tbuckley/cabot-search huggingface dataset:
Is Acquired Activated Protein C Resistance a Cardiovascular Risk?
Authors: Kazuomi Kario, Toshiyuki Sakata, Toshiyuki Miyata
Journal: Circulation (2000)

We have read the article by Kiechl et al 1 demonstrating that acquired activated protein C resistance (APC) may be a risk factor for atherosclerosis and arterial thrombosis in whites.We 2 previously demonstrated that acquired APC resistance is associated not only with venous thrombosis (deep vein thrombosis and pulmonary thromboembolism) but also with arterial thrombotic disease (cerebral infarction and coronary artery disease) in the Japanese population.It is well known that no Japanese has factor V Leiden mutation because of the founder effect of this mutation. 3Thus, it is likely that in Japanese, some environmental factors might contribute to APC resistance.In addition, we demonstrated a positive association of APC sensitivity ratio with plasma levels of the activated form of factor VII (FVIIa, an activation marker of the early phase of the tissue factor pathway of coagulation 4 in healthy subjects; correlation coefficient Ϫ0.38, PϽ0.05, nϭ33). 2 This association was also found in subjects with a predisposing condition of thrombosis, namely, protein C deficiency (correlation coefficient Ϫ0.40, PϽ0.005, nϭ53).More recently, pregnancy-related APC resistance has also been reported 5 to be associated with thrombin-antithrombin complex (an indicator of in vivo thrombin generation) (correlation coefficient with APC sensitivity ratio Ϫ0.274, Pϭ0.01, nϭ128).Thus, the APC resistance may reflect the global insensitivity of APC and may provide a good method to assess the hypercoagulable state in vivo.The hypercoagulable state induced by acquired APC resistance should be given greater emphasis in clinical practice in the future.
Efficient degradation of gluten by a prolyl endoprotease in a gastrointestinal model: implications for coeliac disease
Authors: C Mitea, R Havenaar, J W. Drijfhout, L Edens, L Dekking, F Koning
Journal: Gut (2007)

Coeliac disease is caused by an immune response to gluten. As gluten proteins are proline rich they are resistant to enzymatic digestion in the gastrointestinal tract, a property that probably contributes to the immunogenic nature of gluten.This study determined the efficiency of gluten degradation by a post-proline cutting enzyme, Aspergillus niger prolyl endoprotease (AN-PEP), in a dynamic system that closely mimics the human gastrointestinal tract (TIM system).Two experiments were performed. In the first, a slice of bread was processed in the TIM system with and without co-administration of AN-PEP. In the second, a standard fast food menu was used. Samples of the digesting meals were taken from the stomach, duodenum, jejunum and ileum compartments at time zero until 4 hours after the start of the experiment. In these samples the levels of immunogenic peptides from gliadins and glutenins were assessed by monoclonal antibody-based competition assays, Western blot analysis and proliferation T-cell assays.AN-PEP accelerated the degradation of gluten in the stomach compartment to such an extent that hardly any gluten reached the duodenum compartment.AN-PEP is capable of accelerating the degradation of gluten in a gastrointestinal system that closely mimics in-vivo digestion. This implies that the co-administration of AN-PEP with a gluten-containing meal might eliminate gluten toxicity, thus offering patients the possibility of abandoning (occasionally) their strict gluten-free diet.
Academics face court clash with tobacco giants
Authors: C. Marwick
Journal: BMJ (2002)

Nine major US universities are preparing to go to court to contest a demand by US tobacco manufacturers that they turn over documents going back over 50 years relating to research on smoking by faculty members. The institutions describe the demands as a “fishing expedition.”

The universities concerned are Harvard, New York University School of Medicine, four universities in the California state system, the universities of Arizona and Kentucky, and Johns Hopkins University. One institution, North Carolina State University, has complied with the tobacco industry's request.

The tobacco …
Prospective study of hospitalization for asthma. A preliminary risk factor model.
Authors: D Li, D German, S Lulla, R G Thomas, S R Wilson
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

We conducted an exploratory analysis of several prospectively obtained objective measures of disease activity to derive a predictive model of hospitalization for asthma among 310 adults, ages 18 to 50 yr, with moderate to severe asthma. Baseline characteristics associated with increased risk of hospitalization in the succeeding year include (1) prior year hospitalization, (2) moderate or severe respiratory impairment, (3) a medication regimen consistent with severe asthma, (4) a history of significant systemic steroid use, (5) maximum overnight PEF variability > 40%, and (6) mean evening PEF < 60% of predicted (relative risk = 6.5, 6.9, 8.1, 3.7, 3.0, and 3.2, respectively). Recursive partitioning analysis, depicted as a "classification tree," provided a more sensitive (94%) and specific (68%) multivariate description of the data set than either logistic regression (87 and 48%, respectively) or a simple additive risk model (46 and 93%, respectively). Patients with very high (> 50%), moderately elevated (10 to 15%), and very low (< 5%) risk of hospitalization were identified on the basis of particular combinations of prior hospitalization history, level of respiratory impairment, and medication regimen. Overnight variability and mean evening PEF measured at home over a 2-wk period proved less informative for risk stratification than respiratory impairment determined once at baseline by office spirometry. The findings warrant replication and extension in other populations with the goal of developing decision rules for risk stratification and effective interventions for risk reduction.
Transforming growth factor beta signaling in hepatocytes participates in steatohepatitis through regulation of cell death and lipid metabolism in mice
Authors: Ling Yang, Yoon Seok Roh, Jingyi Song, Bi Zhang, Cheng Liu, Rohit Loomba, Ekihiro Seki
Journal: Hepatology (2013)

Transforming growth factor beta (TGF-β) signaling activates Smad- and TGF-β-activated kinase 1 (TAK1)-dependent signaling to regulate cell survival, proliferation, fibrosis, and tumorigenesis. The effects of TGF-β signaling on metabolic syndrome, including nonalcoholic fatty liver disease, remain elusive. Wild-type (WT) and hepatocyte-specific TGF-β receptor type II-deficient (Tgfbr2ΔHEP) mice were fed a choline-deficient amino acid (CDAA)-defined diet for 22 weeks to induce NASH. WT mice fed a CDAA diet displayed increased activation of Smad2/3 and had marked lipid accumulation, inflammatory cell infiltration, hepatocyte death, and fibrosis; in comparison, Tgfbr2ΔHEP mice fed a CDAA diet had suppressed liver steatosis, inflammation, and fibrosis. Both palmitate-induced steatotic hepatocytes and hepatocytes isolated from WT mice fed a CDAA diet had increased susceptibility to TGF-β-mediated death. TGF-β-mediated death in steatotic hepatocytes was inhibited by silencing Smad2 or blocking reactive oxygen species (ROS) production and was enhanced by inhibiting TAK1 or nuclear factor kappa B. Increased hepatic steatosis in WT mice fed a CDAA diet was associated with the increased expression of lipogenesis genes (Dgat1 and Srebp1c), whereas the decreased steatosis in Tgfbr2ΔHEP mice was accompanied by the increased expression of genes involved in β-oxidation (Cpt1 and Acox1). In combination with palmitate treatment, TGF-β signaling promoted lipid accumulation with induction of lipogenesis-related genes and suppression of β-oxidation-related genes in hepatocytes. Silencing Smad2 decreased TGF-β-mediated lipid accumulation and corrected altered gene expression related to lipid metabolism in hepatocytes. Finally, we confirmed that livers from patients with nonalcoholic steatohepatitis (NASH) displayed phosphorylation and nuclear translocation of Smad2/3. TGF-β signaling in hepatocytes contributes to hepatocyte death and lipid accumulation through Smad signaling and ROS production that promote the development of NASH.
Chromogranin A Restricts Drug Penetration and Limits the Ability of NGR-TNF to Enhance Chemotherapeutic Efficacy
Authors: Eleonora Dondossola, Anna Maria Gasparri, Barbara Colombo, Angelina Sacchi, Flavio Curnis, Angelo Corti
Journal: Cancer Research (2011)

Abstract NGR-TNF is a derivative of TNF-α that targets tumor blood vessels and enhances penetration of chemotherapeutic drugs. Because of this property, NGR-TNF is being tested in combination with chemotherapy in various phase II and III clinical trials. Here we report that chromogranin A (CgA), a protein present in variable amounts in the blood of normal subjects and cancer patients, inhibits the synergism of NGR-TNF with doxorubicin and melphalan in mouse models of lymphoma and melanoma. Pathophysiologically relevant levels of circulating CgA blocked NGR-TNF–induced drug penetration by enhancing endothelial barrier function and reducing drug extravasation in tumors. Mechanistic investigations done in endothelial cell monolayers in vitro showed that CgA inhibited phosphorylation of p38 MAP kinase, disassembly of VE-cadherin–dependent adherence junctions, paracellular macromolecule transport, and NGR-TNF–induced drug permeability. In this system, the N-terminal fragment of CgA known as vasostatin-1 also inhibited drug penetration and NGR-TNF synergism. Together, our results suggest that increased levels of circulating CgA and its fragments, as it may occur in certain cancer patients with nonneuroendocrine tumors, may reduce drug delivery to tumor cells particularly as induced by NGR-TNF. Measuring CgA and its fragments may assist the selection of patients that can respond better to NGR-TNF/chemotherapy combinations in clinical trials. Cancer Res; 71(17); 5881–90. ©2011 AACR.
Fetal lamb coagulation system during normal birth
Authors: M. Andrew, H. O'Brodovich, L. Mitchell
Journal: American Journal of Hematology (1988)

Abstract The contribution of the birth process to the unique coagulation system in the young was Investigated using the fetal lamb model. Specific components of the coagulation system were measured prior to and immediately following delivery of the lamb. The results show that the birth process itself does not contribute to the physiologically low levels of coagulation factors present in the newborn.
The mitogen-activated protein kinase ERK5 regulates the development and growth of hepatocellular carcinoma
Authors: Elisabetta Rovida, Giovanni Di Maira, Ignazia Tusa, Stefania Cannito, Claudia Paternostro, Nadia Navari, Elisa Vivoli, Xianming Deng, Nathanael S Gray, Azucena Esparís-Ogando, Ezio David, Atanasio Pandiella, Persio Dello Sbarba, Maurizio Parola, Fabio Marra
Journal: Gut (2014)

<h3>Objective</h3> The extracellular signal-regulated kinase 5 (ERK5 or BMK1) is involved in tumour development. The ERK5 gene may be amplified in hepatocellular carcinoma (HCC), but its biological role has not been clarified. In this study, we explored the role of ERK5 expression and activity in HCC in vitro and in vivo. <h3>Design</h3> ERK5 expression was evaluated in human liver tissue. Cultured HepG2 and Huh-7 were studied after ERK5 knockdown by siRNA or in the presence of the specific pharmacological inhibitor, XMD8-92. The role of ERK5 in vivo was assessed using mouse Huh-7 xenografts. <h3>Results</h3> In tissue specimens from patients with HCC, a higher percentage of cells with nuclear ERK5 expression was found both in HCC and in the surrounding cirrhotic tissue compared with normal liver tissue. Inhibition of ERK5 decreased HCC cell proliferation and increased the proportion of cells in G0/G1 phase. These effects were associated with increased expression of p27 and p15 and decreased CCND1. Treatment with XMD8-92 or ERK5 silencing prevented cell migration induced by epidermal growth factor or hypoxia and caused cytoskeletal remodelling. In mouse xenografts, the rate of tumour appearance and the size of tumours were significantly lower when Huh-7 was silenced for ERK5. Moreover, systemic treatment with XMD8-92 of mice with established HCC xenografts markedly reduced tumour growth and decreased the expression of the proto-oncogene c-Rel. <h3>Conclusions</h3> ERK5 regulates the biology of HCC cells and modulates tumour development and growth in vivo. This pathway should be investigated as a possible therapeutic target in HCC.
MMP profile in paired serum and synovial fluid samples of patients with rheumatoid arthritis
Authors: I Tchetverikov
Journal: Annals of the Rheumatic Diseases (2004)

<b>Objective:</b> To analyse matrix metalloproteinases (MMPs) and tissue inhibitor-1 of MMPs (TIMP-1) levels in the systemic circulation and synovial fluid (SF) of patients with RA and to compare these levels with inflammatory and collagen degradation markers. <b>Methods:</b> ProMMP-1, -2, -3, -8, -9, TIMP-1, levels of MMP/α<sub>2</sub>-macroglobulin complexes, and collagen degradation products were measured by sandwich ELISA, activity assays, and HPLC in paired SF and serum samples from 15 patients with RA and 13 with OA. <b>Results:</b> MMPs were higher in SF of patients with RA than in OA or controls. MMP levels in SF of patients with OA were higher than in controls. In serum, levels of proMMP-3, -8 and -9 were higher in patients with RA than in OA or controls, whereas only proMMP-8 and -9 were higher in serum of patients with OA than in controls. A strong correlation was seen between serum and SF levels of MMP-8 and -9 in RA. Increased levels of MMP/α<sub>2</sub>-macroglobulin complexes indicated an MMP/TIMP imbalance in serum and SF in RA. SF hydroxyproline correlated significantly with SF levels of proMMP-9 in RA. <b>Conclusions:</b> Systemic MMP-8 and -9 levels represent the situation in the inflamed joint; MMP-9 is likely to be involved in degradation of joint collagen. The hypothesis of MMP/TIMP imbalance in RA is strengthened.
Enalapril to Prevent Cardiac Function Decline in Long-Term Survivors of Pediatric Cancer Exposed to Anthracyclines
Authors: Jeffrey H. Silber, Avital Cnaan, Bernard J. Clark, Stephen M. Paridon, Alvin J. Chin, Jack Rychik, Alexa N. Hogarty, Mitchell I. Cohen, Gerald Barber, Monika Rutkowski, Thomas R. Kimball, Cynthia Delaat, Laurel J. Steinherz, Huaqing Zhao
Journal: Journal of Clinical Oncology (2004)

To determine whether an angiotensin-converting enzyme (ACE) inhibitor, enalapril, prevents cardiac function deterioration (defined using maximal cardiac index [MCI] on exercise testing or increase in left ventricular end-systolic wall stress [LVESWS]) in long-term survivors of pediatric cancer.This was a randomized, double-blind, controlled clinical trial comparing enalapril to placebo in 135 long-term survivors of pediatric cancer who had at least one cardiac abnormality identified at any time after anthracycline exposure.There was no difference in the rate of change in MCI per year between enalapril and placebo groups (0.30 v 0.18 L/min/m(2); P =.55). However, during the first year of treatment, the rate of change in LVESWS was greater in the enalapril group than in the placebo group (-8.59 v 1.85 g/cm(2); P =.033) and this difference was maintained over the study period, resulting in a 9% reduction in estimated LVESWS by year 5 in the enalapril group. Six of seven patients removed from random assignment to treatment because of cardiac deterioration were initially treated with placebo (P =.11), and one has died as a result of heart failure. Side effects from enalapril included dizziness or hypotension (22% v 3% in the placebo group; P =.0003) and fatigue (10% v 0%; P =.013).Enalapril treatment did not influence exercise performance, but did reduce LVESWS in the first year; this reduction was maintained over the study period. Any theoretical benefits of LVESWS reduction in this anthracycline-exposed population must be weighed against potential side effects from ACE inhibitors when making treatment decisions.
The Importance of Extinguishing Secondhand Smoke
Authors: Andrew M. Tonkin, Alison Beauchamp, Christopher Stevenson
Journal: Circulation (2009)

overnment policies have enormous influence on the health of nations.Arguably, this is illustrated most vividly with tobacco control.However, smoking continues to be a global problem and the major cause of preventable death.The countries with the highest per-capita smoking prevalence rates include (alphabetically) Bangladesh (20.9% of adults), Brazil (16.2% of adults), China (31.4% of adults), Germany (27.2% of adults), India (32.7% of men, 1.4% of women), Indonesia (34.5% of adults), Japan (43.3% of men and 12% of women), the Russian Federation (60.4% of men, 15.5% of women), Turkey (34.6%), and the United States(23.2%). 1 Prevalence rates among younger people vary, but in the United States, 18.4% of youths still smoke.
Hand-out Britain
Authors: S. Reed
Journal: BMJ (2011)

Has a dependency culture made us sick, asks Steve Reed 

Our society operates on the basis that you make the rich work harder by paying them more, but you make the poor work harder by paying them less. Compare the multimillion pound bonuses handed out to London’s City financiers with the benefit cuts intended to encourage the poor into work.

The British government is cutting incapacity benefits because of the vast sums lost to alleged benefit cheats. Let’s put the problem in perspective. According to the charity ActionAid, more than 12 times as much money is lost through offshore corporate tax havens as through benefit fraud.1 Yet the government is planning to relax legislation aimed at reducing tax haven abuse.2

Of course there are cheats in any system and they deserve to be exposed. But Britain has high numbers of people receiving incapacity benefit not because of an over-generous welfare system but because the way we treat poor people makes them ill. People who have had power taken away from them are more likely to have high levels of stress. Many poor people are denied the chance of a decent job and a decent home, yet they see all around them a voracious consumer society that has locked them out.

Many of the coalition government’s reforms are making life harder for the very poorest people. Caps on housing benefit are moving poor families away from where there are jobs and people they know to unfamiliar areas with higher unemployment. Proposed cuts in council tax benefit will hit the working poor hardest. Job cuts in the public sector are disproportionately affecting low paid women, while working women are being clobbered with more responsibility for childcare and care for elderly relatives as public services are reined back. Cuts to local …
THE ENZYMATIC DEGRADATION OF HEMOGLOBIN TO BILE PIGMENTS BY MACROPHAGES
Authors: Neville R. Pimstone, Raimo Tenhunen, Paul T. Seitz, Harvey S. Marver, Rudi Schmid
Journal: The Journal of Experimental Medicine (1971)

Recent studies have identified and characterized the enzymatic mechanism by which hemoglobin-heme is converted to bilirubin. Under physiologic conditions the enzyme system, microsomal heme-oxygenase, is most active in the spleen followed by the liver and bone marrow, all of which are tissues that normally are involved in the sequestration and metabolism of red cells. Indirect evidence suggested that the reticuloendothelial system is important in this process. To test this hypothesis, conversion of heme to bilirubin was studied in macrophages obtained by chemical or immunological means from the peritoneal cavity or from the lungs of rodents. Homogenates of pure populations of these cells were devoid of heme-oxygenase activity, unless before harvesting the macrophages had been exposed to methemalbumin, microcrystalline hemin, or hemoglobin in vivo. In macrophages exposed to heme pigments, the specific activity of heme-oxygenase was far in excess of that in the spleen or liver. Enzyme activity was also present in the granulomatous tissue surrounding subcutaneous hematomas. The heme-oxygenase system in macrophages resembles that in the spleen and liver in that it is localized in the microsomal fraction, has an absolute requirement for molecular oxygen and NADPH, is inhibited by carbon monoxide, and has a similar K(m). These findings indicate that cells of the reticuloendothelial system, presumably including the Kupffer cells of the liver and the macrophages of the spleen, possess the enzymatic machinery for converting hemoglobin-heme to bilirubin. The reaction is a mixed function oxidation, probably involving cytochrome P450 as the terminal oxidase. Enzyme activity in macrophages is capable of regulatory adaptation in response to substrate loads. In the standard assay system for the enzyme, disappearance of heme always was in excess of the amount of bilirubin formed, suggesting the simultaneous presence of alternate routes of heme degradation not involving bilirubin as an end product or intermediate.
High density lipoprotein is targeted for oxidation by myeloperoxidase in rheumatoid arthritis
Authors: Anuradha Vivekanandan-Giri, Jessica L Slocum, Jaeman Byun, Chongren Tang, Robin L Sands, Brenda W Gillespie, Jay W Heinecke, Rajiv Saran, Mariana J Kaplan, Subramaniam Pennathur
Journal: Annals of the Rheumatic Diseases (2013)

Phagocyte-derived myeloperoxidase (MPO) and pro-inflammatory high density lipoprotein (HDL) associate with rheumatoid arthritis (RA), but the link between MPO and HDL has not been systematically examined. In this study, we investigated whether MPO can oxidise HDL and determined MPO-specific oxidative signature by apoA-1 by peptide mapping in RA subjects with and without known cardiovascular disease (CVD).Two MPO oxidation products, 3-chlorotyrosine and 3-nitrotyrosine, were quantified by tandem mass spectrometry (MS/MS) in in vitro model system studies and in plasma and HDL derived from healthy controls and RA subjects. MPO levels and cholesterol efflux were determined. Site-specific nitration and chlorination of apoA-1 peptides were quantified by MS/MS.RA subjects demonstrated higher levels of MPO, MPO-oxidised HDL and diminished cholesterol efflux. There was marked increase in MPO-specific 3-chlorotyrosine and 3-nitrotyrosine content in HDL in RA subjects consistent with specific targeting of HDL, with increased nitration in RA subjects with CVD. Cholesterol efflux capacity was diminished in RA subjects and correlated inversely with HDL 3-chlorotyrosine suggesting a mechanistic role for MPO. Nitrated HDL was elevated in RACVD subjects compared with RA subjects without CVD. Oxidative peptide mapping revealed site-specific unique oxidation signatures on apoA-1 for RA subjects with and without CVD.We report an increase in MPO-mediated HDL oxidation that is regiospecific in RA and accentuated in those with CVD. Decreased cholesterol efflux capacity due to MPO-mediated chlorination is a potential mechanism for atherosclerosis in RA and raises the possibility that oxidant resistant forms of HDL may attenuate this increased risk.
Effect of High-Dose Vitamin E on Insulin Resistance and Associated Parameters in Overweight Subjects
Authors: Salvador Vale
Journal: Diabetes Care (2005)

In the report of Manning et al. (1), patient’s plasma peroxides were decreased by 29% at 6 months with a transient reduction in insulin resistance. Consequently, they postulate that vitamin E improves oxidative stress and hepatocellular function in overweight patients and suggest that “vitamin E could have a role to play in delaying the onset of diabetes in at-risk individuals (1).”

The rationale for …