and constitutively active mutant form of epidermal growth factor receptor (EGFR), Lgl1 inactivation led to increased tumor invasiveness. Our data suggest that disruption of ACD in glioma precursor cells promotes maintenance of progenitor features and hampers differentiation. At later stages of gliomagenesis, loss of ACD and cell polarity controls may contribute to tumor invasiveness. Citation Format: Sandra Gomez-Lopez, Robin G. Lerner, Claudia Petritsch. Lgl1 loss promotes stemness and invasion in EGFRvIII-driven gliomas. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1942. doi:10.1158/1538-7445.AM2014-1942
ABT-869 a novel multi-targeted receptor tyrosine kinase inhibitor: characterization of FLT3 phosphorylation in a model of acute myelogenous leukemia
Authors: Junling Li, Lori J. Pease, Paul Tapang, J. Owen McCall, Ru-Qi Wei, Daniel H. Albert, Yujia Dai, Kresna Hartandi, Michael R. Michaelides, Steven K. Davidsen, Keith B. Glaser
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

5981 

Acute myeloid leukemia (AML) is associated with dysregulated hematopoietic cell proliferation, and in 15-30% of AML patients the aberrant proliferation is a consequence of a mutation in the juxtamembrane region of the FLT3 gene (FLT3-ITD) that causes the kinase to be constitutively active. Clinically, the FLT3-ITD mutation is a negative prognostic factor in AML. ABT-869 is a potent small molecule inhibitor of FLT3, as well as other VEGFR and PDGFR family members. In vitro , ABT-869 inhibited the phosphorylation of KDR, PDGFRβ, c-Kit, and FLT3 in a variety of endothelial, engineered and cancer cell lines. The proliferation of MV-4-11 AML cells is dependent on the FLT3-ITD mutation and ABT-869 potently inhibited their proliferation (IC50 value of 4 nM), but was less effective against cells harboring wt-FLT3. In addition to inhibition of FLT3 phosphorylation in MV-4-11 cells, ABT-869 also inhibited the phosphorylation of the downstream kinase signaling molecules STAT5 and ERK. In vivo ABT-869 demonstrated pronounced regression of established MV-4-11 xenograft tumors and inhibition of FLT3 phosphorylation in the MV-4-11 tumors grown in the flank of SCID mice. As cells in normal human peripheral blood do not contain measurable amounts of FLT3, an ex vivo model was developed where AML cells were spiked into human blood, mimicking the clinical setting and enabling a more rigorous analysis of the effects of ABT-869. Human peripheral blood was taken from healthy donors, spiked with MV-4-11 cells, incubated with ABT-869 for 2 hr to inhibit the constitutive FLT3-ITD and lysed for analysis. Phosphorylated FLT3 was detected by immunoprecipitation with an anti-FLT3 antibody followed by Western analysis using a phosphotyrosine specific antibody (4G10). Inhibition of FLT3 phosphorylation was observed with an approximate IC50 value of 100 nM for ABT-869. Concentration-dependent inhibition of phosphorylation of STAT5 and ERK by ABT-869 were also observed in this AML model. In normal human bone marrow containing wild-type FLT3, ABT-869 inhibited FLT3 ligand-induced auto-phosphorylation with an IC50 value of 10 nM. These results provide some insight into the mechanism of action of ABT-869 that could be transferred to the clinical setting as a biomarker of ABT-869 activity.
PPAR-α and PPAR-γ activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway
Authors: Giulia Chinetti, Sophie Lestavel, Virginie Bocher, Alan T. Remaley, Bernadette Neve, Inés Pineda Torra, Elisabeth Teissier, Anne Minnich, Michael Jaye, Nicolas Duverger, H. Bryan Brewer, Jean-Charles Fruchart, Véronique Clavey, Bart Staels
Journal: Nature Medicine (2001)
The Soluble Interleukin-6 (IL-6) Receptor/IL-6 Fusion Protein Enhances In Vitro Maintenance and Proliferation of Human CD34+CD38−/low Cells Capable of Repopulating Severe Combined Immunodeficiency Mice
Authors: Orit Kollet, Ronit Aviram, Judith Chebath, Herzl ben-Hur, Arnon Nagler, Leonard Shultz, Michel Revel, Tsvee Lapidot
Journal: Blood (1999)
Abstract 271: Rising rates of acute lymphocytic leukemia in Hispanic children: A review of trends in childhood leukemia incidence from 1973-2010
Authors: Jessica Barrington-Trimis, Myles Cockburn, Catherine Metayer, W. James Gauderman, Joseph Wiemels, Roberta McKean-Cowdin
Journal: Cancer Research (2014)

Abstract Background: Childhood leukemia is the most common cancer in children under 20 years of age in the United States, and incidence rates have increased over the last few decades. The incidence rate for all childhood leukemia is higher among Hispanic children [2006-2010 age-adjusted incidence rate (AAIR)= 5.71; 95%CI: 5.47, 5.97] than among non-Hispanic White children (2006-2010 AAIR=3.95; 95%CI: 3.81, 4.09). This analysis aims to describe secular trends from 1992-2010 in the incidence of childhood leukemia, independently for Hispanic and non-Hispanic children. Methods: Surveillance, Epidemiology and End Results (SEER) data were used to evaluate trends in the incidence of childhood leukemia diagnosed in children less than 20 years of age between 1992-2010 by ethnicity. Trends among Hispanic and non-Hispanic children were examined overall and by age, gender, and histologic subtype. AAIRs, annual percent change (APC) estimates, and 95% confidence intervals (95%CIs) were calculated using SEER*stat v.8.0.4. Results: Hispanic children were more likely than non-Hispanic children to be diagnosed with leukemia (all subtypes combined), and with acute lymphocytic leukemia when examined by gender and by age (0-4, 5-9, 10-14, 15-19 years at diagnosis). A greater increase in AAIRs was observed for Hispanic children as compared to non-Hispanic children for all types of leukemia from 1992-2010 (APCHispanic=1.16; 95%CI: 0.55, 1.76; APCnon-Hispanic=0.52; 95%CI: 0.01, 1.03). When restricting to acute lymphocytic leukemias (ALL), statistically significant increases were observed for Hispanic children (APC=1.31; 95%CI:0.68, 1.94), but not for non-Hispanic children (APC=0.50; 95%CI: -0.19, 1.19). Among Hispanic children, the strongest increase was found among children diagnosed from 10-19 years of age. Incidence rates were higher for Hispanic males (AAIR=5.26; 95%CI: 4.93, 5.60;) than for Hispanic females (AAIR=4.07; 95%CI: 3.78, 4.39). Conclusion: Incidence rates of childhood leukemia rose from 1992-2010, with the greatest increase for ALL among older Hispanic children (aged 10-19 years). In future studies aimed at evaluating exposures responsible for increasing incidence rates of childhood ALL, researchers should consider risk factors that may explain the rising rates among Hispanic children. Citation Format: Jessica Barrington-Trimis, Myles Cockburn, Catherine Metayer, W. James Gauderman, Joseph Wiemels, Roberta McKean-Cowdin. Rising rates of acute lymphocytic leukemia in Hispanic children: A review of trends in childhood leukemia incidence from 1973-2010. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 271. doi:10.1158/1538-7445.AM2014-271
The Role of Physicians in the Era of Predictive Analytics
Authors: Allan D. Sniderman, Ralph B. D’Agostino Sr, Michael J. Pencina
Journal: JAMA (2015)

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Evaluation of Acute Dual-Chamber Pacing With a Range of Atrioventricular Delays on Cardiac Performance in Refractory Heart Failure 11All editorial decisions for this article, including selection of referees, were made by a Guest Editor. This policy applies to all articles with authors from the University of California San Francisco.
Authors: Jerold S Shinbane, Edward Chu, Teresa DeMarco, Yuri Sobol, Adam P Fitzpatrick, Debra M Lau, Cindy Klinski, Nelson B Schiller, Jerry C Griffin, Kanu Chatterjee
Journal: Journal of the American College of Cardiology (1997)
RAS mutations are rare events in Philadelphia chromosome-negative/bcr gene rearrangement-negative chronic myelogenous leukemia, but are prevalent in chronic myelomonocytic leukemia
Authors: C Hirsch-Ginsberg, AC LeMaistre, H Kantarjian, M Talpaz, A Cork, EJ Freireich, JM Trujillo, MS Lee, SA Stass
Journal: Blood (1990)
Endovascular Presence of Viable Chlamydia pneumoniaeIs a Common Phenomenon in Coronary Artery Disease 11This study was supported in part by the Research Commission of the Medical University of Lübeck (8/96) and the Deutsche Forschungsgemeinschaft (SFB 367/B2), Bonn, Germany.
Authors: Matthias Maass, Claus Bartels, Peter M Engel, Uwe Mamat, Hans-Hinrich Sievers
Journal: Journal of the American College of Cardiology (1998)
Gene Transfer of a Broad Spectrum CC-Chemokine Inhibitor Reduces Vein Graft Atherosclerosis in Apolipoprotein E–Knockout Mice
Authors: Ziad A. Ali, Christina A. Bursill, Yanhua Hu, Robin P. Choudhury, Qingbo Xu, David R. Greaves, Keith M. Channon
Journal: Circulation (2005)

Background— Accelerated atherosclerosis is a major cause of vein graft failure after bypass surgery. Several CC-chemokines (CC-CKs) mediate monocyte/macrophage recruitment in native atherosclerotic plaques; we hypothesized that CC-CKs may be critical in the development of accelerated atherosclerosis in vein grafts. Methods and Results— Using in vivo gene transfer, we administered a soluble CC-CK binding protein (“35K”) to apolipoprotein E–knockout (ApoE−/−) mice that underwent interposition bypass grafting of the vena cava from isogenic donor mice to the common carotid artery. Two days before operation, a recombinant adenovirus encoding either 35K (Ad35K) or green fluorescent protein (AdGFP; control) was injected into recipient mice via the tail vein. 35K greatly reduced CC-CK activity in mouse plasma. After 14 days, vein graft atherosclerotic lesion area, smooth muscle α-actin–positive neointimal area, and total vessel wall thickness were strikingly reduced by Ad35K gene transfer compared with AdGFP controls. Furthermore, 35K gene transfer dramatically reduced macrophage content by ≈90% and cell proliferation by 95%. After 28 days, lesion area and vessel wall thickness remained significantly less in Ad35K mice. Conclusion— A single intravenous injection of the CC-CK inhibitor 35K significantly reduced atherosclerosis in carotid–caval vein grafts in ApoE−/− mice. This study highlights the importance of the CC-CK class in accelerated atherosclerosis, and its role as a potential target for improving vein graft patency.