tbuckley/cabot-search huggingface dataset:
Hypercholesterolemia induces regression in neointimal thickening due to apoptosis of vascular smooth muscle cells in the hamster endothelial injury model
Authors: A Matsuda
Journal: Cardiovascular Research (2002)

Hypercholesterolemia is a major risk factor in the development of atherosclerosis. Although matrix metalloproteinase may play a key role in plaque rupture, apoptosis of vascular smooth muscle cells (VSMCs), which is induced by cholesterol and its oxides may also contribute to instability and rupture of plaque. Thus, we investigated the roles of hypercholesterolemia in vascular remodeling following endothelial injury in the hamster femoral artery.The endothelium was injured by photochemical reaction between green light and the photosensitizer dye, Rose Bengal. Photochemical reaction is routinely used in our laboratory to produce endothelial injury without mechanical stretching in experimental animals.In normocholesterolemic hamsters (NCH), neointimal thickening gradually progressed within a 3-week observation period after endothelial injury. In hypercholesterolemic hamsters (HCH), neointimal thickening gradually progressed until the second week after endothelial injury. In contrast, at the third week neointimal thickening regressed and was thinner than that at the second week. There was no significant difference in in vivo proliferation of VSMCs detected by in vivo BrdU uptake between HCH and NCH. Apoptotic cells in the neointima and the media were observed in HCH from 2 to 4 weeks after endothelial injury, but not in NCH. At 2 weeks after endothelial injury, the numbers of TUNEL-positive VSMCs in HCH were significantly higher than those in NCH (neointima; 1.2 +/- 0.3 vs. 0.3 +/- 0.1%, P<0.05, media; 2.9 +/- 0.6 vs. 0.6 +/- 0.2%, P<0.01). Cholesterol deposit, which is detected by oil red O staining was observed in a neointimal or medial area in HCH, but not in NCH.These findings suggest that hypercholesterolemia with endothelial injury may induce VSMC apoptosis, followed by the regression of neointimal thickening, further hypercholesteremia might play a role in inducing plaque rupture through apoptosis of VSMC.
Decline in lung function after exposure to fumes from military small arms
Authors: Anne-Katrine Borander, Øyvind Voie, Liv Ingunn Bjoner Sikkeland, Leiv Sandvik, Kjetil Sager Longva, Tor Erik Danielsen, Svein Grahnstedt, Johny Kongerud
Journal: European Respiratory Journal (2013)

Background:  Norwegian Armed Forces received reports of acute respiratory symptoms after exposure to fumes from firing small arms HK416 using lead free ammunition. The aim of this study was to examine lung function before and after exposure to fumes from HK416 in an experimental setting using three different types of ammunition.   Methods:  Fifty-five healthy, non-smoking males (age 19-62 years) were randomized to three groups using one of three types of ammunition (SS109 (leaded), NM229 and NM255 (lead free)). Tests of lung function included spirometry and DLCO. The tests were performed less than 14 days before (T 0 ), shortly after (T 1 ) and 24 hours after (T 2 ) shooting. A tent was used for achieving control of the exposure. Exposure was monitored by measuring CO and regulated to keep the level between 200 and 300 ppm   Results:   FVC, DLCO, NO show the same trend as for FEV1.  There are no significant differences (one way Anova) between the different types of ammunition concerning FEV1, FVC, DLCO, NO.   Conclusions:  All groups show a decline in FEV1 shortly after shooting. 24 hours after exposure FEV1 are still significantly reduced compared to the pretest values (T0). Other lung function tests show the same trend as for FEV1. We believe this is caused by an inflammatory process of the airways.
The use of the Berlin definition for acute respiratory distress syndrome during infancy and early childhood: multicenter evaluation and expert consensus
Authors: Daniele De Luca, Marco Piastra, Giovanna Chidini, Pierre Tissieres, Edoardo Calderini, Sandrine Essouri, Alberto Medina Villanueva, Ana Vivanco Allende, Marti Pons-Odena, Luis Perez-Baena, Michael Hermon, Ascanio Tridente, Giorgio Conti, Massimo Antonelli, Martin Kneyber
Journal: Intensive Care Medicine (2013)
Inhibition of Mitogen-Elicited Signal Transduction and Growth in Prostate Cancer with a Small Peptide Derived from the Functional Domain of DOC-2/DAB2 Delivered by a Unique Vehicle
Authors: Jian Zhou, Jinhai Fan, Jer-Tsong Hsieh
Journal: Cancer Research (2006)

Abstract Differentially expressed in ovarian cancer-2/disabled 2 (DOC-2/DAB2) protein, often lost in prostate cancer and other cancer types, is a part of homeostatic machinery in normal prostate epithelium. DOC-2/DAB2 modulates mitogen-elicited mitogen-activated protein kinase (MAPK) signal transduction by sequestering several adaptor or effector molecules, such as growth factor receptor bound protein 2 and c-Src. We have shown that the proline-rich sequence in DOC-2/DAB2 is the key functional domain for this action. In this study, we further synthesized peptide based on the functional proline-rich domain and examined its biological function in prostate cancer using cell-permeable peptide (CPP) as a delivery system. From screening of several CPPs in prostate cancer cell lines, a polyarginine peptide (R11) seemed to be the best delivery vehicle because of its highly efficient uptake. In addition, we also observed a similar in vitro half-life and cellular location of R11 in four different prostate cancer cell lines. By conjugating a proline-rich sequence (PPL) or control sequence (AAL) derived from DOC-2/DAB2 to the COOH terminus of R11, we showed that R11PPL but not R11 or R11AAL was able to suppress either serum- or androgen-induced cell proliferation in prostate cancer cells without endogenous DOC-2/DAB2 expression. Consistently, the activation status of MAPK elicited by these mitogens was significantly inhibited by R11PPL but not by R11AAL or R11. Taken together, we conclude that a functional peptide derived from proline-rich domain in DOC-2/DAB2 has growth-inhibitory activity as its native protein, and CPP seems to be an efficient delivery system in prostate cancer cells. (Cancer Res 2006; 66(18): 8954-8)
The genetic relationship between handedness and neurodevelopmental disorders
Authors: William M. Brandler, Silvia Paracchini
Journal: Trends in Molecular Medicine (2013)

Handedness and brain asymmetry have been linked to neurodevelopmental disorders such as dyslexia and schizophrenia.The genetic nature of this correlation is not understood.Recent discoveries have shown handedness is determined in part by the biological pathways that establish left/right (LR) body asymmetry during development.Cilia play a key role in this process, and candidate genes for dyslexia have also been recently shown to be involved in cilia formation.Defective cilia result not only in LR body asymmetry phenotypes but also brain midline phenotypes such as an absent corpus callosum.These findings suggest that the mechanisms for establishing LR asymmetry in the body are reused for brain midline development, which in turn influences traits such as handedness and reading ability.
Delayed Lymphoid Repopulation with Defects in IL-4–Driven Responses Produced by Inactivation of NF-ATc
Authors: Ann M Ranger, Martin R Hodge, Ellen M Gravallese, Mohammed Oukka, Laurie Davidson, Frederick W Alt, Fabienne C de la Brousse, Timothy Hoey, Michael Grusby, Laurie H Glimcher
Journal: Immunity (1998)
PTPN22 splice forms: a new role in rheumatoid arthritis
Authors: Lina-Marcela Diaz-Gallo, Javier Martin
Journal: Genome Medicine (2012)

Genetic variation in the protein tyrosine phosphatase non-receptor type gene 22 (PTPN22, encoding lymphoid tyrosine phosphatase, LYP) influences the risk of developing multiple autoimmune diseases, but the underlying mechanisms are not completely understood. In a recent study published in Genome Medicine, Ronninger et al. showed that there are differences in the expression of PTPN22 isoforms between peripheral blood mononuclear cells from rheumatoid arthritis patients and those of healthy controls. This study provides new insights into the role of PTPN22 in autoimmune diseases.
Inhibition of Integrin αvβ6, an Activator of Latent Transforming Growth Factor-β, Prevents Radiation-induced Lung Fibrosis
Authors: Khalid Puthawala, Nicos Hadjiangelis, Steven C. Jacoby, Emmanuel Bayongan, Zhicheng Zhao, Zhiwei Yang, Mary Louise Devitt, Gerald S. Horan, Paul H. Weinreb, Matvey E. Lukashev, Shelia M. Violette, Kristen S. Grant, Cristina Colarossi, Silvia C. Formenti, John S. Munger
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

In experimental models, lung fibrosis is dependent on transforming growth factor (TGF)-beta signaling. TGF-beta is secreted in a latent complex with its propeptide, and TGF-beta activators release TGF-beta from this complex. Because the integrin alpha(v)beta6 is a major TGF-beta activator in the lung, inhibition of alpha(v)beta6-mediated TGF-beta activation is a logical strategy to treat lung fibrosis.To determine, by genetic and pharmacologic approaches, whether murine radiation-induced lung fibrosis is dependent on alpha(v)beta6.Wild-type mice, alpha(v)beta6-deficient (Itgb6-/-) mice, and mice heterozygous for a Tgfb1 mutation that eliminates integrin-mediated activation (Tgfb1(+/RGE)) were exposed to 14 Gy thoracic radiation. Some mice were treated with an anti-alpha(v)beta6 monoclonal antibody or a soluble TGF-beta receptor fusion protein. Alpha(v)beta6 expression was determined by immunohistochemistry. Fibrosis, inflammation, and gene expression patterns were assessed 20-32 weeks postirradiation.Beta6 integrin expression increased within the alveolar epithelium 18 weeks postirradiation, just before onset of fibrosis. Itgb6-/- mice were completely protected from fibrosis, but not from late radiation-induced mortality. Anti-alpha(v)beta6 therapy (1-10 mg/kg/wk) prevented fibrosis, but only higher doses (6-10 mg/kg/wk) caused lung inflammation similar to that in Itgb6-/- mice. Tgfb1-haploinsufficient mice were also protected from fibrosis.Alpha(v)beta6-mediated TGF-beta activation is required for radiation-induced lung fibrosis. Together with previous data, our results demonstrate a robust requirement for alpha(v)beta6 in distinct fibrosis models. Inhibition of alphavbeta6-mediated TGF-beta activation is a promising new approach for antifibrosis therapy.
Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature
Authors: Gillian I Rice, Paul R Kasher, Gabriella M A Forte, Niamh M Mannion, Sam M Greenwood, Marcin Szynkiewicz, Jonathan E Dickerson, Sanjeev S Bhaskar, Massimiliano Zampini, Tracy A Briggs, Emma M Jenkinson, Carlos A Bacino, Roberta Battini, Enrico Bertini, Paul A Brogan, Louise A Brueton, Marialuisa Carpanelli, Corinne De Laet, Pascale de Lonlay, Mireia del Toro, Isabelle Desguerre, Elisa Fazzi, Àngels Garcia-Cazorla, Arvid Heiberg, Masakazu Kawaguchi, Ram Kumar, Jean-Pierre S-M Lin, Charles M Lourenco, Alison M Male, Wilson Marques, Cyril Mignot, Ivana Olivieri, Simona Orcesi, Prab Prabhakar, Magnhild Rasmussen, Robert A Robinson, Flore Rozenberg, Johanna L Schmidt, Katharina Steindl, Tiong Y Tan, William G van der Merwe, Adeline Vanderver, Grace Vassallo, Emma L Wakeling, Evangeline Wassmer, Elizabeth Whittaker, John H Livingston, Pierre Lebon, Tamio Suzuki, Paul J McLaughlin, Liam P Keegan, Mary A O'Connell, Simon C Lovell, Yanick J Crow
Journal: Nature Genetics (2012)
Significance of low molecular weight C1q in systemic lupus erythematosus.
Authors: R Hoekzema, A J Swaak, M C Brouwer, A van Rooijen, E J Nieuwenhuys, C E Hack
Journal: Annals of the Rheumatic Diseases (1990)

The significance of high serum concentrations of low molecular weight C1q (LMW-C1q) in patients with systemic lupus erythematosus (SLE) was studied. Concentrations of LMW-C1q were increased in SLE, but not in rheumatoid arthritis or acute poststreptococcal glomerulonephritis. Concentrations of LMW-C1q in SLE serum samples correlated with titres of anti-dsDNA and were inversely related to concentrations of normal C1q and C3. Serial studies in six patients, who had rising anti-dsDNA titres and who developed a major exacerbation requiring admission to hospital, showed that LMW-C1q increased in parallel with anti-dsDNA, reaching peak values of more than 2000% of normal just before or at the time of clinical relapse and decreasing during convalescence. Most marked increases in LMW-C1q were noted in the three patients in whom C1q concentrations remained normal, whereas increases were less in the three patients who had strongly depressed concentrations of normal C1q. A study of C1q biosynthesis by macrophages cultured from patients with SLE and high serum concentrations of LMW-C1q did not show impaired secretion of normal C1q in favour of LMW-C1q, but indicated that serum concentrations of LMW-C1q may reflect the synthetic rate of C1q in vivo. The results show that increased serum concentrations of LMW-C1q may be helpful in diagnosing SLE and suggest that serial determination of LMW-C1q in serum may have predictive value in monitoring patients with SLE.
Interactions of C-reactive protein with the complement system. II. C-reactive protein-mediated consumption of complement by poly-L-lysine polymers and other polycations.
Authors: J Siegel, A P Osmand, M F Wilson, H Gewurz
Journal: The Journal of Experimental Medicine (1975)

Cationic homopolymers of poly-L-lysine were found to activate complement (C) via C-reactive protein (CRP) and deplete C3 and C5 as well as early-acting C components. Maximum C consumption was obtained with polymers of 2,000-8,000 daltons; polymers of 1,700, 11,000, and 23,000 daltons were intermediate in reactivity, while L-lysine, lysyl-L-lysine, tetra-L-lysine, and polymers of 70,000-400,000 daltons lacked significant C-consuming activity. Naturally occurring polycations which consumed C in the presence of CRP included myelin basic proteins, cationic proteins of rabbit leukocytes, and both lysine- and arginine-rich histones; poly-L-arginine polymers of 17,000 but not 65,000 daltons also were C-consuming. Polycations without such reactivity included poly-L-orithine (5,000 and 165,000 daltons), egg white and human lysozymes, and Polybrene. The polycations which failed to induce C consumption via CRP, inhibited its consumption by both active polycations and by C-polysaccharide (CPS). The relative inhibitory capacity of phosphorylcholine and polycations in CPS- and polycations-CRP systems was consistent with the concept that phosphate esters and polycations react at the same or an overlapping combining site. The ability of certain polycations to activate C via CRP increases the potential for initiation of host reactions via C. The capacity of other polycations to inhibit C activation via CRP introduces a potential for physiologic or pharmacologic manipulation. These considerations would seem to expand the potential role of CRP in the initiation and modulation of the inflammatory response.
Risk of Malignant Arrhythmias in Initially Symptomatic Patients With Wolff-Parkinson-White Syndrome
Authors: Carlo Pappone, Gabriele Vicedomini, Francesco Manguso, Mario Baldi, Alessia Pappone, Andrea Petretta, Raffaele Vitale, Massimo Saviano, Cristiano Ciaccio, Luigi Giannelli, Zarko Calovic, Luigi Tavazzi, Vincenzo Santinelli
Journal: Circulation (2012)

The available amount of detailed long-term data in patients with Wolff-Parkinson-White syndrome is limited, and no prospective electrophysiological studies looking at predictors of malignant arrhythmia are available.Among 8575 symptomatic Wolff-Parkinson-White patients with atrioventricular reentrant tachycardia referred for electrophysiological test, 369 (mean age, 23±12.5 years) declined catheter ablation and were followed up. The primary end point of the study was to evaluate over a 5-year follow-up the predictors and characteristics of patients who develop malignant arrhythmias. After a mean follow-up of 42.1±10 months, malignant arrhythmias developed in 29 patients (mean age, 13.9±5.6 years; 26 male), resulting in presyncope/syncope (25 patients), hemodynamic collapse (3 patients), or cardiac arrest caused by ventricular fibrillation (1 patient). Of the remaining 340 patients, 168 (mean age, 34.2±9.0 years) remained asymptomatic up to 5 years, and 172 (mean age, 13.6±5.1 years) had benign recurrence, including sustained atrioventricular reentrant tachycardia (132 patients) or atrial fibrillation (40 patients). Compared with the group with no malignant arrhythmias, the group with malignant arrhythmias showed shorter accessory-pathway effective refractory period (P<0.001) and more often exhibited multiple accessory pathways (P<0.001), and atrioventricular reentrant tachycardia triggering sustained pre-excited atrial fibrillation was more frequently inducible (P<0.001). Multivariable analysis demonstrated that short accessory-pathway effective refractory period (P<0.001) and atrioventricular reentrant tachycardia triggering sustained pre-excited atrial fibrillation (P<0.001) were independent predictors of malignant arrhythmias.Symptomatic patients with Wolff-Parkinson-White syndrome generally have a good outcome, and predictors of malignant arrhythmias are similar to those reported for asymptomatic patients with ventricular pre-excitation.
A rat virus visits the clinic: translating basic discoveries into clinical medicine in the 21st century
Authors: C R Boland
Journal: Gut (2002)

In all reported clinical studies with <sup>18</sup>F-FDG–labeled leukocytes, heparin was used as an anticoagulant during labeling. Theoretically, the substitution of heparin with citrate should be advantageous. <b>Methods:</b> Blood from healthy controls was sampled in duplicate, anticoagulated with citrate or heparin, and labeled with <sup>18</sup>F-FDG, and the labeling yield was measured. Viability was checked with the trypan blue exclusion technique. Moreover, 4 in vivo PET/CT studies were performed after the reinjection of leukocytes labeled after citrate anticoagulation. <b>Results:</b> The labeling yields obtained with citrate and heparin were not significantly different (<i>P</i> = 0.447). Viability was greater than or equal to 99%. The quality of the PET/CT studies was excellent. In the in vivo studies, the mean labeling yield was 78%—better than or equal to that reported with heparin as an anticoagulant. <b>Conclusion:</b> Citrate is at least as effective as heparin as an anticoagulant, does not (unlike heparin) increase granulocyte activation, and should be the preferred anticoagulant for <sup>18</sup>F-FDG labeling of leukocytes.
Glycotoxins: A Missing Link in the “Relationship of Dietary Fat and Meat Intake in Relation to Risk of Type 2 Diabetes in Men”
Authors: Melpomeni Peppa, Teresia Goldberg, Weijing Cai, Elliot Rayfield, Helen Vlassara
Journal: Diabetes Care (2002)

We have read with great interest the article entitled “Dietary Fat and Meat Intake in Relation to Risk of Type 2 Diabetes in Men,” by Van Dam et al. (1), which suggests a relationship between increased consumption of animal fat and red and processed meats and higher risk of type 2 diabetes in men.

We propose that the recently recognized toxic derivatives of advanced glycation and lipoxidation abundant in diets may explain the associations observed. Advanced glycation end products (AGEs) and lipoxidation end products (ALEs) are well-known glucose-derived factors contributing to diabetes-related complications (2). In addition to endogenous glucose, diet constitutes an important exogenous source of …
Garlic Constituent Diallyl Trisulfide Prevents Development of Poorly Differentiated Prostate Cancer and Pulmonary Metastasis Multiplicity in TRAMP Mice
Authors: Shivendra V. Singh, Anna A. Powolny, Silvia D. Stan, Dong Xiao, Julie A. Arlotti, Renaud Warin, Eun-Ryeong Hahm, Stanley W. Marynowski, Ajay Bommareddy, Douglas M. Potter, Rajiv Dhir
Journal: Cancer Research (2008)

Abstract Identification of agents that are nontoxic but can delay onset and/or progression of prostate cancer, which is the second leading cause of cancer-related deaths among men in the United States, is highly desirable. We now show that p.o. gavage of garlic constituent diallyl trisulfide (DATS; 1 and 2 mg/day, thrice/week for 13 weeks beginning at age 8 weeks) significantly inhibits progression to poorly differentiated prostate carcinoma and pulmonary metastasis multiplicity in transgenic adenocarcinoma of mouse prostate (TRAMP) mice without any side effects. There was a trend of a decrease in average wet weights of the urogenital tract and prostate gland in 1 and 2 mg DATS–treated mice compared with controls (∼25–46% decrease in DATS-treated mice compared with controls). The incidence and the area of the dorsolateral prostate occupied by the poorly differentiated carcinoma were significantly lower in both 1 and 2 mg DATS–treated mice compared with control mice. In addition, DATS administration resulted in a statistically significant decrease in pulmonary metastasis multiplicity compared with controls (P = 0.002). The dorsolateral prostate from DATS-treated TRAMP mice exhibited decreased cellular proliferation in association with induction of cyclinB1 and securin protein levels, and suppression of the expression of neuroendocrine marker synaptophysin. However, DATS administration did not have any appreciable effect on apoptosis induction, angiogenesis, or natural killer and dendritic cell function. In conclusion, the results of the present study show, for the first time, that DATS administration prevents progression to invasive carcinoma and lung metastasis in TRAMP mice. [Cancer Res 2008;68(22):9503–11]
Rnf8 deficiency impairs class switch recombination, spermatogenesis, and genomic integrity and predisposes for cancer
Authors: Li Li, Marie-Jo Halaby, Anne Hakem, Renato Cardoso, Samah El Ghamrasni, Shane Harding, Norman Chan, Robert Bristow, Otto Sanchez, Daniel Durocher, Razqallah Hakem
Journal: The Journal of Experimental Medicine (2010)

Signaling and repair of DNA double-strand breaks (DSBs) are critical for preventing immunodeficiency and cancer. These DNA breaks result from exogenous and endogenous DNA insults but are also programmed to occur during physiological processes such as meiosis and immunoglobulin heavy chain (IgH) class switch recombination (CSR). Recent studies reported that the E3 ligase RNF8 plays important roles in propagating DNA DSB signals and thereby facilitating the recruitment of various DNA damage response proteins, such as 53BP1 and BRCA1, to sites of damage. Using mouse models for Rnf8 mutation, we report that Rnf8 deficiency leads to impaired spermatogenesis and increased sensitivity to ionizing radiation both in vitro and in vivo. We also demonstrate the existence of alternative Rnf8-independent mechanisms that respond to irradiation and accounts for the partial recruitment of 53bp1 to sites of DNA damage in activated Rnf8(-/-) B cells. Remarkably, IgH CSR is impaired in a gene dose-dependent manner in Rnf8 mutant mice, revealing that these mice are immunodeficient. In addition, Rnf8(-/-) mice exhibit increased genomic instability and elevated risks for tumorigenesis indicating that Rnf8 is a novel tumor suppressor. These data unravel the in vivo pleiotropic effects of Rnf8.