tbuckley/cabot-search huggingface dataset:
Antigen specificity of antihistone antibodies in systemic sclerosis
Authors: M. Hasegawa, S. Sato, K. Kikuchi, K. Takehara
Journal: Annals of the Rheumatic Diseases (1998)

OBJECTIVES The aim of the study was to determine the prevalence and clinical significance of antibodies to individual histone components in systemic sclerosis (SSc). METHODS Serum samples from patients with limited cutaneous SSc (lSSc; n=42) and diffuse cutaneous SSc (dSSc; n=28) were examined for IgG and/or IgM antibodies to individual histone components and complexes by enzyme linked immunosorbent assay (ELISA). RESULTS The level of IgG antibody to total histones was significantly higher in lSSc and dSSc than in normal controls. The level of IgM antibody to total histones was significantly higher in lSSc, but not in dSSc, than in normal controls. IgG antibody to total histones tended to be increased in dSSc when compared with that in lSSc. On the other hand, IgM antibody to total histones tended to be increased in lSSc when compared with that in dSSc. Although SSc showed various antihistone specificities, H2B, H2A-H2B, (H2A-H2B)-dsDNA were main antigens recognised by IgG antibodies in both lSSc and dSSc. Although IgM antibodies to H2B and H2A-H2B were also detected in both lSSc and dSSc, serum samples from lSSc patients exhibited highest IgM reactivity with H1. CONCLUSION SSc may be included among conditions in which heterogeneous antihistone antibodies are produced. IgM antibodies to the most accessible histone H1 may be related to mild clinical features (lSSc) and IgG antibodies to the inner core molecules of native histone such as H2B or complexes including H2B may be associated with severe clinical features (dSSc) in Ssc.
The Oncoprotein SF2/ASF Promotes Non–Small Cell Lung Cancer Survival by Enhancing Survivin Expression
Authors: Teresa Ezponda, María J. Pajares, Jackeline Agorreta, José I. Echeveste, José M. López-Picazo, Wenceslao Torre, Ruben Pio, Luis M. Montuenga
Journal: Clinical Cancer Research (2010)

SF2/ASF is a splicing factor recently described as an oncoprotein. In the present work, we examined the role of SF2/ASF in human non-small cell lung cancer (NSCLC) and analyzed the molecular mechanisms involved in SF2/ASF-related carcinogenesis.SF2/ASF protein levels were analyzed in 81 NSCLC patients by immunohistochemistry. SF2/ASF downregulation cellular models were generated using small interfering RNAs, and the effects on proliferation and apoptosis were evaluated. Survivin and SF2/ASF expression in lung tumors was analyzed by Western blot and immunohistochemistry. Survival curves and log-rank test were used to identify the association between the expression of the proteins and time to progression.Overexpression of SF2/ASF was found in most human primary NSCLC tumors. In vitro downregulation of SF2/ASF induced apoptosis in NSCLC cell lines. This effect was associated with a reduction in the expression of survivin, an antiapoptotic protein widely upregulated in cancer. In fact, SF2/ASF specifically bound survivin mRNA and enhanced its translation, via a mammalian target of rapamycin complex 1 (mTORC1) pathway-dependent mechanism, through the phosphorylation and inactivation of the translational repressor 4E-BP1. Moreover, SF2/ASF promoted the stability of survivin mRNA. A strong correlation was observed between the expression of SF2/ASF and survivin in tumor biopsies from NSCLC patients, supporting the concept that survivin expression levels are controlled by SF2/ASF. Furthermore, combined expression of these proteins was associated with prognosis.This study provides novel data on the mTORC1- and survivin-dependent mechanisms of SF2/ASF-related carcinogenic potential, and shows that SF2/ASF and survivin expression is involved in NSCLC progression.
Blood Coagulation Changes in Rats Fed High Fat Diets
Authors: Lyman M. Fisher, Eugene Kagan, Henry G. Kupfer
Journal: Circulation Research (1963)

High fat diets were given ad libitum or force-fed to rats. The incidence of thrombosis in animals fed a cow butter diet was higher than in those fed a cocoa butter diet. No thrombosis was found in rats fed a diet containing peanut oil. Coagulation studies performed at weekly intervals on blood samples obtained from a tail vein of rats fed the diets ad libitum showed that there was a gradual but marked increase in the levels of Factors II, VII, and X of animals fed a diet containing cow or cocoa butter, but not one containing peanut oil. Several weeks prior to death, however, the level of all coagulation factors, including Factors I and V, fell. A significant prolongation of the values for the partial thromboplastin time was found in animals killed at the time when levels of plasma coagulation factors decreased. The pattern of changes in concentration of plasma coagulation factors was similar in the groups of animals dying with proven thrombosis and in those in which thrombosis was not found. All rats force-fed the above two diets died within two weeks, showing a marked fall in all coagulation factors and no thrombosis. Weight loss was more pronounced in the groups of animals fed the diet containing cow butter and cocoa butter than in animals fed Purina chow. Autopsy findings were: intra-ventricular thrombi with myocardial infarction, lung hemorrhage, pneumonia, and rarely jaundice. No cause of death other than inanition was discernible in some of the animals. Marked fatty infiltration of the liver was a feature of all animals autopsied.
Genomic insights into early-onset obesity
Authors: Hélène Choquet, David Meyre
Journal: Genome Medicine (2010)

The biological causes of childhood obesity are complex. Environmental factors, such as massive marketing campaigns for food leading to over-nutrition and snacking and the decline in physical activity, have undoubtedly contributed to the increased prevalence of overweight and obesity in children, but these cannot be considered as the only causes. Susceptibility to obesity is also determined to a great extent by genetic factors. Furthermore, molecular mechanisms involved in the regulation of gene expression, such as epigenetic mechanisms, can increase the risk of developing early-onset obesity. There is evidence that early-onset obesity is a heritable disorder, and a range of genetic factors have recently been shown to cause monogenic, syndromic and polygenic forms of obesity, in some cases interacting with environmental exposures. Modifications of the transcriptome can lead to increased adiposity, and the gut microbiome has recently been shown to be key to the genesis of obesity. These new genomic discoveries complement previous knowledge on the development of early-onset obesity and provide new perspectives for research on the complex molecular and physiological mechanisms involved in this disease. Personalized preventive strategies and genomic medicine may become possible in the near future.
Influence of Sympathomimetic Pressor Drugs on Arrhythmias Caused by Multiple Stimuli
Authors: J. L. GILBERT, GERTRUDE LANGE, C. McC. BROOKS
Journal: Circulation Research (1959)

A technic of administering successive stimuli to the heart at various ectopic foci was devised. Under normal circumstances the heart had sufficient power of integration to resist disorganization of its action by these multiple stimuli. Methoxamine, mephentermine and metaraminol had less tendency to increase vulnerability to fibrillation than did levarterenol under these conditions of stress. A new compound (Lilly #20522) blocked for a time the arrhythmia-producing action of levarterenol.
Control of Ocular Tumor Growth and Metastatic Spread by Soluble and Membrane Fas Ligand
Authors: Meredith S. Gregory, Rebecca R. Saff, Ann Marshak-Rothstein, Bruce R. Ksander
Journal: Cancer Research (2007)

Abstract Fas ligand (FasL) can be either membrane bound, or cleaved by metalloproteinases (MMP) to produce a soluble protein. The two different forms of FasL are reported to have opposite functions—membrane-bound FasL (mFasL) is proinflammatory and soluble FasL (sFasL) is antiinflammatory. We previously showed that, within the immune-privileged eye, tumors expressing high levels of mFasL overcame the suppressive ocular environment, triggered an inflammatory response, and were subsequently rejected. By contrast, eye tumors expressing low levels of mFasL grew progressively. To evaluate the effect of sFasL on the tumor growth and metastatic potential of ocular FasL-expressing tumors, we compared tumor cell clones that expressed equal amounts of (low) mFasL in the presence or absence of sFasL. Tumor cells transfected with a modified FasL gene expressed only mFasL (noncleavable), grew progressively within the eye, and induced systemic protective immunity that prevented metastatic spread of tumor cells to the liver. Unexpectedly, tumors transfected with wild-type FasL (wtFasL; cleavable), which could produce both sFasL and mFasL, elicited considerably more inflammation and grew more slowly within the eye. However, the cleavable wtFasL eye tumors failed to trigger protective immunity and gave rise to liver metastases. Interestingly, exposure to the ocular environment was required for the wtFasL tumors to gain metastatic potential. We conclude that the fate of FasL-expressing tumors is determined by a combination of the following: (a) the relative proportion of membrane and sFasL, and (b) the local environment that determines the extent of FasL cleavage. [Cancer Res 2007;67(24):11951–58]
Oxygen desaturation on the six-minute walk test and mortality in untreated primary pulmonary hypertension
Authors: G. Paciocco, F.J. Martinez, E. Bossone, E. Pielsticker, B. Gillespie, M. Rubenfire
Journal: European Respiratory Journal (2001)

There are no reliable predictors of mortality in primary pulmonary hypertension (PPH). This study assessed whether exercise oxygen desaturation and distance achieved during a six-minute walk are associated with mortality in moderately symptomatic patients with PPH. Thirty-four patients with PPH underwent a pretreatment six-minute walk test, and an invasive haemodynamic assessment of pulmonary vasodilator reserve, to select the best treatment option (epoprostenol in 27 and nifedipine in 7). Median follow-up was 26 months (12 months for the nonsurvivors was 26%), and median survival, &gt;46 months by Kaplan-Maier estimate. The mean±sd distance walked was 275±155 m and reduction in arterial oxygen saturation ( S a,O 2 ) at maximal distance (Δ S a,O 2 ) was 8.4±4.5%. A distance ≤300 m increased mortality risk by 2.4, and a Δ S a,O 2 of ≥10 % increased mortality risk by 2.9. Only S a,O 2 at peak distance, Δ S a,O 2 and pulmonary vascular resistance (PVR) were related to mortality. After adjusting for PVR, there remained a 27% increase in risk of death for each per cent decrease in S a,O 2 . The six-minute walk distance and exercise oxygen saturation may be helpful in selecting patients with primary pulmonary hypertension for whom transplant listing is appropriate.
Circulating Immunoreactive Interleukin-6 in Cystic Fibrosis
Authors: LISETTE S. NIXON, BERNARD YUNG, SCOTT C. BELL, J. STUART ELBORN, DENNIS J. SHALE
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

We measured circulating and sputum-sol concentrations of interleukin-6 (IL-6), tumor necrosis factor- α (TNF- α ), neutrophil elastase- α1-antiproteinase complex (NEAPC), and C-reactive protein (CRP) in an exacerbation, after antibiotic treatment, and in clinically stable patients with cystic fibrosis and chronic pulmonary infection with Pseudomonas aeruginosa. The aim was to determine the compartmental patterns of a proinflammatory and anti-inflammatory cytokine compared with other markers of inflammatory activity in cystic fibrosis. IL-6, NEAPC, CRP, and absolute neutrophil count were reduced after antibiotic treatment, p < 0.01. IL-6 and CRP concentrations were greater, p = 0.007, and p = 0.01, respectively, in a stable group of patients compared with those at the end of an exacerbation. IL-6 and CRP concentrations were related (r = 0.836, p < 0.0001), and both were greater than in matched control subjects (p < 0.001) at all times studied. Sputum-sol concentrations of IL-6 after treatment were positively related to FEV1 and FVC and inversely related to concentrations of neutrophil elastase. The separation between patients and healthy subjects, and the reduction of IL-6 after antibiotic treatment indicates it could be used as a marker of inflammation, but its relationship to other markers depends on the compartment in which it is measured.
IL-6 targeting compared to TNF targeting in rheumatoid arthritis: studies of olokizumab, sarilumab and sirukumab
Authors: Yoshiya Tanaka, Emilio Martin Mola
Journal: Annals of the Rheumatic Diseases (2014)

The combination of synthetic disease-modifying anti-rheumatic drugs (sDMARDs) such as methotrexate (MTX) and biologic DMARDs (bDMARDs) targeting inflammatory cytokines such as tumour necrosis factor (TNF) has enabled markedly efficient control of disease activity in patients with rheumatoid arthritis (RA) with inadequate response to MTX (MTX-IR).1–7 Although TNF inhibitors have offered pivotal strategies for rheumatologists in daily practice and 20–50% of RA patients treated with TNF inhibitors achieve clinical remission within 6 months, the remaining patients still have active disease and progressive disability. IL-6 is also a pleiotropic cytokine with diverse activities and plays a central role in the pathogenesis of RA by contributing to T cell activation, B cell activation, synoviocyte stimulation, endothelial activation, osteoclast maturation and production of acute-phase proteins. Serum levels of IL-6 and soluble IL-6 receptor (IL-6R) are elevated and correlate with disease activity in RA patients and so blocking IL-6/IL-6R has been considered beneficial for the treatment of RA. In accordance with this, accumulated evidence has shown the clinical efficacy as well as the adequate safety of tocilizumab, a humanised anti-IL-6R monoclonal antibody (mAb), as monotherapy or in combination with sDMARDs such as MTX in patients who are sDMARD naive and have an inadequate response to TNF inhibitors (TNF-IR).8–13 Tocilizumab was, therefore, approved as a first-line bDMARD in patients responding insufficiently to MTX or other sDMARDs in Japan and Europe. Also, in the 2013 EULAR recommendations for the management of RA, tocilizumab was listed as a first-line TNF inhibitor in patients with sDMARD-IR.14 The successful treatment of RA by tocilizumab has encouraged the development of novel bDMARDs targeting IL-6 or IL-6R. In addition to tocilizumab, the phase II clinical trials of olokizumab, sarilumab and sirukumab, three new bDMARDs targeting IL-6, are reported.

Olokizumab is a humanised anti-IL-6 mAb. Genovese et al 15 report the …
Thyroid hormones and the hepatic handling of bilirubin. I. Effects of hypothyroidism and hyperthyroidism on the hepatic transport of bilirubin mono- and diconjugates in the wistar rat
Authors: Werner Van Steenbergen, Johan Fevery, Rita De Vos, Roger Leyten, Karel P. M. Heirwegh, Jan De Groote
Journal: Hepatology (1989)

The effects of thyroidectomy and of thyroid hormone administration on the hepatic transport of endogenous bilirubin were investigated in the Wistar R/APfd rat. Hypothyroidism resulted in an enhanced hepatic bilirubin UDP-glucuronosyltransferase activity and in a decreased p -nitrophenol transferase activity. It caused a cholestatic condition with a 50% decrease in bile flow and bile salt excretion, and an increased proportion of conjugated bilirubin in serum. The biliary output of unconjugated and monoconjugated bilirubins decreased in parallel by about 65%, whereas the excretion rate of the diconjugate dropped by only 47%, resulting in an increased di-to monoconjugate ratio in bile. Hyperthyroidism was characterized by a decreased bilirubin and an increased p -nitrophenol transferase activity, and by an augmented bilirubin output in bile. The output of unconjugated and monoconjugated bilirubins increased in parallel by about 50 or 100%, whereas the excretion of the diconjugate increased by only 20 to 50%, depending on the dose of thyroxine administered; this resulted in a decreased di-to monoconjugate ratio in bile. A linear positive relationship was found between bilirubin UDP-glucuronosyltransferase activity and the ratio of bilirubin di-to monoconjugates present in bile or formed by in vitro incubation of liver homogenates at low concentration of bilirubin (10 to 15 μ M ), indicating that bile pigment composition is mainly determined by the conjugation activity in the liver. The inverse relationship observed between hepatic β-glucuronidase activity and the ratio of di-to monoconjugates in bile warrants further investigation to analyze whether this enzyme activity also plays a possible role in the changes in bile pigment composition in hypo-and hyperthyroid rats.
Targeting Platelet–Leukocyte Interactions
Authors: Raila Ehlers, Valentin Ustinov, Zhiping Chen, Xiaobin Zhang, Ravi Rao, F. William Luscinskas, Jose Lopez, Edward Plow, Daniel I. Simon
Journal: The Journal of Experimental Medicine (2003)

The firm adhesion and transplatelet migration of leukocytes on vascular thrombus are dependent on the interaction of the leukocyte integrin Mac-1 (αMβ2, CD11b/CD18) and the platelet counter receptor glycoprotein (GP) Ibα. Previous studies have established a central role for the I domain, a stretch of ∼200 amino acids within the αM subunit, in the binding of GP Ibα. This study was undertaken to establish the molecular basis of GP Ibα recognition by αMβ2. The P201–K217 sequence, which spans an exposed loop and amphipathic α4 helix in the three-dimensional structure of the αMI domain, was identified as the binding site for GP Ibα. Mutant cell lines in which the αMI domain segments P201–G207 and R208–K217 were switched to the homologous, but non-GP Ibα binding, αL domain segments failed to support adhesion to GP Ibα. Mutation of amino acid residues within P201–K217, H210–A212, T213–I215, and R216–K217 resulted in the loss of the binding function of the recombinant αMI domains to GP Ibα. Synthetic peptides duplicating the P201–K217, but not scrambled versions, directly bound GP Ibα and inhibited αMβ2-dependent adhesion to GP Ibα and adherent platelets. Finally, grafting critical amino acids within the P201–K217 sequence onto αL, converted αLβ2 into a GP Ibα binding integrin. Thus, the P201–K217 sequence within the αMI domain is necessary and sufficient for GP Ibα binding. These observations provide a molecular target for disrupting leukocyte–platelet complexes that promote vascular inflammation in thrombosis, atherosclerosis, and angioplasty-related restenosis.
Moving models of motion forward: Explication and a new concept
Authors: Thomas G. Fikes, James T. Townsend
Journal: Behavioral and Brain Sciences (1995)

Abstract We affirm the dynamical systems approach taken by Feldman and Levin, but argue that a more mathematically rigorous and standard exposition of the model according to dynamical systems theory would greatly increase readability and testability. Such an explication would also have heuristic value, suggesting new variations of the model. We present one such variant, a new solution to the redundancy problem.
Targeting Continued Androgen Receptor Signaling in Prostate Cancer
Authors: Christophe Massard, Karim Fizazi
Journal: Clinical Cancer Research (2011)

Prostate cancer is the most common cancer and the second leading cause of death from cancer in males in most Western countries. Prostate cancer has an exquisite sensitivity to androgen deprivation therapy and is the most endocrine-sensitive solid neoplasm, although advanced disease eventually progresses to castration-resistant prostate cancer (CRPC). Recent evidence has shown that cancer progression at the CRPC stage is often mediated by androgen receptor signaling, so that subsequent androgen receptor targeting may further contribute to disease control and, eventually, survival improvement. Abiraterone acetate, an androgen biosynthesis inhibitor, was tested in patients with CRPC pretreated with docetaxel in a phase III trial with demonstration of an overall survival benefit, confirming that CRPC remains hormone driven, even in advanced stages of the disease. Several novel agents also targeting androgen receptor signaling are currently being evaluated, including MDV3100 and orteronel (TAK-700). With the availability of newer endocrine treatments and also nonendocrine treatments (e.g., chemotherapy, immunotherapy, and bone-targeting agents), data supporting a more rational use of therapeutic agents are urgently required in patients with CRPC. It is likely that molecular characterization of prostate cancer will lead to the identification of different subsets of prostate cancer disease with a different natural history, sensitivity, and resistance to treatment; efforts to develop, validate, and implement predictive biomarkers in clinical trials and eventually in routine care should now be strongly supported.
Immune reconstitution without graft-versus-host disease after haemopoietic stem-cell transplantation: a phase 1/2 study
Authors: Isabelle André-Schmutz, Françoise Le Deist, Salima Hacein-Bey-Abina, Ellen Vitetta, John Schindler, Gaelle Chedeville, Etienne Vilmer, Alain Fischer, Marina Cavazzana-Calvo
Journal: The Lancet (2002)
Secretory Leukocyte Protease Inhibitor Binds to Annexin II, a Cofactor for Macrophage HIV-1 Infection
Authors: Ge Ma, Teresa Greenwell-Wild, Kejian Lei, Wenwen Jin, Jennifer Swisher, Neil Hardegen, Carl T. Wild, Sharon M. Wahl
Journal: The Journal of Experimental Medicine (2004)

The distribution of secretory leukocyte protease inhibitor (SLPI) at entry portals indicates its involvement in defending the host from pathogens, consistent with the ability of SLPI to inhibit human immunodeficiency virus (HIV)-1 infection by an unknown mechanism. We now demonstrate that SLPI binds to the membrane of human macrophages through the phospholipid-binding protein, annexin II. Based on the recent identification of human cell membrane phosphatidylserine (PS) in the outer coat of HIV-1, we define a novel role for annexin II, a PS-binding moiety, as a cellular cofactor supporting macrophage HIV-1 infection. Moreover, this HIV-1 PS interaction with annexin II can be disrupted by SLPI or other annexin II–specific inhibitors. The PS–annexin II connection may represent a new target to prevent HIV-1 infection.
A Multicomponent Intervention to Prevent Delirium in Hospitalized Older Patients
Authors: Sharon K. Inouye, Sidney T. Bogardus, Peter A. Charpentier, Linda Leo-Summers, Denise Acampora, Theodore R. Holford, Leo M. Cooney
Journal: New England Journal of Medicine (1999)

Since in hospitalized older patients delirium is associated with poor outcomes, we evaluated the effectiveness of a multicomponent strategy for the prevention of delirium.