tbuckley/cabot-search huggingface dataset:
Evidence for Distinct Pathomechanisms in Genetic Subgroups of Chronic Lymphocytic Leukemia Revealed by Quantitative Expression Analysis of Cell Cycle, Activation, and Apoptosis-Associated Genes
Authors: Dirk L. Kienle, Christian Korz, Beate Hosch, Axel Benner, Daniel Mertens, Annett Habermann, Alexander Kröber, Ulrich Jäger, Peter Lichter, Hartmut Döhner, Stephan Stilgenbauer
Journal: Journal of Clinical Oncology (2005)

In patients with chronic lymphocytic leukemia (CLL), the VH mutation status and genomic aberrations (13q-, +12q, 11q-, 17p-) identify distinct prognostic subgroups. The aim was to elucidate biologic mechanisms through which these genetic markers may exert their pathogenic influence.Twenty-four genes involved in apoptosis, cell cycle, B-cell activation, and B-cell receptor (BCR) signaling were analyzed by real-time quantitative reverse transcription polymerase chain reaction (RQ-PCR) in 82 CLL cases constituting prototypic genetic CLL subgroups as defined by the VH mutation status and the genomic aberrations 13q-, +12, 11q-, and 17p-.The VH mutation subgroups were characterized by a differential expression of the BCR associated genes ZAP70 and PI3K. Among the subgroups defined by genomic aberrations, there was a deregulation of candidate genes from the affected critical genomic regions such as CDK4 (up), ATM (down), and TP53 (down) in the groups +12, 11q-, and 17p-, respectively. Additionally, the genomic subgroups were characterized by a significant deregulation of cell cycle and apoptosis regulators: AKT (up) in 13q, E2F1 (up) in +12, MYC (up) and BCL-2 (down) in 17p-, and CCND3 (down) in 11q- as well as 17p-. The 17p- subgroup showed an additional down-regulation of BCR-associated genes such as SYK and PI3K.The characteristic gene expression patterns observed implicate a differential regulation of cell cycle, apoptosis, and BCR signaling in the genetic subgroups illustrating distinct pathomechanisms and are evidence for a gene dosage effect being operative in CLL. These findings link the biologic diversity and clinical heterogeneity of CLL.
Very-Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency in Mice
Authors: Vernat J. Exil, Richard L. Roberts, Harold Sims, Jacquelin E. McLaughlin, Robert A. Malkin, Carla D. Gardner, Gemin Ni, Jeffrey N. Rottman, Arnold W. Strauss
Journal: Circulation Research (2003)

Fatty acid oxidation (FAO) defects are inborn errors of metabolism clinically associated with cardiomyopathy and sudden infant death syndrome (SIDS). FAO disorders often present in infancy with myocardial dysfunction and arrhythmias after exposure to stresses such as fasting, exercise, or intercurrent viral illness. It is uncertain whether the heart, in the absence of stress, is normal. We generated very-long-chain acyl-coenzyme A dehydrogenase (VLCAD)-deficient mice by homologous recombination to define the onset and molecular mechanism of myocardial disease. We found that VLCAD-deficient hearts have microvesicular lipid accumulation, marked mitochondrial proliferation, and demonstrated facilitated induction of polymorphic ventricular tachycardia, without antecedent stress. The expression of acyl-CoA synthase (ACS1), adipophilin, activator protein 2, cytochrome c , and the peroxisome proliferator activated receptor γ coactivator-1 were increased immediately after birth, preceding overt histological lipidosis, whereas ACS1 expression was markedly downregulated in the adult heart. We conclude that mice with VLCAD deficiency have altered expression of a variety of genes in the fatty acid metabolic pathway from birth, reflecting metabolic feedback circuits, with progression to ultrastructural and physiological correlates of the associated human disease in the absence of stress.
Points: The so-called Miller-Fisher syndrome: a misnomer
Authors: F C. Rose
Journal: BMJ (1982)

September, p 77) express surprise that deaths due to smothering of a baby by a cat do not occur more often.They do not occur more often because most mothers are well aware of the danger.A cat net is a standard piece of baby equipment which is routinely stretched over the pram when it is left unattended in a garden or anywhere frequented by cats.I am astonished that this simple expedient, dictated by common sense rather than by epidemiology, gets no mention in your "Any Questions."'
Respiratory symptoms and airway responsiveness in apparently healthy workers exposed to flour dust
Authors: AB Bohadana, N Massin, P Wild, MN Kolopp, JP Toamain
Journal: European Respiratory Journal (1994)

Our aim was to measure the levels of exposure to wheat flour dust in a modern industrial bakery, and to assess the relationship between respiratory symptoms, sensitization to wheat flour antigens and airway responsiveness in the workforce. Forty four flour-exposed male workers and 164 unexposed controls were examined. Inspirable dust concentrations were measured using personal samplers. Respiratory symptoms were assessed by questionnaire, sensitization to wheat flour antigens by skin-prick tests, and methacholine airway challenge (MAC) test using an abbreviated method. Subjects were labelled MAC+ if forced expiratory volume in one second (FEV1) fell by 20% or more. The linear dose-response slope (DRS) was calculated as the percentage fall in FEV1 at last dose divided by the total dose administered. Inspirable dust concentrations were within acceptable limits in all working areas but one. The proportion of subjects with one or more symptoms and with airway hyperresponsiveness was significantly greater among flour-exposed workers than among controls. Using logistic or linear regression analysis, airway responsiveness was found to be strongly related to working at the bakery and to the baseline level of lung function. A positive skin-prick test was found in only 11% of flour-exposed workers and 6% of controls. In conclusion, our data show that despite exposure to relatively low concentration levels of inspirable flour dust, subjects working in the baking industry are at risk of developing both respiratory symptoms and airway hyperresponsiveness.
Limbal Stem-Cell Therapy and Long-Term Corneal Regeneration
Authors: Paolo Rama, Stanislav Matuska, Giorgio Paganoni, Alessandra Spinelli, Michele De Luca, Graziella Pellegrini
Journal: New England Journal of Medicine (2010)

Corneal renewal and repair are mediated by stem cells of the limbus, the narrow zone between the cornea and the bulbar conjunctiva. Ocular burns may destroy the limbus, causing limbal stem-cell deficiency. We investigated the long-term clinical results of cell therapy in patients with burn-related corneal destruction associated with limbal stem-cell deficiency, a highly disabling ocular disease.We used autologous limbal stem cells cultivated on fibrin to treat 112 patients with corneal damage, most of whom had burn-dependent limbal stem-cell deficiency. Clinical results were assessed by means of Kaplan-Meier, Kruskal-Wallis, and univariate and multivariate logistic-regression analyses. We also assessed the clinical outcome according to the percentage of holoclone-forming stem cells, detected as cells that stain intensely (p63-bright cells) in the cultures.Permanent restoration of a transparent, renewing corneal epithelium was attained in 76.6% of eyes. The failures occurred within the first year. Restored eyes remained stable over time, with up to 10 years of follow-up (mean, 2.91+/-1.99; median, 1.93). In post hoc analyses, success--that is, the generation of normal epithelium on donor stroma--was associated with the percentage of p63-bright holoclone-forming stem cells in culture. Cultures in which p63-bright cells constituted more than 3% of the total number of clonogenic cells were associated with successful transplantation in 78% of patients. In contrast, cultures in which such cells made up 3% or less of the total number of cells were associated with successful transplantation in only 11% of patients. Graft failure was also associated with the type of initial ocular damage and postoperative complications.Cultures of limbal stem cells represent a source of cells for transplantation in the treatment of destruction of the human cornea due to burns.
PREDICTION OF SEVERITY IN ACUTE PANCREATITIS: PROSPECTIVE COMPARISON OF THREE PROGNOSTIC INDICES
Authors: A.P. Corfield, R.C.N. Williamson, M.J. Mcmahon, M.G. Shearer, M.J. Cooper, A.D. Mayer, A.P. Dickson, C.W. Imrie
Journal: The Lancet (1985)
Four-month metacarpal bone mineral density loss predicts radiological joint damage progression after 1 year in patients with early rheumatoid arthritis: exploratory analyses from the IMPROVED study
Authors: K V C Wevers-de Boer, L Heimans, K Visser, J Kälvesten, R J Goekoop, M van Oosterhout, J B Harbers, C Bijkerk, M Steup-Beekman, M P D M de Buck, P B J de Sonnaville, T W J Huizinga, C F Allaart
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Aim</h3> To assess whether in early (rheumatoid) arthritis (RA) patients, metacarpal bone mineral density (BMD) loss after 4 months predicts radiological progression after 1 year of antirheumatic treatment. <h3>Methods</h3> Metacarpal BMD was measured 4 monthly during the first year by digital X-ray radiogrammetry (DXR-BMD) in patients participating in the IMPROVED study, a clinical trial in 610 patients with recent onset RA (2010 criteria) or undifferentiated arthritis, treated according to a remission (disease activity score&lt;1.6) steered strategy. With Sharp/van der Heijde progression ≥0.5 points after 1 year (yes/no) as dependent variable, univariate and multivariate logistic regression analyses were performed. <h3>Results</h3> Of 428 patients with DXR-BMD results and progression scores available, 28 (7%) had radiological progression after 1 year. Independent predictors for radiological progression were presence of baseline erosions (OR (95% CI) 6.5 (1.7 to 25)) and early DXR-BMD loss (OR (95% CI) 1.5 (1.1 to 2.0)). In 366 (86%) patients without baseline erosions, early DXR-BMD loss was the only independent predictor of progression (OR (95% CI) 2.0 (1.4 to 2.9)). <h3>Conclusions</h3> In early RA patients, metacarpal BMD loss after 4 months of treatment is an independent predictor of radiological progression after 1 year. In patients without baseline erosions, early metacarpal BMD loss is the main predictor of radiological progression.
Severe fibrotic changes and altered expression of angiogenic factors in maternal scleroderma: placental findings
Authors: L Ibba-Manneschi, M Manetti, A F Milia, I Miniati, G Benelli, S Guiducci, F Mecacci, G Mello, S Di Lollo, M Matucci-Cerinic
Journal: Annals of the Rheumatic Diseases (2009)

Objective: Pregnant women with systemic sclerosis (SSc; scleroderma) have an increased risk of premature delivery and small full-term infants. During placental development, angiogenesis and vascular remodelling are essential for a successful pregnancy outcome. An analysis was made of the pathological changes and expression of angiogenic factors in SSc placentas. Methods: Placenta biopsies were obtained from three patients with SSc and four healthy uncomplicated pregnancies after delivery at 34–38 weeks of gestation. The sections were stained with Masson’s trichrome and phosphotungstic-acid-haematoxylin and immunostained for connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA), vascular endothelial growth factor (VEGF), placenta growth factor (PlGF) and receptors VEGFR-1 and VEGFR-2. Results: The pathological findings were signs of decidual vasculopathy, increased syncytiotrophoblast knotting, placental infarcts and villous hypoplasia. Severe and diffuse perivascular and stromal fibrosis of decidua and chorionic villi, and extensive deposition of fibrinoid material around decidual vessels and in intervillous spaces were observed. Strong CTGF expression in the vessel wall, decidual cells and fibroblasts and α-SMA+ myofibroblasts were found. VEGF and VEGFR-2 expression was stronger in SSc than in healthy placentas, while VEGFR-1 expression was similar to controls. PlGF immunopositivity was weaker in SSc. Conclusion: In SSc placentas, severe fibrosis and abnormal vascular remodelling were detected. This may result in reduced blood flow leading to deep sufferance of maternal placenta and possible premature delivery.
WEE1 Kinase As a Target for Cancer Therapy
Authors: Sabine Mueller, Daphne A. Haas-Kogan
Journal: Journal of Clinical Oncology (2015)

Article Tools UNDERSTANDING THE PATHWAY Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2015.62.2290 Journal of Clinical Oncology - published online before print July 27, 2015 PMID: 26215953 WEE1 Kinase As a Target for Cancer Therapy Sabine MuellerxSabine MuellerSearch for articles by this author , Daphne A. Haas-KoganxDaphne A. Haas-KoganSearch for articles by this author Show More University of California at San Francisco, San Francisco, CA https://doi.org/10.1200/JCO.2015.62.2290 First Page Full Text PDF Figures and Tables © 2015 by American Society of Clinical Oncology
Intracellular degradation of beta4 integrin in lethal junctional epidermolysis bullosa with pyloric atresia
Authors: A. Micheloni, N. De Luca, G. Tadini, G. Zambruno, M. D'Alessio
Journal: British Journal of Dermatology (2004)

Journal Article Intracellular degradation of β4 integrin in lethal junctional epidermolysis bullosa with pyloric atresia Get access A. Micheloni, A. Micheloni Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata, IRCCS, Via dei Monti di Creta 104, 00167 Roma, Italy *Institute of Dermatological Science, Policlinico di Milano, IRCCS, Italy Search for other works by this author on: Oxford Academic Google Scholar N. De Luca, N. De Luca Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata, IRCCS, Via dei Monti di Creta 104, 00167 Roma, Italy *Institute of Dermatological Science, Policlinico di Milano, IRCCS, Italy Search for other works by this author on: Oxford Academic Google Scholar G. Tadini, G. Tadini Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata, IRCCS, Via dei Monti di Creta 104, 00167 Roma, Italy *Institute of Dermatological Science, Policlinico di Milano, IRCCS, Italy Search for other works by this author on: Oxford Academic Google Scholar G. Zambruno, G. Zambruno Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata, IRCCS, Via dei Monti di Creta 104, 00167 Roma, Italy *Institute of Dermatological Science, Policlinico di Milano, IRCCS, Italy Search for other works by this author on: Oxford Academic Google Scholar M. D'Alessio M. D'Alessio Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata, IRCCS, Via dei Monti di Creta 104, 00167 Roma, Italy *Institute of Dermatological Science, Policlinico di Milano, IRCCS, Italy Marina D'Alessio, Ph.D. E‐mail: dalessio@idi.it Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 151, Issue 4, 1 October 2004, Pages 796–802, https://doi.org/10.1111/j.1365-2133.2004.06206.x Published: 01 October 2004 Article history Accepted: 08 March 2004 Published: 01 October 2004
Therapeutic Inhibition of MAP Kinase Interacting Kinase Blocks Eukaryotic Initiation Factor 4E Phosphorylation and Suppresses Outgrowth of Experimental Lung Metastases
Authors: Bruce W. Konicek, Jennifer R. Stephens, Ann M. McNulty, Nathaniel Robichaud, Robert B. Peery, Chad A. Dumstorf, Michele S. Dowless, Philip W. Iversen, Stephen Parsons, Karen E. Ellis, Denis J. McCann, Jerry Pelletier, Luc Furic, Jonathan M. Yingling, Louis F. Stancato, Nahum Sonenberg, Jeremy R. Graff
Journal: Cancer Research (2011)

Activation of the translation initiation factor 4E (eIF4E) promotes malignant transformation and metastasis. Signaling through the AKT-mTOR pathway activates eIF4E by phosphorylating the inhibitory 4E binding proteins (4E-BP). This liberates eIF4E and allows binding to eIF4G. eIF4E can then be phosphorylated at serine 209 by the MAPK-interacting kinases (Mnk), which also interact with eIF4G. Although dispensable for normal development, Mnk function and eIF4E phosphorylation promote cellular proliferation and survival and are critical for malignant transformation. Accordingly, Mnk inhibition may serve as an attractive cancer therapy. We now report the identification of a potent, selective and orally bioavailable Mnk inhibitor that effectively blocks 4E phosphorylation both in vitro and in vivo. In cultured cancer cell lines, Mnk inhibitor treatment induces apoptosis and suppresses proliferation and soft agar colonization. Importantly, a single, orally administered dose of this Mnk inhibitor substantially suppresses eIF4E phosphorylation for at least 4 hours in human xenograft tumor tissue and mouse liver tissue. Moreover, oral dosing with the Mnk inhibitor significantly suppresses outgrowth of experimental B16 melanoma pulmonary metastases as well as growth of subcutaneous HCT116 colon carcinoma xenograft tumors, without affecting body weight. These findings offer the first description of a novel, orally bioavailable MNK inhibitor and the first preclinical proof-of-concept that MNK inhibition may provide a tractable cancer therapeutic approach.
Ankylosing spondylitis and trauma: the medicolegal implications. A comparative study of patients with non-specific back pain.
Authors: R K Jacoby, R L Newell, P Hickling
Journal: Annals of the Rheumatic Diseases (1985)

Ankylosing spondylitis (AS) arising as a result of injury was reported by five of 113 hospital patients who completed questionnaires on the historical and symptomatic features of their disease. Identical questionnaires were given to a group of 51 patients with non-specific back pain (NSBP) attending an orthopaedic clinic. Five of these patients developed their first symptoms after trauma. A further four patients with ankylosing spondylitis believed that their disease was initiated by injury, however, x-ray photographs showed that they had already developed AS at the time of their injuries. It is suggested that injury does not cause AS but brings it to the patient9s attention, possibly through immobilisation, in 7% of hospital cases.
IL5RA and TNFRSF6B Gene Variants Are Associated With Sporadic IgA Nephropathy
Authors: Xiao-Qing Liu, Andrew D. Paterson, Ning He, Peter St. George-Hyslop, Virpi Rauta, Carola Gronhagen-Riska, Markku Laakso, Lise Thibaudin, Francois Berthoux, Daniel Cattran, York Pei
Journal: Journal of the American Society of Nephrology (2008)

Familial clustering and genome-wide linkage scans strongly support a genetic susceptibility to familial IgA nephropathy (IgAN), but genetic factors that predispose to sporadic IgAN are unknown. A high-throughput single nucleotide polymorphism (SNP) association study was conducted using a customized Illumina BeadChip in 732 white patients with biopsy-proven IgAN and 503 control subjects from Canada, France, and Finland. Approximately 93% of 1536 SNPs on the array were tag SNPs from Phase I+II of the HapMap with a minor allele frequency > or =5%, designed to capture the common variants of genes within the critical interval of IGAN1 on chromosome 6q22 and 69 biologic candidate genes for IgAN. SNPs of suggestive or significant association were identified by using logistic regression to adjust for age, gender, study site, and population stratification. Despite using a dense marker set that covered an average interval of 6.5 kb between SNPs, there was no strong and consistent association signal within the IGAN1 critical interval. Among the biologic candidate genes examined, two significant association signals were found at IL5RA and TNFRSF6B, the latter being particularly interesting because this gene encodes a decoy receptor for a TNF family ligand that causes IgAN in mice when overexpressed. Pending replication, these data suggest that variants of IL5RA and TNFRSF6B may predispose to sporadic IgAN.
DELAYED HYPERSENSITIVITY TO HAPTEN-PROTEIN CONJUGATES
Authors: P. G. H. Cell, Arthur M. Silverstein
Journal: The Journal of Experimental Medicine (1962)

Further data have been presented showing that the specificity of the delayed hypersensitivity reaction in the guinea pig to hapten-protein conjugates involves to a considerable degree a contribution by the protein carrier. The carrier contribution is such that sensitization to guinea pig albumin-m-azobenzenesulfonate, for example, does not result in cross-reaction with conjugates of the same hapten with unrelated proteins such as ovalbumin or human gamma globulin, nor were cross-reactions observed between conjugates prepared with the same hapten, coupled to the same protein, but by two different chemical routes, such that the point of attachment of the hapten to the protein differed. It thus appears that in this system both hapten and carrier protein are necessary, but that neither alone is in general sufficient to stimulate the delayed sensitive cell. Desensitization experiments with cross-reacting hapten-protein conjugates have suggested the presence of a multiplicity of antigenic determinants participating in the elicitation of the delayed lesion, and of a concomitant development of a heterogeneity of specificities in the population of delayed sensitive cells in the sensitized animal. The data are discussed in terms of the apparent requirement of the delayed sensitivity mechanism for a larger functional antigenic determinant than that required for interaction with circulating antibodies. Some possible explanations for this difference, and some of its consequences, are discussed.
Core Histones of the Amitochondriate Protist, Giardia lamblia
Authors: Gang Wu, Andrew G. McArthur, András Fiser, Andrej Šali‡, Mitchell L. Sogin, Miklós M
Journal: Molecular Biology and Evolution (2000)

Genes coding for the core histones H2a, H2b, H3, and H4 of Giardia lamblia were sequenced. A conserved organism- and gene-specific element, GRGCGCAGATTTVGG, was found upstream of the coding region in all core histone genes. The derived amino acid sequences of all four histones were similar to their homologs in other eukaryotes, although they were among the most divergent members of this protein family. Comparative protein structure modeling combined with energy evaluation of the resulting models indicated that the G. lamblia core histones individually and together can assume the same three-dimensional structures that were established by X-ray crystallography for Xenopus laevis histones and the nucleosome core particle. Since G. lamblia represents one of the earliest-diverging eukaryotes in many different molecular trees, the structure of its histones is potentially of relevance to understanding histone evolution. The G. lamblia proteins do not represent an intermediate stage between archaeal and eukaryotic histones.