tbuckley/cabot-search huggingface dataset:
Interaction between anti-DNA and anti-DNA-binding protein autoantibodies in cryoglobulins from sera of patients with systemic lupus erythematosus.
Authors: W H Reeves, N Chiorazzi
Journal: The Journal of Experimental Medicine (1986)

We have previously shown that sera from some patients with SLE and related disorders contain autoantibodies to a DNA-binding protein complex designated p70/p80. The present study shows that anti-p70/p80 autoantibodies are frequently accompanied by anti-DNA antibodies and cryoglobulins. When the cryoglobulins were isolated, they were found to be specifically enriched in both anti-p70/p80 and anti-DNA activities. The anti-p70/p80 and anti-DNA antibodies were found to be distinct populations of autoantibodies rather than a single crossreactive species, since they could be separated from one another by chromatography on DNA-cellulose. Certain human anti-DNA mAbs could inhibit the binding of autoimmune polyclonal anti-p70/p80 antibodies to p70/p80, suggesting that anti-DNA antibodies might also associate with the variable regions of some anti-p70/p80 antibodies in the cryoglobulins. Binding of one murine anti-p70/p80 mAb (111-12) also was inhibited by certain human anti-DNA mAbs, but the binding of another murine mAb (162-11) to a different epitope of p70/p80 was not. These studies suggest that certain anti-DNA antibodies may interact with the variable regions of a population of anti-p70/p80 antibodies. The cryoglobulins found in the sera containing both anti-p70/p80 and anti-DNA antibodies may represent immune complexes consisting, in part, of idiotype and antiidiotype.
Parallelism and Epistasis in Skeletal Evolution Identified through Use of Phylogenomic Mapping Strategies
Authors: Jacob M. Daane, Nicolas Rohner, Peter Konstantinidis, Sergej Djuranovic, Matthew P. Harris
Journal: Molecular Biology and Evolution (2015)

The identification of genetic mechanisms underlying evolutionary change is critical to our understanding of natural diversity, but is presently limited by the lack of genetic and genomic resources for most species. Here, we present a new comparative genomic approach that can be applied to a broad taxonomic sampling of nonmodel species to investigate the genetic basis of evolutionary change. Using our analysis pipeline, we show that duplication and divergence of fgfr1a is correlated with the reduction of scales within fishes of the genus Phoxinellus. As a parallel genetic mechanism is observed in scale-reduction within independent lineages of cypriniforms, our finding exposes significant developmental constraint guiding morphological evolution. In addition, we identified fixed variation in fgf20a within Phoxinellus and demonstrated that combinatorial loss-of-function of fgfr1a and fgf20a within zebrafish phenocopies the evolved scalation pattern. Together, these findings reveal epistatic interactions between fgfr1a and fgf20a as a developmental mechanism regulating skeletal variation among fishes.
Deletions of <i>CDKN2C</i> in Multiple Myeloma: Biological and Clinical Implications
Authors: Paola E. Leone, Brian A. Walker, Matthew W. Jenner, Laura Chiecchio, GianPaolo Dagrada, Rebecca K.M. Protheroe, David C. Johnson, Nicholas J. Dickens, Jose Luis Brito, Monica Else, David Gonzalez, Fiona M. Ross, Selina Chen-Kiang, Faith E. Davies, Gareth J. Morgan
Journal: Clinical Cancer Research (2008)

Deletions of chromosome 1 have been described in 7% to 40% of cases of myeloma with inconsistent clinical consequences. CDKN2C at 1p32.3 has been identified in myeloma cell lines as the potential target of the deletion. We tested the clinical impact of 1p deletion and used high-resolution techniques to define the role of CDKN2C in primary patient material.We analyzed 515 cases of monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and newly diagnosed multiple myeloma using fluorescence in situ hybridization (FISH) for deletions of CDKN2C. In 78 myeloma cases, we carried out Affymetrix single nucleotide polymorphism mapping and U133 Plus 2.0 expression arrays. In addition, we did mutation, methylation, and Western blotting analysis.By FISH we identified deletion of 1p32.3 (CDKN2C) in 3 of 66 MGUS (4.5%), 4 of 39 SMM (10.3%), and 55 of 369 multiple myeloma cases (15%). We examined the impact of copy number change at CDKN2C on overall survival (OS), and found that the cases with either hemizygous or homozygous deletion of CDKN2C had a worse OS compared with cases that were intact at this region (22 months versus 38 months; P = 0.003). Using gene mapping we identified three homozygous deletions at 1p32.3, containing CDKN2C, all of which lacked expression of CDKN2C. Cases with homozygous deletions of CDKN2C were the most proliferative myelomas, defined by an expression-based proliferation index, consistent with its biological function as a cyclin-dependent kinase inhibitor.Our results suggest that deletions of CDKN2C are important in the progression and clinical outcome of myeloma.
New molecular aspects in pathogenesis and progression of pancreatic cancer
Authors: Peter Büchler, Markus W Büchler, Helmut Friess
Journal: Molecular Cancer (2003)

Editorial Pancreatic cancer is the second most common cause of cancer death among all gastrointestinal cancers. It continues to be a devastating disease and only a limited number of patients can be cured. Within the last decade there was truly significant progress in understanding basic cellular and molecular pathways which influence the course of this disease. Therefore, there are reasons to believe that these advances in molecular research represent on of the most likely resource from which significant improvements in the management of pancreatic cancer are to come for the future.
Rhinovirus induces MUC5AC in a human infection model and in vitro via NF- B and EGFR pathways
Authors: C.A. Hewson, J.J. Haas, N.W. Bartlett, S.D. Message, V. Laza-Stanca, T. Kebadze, G. Caramori, J. Zhu, M.R. Edbrooke, L.A. Stanciu, O.M. Kon, A. Papi, P.K. Jeffery, M.R. Edwards, S.L. Johnston
Journal: European Respiratory Journal (2010)

Rhinovirus (RV) infections are the major cause of asthma exacerbations, the major cause of morbidity and mortality in asthma. MUC5AC is the major mucin produced by bronchial epithelial cells. Whether RV infection upregulates MUC5AC in vivo is unknown and the molecular mechanisms involved are incompletely understood. We investigated RV induction of MUC5AC in vivo and in vitro to identify targets for development of new therapies for asthma exacerbations. RV infection increased MUC5AC release in normal and asthmatic volunteers experimentally infected with RV-16, and in asthmatic, but not normal, subjects, this was related to virus load. Bronchial epithelial cells were confirmed a source of MUC5AC in vivo . RV induction of MUC5AC in bronchial epithelial cells in vitro occurred via nuclear factor-κB-dependent induction of matrix metalloproteinase-mediated transforming growth factor-α release, thereby activating an epidermal growth factor receptor-dependent cascade culminating, via mitogen-activated protein kinase activation, in specificity protein-1 transactivation of the MUC5AC promoter. RV induction of MUC5AC may be an important mechanism in RV-induced asthma exacerbations in vivo . Revealing the complex serial signalling cascade involved identifies targets for development of pharmacologic intervention to treat mucus hypersecretion in RV-induced illness.
Prognostic Significance of Epithelial-Mesenchymal and Mesenchymal-Epithelial Transition Protein Expression in Non–Small Cell Lung Cancer
Authors: Alex Soltermann, Verena Tischler, Stefanie Arbogast, Julia Braun, Nicole Probst-Hensch, Walter Weder, Holger Moch, Glen Kristiansen
Journal: Clinical Cancer Research (2008)

Abstract Purpose: In carcinomas, invasive tumor growth is accompanied by desmoplastic stroma reaction and facilitated by epithelial-mesenchymal transition (EMT) of cancer cells. We investigated the prognostic significance of the EMT indicator proteins periostin and vimentin in comparison with versican, a putative indicator of the opposite mechanism mesenchymal-epithelial transition (MET), and to the desmoplasia proteins collagen and elastin in non-small cell lung cancer (NSCLC). Experimental Design: Tumor of 533 patients with surgically resected NSCLC was used for analysis of stromal and epithelial protein expression by immunohistochemistry (EMT-MET proteins) and Elastica van Gieson histochemical staining (collagen and elastin). A semiquantitative sum scoring system was done on three tissue microarrays. Results: Of the 533 patients, 48% had squamous cell carcinoma, 47% adenocarcinoma, and 5% adenosquamous carcinoma. High expression of periostin in either stroma or tumor epithelia, independently scored by two pathologists, correlated with male gender, higher stage, higher pT category, and larger tumor size, and in only stroma with tumor relapse. High expression of versican in either stroma or epithelia as well as of stromal collagen had fewer but concordant associations with advanced tumor and periostin, respectively. High expression of elastin was oppositely associated with less advanced disease. Associations of high vimentin were inconsistent (all P values &amp;lt;0.05). High stromal periostin was found to be a prognostic factor for decreased progression-free survival on univariate analysis (P = 0.007). Conclusions: Because up-regulation is frequently observed in the stromal and epithelial tumor compartment, EMT-MET indicator proteins may be integrated in progression models of NSCLC.
Viability and function in primary culture of adult hepatocytes from various animal species and human beings after cryopreservation
Authors: Christophe Chesné, Claire Guyomard, Alain Fautrel, Marie-gwenaëlle Poullain, Benjamin Frémond, Hendrik de Jong, André Guillouz
Journal: Hepatology (1993)

Cryopreserved hepatocytes from various animal species and human beings were tested for their ability to survive and function in primary culture. The freeze/thaw protocol primarily designed for rat hepatocytes was used with slight modifications for the cells of all other species; it consisted of suspending parenchymal cells in the Leibovitz L15 medium containing 10% fetal calf serum and 10% to 16% dimethyl sulfoxide. After transient storage at 4 degrees C cell suspensions were transferred to -20 degrees C and then to -70 degrees C before being plunged in liquid nitrogen. Hepatocytes were stored for a few weeks to 4 yr. Prolonged storage did not augment loss of cell viability and function. Cell viability after thawing was estimated by the trypan blue exclusion test, and attachment efficiency to plastic was estimated by measuring intracellular lactate dehydrogenase content. Similar values were obtained for most species tested; after cryopreservation cell viability and attachment were decreased by 10% to 25% and by 40% to 50%, respectively. A lower attachment rate was found with dog hepatocytes. Total cytochrome P-450 and protein synthesis were compared in fresh and cryopreserved cells from four species after 4, 24, 48 or 72 hr of culture. Similar values were found in both cells after 24 or 48 hr of culture. In addition, drug-metabolizing activities were measured in human hepatocytes from five donors. In most cases phenacetin deethylation activity was decreased whereas procainamide N-acetylation and paracetamol sulfoconjugation and glucuronidation were increased in cryopreserved cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Risk adjustment for hospital use using social security data: cross sectional small area analysis
Authors: R. A Carr-Hill
Journal: BMJ (2002)

<h3>Abstract</h3> <b>Objectives:</b> To identify demographic and socioeconomic determinants of need for acute hospital treatment at small area level. To establish whether there is a relation between poverty and use of inpatient services. To devise a risk adjustment formula for distributing public funds for hospital services using, as far as possible, variables that can be updated between censuses. <b>Design:</b> Cross sectional analysis. Spatial interactive modelling was used to quantify the proximity of the population to health service facilities. Two stage weighted least squares regression was used to model use against supply of hospital and community services and a wide range of potential needs drivers including health, socioeconomic census variables, uptake of income support and family credit, and religious denomination. <b>Setting:</b> Northern Ireland. <b>Main outcome measure:</b> Intensity of use of inpatient services. <b>Results:</b> After endogeneity of supply and use was taken into account, a statistical model was produced that predicted use based on five variables: income support, family credit, elderly people living alone, all ages standardised mortality ratio, and low birth weight. The main effect of the formula produced is to move resources from urban to rural areas. <b>Conclusions:</b> This work has produced a population risk adjustment formula for acute hospital treatment in which four of the five variables can be updated annually rather than relying on census derived data. Inclusion of the social security data makes a substantial difference to the model and to the results produced by the formula. <h3>What is already known on this topic</h3> Use of hospital services at small area level is related to supply and census derived proxy measures of socioeconomic status as well as morbidity Changes to census data can be determined only every 10 years <h3>What this study adds</h3> Social security data directly reflecting household income predicts use of inpatient services Use of social security data allowed development of a risk adjustment model in which four of the five variables can be updated annually The main effect of the resulting formula is to move resources from urban to rural areas
Guidelines for treatment of onychomycosis
Authors: D.T. Roberts, W.D. Taylor, J. Boyle
Journal: British Journal of Dermatology (2003)

These guidelines for management of onychomycosis have been prepared for dermatologists on behalf of the British Association of Dermatologists. They present evidence-based guidance for treatment, with identification of the strength of evidence available at the time of preparation of the guidelines, and a brief overview of epidemiological aspects, diagnosis and investigation.
Urinary concentrating ability in early experimental pyelonephritis
Authors: Donald Kaye, Heonir Rocha
Journal: Journal of Clinical Investigation (1970)

The effect of early bilateral pyelonephritis on urinary concentrating ability was studied in rats injected intravenously with enterococci or Staphylococcus aureus and in rats inoculated with Escherichia coli into the medullae of both kidneys. The mean maximum urinary osmolality of normal rats was 2352 mOsm/kg of water. Inoculation of E. coli caused reversible pyelonephritis with sterilization of the kidneys within 12 wk. By 1 day after injection the mean maximum urinary osmolality had decreased to about 1100 mOsm. remained at this level for 3 wk, and then rose to normal by 12 wk. After injection of enterococci and staphylococci, the mean maximum urine osmolality decreased over 3-4 days to about 1000 and 800 mOsm respectively. In the enterococcal infection (which is chronic) the maximum urine osmolality remained about 1200 mOsm for at least 12 wk whereas in the staphylococcal infection (which is reversible) the osmolality gradually rose. Antimicrobial therapy of E. coli renal infection with colistimethate sodium and S. aureus infection with ampicillin rapidly reduced bacterial titers in the kidneys with an associated rise in maximum urinary osmolality. Therapy of enterococcal renal infection with ampicillin produced less impressive decreases in bacterial titers in the kidneys and little or no improvement in urinary concentrating ability. With antimicrobial therapy or with the self-limited infections, the rate of increase in concentrating ability was directly correlated with the rate of decrease of bacterial titers. However, there was poor correlation between histological findings in the kidneys and urinary concentrating ability. These studies demonstrate that early experimental pyelonephritis is associated with a concentrating defect that can be rapidly reversed and therefore is not related to permanent renal damage.
Rituximab Improves the Efficacy of High-Dose Chemotherapy With Autograft for High-Risk Follicular and Diffuse Large B-Cell Lymphoma: A Multicenter Gruppo Italiano Terapie Innnovative nei Linfomi Survey
Authors: Corrado Tarella, Manuela Zanni, Michele Magni, Fabio Benedetti, Caterina Patti, Tiziano Barbui, Alessandro Pileri, Mario Boccadoro, Fabio Ciceri, Andrea Gallamini, Sergio Cortelazzo, Ignazio Majolino, Salvo Mirto, Paolo Corradini, Roberto Passera, Giovanni Pizzolo, Alessandro M. Gianni, Alessandro Rambaldi
Journal: Journal of Clinical Oncology (2008)

To investigate the impact of adding rituximab to intensive chemotherapy with peripheral-blood progenitor cell (PBPC) autograft for high-risk diffuse large B-cell lymphoma (DLB-CL) and follicular lymphoma (FL).Data were collected from 10 centers associated with Gruppo Italiano Terapie Innnovative nei Linfomi for 522 patients with DLB-CL and 223 patients with FL (median age, 47 years) who received the original or a modified high-dose sequential (HDS) chemotherapy regimen. HDS was delivered to 396 patients without (R-) and to 349 patients with (R+) rituximab; 154 (39%) and 178 patients (51%) in the R- and R+ subsets, respectively, underwent HDS for relapsed/refractory disease.A total of 355 R- (90%) and 309 R+ patients (88%) completed the final PBPC autograft. Early treatment-related mortality was 3.3% for R- and 2.8% for R+ (P = not significant). Two parameters significantly influenced the outcome: disease status at HDS, with 5-year overall survival (OS) projections of 69% versus 57% for diagnosis versus refractory/relapsed status, respectively, and rituximab addition, with 5-year OS of 69% versus 60% in the R+ versus R- groups, respectively. In the multivariate analysis, these two variables maintained an independent prognostic value. The marked benefit of rituximab was evident in patients receiving HDS as salvage treatment: the 5-year OS projections for R+ versus R- were, respectively, 64% versus 38%, for patients with refractory disease or early relapse and 71% versus 57%, for patients with late relapse, partial response, or second/third relapse.The results of this large series indicate that rituximab should be included in the current practice of PBPC autograft for DLB-CL and FL.
Interleukin-1 and nitric oxide protect against tumor necrosis factor α-induced liver injury through distinct pathways
Authors: Ines Bohlinger, Marcel Leist, Johannes Barsig, Tefan Uhlig, Gisa Tiegs, Albrecht Wendel
Journal: Hepatology (1995)

Mice sensitized with d-galactosamine (GalN) and challenged with recombinant murine tumor necrosis factor α (TNFα) developed severe apoptotic and secondary necrotic liver injury as assessed by histology, measurement of cytosolic DNA fragments, and determination of liver specific enzymes in plasma. Pretreatment with recombinant human interleukin-1β (IL-1) rendered mice insensitive to this TNFα toxicity. Coadministration of the liver-specific transcriptional inhibitor GalN with IL-1 prevented the development of tolerance, implicating de novo synthesis of liver specific proteins in the induction of tolerance. Pretreatment of mice with IL-1 resulted in elevated levels of nitrite/nitrate in serum and in enhanced nitric oxide synthase (NOS) activity in liver cells isolated from these animals. In addition, pharmacological doses of the nitric oxide (NO) donor sodium nitroprusside conferred complete protection against TNFα-induced liver injury in galactosamine-sensitized mice, suggesting a possible link between IL-1- and NO-in-duced protection. However, prevention of NO-synthesis by N G -monomethyl-l-arginine (NMMA) did not abolish IL-1-induced tolerance to TNFα in vivo . Cytotoxicity of TNFα to isolated hepatocytes sensitized with actinomycin D (ActD) was not significantly altered by inhibition of endogenous nitrite release. Also, enhanced NO production elicited in vitro by glycerol trinitrate or ex vivo by pretreatment with IL-1 had no significant effect in this system. We conclude that IL-1- and NO-induced protection of mice against TNFα-mediated liver damage follow distinct pathways. (Hepatology 1995; 22:1829-1837).
The generation and specificity of cytotoxic T cells raised against syngeneic tumor cells bearing AKR/gross murine leukemia virus antigens
Authors: WR Green, RC Nowinski, CS Henney
Journal: The Journal of Experimental Medicine (1979)

Efforts were made to generate C57BL/6 cytotoxic effector cells to a syngeneic leukemia (E{male}G2) bearing AKR/Gross virus antigens. As we were unable to induce significant cytotoxic activity by immunization with up to 10(8) irradiated E{male}G2 cells, even when cells from such primed animals were subsequently restimulated with E{male}G2 cells in vitro, C57BL/6 mice were immunized with an aliogeneic, virus-producing AKR leukemic cell line (AKR SL3). Peritoneal exudate cells and, to a lesser degree, spleen cells from these mice showed significant lytic activity toward the immunizing allogeneic tumor but not toward E{male}G2. When spleen cells were harvested from animals {approximately equal to}10 d after injection of AKR SL3 and rechallenged in vitro with either E{male}G2 or AKR.H-2(b) SL1, another tumor that displays AKR/Gross virus antigens, then a vigorous cytotoxic response against E{male}G2 and AKR. H-2(b) SL1 was obtained. Effector cells generated by AKR SL3 priming followed by in vitro stimulation with E{male}G2 or AKR.H-2(b) SL1 lysed only cells of H-2(b) haplotype which were strongly positive for the display of serologically detectable AKR/Gross virus antigens. Thus, AKR SL3 cells were not lysed nor were EL4 cells (H-2(b); but only weakly positive for gp70). Cells not bearing the MuLV antigens tested for, such as P815 mastocytoma cells and spleen cell "blasts" from C57BL/6 and CBA (H-2(k)) mice, were also insusceptible to attack. The cytotoxic effector cells induced bore Thy 1.2 alloantigen and were of the Lyt 1+2+ phenotype. Collectively, these findings are consistent with the conclusion that the cytotoxic T cells raised against E{male}G2 are directed against AKR/Gross virus-associated antigens and are H-2 restricted. It will be of interest to determine the relevance of such effector cells to the known resistance of the C57BL/6 mouse to AKR/Gross virus-induced leukemia.