tbuckley/cabot-search huggingface dataset:
Role of Neutral Amino Acid Transport and Protein Breakdown for Substrate Supply of Nitric Oxide Synthase in Human Endothelial Cells
Authors: Alexandra Simon, Lars Plies, Alice Habermeier, Ursula Martiné, Marco Reining, Ellen I. Closs
Journal: Circulation Research (2003)

Endothelial dysfunction is often associated with a relative substrate deficiency of the endothelial nitric oxide synthase (eNOS) in spite of apparently high intracellular arginine concentrations. For a better understanding of the underlying pathophysiological mechanisms, we aimed to characterize the intracellular arginine sources of eNOS. Our previous studies in human endothelial EA.hy926 cells suggested the existence of two arginine pools: pool I can be depleted by extracellular lysine, whereas pool II is not freely exchangeable with the extracellular space, but accessible to eNOS. In this study, we demonstrate that the eNOS accessible pool II is also present in human umbilical vein endothelial cells (HUVECs), but not in ECV bladder carcinoma cells transfected with an expression plasmid for eNOS. In the endothelial cells, one part of pool II (referred to as pool IIA) consisted of recycling of citrulline to arginine. This part could be depleted by neutral amino acids that match the substrate profile of system N transporter 1 (SN1), presumably by the removal of intracellular citrulline. SN1 was expressed in EA.hy926 cells and HUVECs as shown by real-time RT-PCR. The second part of pool II (referred to as pool IIB) could not be depleted by any of the cationic or neutral amino acids tested. Our data demonstrate that pool IIB is nourished by protein breakdown and thus represents a substrate pool likely to accumulate protein-derived endogenous inhibitors of eNOS. Preferential use of the arginine pool IIB under pathophysiological conditions might therefore explain the arginine paradox.
Microarray Analyses Uncover UBE1L as a Candidate Target Gene for Lung Cancer Chemoprevention
Authors: Ian Pitha-Rowe, W. Jeffrey Petty, Qing Feng, Petra H. Koza-Taylor, Debra A. DiMattia, Lynn Pinder, Konstantin H. Dragnev, Natalie Memoli, Vincent Memoli, Tom Turi, Jean Beebe, Sutisak Kitareewan, Ethan Dmitrovsky
Journal: Cancer Research (2004)

Abstract Retinoids, natural and synthetic derivatives of vitamin A, are active in cancer therapy and chemoprevention. We reported previously that all-trans-retinoic acid (RA) treatment prevented carcinogen-induced transformation of immortalized human bronchial epithelial (HBE) cells. To identify cancer chemopreventive mechanisms, immortalized (BEAS-2B), carcinogen-transformed (BEAS-2BNNK), and RA-chemoprevented (BEAS-2BNNK/RA) HBE cells were used to conduct microarray analyses independently. Species increased in chemoprevented as compared with immortalized HBE cells (group I) and those augmented in chemoprevented as compared with transformed HBE cells (group II) included known RA-target genes as well as previously unrecognized RA-target genes in HBE cells. Unexpectedly, both groups were also enriched for interferon-stimulated genes. One interferon-stimulated gene of particular interest was UBE1L, the ubiquitin-activating enzyme E1-like protein. UBE1L expression was also induced after prolonged RA-treatment of immortalized HBE cells. UBE1L mRNA was shown previously as repressed in certain lung cancer cell lines, directly implicating UBE1L in lung carcinogenesis. Notably, UBE1L immunoblot expression was reduced in a subset of malignant as compared with adjacent normal lung tissues that were examined. Immunohistochemical analyses were performed using a new assay developed to detect this species using rabbit polyclonal anti-UBE1L antibodies independently raised against the amino- or carboxyl-termini of UBE1L. Studies done on paraffin-embedded and fixed tissues revealed abundant UBE1L, but low levels of cyclin D1 expression in the normal human bronchial epithelium, indicating an inverse relationship existed between these species. To study this further, cotransfection into HBE cells of wild-type or mutant UBE1L species was accomplished. In a dose-dependent manner, wild-type but not mutant UBE1L species repressed cyclin D1 expression. This implicated UBE1L in a retinoid chemoprevention mechanism involving cyclin D1 repression described previously. Taken together, these findings directly implicate UBE1L as a candidate-pharmacologic target for lung cancer chemoprevention. These findings also provide a mechanistic basis for the tumor suppressive effects of UBE1L through cyclin D1 repression.
Effects of HDV infection and pegylated interferon α treatment on the natural killer cell compartment in chronically infected individuals
Authors: Sebastian Lunemann, David F G Malone, Jan Grabowski, Kerstin Port, Vivien Béziat, Birgit Bremer, Karl-Johan Malmberg, Michael P Manns, Johan K Sandberg, Markus Cornberg, Hans-Gustaf Ljunggren, Heiner Wedemeyer, Niklas K Björkström
Journal: Gut (2014)

<h3>Objective</h3> Although hepatitis delta is considered an immune-mediated disease, adaptive immune responses to hepatitis delta virus (HDV) are hardly detectable. Thus, the role of other immune responses, including those mediated by natural killer (NK) cells, must be considered in HDV pathogenesis and in treatments with immune-stimulating agents such as interferon (IFN)α. However, the phenotype and function of NK cells in chronic HDV infection, or in HDV-infected individuals undergoing IFNα treatment, have not been extensively studied. <h3>Design</h3> We performed an extensive analysis of NK cells in chronically HDV-infected patients before and during treatment with IFNα, and compared the results with those for patients with HBV mono-infection as well as healthy controls. <h3>Results</h3> In untreated HDV-infected patients, a higher than normal frequency of NK cells was observed in peripheral blood with unaltered phenotypic NK cell differentiation status. In contrast, long-term IFNα treatment of HDV-infected patients caused a significant change in NK cell differentiation status, with selective loss of terminally differentiated NK cells and, in parallel, a relative enrichment in immature NK cell subsets. Treatment was associated with marked functional impairment of the NK cells, which was independent of the changes in NK cell differentiation status. Furthermore, treatment polarised NK cell IFN signalling from STAT4 towards STAT1 dependency. Strikingly, a high frequency of CD56<sup>dim</sup> NK cells at baseline was positively associated with IFNα treatment outcome in the patients. <h3>Conclusions</h3> We describe in detail how HDV infection, and IFNα treatment of this infection, affects the NK cell compartment and what consequences this has for the functional capacity of NK cells.
Clinical Significance of Insulin Antibodies in Insulin-Treated Diabetic Patients
Authors: Timon W Van Haeften
Journal: Diabetes Care (1989)

The prevalence and titers of insulin antibodies in insulin-treated patients have markedly decreased, mainly as a consequence of the improvements in the purity of insulin preparations and to a lesser degree because of the changes of species of insulin (human insulin). However, numerous patients still produce antibody levels that may alter insulin pharmacokinetics, leading to higher postprandial blood glucose levels and to an increased risk for delayed hypoglycemia. Although the effects of antibodies on long-term glycemic control are less clear, the metabolic consequences of altered pharmacokinetics are clinically evident in patients in whom near normoglycemia is the goal and who are treated predominantly with short-acting insulin. Lipoatrophy and immunological insulin resistance, which are also antibody-induced phenomena, have become rare. Whether pregnancies in diabetic mothers with antibodies carry an increased risk for serious or fatal complications is not clear; neonates of these mothers are probably at increased risk for neonatal hypoglycemia.
Effect of Self-monitoring and Medication Self-titration on Systolic Blood Pressure in Hypertensive Patients at High Risk of Cardiovascular Disease
Authors: Richard J. McManus, Jonathan Mant, M. Sayeed Haque, Emma P. Bray, Stirling Bryan, Sheila M. Greenfield, Miren I. Jones, Sue Jowett, Paul Little, Cristina Penaloza, Claire Schwartz, Helen Shackleford, Claire Shovelton, Jinu Varghese, Bryan Williams, F.D. Richard Hobbs
Journal: JAMA (2014)

Self-monitoring of blood pressure with self-titration of antihypertensives (self-management) results in lower blood pressure in patients with hypertension, but there are no data about patients in high-risk groups.To determine the effect of self-monitoring with self-titration of antihypertensive medication compared with usual care on systolic blood pressure among patients with cardiovascular disease, diabetes, or chronic kidney disease.A primary care, unblinded, randomized clinical trial involving 552 patients who were aged at least 35 years with a history of stroke, coronary heart disease, diabetes, or chronic kidney disease and with baseline blood pressure of at least 130/80 mm Hg being treated at 59 UK primary care practices was conducted between March 2011 and January 2013.Self-monitoring of blood pressure combined with an individualized self-titration algorithm. During the study period, the office visit blood pressure measurement target was 130/80 mm Hg and the home measurement target was 120/75 mm Hg. Control patients received usual care consisting of seeing their health care clinician for routine blood pressure measurement and adjustment of medication if necessary.The primary outcome was the difference in systolic blood pressure between intervention and control groups at the 12-month office visit.Primary outcome data were available from 450 patients (81%). The mean baseline blood pressure was 143.1/80.5 mm Hg in the intervention group and 143.6/79.5 mm Hg in the control group. After 12 months, the mean blood pressure had decreased to 128.2/73.8 mm Hg in the intervention group and to 137.8/76.3 mm Hg in the control group, a difference of 9.2 mm Hg (95% CI, 5.7-12.7) in systolic and 3.4 mm Hg (95% CI, 1.8-5.0) in diastolic blood pressure following correction for baseline blood pressure. Multiple imputation for missing values gave similar results: the mean baseline was 143.5/80.2 mm Hg in the intervention group vs 144.2/79.9 mm Hg in the control group, and at 12 months, the mean was 128.6/73.6 mm Hg in the intervention group vs 138.2/76.4 mm Hg in the control group, with a difference of 8.8 mm Hg (95% CI, 4.9-12.7) for systolic and 3.1 mm Hg (95% CI, 0.7-5.5) for diastolic blood pressure between groups. These results were comparable in all subgroups, without excessive adverse events.Among patients with hypertension at high risk of cardiovascular disease, self-monitoring with self-titration of antihypertensive medication compared with usual care resulted in lower systolic blood pressure at 12 months.isrctn.org Identifier: ISRCTN87171227.
Peptides related to the carboxyl terminus of human platelet factor IV with antibacterial activity.
Authors: R P Darveau, J Blake, C L Seachord, W L Cosand, M D Cunningham, L Cassiano-Clough, G Maloney
Journal: Journal of Clinical Investigation (1992)

A peptide (C13) corresponding to the last 13 amino acids of the carboxyl terminus of human platelet factor IV was found to be antibacterial. Amino acid substitutions predicted to disrupt either the amphipathic or alpha-helical nature of C13 rendered the peptide inactive. Antibacterial activity was demonstrated in normal human serum on bacteria which had been previously exposed to low levels of cefepime, a beta-lactam antibiotic. Peptide analogues were examined for more potent antibacterial activity in an antibacterial assay that employed normal human serum and low levels of cefepime. A peptide analogue (C18G) with 80-fold more antibacterial activity than C13 was identified. Studies in C8-deficient sera confirmed an essential role of human serum complement for optimal antibacterial activity. Additional studies showed low levels of cefepime, although not essential, enhanced the antibacterial activity of C18G. Animal protection experiments demonstrated that either peptide C18G or an analogue with all D amino acids (C18X) significantly increased the survival of neutropenic mice when coadministered with a low level of cefepime. This work has resulted in the identification of a new group of antibacterial peptides.
A study of aspirin and clopidogrel in idiopathic pulmonary arterial hypertension
Authors: I. M. Robbins, S. M. Kawut, D. Yung, M. P. Reilly, W. Lloyd, G. Cunningham, J. Loscalzo, S. E. Kimmel, B. W. Christman, R. J. Barst
Journal: European Respiratory Journal (2006)

Idiopathic pulmonary arterial hypertension (IPAH) is characterised by in situ thrombosis and increased thromboxane (Tx) A 2 synthesis; however, there are no studies of antiplatelet therapy in IPAH. The aim of the current study was to determine the biochemical effects of aspirin (ASA) and clopidogrel on platelet function and eicosanoid metabolism in patients with IPAH. A randomised, double-blind, placebo-controlled crossover study of ASA 81 mg once daily and clopidogrel 75 mg once daily was performed. Plasma P-selectin levels and aggregometry were measured after exposure to adenosine diphosphate, arachidonic acid and collagen. Serum levels of TxB 2 and urinary metabolites of TxA 2 and prostaglandin I 2 (Tx-M and PGI-M, respectively) were assessed. A total of 19 IPAH patients were enrolled, of whom nine were being treated with continuous intravenous epoprostenol. ASA and clopidogrel significantly reduced platelet aggregation to arachidonic acid and adenosine diphosphate, respectively. ASA significantly decreased serum TxB 2 , urinary Tx-M levels and the Tx-M/PGI-M ratio, whereas clopidogrel had no effect on eicosanoid levels. Neither drug significantly lowered plasma P-selectin levels. Epoprostenol use did not affect the results. In conclusion, aspirin and clopidogrel inhibited platelet aggregation, and aspirin reduced thromboxane metabolite production without affecting prostaglandin I 2 metabolite synthesis. Further clinical trials of aspirin in patients with idiopathic pulmonary arterial hypertension should be performed.
The Mitochondrial Genome of the Moss Physcomitrella patens Sheds New Light on Mitochondrial Evolution in Land Plants
Authors: Kimihiro Terasawa, Masaki Odahara, Yukihiro Kabeya, Tatsuhiko Kikugawa, Yasuhiko Sekine, Makoto Fujiwara, Naoki Sato
Journal: Molecular Biology and Evolution (2006)

The phylogenetic positions of bryophytes and charophytes, together with their genome features, are important for understanding early land plant evolution. Here we report the complete nucleotide sequence (105,340 bp) of the circular-mapping mitochondrial DNA of the moss Physcomitrella patens. Available evidence suggests that the multipartite structure of the mitochondrial genome in flowering plants does not occur in Physcomitrella. It contains genes for 3 rRNAs (rnl, rns, and rrn5), 24 tRNAs, and 42 conserved mitochondrial proteins (14 ribosomal proteins, 4 ccm proteins, 9 nicotinamide adenine dinucleotide dehydrogenase subunits, 5 ATPase subunits, 2 succinate dehydrogenase subunits, apocytochrome b, 3 cytochrome oxidase subunits, and 4 other proteins). We estimate that 5 tRNA genes are missing that might be encoded by the nuclear genome. The overall mitochondrial genome structure is similar in Physcomitrella, Chara vulgaris, Chaetosphaeridium globosum, and Marchantia polymorpha, with easily identifiable inversions and translocations. Significant synteny with angiosperm and chlorophyte mitochondrial genomes was not detected. Phylogenetic analysis of 18 conserved proteins suggests that the moss-liverwort clade is sister to angiosperms, which is consistent with a previous analysis of chloroplast genes but is not consistent with some analyses using mitochondrial sequences. In Physcomitrella, 27 introns are present within 16 genes. Nine of its intron positions are shared with angiosperms and 4 with Marchantia, which in turn shares only one intron position with angiosperms. The phylogenetic analysis as well as the syntenic structure suggest that the mitochondrial genomes of Physcomitrella and Marchantia retain prototype features among land plant mitochondrial genomes.
Long-term survival results of a randomized trial comparing gemcitabine/cisplatin and methotrexate/vinblastine/doxorubicin/cisplatin in patients with locally advanced and metastatic bladder cancer
Authors: J.T. Roberts, H. von der Maase, L. Sengeløv, P.F. Conte, L. Dogliotti, T. Oliver, M.J. Moore, A. Zimmermann, M. Arning
Journal: Annals of Oncology (2006)
Bronchiectasis in association with coeliac disease
Authors: R. Mahadeva, C. Flower, J. Shneerson
Journal: Thorax (1998)

A 48 year old woman presented with a history of fatigue, regular sputum production, and wheeze. High resolution computed tomographic scanning of the thorax demonstrated widespread bronchiectasis. Coeliac disease was diagnosed on the basis of an iron deficiency anaemia, subtotal villous atrophy on small bowel biopsy, and raised anti-gliadin and antiendomysial antibodies. The temporal relationship of the bronchiectasis and coeliac disease, and the subsequent stabilisation of her clinical symptoms and improvement in pulmonary physiology following treatment with inhaled corticosteroids, suggests a relationship between the two conditions which may be due to immunological mechanisms.
Characteristics of pulmonary function of COPD with and without arterial pulmonary hypertension
Authors: Kenji Yazaki, Naoko Kamada, Kenichi Asakura, Rei Oba, Etsuko Sato, Mitsuko Sato, Tazuko Sato, Kenji Kikuchi
Journal: European Respiratory Journal (2014)

Patients with low levels of diffusing capacity of the lung for carbon monoxide (Dlco) do not always have pulmonary arterial hypertension (PAH) as part of chronic obstructive pulmonary disease (COPD).

The aim of this study is to investigate the characteristics of pulmonary function of COPD with and without PAH and compare ratios of vital capacity (VC), forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), or inspiratory capacity (IC) to Dlco versus alveolar volume (Dlco/VA)

All subjects who needed oxygen therapy and also underwent lung function testing and Doppler echocardiography were reviewed, retrospectively, from September 1, 2011, to January 31, 2014. Fifteen subjects, all ex-smokers, were included(80.6±6.6 age, FEV1 % 41.16±13.15%, FEV1 %predicted 49.14±19.61%, Dlco 5.00±2.83ml/min/mmHg). PAH was defined as the estimated systolic pulmonary arterial pressure (sPAP)≥40mmHg at rest and a diagnosis of PAH by cardiologists. There was no heart failure among any of the subjects with PAH.

Six subjects had PAH. In the non-PAH group, Dlco was 4.94±1.40 ml/min/mmHg, and Dlco/VAwas 1.12±0.41 ml/min/mmHg/L. In the PAH group, Dlco was 5.08±4.38 ml/min/mmHg, and Dlco/VA was 0.95±0.59 ml/min/mmHg/L. There were no significant differences between non-PAH and PAH. In the ratio of average PAH to non-PAH, VC/Dlco/VAwas 1.91, FVC/Dlco/VA was 1.87, FEV1/Dlco/VA was 2.01, and IC/Dlco/VA was 2.13. All subjects in the PAH group were significantly correlated with sPAP(r=0.771, 0.771, 0.942, and 0.829, respectively, p<0.05).

This report suggests that VC/Dlco/VA, FVC/Dlco/VA, FEV1/Dlco/VA, and IC/Dlco/VA might be useful to assist in diagnosing PAH in COPD.
Differences in descriptions of Kellgren and Lawrence grades of knee osteoarthritis
Authors: D Schiphof, M Boers, S M A Bierma-Zeinstra
Journal: Annals of the Rheumatic Diseases (2008)

<h3>Objective:</h3> Correct application of the Kellgren and Lawrence (K&amp;L) classification system is difficult due to inexact wording of the descriptors. We summarised different descriptions and searched for evidence on the impact of such variations on classification of knee osteoarthritis (OA) in epidemiological studies. <h3>Methods:</h3> We searched Medline/Pubmed (1966 to August 2006) for studies of epidemiological cohorts that professed use of the original K&amp;L scale (grades 0–4, with 0 being normal and 4 severe OA), and recorded their descriptions of the five grades. The descriptions were compared with each other and with the original description. <h3>Results:</h3> We identified five different descriptions. In grade 2, often used as a cut-off to classify OA, one description replaced "definite osteophytes and possible narrowing of joint space" (K&amp;L) by "definite osteophyte, unimpaired joint space". Another description for grade 2 was "minimal osteophytes, possible narrowing, cysts, and sclerosis". In some cohort studies, descriptions changed during follow-up. None of the included articles studied the impact of the use of different descriptions. <h3>Conclusion:</h3> Major OA cohort studies disagree between each other and even among themselves on the definition and grading of disease according to the original K&amp;L system. The impact of this disagreement warrants further study, but consensus urgently needs to be reached on a single valid and feasible classification system.
Adalimumab Induction Therapy for Crohn Disease Previously Treated with Infliximab
Authors: William J. Sandborn, Paul Rutgeerts, Robert Enns, Stephen B. Hanauer, Jean-Frédéric Colombel, Remo Panaccione, Geert D'Haens, Ju Li, Marie R. Rosenfeld, Jeffrey D. Kent, Paul F. Pollack
Journal: Annals of Internal Medicine (2007)

Background: Adalimumab, a fully human tumor necrosis factor (TNF) antagonist, is an effective treatment for patients with Crohn disease who are naive to the chimeric TNF antagonist, infliximab. No anti-TNF agent has been evaluated prospectively in patients with Crohn disease who had responded to another anti-TNF agent and then lost that response or were intolerant of the agent. Objective: To determine whether adalimumab induces remissions more frequently than placebo in adult patients with Crohn disease who have symptoms despite infliximab therapy or who cannot take infliximab because of adverse events. Design: 4-week, randomized, double-blind, placebo-controlled trial (November 2004 to December 2005). Setting: 52 sites in the United States, Canada, and Europe. Patients: 325 adults 18 to 75 years of age who had a history of Crohn disease for 4 months or more that was moderate to severe at baseline (Crohn's Disease Activity Index [CDAI] score, 220 to 450 points). Intervention: Patients were randomly assigned to receive induction doses of adalimumab, 160 mg and 80 mg, at weeks 0 and 2, respectively, or placebo at the same time points. Measurements: The primary end point was induction of remission at week 4. Decreases in CDAI score by 70 or more and 100 or more points (secondary end points) were also measured. Results: A total of 301 patients completed the trial. Twenty-one percent (34 of 159) of patients in the adalimumab group versus 7% (12 of 166) of those in the placebo group achieved remission at week 4 (P < 0.001). The absolute difference in clinical remission rates was 14.2 percentage points (95% CI, 6.7 to 21.6 percentage points). A 70-point response occurred at week 4 in 52% (82 of 159) of patients in the adalimumab group versus 34% (56 of 166) of patients in the placebo group (P = 0.001). The absolute difference in 70-point response rates was 17.8 percentage points (CI, 7.3 to 28.4 percentage points). Two of 159 patients in the adalimumab group and 4 of 166 patients in the placebo group discontinued treatment because of adverse events. No patients in the adalimumab group and 4 of 166 patients in the placebo group had a serious infection. Limitations: The trial did not directly compare alternative active treatments and did not evaluate maintenance of response or long-term immunogenicity of adalimumab. Conclusion: Adalimumab induces remissions more frequently than placebo in adult patients with Crohn disease who cannot tolerate infliximab or have symptoms despite receiving infliximab therapy. ClinicalTrials.gov registration number: NCT00105300.