tbuckley/cabot-search huggingface dataset:
EPOXIDE HYDROLASES: Mechanisms, Inhibitor Designs, and Biological Roles
Authors: Christophe Morisseau, Bruce D. Hammock
Journal: The Annual Review of Pharmacology and Toxicology (2004)

Organisms are exposed to epoxide-containing compounds from both exogenous and endogenous sources. In mammals, the hydration of these compounds by various epoxide hydrolases (EHs) can not only regulate their genotoxicity but also, for lipid-derived epoxides, their endogenous roles as chemical mediators. Recent findings suggest that the EHs as a family represent novel drug discovery targets for regulation of blood pressure, inflammation, cancer progression, and the onset of several other diseases. Knowledge of the EH mechanism provides a solid foundation for the rational design of inhibitors, and this review summarizes the current understanding of the catalytic mechanism of the EHs. Although the overall EH mechanism is now known, the molecular basis of substrate selectivity, possible allosteric regulation, and many fine details of the catalytic mechanism remain to be solved. Finally, recent development in the design of EH inhibitors and the EH biological role are discussed.
Assessing Changes in the Impact of Cancer on Population Survival Without Considering Cause of Death
Authors: B. W. Brown, C. Brauner, L. B. Levy
Journal: JNCI Journal of the National Cancer Institute (1997)

Background: We have previously argued against the calculation of cancer-specific death rates as philosophically undefined and biased. Deaths attributed to cancer during a particular year occur in patients diagnosed during an unknown distribution of past times, so cancer-specific death rates cannot be used to assess changes in the impact of cancer on survival of the population at specific periods of diagnosis. Purpose: Our goal was to develop and analyze three measures of the impact of cancer on population survival that do not use the attributed cause of death: 1) the age-adjusted proportion of the population diagnosed with cancer in a particular year and projected to be dead of any cause by a particular age; 2) the same measure corrected for population mortality; and 3) the expected years of life lost to a 20-year-old individual because of the possibility of a diagnosis of cancer. Methods: Data on all adults diagnosed with any cancer during the period from January 1973 through December 1990 were obtained from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute. The measures were calculated separately for various combined sex and race groups. Three 2-year diagnosis periods spaced 5 years apart were considered: 1975–1976, 1980–1981, and 1985–1986. A statistical model was used to extrapolate survival beyond observation; the same model was used for patients diagnosed in the three time periods to minimize the effect of possible model misspecification on changes. Results: Cancer incidence increased for three of the four sex-race groups; age-adjusted changes from 1975 through 1976 to 1985 through 1986 were +11.5% for white men, +6.9% for white women, +15.1% for black men, and −9.2% for black women. Human immunodeficiency virus (HIV)-related cancers were responsible for an increased cancer incidence at early ages in white men in the latest time period studied. There was a decrease in the incidence of gynecologic cancers at early ages; the decrease was greater among black women (−55.1%) than among white women (−39.3%). Age- and incidence-adjusted 5-year survival increased by 17.9% for white men, 2.3% for white women, and 7.4% for black men and decreased by 14.1% for black women. When the data from 1985 through 1986 were compared with those from 1975 through 1976, the expected number of years lost to a 20-year-old individual because of cancer changed as follows for the various sex-race groups: +1.4% for white men (−4.0% if HIV-related cancers were not included in the calculation), +2.1% for white women, +12.2% for black men, and +8.8% for black women. Conclusions: For white men and women, there has been an increase in both the incidence of and survival following the diagnosis of cancer; the two effects nearly cancel in our measures. The experience of black men and women has worsened because of increasing incidence or decreased survival.
Lipid Lowering Promotes Accumulation of Mature Smooth Muscle Cells Expressing Smooth Muscle Myosin Heavy Chain Isoforms in Rabbit Atheroma
Authors: Masanori Aikawa, Elena Rabkin, Sami J. Voglic, Helen Shing, Ryozo Nagai, Frederick J. Schoen, Peter Libby
Journal: Circulation Research (1998)

Smooth muscle cells (SMCs) in the atherosclerotic intima characteristically differ from those in the arterial media, for example, by reduced expression of SMC differentiation/maturation markers such as smooth muscle myosin heavy chain isoforms (SM1 and SM2). This study tested the hypothesis that lipid lowering promotes maturation of intimal SMCs in 33 rabbits subjected to balloon injury and cholesterol feeding (0.3%) for 4 months (Baseline group, n=15); some of which then were switched to a low-cholesterol diet for 8 months (Low group at 8 months, n=3) or 16 months (Low group at 16 months, n=10). The remaining rabbits continued to consume a high-cholesterol diet for 16 months (High group, n=5). We monitored SMC phenotype by expression of immunoreactive alpha-smooth muscle actin, SM1, and SM2. alpha-Actin is an early marker, and SM1 and SM2 are late markers for SMC differentiation/maturation. Only fully differentiated or mature SMCs express SM2. Data are reported as the percentage of the alpha-actin-positive intimal area occupied by smooth muscle myosin-positive SMCs determined by color image analysis of immunostained sections. Levels of SM1 and SM2, highly expressed by SMCs in the normal aortic media (n=5) decreased in the aortic intima of the Baseline and High groups, indicating a less mature phenotype. In contrast, SM1 and SM2 increased in the Low (16 months) group, indicating that intimal SMCs exhibit a more mature phenotype after lipid lowering. Electron microscopy also showed the presence of mature intimal SMCs with abundant myofilaments. Furthermore, lipid lowering reduced levels of platelet-derived growth factor-B in the arterial intima, a factor known to suppress smooth muscle myosin expression. These data demonstrate that lipid lowering favors accumulation of mature SMCs in the atherosclerotic intima in association with reduced levels of platelet-derived growth factor-B expression. Intimal SMCs in the Low group also displayed reduced expression of matrix metalloproteinases-3 and -9 compared with the Baseline and High groups. These findings shed new light on the effects of lipid lowering at the level of the vascular wall, which may influence the biology of the atheroma.
Allogeneic cell transplant expands bone marrow distribution by colonizing previously abandoned areas: an FDG PET/CT analysis
Authors: Francesco Fiz, Cecilia Marini, Cristina Campi, Anna Maria Massone, Marina Podestà, Gianluca Bottoni, Roberta Piva, Francesca Bongioanni, Andrea Bacigalupo, Michele Piana, Gianmario Sambuceti, Francesco Frassoni
Journal: Blood (2015)
Induction of target cell DNA release by the cytotoxic T lymphocyte granule protease granzyme A.
Authors: M P Hayes, G A Berrebi, P A Henkart
Journal: The Journal of Experimental Medicine (1989)

The rapid breakdown of target cell DNA during CTL-mediated lysis has been difficult to explain by the granule exocytosis model of cytotoxicity. The involvement of CTL granule proteases in this process was strongly suggested by experiments in which CTL were pretreated with the serine protease inhibitor PMSF, in combination with agents that raise the pH of acidic intracellular compartments. While PMSF pretreatment alone had little effect on target lysis or DNA breakdown, the combination of PMSF and NH4Cl or monensin profoundly reduced target cell DNA release, while little effect was observed on target lysis, as measured by 51Cr release. CTL granule extracts cause release of 125I-DNA from detergent-permeabilized cells. This nuclear DNA-releasing (NDR) activity is inhibited by serine esterase inhibitors that also inhibit the granule BLT-esterase activity, and is specifically immunoabsorbed by antibodies to the CTL granule protease granzyme A. The NDR activity comigrates with BLT-esterase activity during subcellular fractionation, solubilization, gel filtration, and aprotinin-Sepharose affinity chromatography. SDS-PAGE analysis of the affinity-purified product indicates a molecular mass of 60,000 daltons under non-reducing conditions, which moves to 30,000 daltons upon reduction, consistent with previously reported behavior of granzyme A. When the purified material was reduced and alkylated, both esterase and NDR activities comigrated at 30,000 daltons upon gel filtration. Although fully lytic concentrations of purified LGL granule cytolysin alone failed to induce target cell DNA release, a combination of purified granzyme A and the cytolysin induces substantial DNA release.
X-Linked Inhibitor of Apoptosis Protein Is an Important Regulator of Vascular Endothelial Growth Factor–Dependent Bovine Aortic Endothelial Cell Survival
Authors: Jongmin Kim, Jongbong Park, Seungmin Choi, Sung-Gil Chi, Amy L. Mowbray, Hanjoong Jo, Heonyong Park
Journal: Circulation Research (2008)

Vascular endothelial growth factor (VEGF) is a critical regulator of endothelial cell biology and vascular function. Chronic VEGF treatment has been shown to inhibit tumor necrosis factor-induced apoptosis in endothelial cells. However, the mechanism for this cell survival is unclear. Interestingly, VEGF also enhances the expression of X-linked inhibitor of apoptosis (XIAP), a well-established antiapoptotic factor. XIAP has been shown to suppress apoptosis by blocking caspase activity in cancer cells, but it remains under studied in the endothelium. Therefore, we hypothesized that VEGF affects important endothelial functions, such as apoptosis and cell migration, by regulating XIAP expression and downstream caspase activity. To test this hypothesis, caspase activity, apoptosis, and cell migration were assessed following XIAP overexpression or depletion in bovine aortic endothelial cells. Much like VEGF treatment, ectopic expression of XIAP blocked tumor necrosis factor-induced apoptosis. Surprisingly, the mechanism was caspase-independent. In addition, XIAP-associated cell survival was the result of enhanced nitric oxide (NO) production, and XIAP was partially localized in caveolae. In these lipid rafts, XIAP interacted with a regulator of NO production, caveolin-1, via a binding motif (FtFgtwiY, where the bold letters represent aromatic amino acids) in the baculoviral IAP repeat-3 domain. Endothelial NO synthase binding to caveolin-1 was competitively inhibited by XIAP, suggesting that XIAP acts as a modulator of NO production by releasing endothelial NO synthase from caveolin-1. Further studies showed that endothelial cell migration was also controlled by XIAP-dependent NO. Taken together, these results suggest that XIAP plays a novel role in endothelial cells, interacting with caveolin-1 and acting as a regulator of vascular antiatherogenic function.
The Bitter End
Authors: Cam Patterson, Christopher Ike, Park W. Willis, George A. Stouffer, Monte S. Willis
Journal: Circulation (2007)

Many elements contribute to congestive heart failure: changes in perfusion, hemodynamic stresses, alterations in calcium metabolism, and dysregulation of cell signaling pathways. Intervention in these processes forms the basis for current heart failure therapies. Nevertheless, heart failure is primarily a disease of wear and tear; despite everything we know about cardiac physiology and the clinical manifestations of heart failure, only in rare instances does therapy for heart failure normalize cardiac function. Proteins are especially prone to the forces of wear and tear in the heart because they are the primary mechanisms for stress sensing and force generation. Recent evidence supports a role for protein damage and impaired clearance of damaged proteins in the pathophysiology of human heart failure syndromes. The process of monitoring and protecting cardiac cells from accumulation of damaged proteins is known as protein quality control, and the molecular chaperone and ubiquitin-proteasome systems are the primary effectors of this process. Insights from protein quality-control strategies may lead to new concepts about prevention and treatment of human heart failure. This review provides a general overview of these pathways and their known and postulated roles in human heart failure syndromes, with a focus on providing a clinically oriented understanding of these fundamental mechanisms.
Cytotoxic T cells distinguish between trinitrophenyl- and dinitrophenyl-modified syngeneic cells.
Authors: J Forman
Journal: The Journal of Experimental Medicine (1977)

Spleen cells sensitized against trinitrophenyl (TNP)-modified stimulator cells displayed a cytotoxic effect against syngeneic TNP-modified but not dinitrophenyl (DNP)-modified target cells. The same finding was observed in the opposite direction; that is, effector cells sensitized against DNP-modified stimulator cells did not cross kill TNP-modified targets. The specificity of the anti-TNP effector cells was confirmed in a cold target competition assay. Presensitization in vivo with hapten-modified cells followed by rechallenge and testing in vitro did not alter the specificity of the response between the haptens. These data indicate that the receptor(s) on the cytotoxic T cell can distinguish between two closely related haptenic molecules.
Dexamethasone treatment does not inhibit fibroproliferation in chronic lung disease of prematurity
Authors: W.A. Dik, M.A. Versnel, B.A. Naber, D.J. Janssen, A.H. van Kaam, L.J.I. Zimmermann
Journal: European Respiratory Journal (2003)

Pulmonary fibrosis results from excessive fibroblast proliferation and increased collagen deposition and occurs in chronic lung disease of prematurity (CLD). Platelet-derived growth factor (PDGF)-BB is mitogenic for fibroblasts and levels are increased in fibrotic lung disorders. Systemic dexamethasone (DEX) treatment improves pulmonary function and reduces inflammation in infants with or at risk of CLD. However, the effect of DEX treatment on fibroblast activity, PDGF-BB and collagen synthesis in the lungs of CLD patients is uncertain. Bronchoalveolar lavage (BAL) fluids, obtained from 15 infants at risk of CLD before and after DEX treatment, were analysed for fibroblast mitogenicity, PDGF-BB, N‐terminal propeptide of collagen type III (PIIINP) and interleukin (IL)-1β levels and inflammatory cell numbers. After DEX treatment, the mitogenic activity of BAL fluid for fibroblasts was not reduced but increased. The change in mitogenicity correlated with a change in BAL fluid PDGF-BB levels. Furthermore, BAL fluid-induced fibroblast proliferation was blocked using an inhibitor of the PDGF receptor. DEX treatment did not influence PIIINP levels, but reduced IL-1β levels and inflammatory cell numbers in BAL fluid. This study suggests that dexamethasone treatment does not reduce fibroblast proliferation despite apparent downregulation of inflammation. The present findings do not support the use of dexamethasone for prevention of the fibrotic response in infants at risk of chronic lung disease of prematurity.
A6.14 mTOR Directed Mesenchymal Tissue Response to Inflammation in Arthritis
Authors: T Karonitsch, K Dalwigk, M Glehr, B Niederreiter, CW Steiner, JS Smolen, HP Kiener, G Superti-Furga
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Accumulating evidence supports the concept that fibroblast-like synoviocytes (FLS) actively participate in the destructive, inflammatory process of rheumatoid synovitis. Thus, FLS frame a synovial microenvironment that augments and perpetuates synovial inflammation. Moreover, FLS, together with macrophages form an aggressive mass of cells ("pannus"), which invades and destroys the articular cartilage. The mechanistic target of rapamycin (mTOR) is best known for coupling energy and nutrient abundance to the execution of essential cellular processes, including cell growth and cell survival. More recent data indicate that mTOR directs the cellular response to inflammatory stimuli in cells of the immune system. It remains elusive, however, whether or not this also applies to mesenchymal cells, such as FLS in the context of rheumatoid synovitis. <h3>Materials and Methods</h3> In order to assess mTOR activity by immunhistochemistry (IHC) as well as western blotting (WB), phosphospecific antibodies against mTOR (IHC) and mTOR substrates, including 4E-BP (IHC), AKT (WB), S6K1 (WB), and S6 (IHC) were used. To determine the functional significance of mTOR activity in FLS, Torin-1, a well defined, specific inhibitor of mTOR, was used. To establish a role for mTOR in the mesencyhmal, inflammatory tissue response, we used a previously described simplified 3-D model of the synovial tissue. IL-6 and IL-8 levels in the supernatants of 3-D cultures were measured by ELISA. <h3>Results</h3> mTOR, 4E-BP and S6 were found to be phosphorylated in RA synovial tissues. These activated phospho-proteins were preferentially expressed in FLS, most prominently in the hyperplasic synovial lining layer. In-vitro, TNF stimulation of FLS resulted in the phosphorylation of AKT and S6K1, indicating that TNF activates the mTOR pathway in FLS. Stimulation of the 3D cultures with TNF resulted in hyperplasia of the lining layer at the surface of the spheres. Strikingly, treatment with Torin-1, prevented TNF induced lining layer hyperplasia. Unexpectedly, the combined treatment of 3-D cultures with TNF and Torin-1 resulted in increased production of IL-6 as well as IL-8 when compared to cultures that were solely exposed to TNF. <h3>Conclusions</h3> These studies provide insight into the regulatory circuits that determine the synovial mesenchymal tissue response to inflammation and suggest a multifaceted role for mTOR in arthritis.
Astrocyte Kir4.1 ion channel deficits contribute to neuronal dysfunction in Huntington's disease model mice
Authors: Xiaoping Tong, Yan Ao, Guido C Faas, Sinifunanya E Nwaobi, Ji Xu, Martin D Haustein, Mark A Anderson, Istvan Mody, Michelle L Olsen, Michael V Sofroniew, Baljit S Khakh
Journal: Nature Neuroscience (2014)
Chronic bronchitis in textile workers
Authors: R. M. Niven, A. M. Fletcher, C. A. Pickering, D. Fishwick, C. J. Warburton, J. C. Simpson, H. Francis, L. A. Oldham
Journal: Thorax (1997)

Exposure to cotton is known to produce a specific occupational disease known as byssinosis. A large population of textile workers was investigated to determine whether such exposure was also associated with chronic bronchitis once other possible aetiological factors had been accounted for.A total of 2991 workers were investigated for the presence of symptoms compatible with chronic bronchitis. An MRC adapted respiratory questionnaire and MRC definition of chronic bronchitis were used for diagnostic labelling. Current and lifetime exposure to dust was estimated by personal and work area sampling, and the use of records of retrospective dust levels previously measured over the preceding 10 years. Airborne endotoxin exposure was measured using a quantitative turbidometric assay. Lung function tests were performed to measure forced expiratory volume in one second (FEV1) and forced vital capacity (FVC). A control group of workers exposed to man-made fibre textiles was identified. The comparative prevalence of chronic bronchitis in the two populations was assessed, allowing for sex, age, smoking habit, and ethnic origin. Two case referent studies were also performed; cases of chronic bronchitis were separately matched with controls from the cotton and control populations to determine the effect of the symptomatic state on lung function.After controlling for smoking (pack years), workers in a cotton environment were significantly more likely to suffer from chronic bronchitis and this was most marked in workers over 45 years of age (odds ratio 2.51 (CI 1.3 to 4.9); p < 0.01). Regression analysis of all possible influencing parameters showed that cumulative exposure to cotton dust was significantly associated with chronic bronchitis after the effects of age, sex, smoking, and ethnic group were accounted for (p < 0.0005). In the intra-cotton population case control study a diagnosis of chronic bronchitis was associated with a small decrement in lung function compared with controls: percentage predicted FEV1 in cases 81.4% (95% CI 78.3 to 84.6), controls 86.7% (84.9 to 88.5); FVC in cases 89.9% (95% CI 87.0 to 92.9), controls 94.6% (92.8 to 96.4). After controlling for cumulative past exposure and pack years of smoking the effect of the diagnostic state remained significant for both FEV1 (p < 0.01) and FVC (p < 0.05).Chronic bronchitis is more prevalent in cotton workers than in those working with man-made fibre and exposure is additive to the effect of smoking. The diagnosis of chronic bronchitis is associated with a small but significant decrement in lung function.
Biomechanical investigation of head impacts in football
Authors: C Withnall, N Shewchenko, R Gittens, J Dvorak
Journal: British Journal of Sports Medicine (2005)

Objectives: This study sought to measure the head accelerations induced from upper extremity to head and head to head impact during the game of football and relate this to the risk of mild traumatic brain injury using the Head Impact Power (HIP) index. Furthermore, measurement of upper neck forces and torques will indicate the potential for serious neck injury. More stringent rules or punitive sanctions may be warranted for intentional impact by the upper extremity or head during game play. Methods: Game video of 62 cases of head impact (38% caused by the upper extremity and 30% by the head of the opposing player) was provided by F-MARC. Video analysis revealed the typical impact configurations and representative impact speeds. Upper extremity impacts of elbow strike and lateral hand strike were re-enacted in the laboratory by five volunteer football players striking an instrumented Hybrid III pedestrian model crash test manikin. Head to head impacts were re-enacted using two instrumented test manikins. Results: Elbow to head impacts (1.7–4.6 m/s) and lateral hand strikes (5.2–9.3 m/s) resulted in low risk of concussion (&lt;5%) and severe neck injury (&lt;5%). Head to head impacts (1.5–3.0 m/s) resulted in high concussion risk (up to 67%) but low risk of severe neck injury (&lt;5%). Conclusion: The laboratory simulations suggest little risk of concussion based on head accelerations and maximum HIP. There is no biomechanical justification for harsher penalties in this regard. However, deliberate use of the head to impact another player’s head poses a high risk of concussion, and justifies a harsher position by regulatory bodies. In either case the risk of serious neck injury is very low.