tbuckley/cabot-search huggingface dataset:
Controlling Tumor Growth by Modulating Endogenous Production of Reactive Oxygen Species
Authors: Alexis Laurent, Carole Nicco, Christiane Chéreau, Claire Goulvestre, Jérôme Alexandre, Arnaud Alves, Eva Lévy, Francois Goldwasser, Yves Panis, Olivier Soubrane, Bernard Weill, Frédéric Batteux
Journal: Cancer Research (2005)

Paradoxically, reactive oxygen species (ROS) can promote normal cellular proliferation and carcinogenesis, and can also induce apoptosis of tumor cells. In this report, we study the contribution of ROS to various cellular signals depending on the nature and the level of ROS produced. In nontransformed NIH 3T3 cells, ROS are at low levels and originate from NADPH oxidase. Hydrogen peroxide (H(2)O(2)), controlled by the glutathione system, is pivotal for the modulation of normal cell proliferation. In CT26 (colon) and Hepa 1-6 (liver) tumor cells, high levels of ROS, close to the threshold of cytotoxicity, are produced by mitochondria and H(2)O(2) is controlled by catalase. N-acetylcysteine, which decreases H(2)O(2) levels, inhibits mitogen-activated protein kinase and normal cell proliferation but increases tumor cell proliferation as H(2)O(2) concentration drops from the toxicity threshold. In contrast, antioxidant molecules, such as mimics of superoxide dismutase (SOD), increase H(2)O(2) levels through superoxide anion dismutation, as well as in vitro proliferation of normal cells, but kill tumor cells. CT26 tumors were implanted in mice and treated by oxaliplatin in association with one of the three SOD mimics manganese(III)tetrakis(4-benzoic acid) porphyrin, copper(II)(3,5-diisopropylsalicylate)2, or manganese dipyridoxyl diphosphate. After 1 month, the volumes of tumors were respectively 35%, 31%, and 63% smaller than with oxaliplatin alone (P < 0.001). Similar data were gained with Hepa 1-6 tumors. In conclusion, antioxidant molecules may have opposite effects on tumor growth. SOD mimics can act in synergy with cytotoxic drugs to treat colon and liver cancers.
The Role of Mitochondria in the Pathophysiology of Skeletal Muscle Insulin Resistance
Authors: Ines Pagel-Langenickel, Jianjun Bao, Liyan Pang, Michael N. Sack
Journal: Endocrine Reviews (2009)

Multiple organs contribute to the development of peripheral insulin resistance, with the major contributors being skeletal muscle, liver, and adipose tissue. Because insulin resistance usually precedes the development of type 2 diabetes mellitus (T2DM) by many years, understanding the pathophysiology of insulin resistance should enable development of therapeutic strategies to prevent disease progression. Some subjects with mitochondrial genomic variants/defects and a subset of lean individuals with hereditary predisposition to T2DM exhibit skeletal muscle mitochondrial dysfunction early in the course of insulin resistance. In contrast, in the majority of subjects with T2DM the plurality of evidence implicates skeletal muscle mitochondrial dysfunction as a consequence of perturbations associated with T2DM, and these mitochondrial deficits then contribute to subsequent disease progression. We review the affirmative and contrarian data regarding skeletal muscle mitochondrial biology in the pathogenesis of insulin resistance and explore potential therapeutic options to intrinsically modulate mitochondria as a strategy to combat insulin resistance. Furthermore, an overview of restricted molecular manipulations of skeletal muscle metabolic and mitochondrial biology offers insight into the mitochondrial role in metabolic substrate partitioning and in promoting innate adaptive and maladaptive responses that collectively regulate peripheral insulin sensitivity. We conclude that skeletal muscle mitochondrial dysfunction is not generally a major initiator of the pathophysiology of insulin resistance, although its dysfunction is integral to this pathophysiology and it remains an intriguing target to reverse/delay the progressive perturbations synonymous with T2DM.
Cytotoxic T Lymphocyte Antigen 4 Is Induced in the Thymus upon In Vivo Activation and Its Blockade Prevents Anti-CD3–mediated Depletion of Thymocytes
Authors: Corrado M. Cilio, Michael R. Daws, Anna Malashicheva, Charles L. Sentman, Dan Holmberg
Journal: The Journal of Experimental Medicine (1998)

The development of a normal T cell repertoire in the thymus is dependent on the interplay between signals mediating cell survival (positive selection) and cell death (negative selection or death by neglect). Although the CD28 costimulatory molecule has been implicated in this process, it has been difficult to establish a role for the other major costimulatory molecule, cytotoxic T lymphocyte antigen (CTLA)-4. Here we report that in vivo stimulation through the T cell receptor (TCR)–CD3 complex induces expression of CTLA-4 in thymocytes and leads to the association of CTLA-4 with the SH2 domain–containing phosphatase (SHP)-2 tyrosine phosphatase. Moreover, intrathymic CTLA-4 blockade dramatically inhibits anti-CD3–mediated depletion of CD4+CD8+ double positive immature thymocytes. Similarly, anti-CD3–mediated depletion of CD4+CD8+ double positive cells in fetal thymic organ cultures could also be inhibited by anti–CTLA-4 antibodies. Thus, our data provide evidence for a role of CTLA-4 in thymic selection and suggest a novel mechanism contributing to the regulation of TCR-mediated selection of T cell repertoires.
Heart block in patients with obstructive sleep apnoea: pathogenetic factors and effects of treatment
Authors: U Koehler, E Fus, W Grimm, W Pankow, H Schafer, A Stammnitz, JH Peter
Journal: European Respiratory Journal (1998)

Heart block during sleep has been described in up to 10% of patients with obstructive sleep apnoea. The aim of this study was to determine the relationship between sleep stage, oxygen desaturation and apnoea-associated bradyarrhythmias as well as the effect of nasal continuous positive airway pressure (nCPAP)/nasal bi-level positive airway pressure (nBiPAP) therapy on these arrhythmias in patients without electrophysiological abnormalities. Sixteen patients (14 males and two females, mean age 49.6+/-10.4 yrs) with sleep apnoea and nocturnal heart block underwent polysomnography after exclusion of electrophysiological abnormalities of the sinus node function and atrioventricular (AV) conduction system by invasive electrophysiological evaluation. During sleep, 651 episodes of heart block were recorded, 572 (87.9%) occurred during rapid eye movement (REM) sleep and 79 (12.1%) during nonrapid eye movement (NREM) sleep stages 1 and 2. During REM sleep, the frequency of heart block was significantly higher than during NREM sleep: 0.69+/-0.99 versus 0.02+/-0.04 episodes of heart block x min(-1) of the respective sleep stage (p&lt;0.001). During apnoeas or hypopnoeas, 609 bradyarrhythmias (93.5%) occurred with a desaturation of at least 4%. With nCPAP/ nBiPAP therapy, apnoea/hypopnoea index (AHI) decreased from 75.5+/-39.6 x h(-1) to 3.0+/-6.6 x h(-1) (p&lt;0.01) and the number of arrhythmias from 651 to 72 (p&lt;0.01). We conclude that: 1) 87.9% of apnoea-associated bradyarrhythmias occur during rapid eye movement sleep; 2) the vast majority of heart block episodes occur during a desaturation of at least 4% without a previously described threshold value of 72%; and 3) nasal continuous positive airway pressure or nasal bi-level positive airway pressure is the therapy of choice in patients with apnoea-associated bradyarrhythmias.
Immunoglobulin-like transcript 2 (ILT2) is a biomarker of therapeutic response to oncolytic immunotherapy with vaccinia viruses
Authors: Andrew Zloza, Dae Kim, Seunghee Kim-Schulze, Michael C Jagoda, Vladia Monsurro, Francesco M Marincola, Howard L Kaufman
Journal: Journal for ImmunoTherapy of Cancer (2014)

Oncolytic viruses represent a novel form of cancer immunotherapy. Vaccinia viruses encoding human T cell co-stimulatory molecules have demonstrated clinical activity in phase I clinical trials in patients with advanced melanoma. However, predictive biomarkers of therapeutic response have not yet been identified.A customized microarray was performed to identify changes in peripheral blood mononuclear cell (PBMC) gene expression upon exposure to recombinant oncolytic vaccinia viruses. Up-regulated and down-regulated genes were identified and selected for further analysis using PBMC samples from normal donors and oncolytic virus-treated patients before and after viral injection. Quantitative PCR and flow cytometry of defined T cell subsets was performed to evaluate expression patterns and clinical correlations.The microarray identified 301 genes that were up-regulated and 960 genes that were down-regulated in T cells after exposure to oncolytic vaccinia virus. The B7.1 gene was highly up-regulated and the immunoglobulin-like transcript 2 (ILT2) gene was highly down-regulated by vaccinia-B7.1, which was consistent with the known inverse regulation of these two genes. We observed an inverse association between ILT2 expression in the tumor microenvironment and clinical response and further identified ILT2 as a marker of regulatory CD4+ and suppressor CD8+ T cell responses and whose down-regulation was predictive of therapeutic responses in patients treated with oncolytic virus immunotherapy.ILT2 is a new putative biomarker of T cell and clinical response in patients treated with oncolytic vaccinia virus immunotherapy. Further confirmation of ILT2 as a biomarker requires prospective validation in a larger series of clinical trials.
Asthma and Natural Colds
Authors: MARCIA M. M. PIZZICHINI, EMILIO PIZZICHINI, ANN EFTHIMIADIS, ANOOP J. CHAUHAN, SEBASTIAN L. JOHNSTON, PAT HUSSACK, JIM MAHONY, JERRY DOLOVICH, FREDERICK E. HARGREAVE
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

We examined the feasibility of using induced sputum to evaluate the airway inflammatory response to natural acute respiratory virus infections. We recruited eight asthmatics and nine healthy subjects on Day 4 of a cold. Viral infection was confirmed in six of the asthmatics (influenza A or B) and six of the healthy subjects (influenza A, rhinovirus, adenovirus, respiratory syncytial virus, and coronavirus). In the subjects with confirmed virus infection, five of the asthmatics had an objective exacerbation of asthma during the cold. Their sputum on Day 4 showed a high median total cell count of 19.7 × 106 cells/ml with a modest neutrophilia (58.5%) and high levels of interleukin-8 (IL-8) (16,000 pg/ml), eosinophilic cationic protein (ECP) (1,880 μ g/L) and very high levels of fibrinogen (250 mg/L). In contrast, the proportion (1.3%) and absolute number of eosinophils was low. IL-2 levels were within the normal range, whereas IL-5 and interferon gamma were under the limit of detection of the assays. In the healthy subjects with a confirmed virus infection the sputum findings were qualitatively similar but significantly less prominent. Sputum IL-8 on Day 4 was strongly correlated with neutrophils (rs = 0.8, p < 0.001). This correlation was also significant when each group was analyzed separately. On Day 21 there was a fall in the absolute number of neutrophils and in ECP and fibrinogen levels in both groups. Similar results were found in the two asthmatic and three healthy subjects with a cold of comparable severity but in whom viral infection was not confirmed. We conclude that induced sputum examination can be used to study the effects of natural colds and influenza on the airways of the lungs. The results also suggest that natural colds, on Day 4, cause neutrophilic lower airway inflammation that is greater in asthmatics than in healthy subjects. The greater inflammatory response in asthmatics may be due to the changes associated with trivial eosinophilia or to the different viruses involved.
Binding of digitoxin and some related cardenolides to human plasma proteins
Authors: Daniel S. Lukas, Anthony G. De Martino
Journal: Journal of Clinical Investigation (1969)

Tritium-labeled digitoxin, digitoxigenin, digoxin, and digoxigenin of established purity and chemcal authenticity were used to study the binding of these compounds to human plasma proteins. 97% of digitoxin in plasma was nondialyzable. Continuous flow paper electrophoresis of plasma containing digitoxin and dialysis experiments in which human serum albumin competed for the glycoside with plasma or plasma protein fractions demonstrated that digitoxin was almost exclusively bound by albumin. Equilibrium dialyses revealed that the interaction was characterized by a single binding site on the albumin molecule and an association constant of 9.62 x 10(4) liter/mole at 37 degrees C. At 1 degrees C the association constant was 4.64 x 10(4) liter/mole. The interaction therefore was endothermic; the gain in enthalpy of 3.5 kcal/mole and the free energy change of - 7.06 kcal/mole was derived from a large change in entropy of 33.8 cal/mole per degrees K. The direction of these thermodynamic changes suggested the formation of a hydrophobic bond between digitoxin and albumin. Quenching of the fluorescence of albumin by digitoxin indicated that the conformation of albumin was altered by the binding process.Digitoxigenin, its mono- and didigitoxosides, digoxin, and digoxigenin competed with digitoxn for its binding site on albumin. The affinity of the mono- and didigitoxosides for the site was equal to that of digitoxin, but that of digitoxigenin was only one-third as great. The ability of the digitoxose residues of the glycosides to enhance binding to albumin was also observed with digoxin, which was more extensively bound by the protein than digoxigenin. At concentrations of 2 mug/ml or less in plasma, only 23% of digoxin was bound. Albumin, which interacted with digoxin with an apparent association constant of 9 x 10(2) liter/mole at 37 degrees C, was entirely responsible for the binding. Lowering the temperature from 37 degrees to 1 degrees C decreased the fraction of digoxin bound to albumin by two-thirds. The marked difference in avidity of digitoxin and digoxin for serum albumin is reflected by the higher plasma concentrations, lower rate of urinary excretion, and longer half-time of digitoxin as compared to those of digoxin when these compounds are administered to man.
Possible anti-inflammatory effect of salmeterol against interleukin-8 and neutrophil activation in asthma<i>in vivo</i>
Authors: D.W. Reid, C. Ward, N. Wang, L. Zheng, R. Bish, B. Orsida, E.H. Walters
Journal: European Respiratory Journal (2003)

In-vitro data suggest that long-acting β 2 -agonists may have a neutrophil-stabilising effect. A reduction in airway wall eosinophil number following introduction of salmeterol in persistent asthma has previously been described. There is currently interest in the “neutrophil system” in asthma, and thus the aim of the present study was to investigate the effect of salmeterol on interleukin (IL)-8, neutrophils and myeloperoxidase (MPO) in persistent asthma. In the same 12-week double-blind parallel-group placebo-controlled study as described previously, the effects on bronchoalveolar lavage fluid (BALF) IL-8, neutrophils and MPO of introducing salmeterol (50 µg b.i.d. ) or giving additional inhaled corticosteroid (fluticasone 100 µg b.i.d. ) in 45 subjects with persistent asthma already on low/moderate doses of inhaled corticosteroids were further investigated. At baseline, BALF IL-8 but not neutrophil or MPO levels were significantly raised in the asthmatic subjects compared to normal controls. MPO levels correlated strongly with IL-8 levels, and weakly with BALF neutrophil numbers in the asthmatics. Fluticasone treatment resulted in significantly elevated neutrophil numbers, but not MPO or IL-8 levels. In contrast, introducing salmeterol significantly reduced IL-8 and MPO levels, but did not affect BALF neutrophil numbers. Interestingly, salmeterol and fluticasone showed significantly contrasting effects on MPO and neutrophils, and there was a divergent effect on IL-8 levels that almost reached significance. Excessive interleukin-8 levels may be relevant to asthma pathogenesis, even in the setting of moderate-dose inhaled corticosteroid therapy. Reduction in interleukin-8 production and possibly stabilisation of airway neutrophil numbers may explain the greater clinical benefit of adding a long-acting β 2 -agonist rather than merely increasing inhaled corticosteroid doses. Indeed, high-dose inhaled corticosteroid therapy alone may promote airway neutrophilia.
Incidence of traumatic brain injury in New Zealand: a population-based study
Authors: Valery L Feigin, Alice Theadom, Suzanne Barker-Collo, Nicola J Starkey, Kathryn McPherson, Michael Kahan, Anthony Dowell, Paul Brown, Varsha Parag, Robert Kydd, Kelly Jones, Amy Jones, Shanthi Ameratunga
Journal: The Lancet Neurology (2012)
CD40 induces macrophage anti–Toxoplasma gondii activity by triggering autophagy-dependent fusion of pathogen-containing vacuoles and lysosomes
Authors: Rosa M. Andrade, Matthew Wessendarp, Marc-Jan Gubbels, Boris Striepen, Carlos S. Subauste
Journal: Journal of Clinical Investigation (2006)

Many intracellular pathogens, including Toxoplasma gondii, survive within macrophages by residing in vacuoles that avoid fusion with lysosomes. It is important to determine whether cell-mediated immunity can trigger macrophage antimicrobial activity by rerouting these vacuoles to lysosomes. We report that CD40 stimulation of human and mouse macrophages infected with T. gondii resulted in fusion of parasitophorous vacuoles and late endosomes/lysosomes. Vacuole/lysosome fusion took place even when CD40 was ligated after the formation of parasitophorous vacuoles. Genetic and pharmacological approaches that impaired phosphoinositide-3-class 3 (PIK3C3), Rab7, vacuolar ATPase, and lysosomal enzymes revealed that vacuole/lysosome fusion mediated antimicrobial activity induced by CD40. Ligation of CD40 caused colocalization of parasitophorous vacuoles and LC3, a marker of autophagy, which is a process that controls lysosomal degradation. Vacuole/lysosome fusion and antimicrobial activity were shown to be dependent on autophagy. Thus, cell-mediated immunity through CD40 stimulation can reroute an intracellular pathogen to the lysosomal compartment, resulting in macrophage antimicrobial activity.
Type I interferon signaling in hematopoietic cells is required for survival in mouse polymicrobial sepsis by regulating CXCL10
Authors: Kindra M. Kelly-Scumpia, Philip O. Scumpia, Matthew J. Delano, Jason S. Weinstein, Alex G. Cuenca, James L. Wynn, Lyle L. Moldawer
Journal: The Journal of Experimental Medicine (2010)

Type I interferon (IFN) alpha/beta is critical for host defense. During endotoxicosis or highly lethal bacterial infections where systemic inflammation predominates, mice deficient in IFN-alpha/beta receptor (IFNAR) display decreased systemic inflammation and improved outcome. However, human sepsis mortality often occurs during a prolonged period of immunosuppression and not from exaggerated inflammation. We used a low lethality cecal ligation and puncture (CLP) model of sepsis to determine the role of type I IFNs in host defense during sepsis. Despite increased endotoxin resistance, IFNAR(-/-) and chimeric mice lacking IFNAR in hematopoietic cells display increased mortality to CLP. This was not associated with an altered early systemic inflammatory response, except for decreased CXCL10 production. IFNAR(-/-) mice display persistently elevated peritoneal bacterial counts compared with wild-type mice, reduced peritoneal neutrophil recruitment, and recruitment of neutrophils with poor phagocytic function despite normal to enhanced adaptive immune function during sepsis. Importantly, CXCL10 treatment of IFNAR(-/-) mice improves survival and decreases peritoneal bacterial loads, and CXCL10 increases mouse and human neutrophil phagocytosis. Using a low lethality sepsis model, we identify a critical role of type I IFN-dependent CXCL10 in host defense during polymicrobial sepsis by increasing neutrophil recruitment and function.
The validity and reliability of a novel activity monitor as a measure of walking
Authors: C G Ryan, P M Grant, W W Tigbe, M H Granat
Journal: British Journal of Sports Medicine (2006)

Background: The accurate measurement of physical activity is crucial to understanding the relationship between physical activity and disease prevention and treatment. Objective: The primary purpose of this study was to investigate the validity and reliability of the activ PAL physical activity monitor in measuring step number and cadence. Methods: The ability of the activ PAL monitor to measure step number and cadence in 20 healthy adults (age 34.5±6.9 years; BMI 26.8±4.8 (mean±SD)) was evaluated against video observation. Concurrently, the accuracy of two commonly used pedometers, the Yamax Digi-Walker SW-200 and the Omron HJ-109-E, was compared to observation for measuring step number. Participants walked on a treadmill at five different speeds (0.90, 1.12, 1.33, 1.56, and 1.78 m/s) and outdoors at three self selected speeds (slow, normal, and fast). Results: At all speeds, inter device reliability was excellent for the activ PAL (ICC (2,1)⩾0.99) for both step number and cadence. The absolute percentage error for the activ PAL was &lt;1.11% for step number and cadence regardless of walking speed. The accuracy of the pedometers was adversely affected by slow walking speeds. Conclusion: The activ PAL monitor is a valid and reliable measure of walking in healthy adults. Its accuracy is not influenced by walking speed. The activ PAL may be a useful device in sports medicine.
REACTION OF YOUNG AND ADULT RABBITS TO PNEUMOCOCCI INJECTED INTO THE SKIN
Authors: Jules Freund
Journal: The Journal of Experimental Medicine (1931)

1. Young and adult rabbits react differently to intracutaneous injection of virulent pneumococci. In adult rabbits a very extensive inflammation develops at the site of infection and bacteriemia and death occur only in a relatively few rabbits. Young rabbits fail to develop extensive inflammation and die with bacteriemia. 2. It is probable that the fate of the animals is influenced by the capacity to develop inflammation at the site of injection of pneumococci.