tbuckley/cabot-search huggingface dataset:
Parallel Duplication and Partial Subfunctionalization of -Catenin/Armadillo during Insect Evolution
Authors: R. Bao, T. Fischer, R. Bolognesi, S. J. Brown, M. Friedrich
Journal: Molecular Biology and Evolution (2011)

β-Catenin is a multifunctional scaffolding protein with roles in Wnt signaling, cell adhesion, and centrosome separation. Here, we report on independent duplications of the insect β-Catenin ortholog armadillo (arm) in the red flour beetle Tribolium castaneum and the pea aphid Acyrthosiphon pisum. Detailed sequence analysis shows that in both species, one paralog lost critical residues of the α-Catenin binding domain, which is essential for cell adhesion, and accumulated a dramatically higher number of amino acid substitutions in the central Arm repeat domain. Residues associated with aspects of Wnt signaling, however, are conserved in both paralogs. Consistent with these molecular signatures, the effects of specific and combinatorial knockdown experiments in the Tribolium embryo indicate that the duplication resulted in redundant involvement in Wnt signaling of both β-Catenin paralogs but differential inheritance of the ancestral cell adhesion and centrosome separation functions. We conclude that the duplicated pea aphid and flour beetle β-catenin genes experienced partial subfunctionalization, which appears to be evolutionarily favored. Providing first evidence of genetic separability of the cell adhesion and centrosome separation functions, the duplicated Tribolium and Acyrthosiphon arm paralogs offer new inroads for context-specific analyses of β-Catenin. Our data also revealed the conservation of a C-terminally truncated Arm isoform in both singleton and duplicated homologs, suggesting an as yet unexplored role in Wnt signaling.
Pazopanib plus weekly paclitaxel versus weekly paclitaxel alone for platinum-resistant or platinum-refractory advanced ovarian cancer (MITO 11): a randomised, open-label, phase 2 trial
Authors: Sandro Pignata, Domenica Lorusso, Giovanni Scambia, Daniela Sambataro, Stefano Tamberi, Saverio Cinieri, Anna M Mosconi, Michele Orditura, Alba A Brandes, Valentina Arcangeli, Pierluigi Beneditti Panici, Carmela Pisano, Sabrina C Cecere, Marilena Di Napoli, Francesco Raspagliesi, Giuseppa Maltese, Vanda Salutari, Caterina Ricci, Gennaro Daniele, Maria Carmela Piccirillo, Massimo Di Maio, Ciro Gallo, Francesco Perrone
Journal: The Lancet Oncology (2015)
Simvastatin Inhibits Inflammatory Properties of <i>Staphylococcus aureus</i> α-Toxin
Authors: Diethard Pruefer, Joachim Makowski, Martin Schnell, Ute Buerke, Manfred Dahm, Hellmut Oelert, Ulf Sibelius, Ulrich Grandel, Friedrich Grimminger, Werner Seeger, Jürgen Meyer, Harald Darius, Michael Buerke
Journal: Circulation (2002)

Background— Simvastatin, a 3-hydroxy-methylglutaryl coenzyme A reductase inhibitor, has been shown to lower serum cholesterol levels in clinical use. Moreover, statins exert beneficial effects in vascular diseases by inhibition of leukocyte rolling, adherence, and transmigration. The aim of this study was to determine if pretreatment with simvastatin attenuates Staphylococcus aureus α-toxin–induced increase in leukocyte-endothelial interactions during exotoxemia. Methods and Results— The effects of simvastatin on leukocyte-endothelial cell interactions were observed by intravital microscopy in the rat mesenteric microcirculation. Simvastatin (50 or 100 μg/kg) was administered 18 hours before the study. Activation of microcirculation was induced by bolus administration of 40 μg/kg S aureus α-toxin. Exotoxemia resulted in a significant and time-dependent increase in leukocyte rolling, adherence, and transmigration of leukocytes as well as P-selectin expression on the intestinal vascular endothelium. Pretreatment with simvastatin significantly inhibited exotoxin-induced leukocyte rolling from 71±10 to 14±4.7 cells/min ( P &lt;0.01) and adherence from 14±3.5 to 0.4±0.2 cells ( P &lt;0.01). In addition, simvastatin pretreatment significantly inhibited transmigration of leukocytes from 10.5±1.2 to 4.2±0.9 ( P &lt;0.05) cells. Immunohistochemical detection of endothelial cell adhesion molecule P-selectin showed a 50% decrease in endothelial cell surface expression after simvastatin treatment. Furthermore, simvastatin treatment resulted in enhanced expression of endothelial cell NO synthase III in the intestinal microcirculation. Conclusions— These results demonstrate that simvastatin interferes with exotoxin-induced leukocyte-endothelial cell interactions, which may be relevant in various infectious diseases. Statin treatment may offer a new therapeutic strategy for these clinical conditions.
Decreased production of and response to interleukin-2 by cultured lymphocytes from patients with systemic lupus erythematosus.
Authors: J Alcocer-Varela, D Alarcón-Segovia
Journal: Journal of Clinical Investigation (1982)

We studied the production of and response to interleukin-2 (IL-2) by peripheral blood T lymphocytes from 19 systemic lupus erythematosus (SLE) patients who received no treatment at the time they were studied. Eight had active disease and the rest were in remission. Results were compared with those obtained in 12 healthy subjects of similar age. T cells from SLE patients, whether activated with phytohemagglutinin or in autologous mixed lymphocyte reactions, were found to yield little IL-2, to have a low response to IL-2 from its own, or other sources, and to absorb IL-2 poorly, IL-2 produced by SLE cells, albeit scant, was absorbed normally by activated T cells from normal subjects. Our findings may contribute to the understanding of the immunoregulatory defect in SLE.
Oral contraceptives and hepatocellular carcinoma.
Authors: J Neuberger, D Forman, R Doll, R Williams
Journal: BMJ (1986)

A series of 26 white women aged under 50 who developed hepatocellular carcinoma in a non-cirrhotic liver were studied for the possible role of oral contraceptives. Eighteen of the women had used the "pill" for a median of eight years. Over 1300 women whose use of the pill had been determined in another study served as controls. Patients and controls were divided into five age and four calendar groups and the relative risks associated with oral contraceptives calculated by multivariate analysis. Short term use of the pill was not associated with an increased risk of tumour development; nevertheless, use for eight years or more was associated with a 4.4-fold increased risk (p less than 0.01). When patients with markers of hepatitis B virus infection were excluded the relative risk was 7.2 (p less than 0.01). In both instances the absolute risk for developing hepatoma remained low.
A novel rat model to determine interaction between reflux oesophagitis and bronchial asthma
Authors: T. Sugawa, Y. Fujiwara, H. Yamagami, K. Watanabe, T. Tanigawa, M. Shiba, T. Watanabe, K. Tominaga, N. Oshitani, K. Higuchi, T. Arakawa
Journal: Gut (2008)

Several studies have shown a strong association between reflux oesophagitis (RO) and bronchial asthma (BA). The precise mechanisms of interaction between RO and BA are uncertain, possibly due to lack of animal models.We established a novel rat model and examined pathogenic interaction of RO and BA.RO and BA were induced in Brown-Norway rats by ligating the transitional region between the forestomach and the glandular portion and wrapping the duodenum near the pylorus, and by ovalbumin (OVA) sensitisation and challenge with OVA aerosol. Rats were divided into four groups: control, RO, BA, and RO+BA. OVA-induced airway inflammation was assessed by the number of infiltrating cells and cytokine levels in bronchoalveolar lavage fluid (BALF). Oesophageal lesion index, histology and expression of cytokine mRNA, as determined by real-time RT-PCR, were also examined.Significant increases in the number of cells, especially eosinophils, and IL13 but not IFN-gamma concentration in BALF were observed in the RO+BA group compared with the BA group. These enhancements of OVA-induced airway inflammation were prevented by treatment with rabeprazole. Although the oesophagitis lesion index in the RO+BA group did not differ from that in the RO group, eosinophilic infiltration in the oesophageal submucosa and levels of mRNA expression of cytokines such as IL5, IL10, IL13, and RANTES were significantly increased.We established a novel rat model of RO and BA, and found significant interactions of the two diseases. This model thus appears to be useful for examining the association between gastro-oesophageal reflux disease and bronchial asthma.
Biochemical pathways of apoptosis: nicotinamide adenine dinucleotide-deficient cells are resistant to tumor necrosis factor or ultraviolet light activation of the 24-kD apoptotic protease and DNA fragmentation.
Authors: S C Wright, Q S Wei, D H Kinder, J W Larrick
Journal: The Journal of Experimental Medicine (1996)

The function of nicotinamide adenine dinucleotide (NAD) and adenosine diphosphate (ADP) ribosylation reactions in the mechanism of apoptotic cell death is controversial, although one theory postulates an essential role for NAD depletion by poly-ADP-ribose polymerase. The present study examined the role of intracellular NAD in tumor necrosis factor (TNF) and ultraviolet (UV) light-induced activation of the 24-kD apoptotic protease (AP24) leading to internucleosomal DNA fragmentation and death. Our results demonstrate that nutritional depletion of NAD to undetectable levels in two leukemia lines (U937 and HL-60) renders them completely resistant to apoptosis. This was attributed to a block in the activation of AP24 and subsequent DNA cleavage. Normal cells show an elevation of ADP-ribosyl transferase (ADPRT) in both the cytosol and nucleus after exposure to TNF, but before DNA fragmentation. ADPRT activity as well as cell death was suppressed by an inhibitor specific for mono-ADPRT. Nuclei from NAD-depleted cells were still sensitive to DNA fragmentation induced by exogenous AP24, indicating a selective function for NAD upstream of AP24 activation in the apoptotic pathway. We confirmed a requirement for intracellular NAD, activation of ADPRT, and subsequent NAD depletion during apoptosis in KG1a, YAC-1, and BW1547 leukemia cell lines. However, this mechanism is not universal, since BJAB and Jurkat leukemia cells underwent apoptosis normally, even in the absence of detectable intracellular NAD. We conclude that TNF or UV light-induced apoptotic cell death is not due to NAD depletion in some leukemia cell lines. Rather, NAD-dependent reactions which may involve mono-ADPRT, function in signal transduction leading to activation of AP24, with subsequent DNA fragmentation and cell death.
IMMUNOFLUORESCENT STUDIES OF ADENOVIRUS 12 TUMORS AND OF CELLS TRANSFORMED OR INFECTED BY ADENOVIRUSES
Authors: John H. Pope, Wallace P. Rowe
Journal: The Journal of Experimental Medicine (1964)

Complement-fixing (CF) antibody-positive sera from hamsters bearing adenovirus type 12 (Ad. 12)-induced tumors revealed specific immunofluorescent stainable antigens in essentially all Ad. 12 hamster tumor cells. The antigens were primarily in the form of cytoplasmic flecks; less frequent staining was seen as nuclear flecks or homogeneous staining of nucleus and cytoplasm of a small proportion of cells. Tumor cells did not stain with rabbit antisera to crude Ad. 12 virus or A and C antigens. The hamster serum also stained cytoplasmic flecks in an Ad. 12-induced BALB/c mouse tumor and Ad. 12-"transformed" hamster embryo tissue culture cells. The hamster serum also stained fleck-shaped antigens in hamster and human cell cultures inoculated with homologous and heterologous adenovirus types, although the hamster cells did not react with the rabbit Ad. 12 antiserum. Attempts to identify the fluorescent-stainable fleck-shaped antigens indicated that they are not previously recognized viral antigens and that the cytoplasmic antigens formed in hamster cell cultures inoculated with Ad. 12 are different from those in tumors and in acutely infected human cell cultures.
Wnt5a signaling mediates biliary differentiation of fetal hepatic stem/progenitor cells in mice
Authors: Kei Kiyohashi, Sei Kakinuma, Akihide Kamiya, Naoya Sakamoto, Sayuri Nitta, Hideto Yamanaka, Kouhei Yoshino, Junko Fujiki, Miyako Murakawa, Akiko Kusano-Kitazume, Hiromichi Shimizu, Ryuichi Okamoto, Seishin Azuma, Mina Nakagawa, Yasuhiro Asahina, Naoki Tanimizu, Akira Kikuchi, Hiromitsu Nakauchi, Mamoru Watanabe
Journal: Hepatology (2013)

The molecular mechanisms regulating differentiation of fetal hepatic stem/progenitor cells, called hepatoblasts, which play pivotal roles in liver development, remain obscure. Wnt signaling pathways regulate the development and differentiation of stem cells in various organs. Although a β-catenin-independent noncanonical Wnt pathway is essential for cell adhesion and polarity, the physiological functions of noncanonical Wnt pathways in liver development are unknown. Here we describe a functional role for Wnt5a, a noncanonical Wnt ligand, in the differentiation of mouse hepatoblasts. Wnt5a was expressed in mesenchymal cells and other cells of wild-type (WT) midgestational fetal liver. We analyzed fetal liver phenotypes in Wnt5a-deficient mice using a combination of histological and molecular techniques. Expression levels of Sox9 and the number of hepatocyte nuclear factor (HNF)1β(+) HNF4α(-) biliary precursor cells were significantly higher in Wnt5a-deficient liver relative to WT liver. In Wnt5a-deficient fetal liver, in vivo formation of primitive bile ductal structures was significantly enhanced relative to WT littermates. We also investigated the function of Wnt5a protein and downstream signaling molecules using a three-dimensional culture system that included primary hepatoblasts or a hepatic progenitor cell line. In vitro differentiation assays showed that Wnt5a retarded the formation of bile duct-like structures in hepatoblasts, leading instead to hepatic maturation of such cells. Whereas Wnt5a signaling increased steady-state levels of phosphorylated calcium/calmodulin-dependent protein kinase II (CaMKII) in fetal liver, inhibition of CaMKII activity resulted in the formation of significantly more and larger-sized bile duct-like structures in vitro compared with those in vehicle-supplemented controls.Wnt5a-mediated signaling in fetal hepatic stem/progenitor cells suppresses biliary differentiation. These findings also suggest that activation of CaMKII by Wnt5a signaling suppresses biliary differentiation. (HEPATOLOGY 2013;).
IMMUNOLOGICAL RELATIONSHIP BETWEEN THE SWINE AND HUMAN INFLUENZA VIRUSES IN SWINE
Authors: Richard E. Shope
Journal: The Journal of Experimental Medicine (1937)

Swine recovered from infection with either swine influenza or swine influenza virus alone are usually not only immune but refractory to human influenza infection. Swine recovered from infection with a mixture of human influenza virus and H. influenzae suis are usually immune to swine influenza while those recovered from infection with human influenza virus alone are usually not immune to swine influenza. The possible mechanisms involved in the cross-immunity between the influenza viruses are discussed.
Three-dimensional computed tomography imaging in an animal model of emphysema
Authors: A R Froese, K Ask, R Labiris, T Farncombe, D Warburton, M D Inman, J Gauldie, M Kolb
Journal: European Respiratory Journal (2007)

Emphysema is a major health problem and novel drugs are needed. Animal disease models are pivotal in their development, but the validity and sensitivity of current tools for the evaluation of drug efficacy is limited. The usefulness of micro computed tomography (CT) as an innovative tool to assess emphysema in a mouse model was investigated. Serial CT scans were performed in bi-weekly intervals in Smad3 knockout (KO) mice, which spontaneously develop airspace enlargement. Lung density was quantified in two- and three-dimensional images and correlated to mean linear intercept and lung compliance. CT scans of Smad3 KO lungs revealed a significant decrease in lung density at age 8 weeks and a further progression at age 14 weeks with respect to age-matched wild-type (WT) animals. Emphysema could be reliably assessed with both the two- and three-dimensional approach, but the three-dimensional approach was superior, due to normalisation to lung volumes and less variability. Lung compliance by week 14 was 0.053±0.005 and 0.034±0.002% of maximum volume·cmH 2 O −1 for KO and WT mice, respectively, reflecting significant physiologically relevant emphysema. Small animal computed tomography imaging and density quantification in a reconstructed three-dimensional image is a useful tool for quantifying emphysematous changes in an animal disease model. It adds significant information to conventional assessment.
Increased Mortality after Dronedarone Therapy for Severe Heart Failure
Authors: Lars Køber, Christian Torp-Pedersen, John J.V. McMurray, Ole Gøtzsche, Samuel Lévy, Harry Crijns, Jan Amlie, Jan Carlsen
Journal: New England Journal of Medicine (2008)

Dronedarone is a novel antiarrhythmic drug with electrophysiological properties that are similar to those of amiodarone, but it does not contain iodine and thus does not cause iodine-related adverse reactions. Therefore, it may be of value in the treatment of patients with heart failure.
Inhibition by Protein Kinase C of the K <sub>NDP</sub> Subtype of Vascular Smooth Muscle ATP-Sensitive Potassium Channel
Authors: William C. Cole, Todd Malcolm, Michael P. Walsh, Peter E. Light
Journal: Circulation Research (2000)

Abstract —ATP-sensitive K + channels (K ATP ) contribute to the regulation of tone in vascular smooth muscle cells. We determined the effects of protein kinase C (PKC) activation on the nucleoside diphosphate–activated (K NDP ) subtype of vascular smooth muscle K ATP channel. Phorbol 12,13-dibutyrate (PdBu) and angiotensin II inhibited K NDP activity of C-A patches of rabbit portal vein (PV) myocytes, but an inactive phorbol ester was without effect, and pretreatment with PKC inhibitor prevented the actions of PdBu. Constitutively active PKC inhibited K NDP in I-O patches but was without effect in the presence of a specific peptide inhibitor of PKC. PdBu increased the duration of a long-lived interburst closed state but was without effect on burst duration or intraburst kinetics. PdBu treatment inhibited K NDP , but not a 70-pS K ATP channel of rat PV. The results indicate that the K NDP subtype of vascular smooth muscle K ATP channel is inhibited by activation of PKC. Control of K NDP activity by intracellular signaling cascades involving PKC may, therefore, contribute to control of tone and arterial diameter by vasoconstrictors. (Circ Res. 2000;87:112-117.)
Chinese hamster ovary cell adhesion to human platelet thrombospondin is dependent on cell surface heparan sulfate proteoglycan.
Authors: P R Kaesberg, W B Ershler, J D Esko, D F Mosher
Journal: Journal of Clinical Investigation (1989)

Thrombospondin is a 420-kD platelet alpha-granule glycoprotein that binds specifically to heparin. We examined adhesion to thrombospondin of CHO K1 cells and three mutant CHO lines with varying deficiencies in glycosaminoglycan (GAG) synthesis. In an experiment in which the parent line (K1) had 78% adherence to thrombospondin adsorbed to tissue culture plastic, CHO S745 cells, with less than 6% normal GAG synthesis had 11% adherence. CHO S677 cells, with decreased heparan sulfate proteoglycan but increased chondroitin sulfate proteoglycan, had 42% adherence. CHO S803 cells, with decreased heparan sulfate proteoglycan and normal chondroitin sulfate proteoglycan, had 31% adherence. Heparin inhibited K1 cell adhesion to thrombospondin, but not fibronectin, in a concentration-dependent manner. Dermatan sulfate but not chondroitin sulfate was also inhibitory. There was markedly decreased K1 cell adhesion to a thrombospondin core fragment that lacked the heparin binding NH2-terminal domain. Purified heparin binding domain, although poorly adhesive when adsorbed to substratum, inhibited cell adhesion to intact thrombospondin. Adhesion was better for all cell lines tested, including three human tumor cell lines, when thrombospondin was adsorbed at pH 4.0 compared with pH 7.4. When adsorption of thrombospondin was done at pH 7.4, cell adhesion was better when thrombospondin was adsorbed in the presence of greater than or equal to 0.6 mM calcium, compared to 0.1 mM calcium or EDTA. These findings suggest that thrombospondin can adsorb to plastic with varying degrees of exposure of a cell adhesion domain. We conclude that the thrombospondin cell adhesion receptor on CHO cells is a heparan sulfate proteoglycan, and that cell adhesion to thrombospondin depends on conformation of adsorbed thrombospondin.
Alteration of the serine protease PRSS56 causes angle-closure glaucoma in mice and posterior microphthalmia in humans and mice
Authors: K Saidas Nair, Mounira Hmani-Aifa, Zain Ali, Alison L Kearney, Salma Ben Salem, Danilo G Macalinao, Ioan M Cosma, Walid Bouassida, Bochra Hakim, Zeineb Benzina, Ileana Soto, Peter Söderkvist, Gareth R Howell, Richard S Smith, Hammadi Ayadi, Simon W M John
Journal: Nature Genetics (2011)
Familial Clustering of Hodgkin Lymphoma and Multiple Sclerosis
Authors: Henrik Hjalgrim, Søren Rasmussen, Klaus Rostgaard, Nete Munk Nielsen, Nils Koch-Henriksen, Lars Munksgaard, Hans H Storm, Mads Melbye
Journal: JNCI Journal of the National Cancer Institute (2004)

Background: Epidemiologic similarities between Hodgkin lymphoma in young adults (i.e., between 15 and 44 years old) and multiple sclerosis have led to the suggestion that these diseases may have related etiologies. Previous investigations have not supported this hypothesis, but the negative results could have been caused by methodologic problems. We therefore assessed the risk of developing Hodgkin lymphoma for patients with multiple sclerosis and for their families and the risk of developing multiple sclerosis for patients with Hodgkin lymphoma and for their families. Methods: We identified 11 790 patients with multiple sclerosis and 19 599 of their first-degree relatives in Danish population-based registers and followed them for the occurrence of Hodgkin lymphoma. Analogously, we identified 4381 patients with Hodgkin lymphoma and 7388 of their first-degree relatives and followed them for the occurrence of multiple sclerosis. The relative risks (RRs) of Hodgkin lymphoma and multiple sclerosis were expressed as standardized incidence ratios (i.e., the ratio between observed and expected numbers of outcomes based on age, sex, and period-specific incidence rates). All statistical tests were two-sided. Results: Overall, six cases of Hodgkin lymphoma were identified in patients with multiple sclerosis (RR for Hodgkin lymphoma = 1.40, 95% confidence interval [CI] = 0.63 to 3.12), two of which occurred in young adults (RR = 1.59, 95% CI = 0.40 to 6.37). The risk of young-adult-onset Hodgkin lymphoma was statistically significantly increased in the first-degree relatives of patients with multiple sclerosis (RR = 1.93, 95% CI = 1.01 to 3.71; n = 9 such lymphomas). Two cases of multiple sclerosis were identified among young adult patients with Hodgkin lymphoma (RR for multiple sclerosis = 0.82, 95% CI = 0.20 to 3.27), and the risk for multiple sclerosis was statistically significantly increased in their first-degree relatives (RR = 2.76, 95% CI = 1.44 to 5.31; n = 9 such multiple sclerosis cases). Conclusion: The observed familial clustering of multiple sclerosis and young-adult-onset Hodgkin lymphoma is consistent with the hypothesis that the two conditions share environmental and/or constitutional etiologies.