tbuckley/cabot-search huggingface dataset:
Variable expression of the estrogen receptor in normal and atherosclerotic coronary arteries of premenopausal women.
Authors: D W Losordo, M Kearney, E A Kim, J Jekanowski, J M Isner
Journal: Circulation (1994)

BACKGROUND The relative absence of coronary atherosclerosis in premenopausal women has been established. Estrogen is presumed to play a role in the protection of coronary arteries from atherosclerosis, and part of this protective effect appears to be mediated by amelioration of serum lipid profiles. However, all of the atheroprotective effect of estrogen is not explained by alteration of serum lipids. In this study, we attempt to identify evidence of estrogen receptors in coronary artery specimens of female patients and in human vascular smooth muscle cells. METHODS AND RESULTS Postmortem coronary artery specimens were obtained from premenopausal (n = 18) and postmenopausal (n = 22) women who died with significant coronary artery disease (n = 19) and from noncardiac causes with normal coronary arteries (n = 21). Sections were examined for evidence of estrogen receptor expression using a monoclonal antibody stain. Radioligand binding assays for estrogen receptors were performed on human vascular smooth muscle cells in culture, and gel retardation assays were performed to confirm the presence of functional estrogen receptors. Estrogen receptor expression was identified by immunostaining in a total of 21 coronary arteries, with the majority of normal arteries (15 positive of 21 total, P = .0117) demonstrating evidence of estrogen receptor expression. Conversely, a minority (6 of 19, P = NS) of atherosclerotic arteries were positive for estrogen receptor expression. Furthermore, the relation between estrogen receptor expression and absence of coronary atherosclerosis was most evident in premenopausal subjects, with 10 of 12 normal arteries in this group demonstrating evidence of estrogen receptors, whereas only 1 of 6 atherosclerotic coronary arteries was positive (P = .0062). Radioligand binding assays confirmed the presence of estrogen receptors at significant concentrations in intact human vascular smooth muscle cells. Gel retardation assays also documented the presence of functional estrogen receptors in extracts from human vascular smooth muscle cells. CONCLUSIONS This investigation provides evidence of estrogen receptors in smooth muscle cells from human coronary arteries. The demonstrated relation between the presence of the receptors and the absence of atherosclerosis in premenopausal women suggests that these receptors may play a functional role in coronary atheroprotection.
A novel variant of lysosomal acid lipase in cholesteryl ester storage disease associated with mild phenotype and improvement on lovastatin
Authors: Christoph Gasche, Charalampos Aslanidis, Renate Kain, Markus Exner, Thomas Helbich, Clemens Dejaco, Gerd Schmitz, Peter Ferenci
Journal: Journal of Hepatology (1997)
Cutaneous β-glucuronidase: cleavage of mycophenolic acid by preparations of mouse skin
Authors: EDWARD C. GOMEZ, J. MICHAELOVER, PHILLIP FROST
Journal: British Journal of Dermatology (1977)

Mycophenolic acid, a new chemotherapeutic agent for the treatment of psoriasis, is known to be rapidly conjugated on absorption and to circulate largely in the form of its glucuronide conjugate. Since this metabolite does not readily penetrate intact cells and is cleaved by the enzyme beta-glucuronidase to yield free mycophenolic acid, the ability of preparations of mouse skin to cleave mycophenolic glucuronide was studied. The time course of mycophenolic acid liberation by such preparations and the dependence upon the amount of enzyme preparation were demonstrated. Preparations of mouse skin and mouse liver, kidney, spleen, lung, heart and small intestine were assayed for beta-glucuronidase activity using p-nitrophenyl-beta-D-glucuronide as substrate. Skin yielded preparations with higher beta-glucuronidase activity per/mg protein than any of the other organs tested. When expressed on the basis of beta-glucuronidase activity recovered per milligram of tissue DNA, skin, liver and kidney showed higher levels than the other organs tested.
Detection of Mutant Free Circulating Tumor DNA in the Plasma of Patients with Gastrointestinal Stromal Tumor Harboring Activating Mutations of <i>CKIT</i> or <i>PDGFRA</i>
Authors: Jacqueline Maier, Thoralf Lange, Irina Kerle, Katja Specht, Melanie Bruegel, Claudia Wickenhauser, Philipp Jost, Dietger Niederwieser, Christian Peschel, Justus Duyster, Nikolas von Bubnoff
Journal: Clinical Cancer Research (2013)

Abstract Purpose: In gastrointestinal stromal tumor (GIST), there is no biomarker available that indicates success or failure of therapy. We hypothesized that tumor-specific v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (CKIT)- or platelet-derived growth factor receptor-α (PDGFRA)–mutant DNA fragments can be detected and quantified in plasma samples of patients with GIST. Experimental Design: We prospectively collected 291 plasma samples from 38 subjects with GIST harboring activating mutations of CKIT or PDGFRA detected in tumor tissue, irrespective of current disease status or treatment. We used allele-specific ligation PCR to detect mutant free circulating DNA (fcDNA). Results: We were able to detect fcDNA harboring the tumor mutation in 15 of 38 patients. Patients with active disease displayed significantly higher amounts of mutant fcDNA compared with patients in complete remission (CR). The amount of mutant fcDNA correlated with disease course. We observed repeated positive test results or an increase of mutant fcDNA in five patients with progressive disease or relapse. A decline of tumor fcDNA or conversion from positive to negative was seen in five patients responding to treatment. A negative to positive conversion was seen in two patients with relapse and one patient with progression. In two cases, we aimed to identify additional mutations and found four additional exchanges, including mutations not known from sequentially conducted tumor biopsies. Conclusions: Our results indicate that fcDNA harboring tumor-specific mutations in the plasma of patients with GIST can be used as tumor-specific biomarker. The detection of resistance mutations in plasma samples might allow earlier treatment changes and obviates the need for repeated tumor biopsies. Clin Cancer Res; 19(17); 4854–67. ©2013 AACR.
<i>SETD2</i>histone modifier loss in aggressive GI stromal tumours
Authors: Kie Kyon Huang, John R McPherson, Su Ting Tay, Kakoli Das, Iain Beehuat Tan, Cedric Chuan Young Ng, Na-Yu Chia, Shen Li Zhang, Swe Swe Myint, Longyu Hu, Vikneswari Rajasegaran, Dachuan Huang, Jia Liang Loh, Anna Gan, Alisa Noor Hidayah Sairi, Xin Xiu Sam, Lourdes Trinidad Dominguez, Minghui Lee, Khee Chee Soo, London Lucien Peng Jin Ooi, Hock Soo Ong, Alexander Chung, Pierce Kah-Hoe Chow, Wai Keong Wong, Sathiyamoorthy Selvarajan, Choon Kiat Ong, Kiat Hon Lim, Tannistha Nandi, Steve Rozen, Bin Tean Teh, Richard Quek, Patrick Tan
Journal: Gut (2015)

<h3>Background</h3> GI stromal tumours (GISTs) are clinically heterogenous exhibiting varying degrees of disease aggressiveness in individual patients. <h3>Objectives</h3> We sought to identify genetic alterations associated with high-risk GIST, explore their molecular consequences, and test their utility as prognostic markers. <h3>Designs</h3> Exome sequencing of 18 GISTs was performed (9 patients with high-risk/metastatic and 5 patients with low/intermediate-risk), corresponding to 11 primary and 7 metastatic tumours. Candidate alterations were validated by prevalence screening in an independent patient cohort (n=120). Functional consequences of <i>SETD2</i> mutations were investigated in primary tissues and cell lines. Transcriptomic profiles for 8 GISTs (4 <i>SETD2</i> mutated, 4 <i>SETD2</i> wild type) and DNA methylation profiles for 22 GISTs (10 <i>SETD2</i> mutated, 12 <i>SETD2</i> wild type) were analysed. Statistical associations between molecular, clinicopathological factors, and relapse-free survival were determined. <h3>Results</h3> High-risk GISTs harboured increased numbers of somatic mutations compared with low-risk GISTs (25.2 mutations/high-risk cases vs 6.8 mutations/low-risk cases; two sample t test p=3.1×10<sup>−5</sup>). Somatic alterations in the <i>SETD2</i> histone modifier gene occurred in 3 out of 9 high-risk/metastatic cases but no low/intermediate-risk cases. Prevalence screening identified additional <i>SETD2</i> mutations in 7 out of 80 high-risk/metastatic cases but no low/intermediate-risk cases (n=29). Combined, the frequency of <i>SETD2</i> mutations was 11.2% (10/89) and 0% (0/34) in high-risk and low-risk GISTs respectively. <i>SETD2</i> mutant GISTs exhibited decreased H3K36me3 expression while <i>SETD2</i> silencing promoted DNA damage in GIST-T1 cells. In gastric GISTs, <i>SETD2</i> mutations were associated with overexpression of <i>HOXC</i> cluster genes and a DNA methylation signature of hypomethylated heterochromatin. Gastric GISTs with <i>SETD2</i> mutations, or GISTs with hypomethylated heterochromatin, showed significantly shorter relapse-free survival on univariate analysis (log rank p=4.1×10<sup>−5</sup>). <h3>Conclusions</h3> Our data suggest that <i>SETD2</i> is a novel GIST tumour suppressor gene associated with disease progression. Assessing <i>SETD2</i> genetic status and <i>SETD2</i>-associated epigenomic phenotypes may guide risk stratification and provide insights into mechanisms of GIST clinical aggressiveness.
Spred-2 Suppresses Aorta-Gonad-Mesonephros Hematopoiesis by Inhibiting MAP Kinase Activation
Authors: Ikuo Nobuhisa, Reiko Kato, Hirofumi Inoue, Makiko Takizawa, Keisuke Okita, Akihiko Yoshimura, Tetsuya Taga
Journal: The Journal of Experimental Medicine (2004)

In midgestation mouse embryos, the aorta-gonad-mesonephros (AGM) region generates hematopoietic stem cells and definitive hematopoiesis is regulated by cell–cell interaction and signaling molecules. We showed that a Ras/mitogen-activated protein (MAP) kinase signaling-specific inhibitor and a dominant negative mutant Ras blocked the production of CD45+ hematopoietic cells in embryonic day 11.5 AGM culture, indicating an essential role for the MAP kinase pathway in AGM hematopoiesis. Overexpression of the Ras/MAP kinase pathway regulator, Spred-2, in the AGM culture significantly reduced the number of CD45+ cells. In contrast, production of CD45+ cells from the AGM region of Spred-2–null mice was up-regulated as compared with wild-type littermates. Furthermore, Spred-2–deficient mice exhibited elevated hematopoietic colony formation from vascular endothelial-cadherin+ cells. These data indicate that Spred-2 functions as a negative regulator of AGM hematopoiesis by inhibiting hematopoietic cytokine signaling.
Separation of helper and suppressor T lymphocytes. II. Ly phenotypes and lack of DNA synthesis requirement for the generation of concanavalin A helper and suppressor cells.
Authors: H Y Tse, R W Dutton
Journal: The Journal of Experimental Medicine (1977)

Using a Ficoll velocity sedimentation gradient, we have been able to fractionate concanavalin A (Con A)-induced helper and suppressor cells into separate pools. Cells activated by Con A to mediate helper activity are Ly1+, do not require DNA synthesis for induction, and remain as small cells after activation. Suppressor cells are Ly23+, are found in the blast cell fraction and their induction is not inhibitable by prior treatment with mitomycin C or irradiation, both of which inhibit DNA synthesis. The implications of such findings are discussed.
RhDNase I Aerosol Deposition and Related Factors in Cystic Fibrosis
Authors: PATRICE DIOT, LUCY B. PALMER, ARLENE SMALDONE, JOAN DeCELIE-GERMANA, ROGER GRIMSON, GERALD C. SMALDONE
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

To identify factors influencing lung dose of aerosolized recombinant human deoxyribonuclease (rhDNase I), we used gamma camera and filter techniques to measure deposition in 15 clinically stable patients with cystic fibrosis (CF) (five males and 10 females, age 6-31 yr, mean 16.9) who were on chronic daily therapy. Total and regional deposition were correlated with breathing pattern, pulmonary function, demographic factors, and disease severity. In addition, the effects of each patient's measured lung dose on pulmonary function was estimated by stopping the drug and observing changes in spirometry over a 2-wk follow-up period. After discontinuance of the drug, all patients reported worsening of dyspnea and difficulty producing sputum. There was a significant decrease in FEV1 (% predicted, mean +/- SE, 86.9% +/- 5.57 to 77.8% +/- 5.73, p < 0.005), but all patients completed the study. In some patients, as much as 48% of the deposited aerosol was found in the pharynx (range 0.0 to 0.30 mg, mean 0.089 mg +/- 0.029), and pharyngeal deposition correlated negatively with tidal volume (r = -0.696, p < 0.006) and age (r = -0.743, p < 0.005). For the lungs, deposition ranged between 0.16 mg and 0.78 mg of the 2.5 mg nebulizer dose (mean 0.47 +/- 0.04 mg) and correlated negatively with FEV1 (% predicted, r = -0.611, p = 0.0152). However, the spirometric decrements following cessation of therapy did not correlate with the lung dose of the drug. Analysis of regional deposition within the lungs indicated a wide range of distribution between central and peripheral zones. In conclusion, the deposition pattern of rhDNase I aerosols in patients with CF is largely influenced by respiratory physiology, which itself depends upon age and severity of lung disease. As the patients grow there is a decrease in upper airway deposition and more particles are presented to the lungs where those patients with more airways disease have enhanced pulmonary deposition. Upper airway deposition of rhDNase I is significant, especially in younger patients, and may be related to laryngeal side effects.
Coenzyme A Biosynthesis: Reconstruction of the Pathway in Archaea and an Evolutionary Scenario Based on Comparative Genomics
Authors: U. Genschel
Journal: Molecular Biology and Evolution (2004)

Coenzyme A (CoA) holds a central position in cellular metabolism and therefore can be assumed to be an ancient molecule. Starting from the known E. coli and human enzymes required for the biosynthesis of CoA, phylogenetic profiles and chromosomal proximity methods enabled an almost complete reconstruction of archaeal CoA biosynthesis. This includes the identification of strong candidates for archaeal pantothenate synthetase and pantothenate kinase, which are unrelated to the corresponding bacterial or eukaryotic enzymes. According to this reconstruction, the topology of CoA synthesis from common precursors is essentially conserved across the three domains of life. The CoA pathway is conserved to varying degrees in eukaryotic pathogens like Giardia lamblia or Plasmodium falciparum, indicating that these pathogens have individual uptake-mechanisms for different CoA precursors. Phylogenetic analysis and phyletic distribution of the CoA biosynthetic enzymes suggest that the enzymes required for the synthesis of phosphopantothenate were recruited independently in the bacterial and archaeal lineages by convergent evolution, and that eukaryotes inherited the genes for the synthesis of pantothenate (vitamin B5) from bacteria. Homologues to bacterial enzymes involved in pantothenate biosynthesis are present in a subset of archaeal genomes. The phylogenies of these enzymes indicate that they were acquired from bacterial thermophiles through horizontal gene transfer. Monophyly can be inferred for each of the enzymes catalyzing the four ultimate steps of CoA synthesis, the conversion of phosphopantothenate into CoA. The results support the notion that CoA was initially synthesized from a prebiotic precursor, most likely pantothenate or a related compound.
Low Titers of Serum Antibodies Inhibiting Hemagglutination Predict Fatal Fulminant Influenza A(H1N1) 2009 Infection
Authors: Amélie Guihot, Charles-Edouard Luyt, Antoine Parrot, Dominique Rousset, Jean-Marc Cavaillon, David Boutolleau, Catherine Fitting, Priya Pajanirassa, Alain Mallet, Muriel Fartoukh, Henri Agut, Lucile Musset, Rima Zoorob, Amos Kirilovksy, Béhazine Combadière, Sylvie van der Werf, Brigitte Autran, Guislaine Carcelain
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

The biology of fatal pandemic influenza infection remains undefined.To characterize the virologic and immune parameters associated with severity or death in patients who required mechanical ventilation for A(H1N1) 2009 pneumonia of various degrees of severity during the two waves of the 2009-2011 pandemic in Paris, France.This multicenter study included 34 unvaccinated patients with very severe or fatal confirmed influenza A(H1N1) infections. It analyzed plasma A(H1N1) 2009 reverse-transcriptase polymerase chain reaction, hemagglutinin 222G viral mutation, and humoral and cellular immune responses to the virus, assessed in hemagglutination inhibition (HI), microneutralization, ELISA, lymphoproliferative, ELISpot IFN-γ, and cytokine and chemokine assays.The patients' median age was 35 years. Influenza A(H1N1) 2009 viremia was detected in 4 of 34 cases, and a 222G hemagglutinin mutation in 7 of 17 cases, all of them with sequential organ failure assessment greater than or equal to 8. HI antibodies were detectable in 19 of 26 survivors and undetectable in all six fatal fulminant cases. ELISA and microneutralization titers were concordant. B-cell immunophenotyping and plasma levels of immunoglobulin classes did not differ between patients who survived and died. After immune complex dissociation, influenza ELISA serology became strongly positive in the bronchoalveolar lavage of the two fatal cases tested. H1N1-specific T-cell responses in lymphoproliferative and IFN-γ assays were detectable in survivors' peripheral blood, and lymphoproliferative assays were negative in the three fatal cases tested. Plasma levels of IL-6 and IL-10 were high in fatal cases and correlated with severity. Finally, a negative HI serology 4 days after the onset of influenza symptoms predicted death from fulminant influenza (P = 0.04).Early negative A(H1N1) 2009 HI serology can predict death from influenza. This negative serology in fatal cases in young adults reflects the trapping of anti-H1N1 antibodies in immune complexes in the lungs, associated with poor specific helper T-cell response. Clinical trial registered with www.clinicaltrials.gov (NCT 01089400).
Multicentric Breast Cancer: A New Indication for Sentinel Node Biopsy—A Multi-Institutional Validation Study
Authors: Michael Knauer, Peter Konstantiniuk, Anton Haid, Etienne Wenzl, Michaela Riegler-Keil, Sabine Pöstlberger, Roland Reitsamer, Peter Schrenk
Journal: Journal of Clinical Oncology (2006)

Multicentric breast cancer has been considered to be a contraindication for sentinel node (SN) biopsy (SNB). In this prospective multi-institutional trial, SNB-feasibility and accuracy was evaluated in 142 patients with multicentric cancer from the Austrian Sentinel Node Study Group (ASNSG) and compared with data from 3,216 patients with unicentric cancer.Between 1996 and 2004, 3,730 patients underwent SNB at 15 ASNSG-affiliated hospitals. Patient data were entered in a multicenter database. One hundred forty-two patients presented with multicentric invasive breast cancer and underwent SNB.Intraoperatively, a mean number of 1.67 SNs were excised (identification-rate, 91.5%). The incidence of SN metastases was 60.8% (79 of 130). This was confirmed by axillary lymph node dissection (ALND) in 125 patients. Of patients with positive SNs, 60.8% (48 of 79) showed involvement of nonsentinel nodes (NSNs), as did three patients with negative SNs (false-negative rate, 4.0). Sensitivity, negative predictive value, and overall accuracy were 96.0%, 93.3%, and 97.3%, respectively. Ninety-one percent of the patients underwent mastectomy, and 9% were treated with breast conserving surgery. None of the patients have shown axillary recurrence so far (mean follow-up, 28.8 months). Compared with 3,216 patients with unicentric cancer, there was a significantly higher rate of SN metastases as well as in NSNs, whereas there was no difference in detection and false-negative rates.Multicentric breast cancer is a new indication for SNB without routine ALND in controlled trials. Given adequate quality control and an interdisciplinary teamwork of surgical, nuclear medicine, and pathology units, SNB is both feasible and accurate in this disease entity.
Physical activity to prevent obesity in young children: cluster randomised controlled trial
Authors: John J Reilly, Louise Kelly, Colette Montgomery, Avril Williamson, Abigail Fisher, John H McColl, Rossella Lo Conte, James Y Paton, Stanley Grant
Journal: BMJ (2006)

Objective To assess whether a physical activity intervention reduces body mass index in young children. Design Cluster randomised controlled single blinded trial over 12 months. Setting Thirty six nurseries in Glasgow, Scotland. Participants 545 children in their preschool year, mean age 4.2 years (SD 0.2) at baseline. Intervention Enhanced physical activity programme in nursery (three 30 minute sessions a week over 24 weeks) plus home based health education aimed at increasing physical activity through play and reducing sedentary behaviour. Main outcome measure Body mass index, expressed as a standard deviation score relative to UK 1990 reference data. Secondary measures were objectively measured physical activity and sedentary behaviour; fundamental movement skills; and evaluation of the process. Results Group allocation had no significant effect on the primary outcome measure at six and 12 months or on measures of physical activity and sedentary behaviour by accelerometry. Children in the intervention group had significantly higher performance in movement skills tests than control children at six month follow-up (P=0.0027; 95% confidence interval 0.3 to 1.3) after adjustment for sex and baseline performance. Conclusions Physical activity can significantly improve motor skills but did not reduce body mass index in young children in this trial. Trial registration Current Controlled Trials [ISRCTN36363490][1]. [1]: /external-ref?link_type=ISRCTN&access_num=ISRCTN36363490