tbuckley/cabot-search huggingface dataset:
Smoke and viral infection cause cilia loss detectable by bronchoalveolar lavage cytology and dynein ELISA.
Authors: J H Sisson, A Papi, J D Beckmann, K L Leise, J Wisecarver, B W Brodersen, C L Kelling, J R Spurzem, S I Rennard
Journal: American Journal of Respiratory and Critical Care Medicine (1994)

The purpose of this study was to quantitate cilia loss following airway epithelial cell injury. Two models of airway injury were used: (1) Ex vivo acute cigarette smoke exposure model: Bovine lungs, obtained directly after slaughter, were ventilated with air or cigarette smoke for 5 min followed immediately by bronchoalveolar lavage (BAL). The bronchi were examined histologically and bronchial and alveolar fractions of BAL fluid were examined for cell counts, cell differentials, and cilia dynein concentrations using a specific 13S dynein ELISA. Smoke exposure resulted in a marked loss of ciliated cells from the bronchial luminal surface (2,364 +/- 351 versus 11,090 +/- 542 ciliated cells/mm2; p = 0.0001), a comparable increase in ciliated cells in the bronchial BAL fraction (0.90 x 10(6) cells/mm3 versus 0.15 x 10(6) cells/mm3; p = 0.0003) and a significant increase in bronchial fluid dynein concentrations (24.5 +/- 6.0 micrograms/ml versus 8.9 +/- 2.2 micrograms/ml; p = 0.03) compared with that in air-exposed lungs. The dynein concentrations strongly correlated with the absolute number of ciliated cells recovered in the bronchial lavage (r = 0.80; p < 0.0001). (2) In vivo viral infection model: Healthy cattle underwent bronchoscopy 3 days before and 7 days after inoculation with bovine respiratory syncytial virus (BRSV). BAL fluid was examined as in the first model. Following BRSV inoculation, airway exfoliation of ciliated cells and squamous metaplasia were observed histologically, bronchial ciliated cell counts doubled (0.011 +/- 0.003 x 10(6) cells/mm3 versus 0.026 +/- 0.006 x 10(6) cells/mm3; p = 0.002) and bronchial dynein concentrations increased threefold (2.2 +/- 1.0 micrograms/ml versus 7.2 +/- 1.9 micrograms/ml; p = 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)
Manipulation of inflammation in ARDS: achievable goal or distant target?
Authors: S V Baudouin
Journal: Thorax (2006)

A possible role for thioredoxin

The acute respiratory distress syndrome (ARDS) was only recognised as a distinct clinical entity less than 50 years ago.1 It arose as a consequence of the success of modern resuscitation and organ support and was first described in severely injured military personnel. It is defined by the development of rapidly progressing respiratory failure, usually within 24–48 hours of the initiating insult. Plain chest radiographs show widespread airspace shadowing with a pattern similar to cardiogenic pulmonary oedema. However, when measured, left sided cardiac pressures are normal and the pulmonary oedema fluid has a high protein content.

This picture of normal cardiac filling pressures and high air space protein content suggested that the central pathophysiology was a result of increased pulmonary epithelial/endothelial permeability. Histological examination of biopsy and autopsy specimens showed widespread epithelial and endothelial damage and radioisotope studies confirmed that lung permeability was abnormal.

Histological studies also indicated that an intense inflammatory response was occurring in the lungs of patients with established ARDS.2,3 In addition to proteinaceous material, the air spaces were filled with acute inflammatory cells—predominantly neutrophils and macrophages. This early phase of ARDS has been characterised as the “exudative phase”. Limited studies suggest that this may be rapidly followed by the proliferation of type II pneumocytes with the beginnings of alveolar basement repair. Fibrosis is also a feature of this phase with the migration of fibroblasts and myoblasts into the fibrinous intra-alveolar exudate. A subsequent fibrotic phase can then occur with extensive lung remodelling, and this may produce a situation of irreversible end stage lung disease. It must be emphasised, however, that this orderly pattern is based on very limited biopsy material and many patients with ARDS make a very good functional recovery over a prolonged period of time.

The theme …
Stereotyped B-Cell Receptor Is an Independent Risk Factor of Chronic Lymphocytic Leukemia Transformation to Richter Syndrome
Authors: Davide Rossi, Valeria Spina, Michaela Cerri, Silvia Rasi, Clara Deambrogi, Lorenzo De Paoli, Luca Laurenti, Rossana Maffei, Francesco Forconi, Francesco Bertoni, Emanuele Zucca, Claudio Agostinelli, Antonello Cabras, Marco Lucioni, Maurizio Martini, Michele Magni, Silvia Deaglio, Marco Ladetto, Josep F. Nomdedeu, Caroline Besson, Antonio Ramponi, Vincenzo Canzonieri, Marco Paulli, Roberto Marasca, Luigi M. Larocca, Antonino Carbone, Stefano A. Pileri, Valter Gattei, Gianluca Gaidano
Journal: Clinical Cancer Research (2009)

Few biological prognosticators are useful for prediction of Richter syndrome (RS), representing the transformation of chronic lymphocytic leukemia (CLL) to aggressive lymphoma. Stereotyped B-cell receptors (BCR) may have prognostic effect in CLL progression. We tested the prognostic effect of stereotyped BCR for predicting RS transformation.The prevalence of stereotyped BCR was compared in RS (n = 69) versus nontransformed CLL (n = 714) by a case-control analysis. Subsequently, the effect of stereotyped BCR at CLL diagnosis on risk of RS transformation was actuarially assessed in a consecutive CLL series (n = 753).RS (n = 69) displayed a higher prevalence of stereotyped BCR (P < 0.001) compared with nontransformed CLL. The actuarial risk of RS transformation was significantly higher in CLL carrying stereotyped BCR (P < 0.001). Among BCR subsets most represented in CLL, subset 8 using IGHV4-39/IGHD6-13/IGHJ5 carried the highest risk of RS transformation [hazard ratio (HR), 24.50; P < 0.001]. Multivariate analysis selected stereotyped BCR (HR, 3.33; P = 0.001) and IGHV4-39 usage (HR, 4.03; P = 0.004) as independent predictors of RS transformation. The combination of IGHV4-39 usage and stereotyped BCR in the same patient identified CLL with a very high risk of RS transformation (5-year risk, 68.7%). The risk carried by stereotyped BCR and IGHV4-39 usage was specific for RS transformation and had no effect on CLL progression without transformation.Analysis of BCR features may help identify CLL patients at risk of RS. A close monitoring and a careful biopsy policy may help early recognition of RS in CLL patients using stereotyped BCR, particularly if combined with IGHV4-39.
Ras Induces Vascular Smooth Muscle Cell Senescence and Inflammation in Human Atherosclerosis
Authors: Tohru Minamino, Toshihiko Yoshida, Kaoru Tateno, Hideyuki Miyauchi, Yonzeng Zou, Haruhiro Toko, Issei Komuro
Journal: Circulation (2003)

Vascular cells have a finite cell lifespan and eventually enter an irreversible growth arrest, cellular senescence. The functional changes associated with cellular senescence are thought to contribute to human aging and age-related vascular disorders. Ras, an important signaling molecule involved in atherogenic stimuli, is known to promote aging in yeast and cellular senescence in primary human fibroblasts. The aim of this study was to investigate the role of Ras-induced vascular smooth muscle cell (VSMC) senescence in atherogenesis.We introduced an activated ras allele (H-rasV12) into human VSMCs using retroviral infection. Introduction of H-rasV12 induced a growth arrest with phenotypic characteristics of cellular senescence, such as enlarged cell shapes and increases in expression of cyclin-dependent kinase inhibitors and senescence-associated beta-galactosidase (SA-beta-gal) activity. Activation of Ras drastically increased expression of proinflammatory cytokines, in part through extracellular signal-regulated kinase activation. To determine whether Ras activation induces cellular senescence in vivo, we transduced the adenoviral vector encoding H-rasV12 into rat carotid arteries injured by a balloon catheter. Introduction of Ras into the arteries enhanced vascular inflammation and senescence compared with mock-infected injured arteries. Moreover, SA-beta-gal-positive VSMCs were detected in the intima of advanced human atherosclerotic lesions and exhibited increased levels of extracellular signal-regulated kinase activity and proinflammatory cytokine expression.Our results suggest that atherogenic stimuli mediated by Ras induce VSMC senescence and vascular inflammation, thereby contributing to atherogenesis. This novel mechanism of atherogenesis may provide insights into a new antisenescence treatment for atherosclerosis.
Hydroxyl Radical Inhibits Sarcoplasmic Reticulum Ca <sup>2+</sup> -ATPase Function by Direct Attack on the ATP Binding Site
Authors: Kai Y. Xu, Jay L. Zweier, Lewis C. Becker
Journal: Circulation Research (1997)

Oxygen-derived free radicals have been reported to damage the sarcoplasmic reticulum (SR) Ca 2+ -ATPase, potentially contributing to cellular Ca 2+ overload and myocardial damage after ischemia and reperfusion. To determine whether the ATP binding site on Ca 2+ -ATPase is involved in oxygen radical injury, SR vesicles containing bound Ca 2+ -ATPase were isolated from rabbit cardiac and skeletal muscle and exposed to a hydroxyl radical (·OH)–generating system consisting of H 2 O 2 and Fe 3+ -nitrilotriacetic acid in amounts that generate a magnitude of ·OH similar to that which occurs in the reperfused heart. ·OH exposure completely inhibited Ca 2+ -ATPase activity and SR 45 Ca uptake for both cardiac and skeletal muscle. In contrast, when the purified vesicles were premixed with l mmol/L ATP before exposure to ·OH, complete protection was observed: there was no loss of ATPase activity or 45 Ca transport. No significant protection occurred with adenosine, sucrose, AMP, or ADP (l mmol/L each). SDS–gel electrophoresis indicated that ·OH did not damage the primary structure of the enzyme. Electron paramagnetic resonance spin-trapping experiments demonstrated that ATP did not scavenge ·OH. These results suggest that ·OH denatures the SR Ca 2+ -ATPase by directly attacking the ATP binding site, and occupation of the active site by ATP protects against ·OH-induced loss of enzymatic activity and SR Ca 2+ transport. The depletion of ATP that occurs during ischemia may enhance the toxic effect of ·OH at the time of reperfusion.
Antitumor Activity of Systemically Delivered Ribozymes Targeting Murine Telomerase RNA
Authors: Mehdi Nosrati, Shang Li, Sepideh Bagheri, David Ginzinger, Elizabeth H. Blackburn, Robert J. Debs, Mohammed Kashani-Sabet
Journal: Clinical Cancer Research (2004)

Abstract Purpose: To test ribozymes targeting mouse telomerase RNA (mTER) for suppression of the progression of B16-F10 murine melanoma metastases in vivo. Experimental Design: Hammerhead ribozymes were designed to target mTER. The ribozyme sequences were cloned into a plasmid expression vector containing EBV genomic elements that substantially prolong expression of genes delivered in vivo. The activity of various antitelomerase ribozymes or control constructs was examined after i.v. injection of cationic liposome:DNA complexes containing control or ribozyme constructs. Expression of ribozymes and mTER at various time points were evaluated by quantitative real-time PCR. Telomerase activity was examined using the telomeric repeat amplification protocol. Results: Systemic administration of cationic liposome:DNA complexes containing a plasmid-expressed ribozyme specifically targeting a cleavage site at mTER nucleotide 180 significantly reduced the metastatic progression of B16-F10 murine melanoma. The antitumor activity of the anti-TER 180 ribozyme in mice was abolished by a single inactivating base mutation in the ribozyme catalytic core. The EBV-based expression plasmid produced sustained levels of ribozyme expression for the full duration of the antitumor studies. In addition to antitumor activity, cationic liposome:DNA complex-based ribozyme treatment also produced reductions in both TER levels and telomerase enzymatic activity in tumor-bearing mice. Conclusions: Systemic, plasmid-based ribozymes specifically targeting TER can reduce both telomerase activity and metastatic progression in tumor-bearing hosts. The work reported here demonstrates the potential utility of plasmid-based anti-TER ribozymes in the therapy of melanoma metastasis.
The impact of human and mouse differences in NOS2 gene expression on the brain’s redox and immune environment
Authors: Michael D Hoos, Michael P Vitek, Lisa A Ridnour, Joan Wilson, Marilyn Jansen, Angela Everhart, David A Wink, Carol A Colton
Journal: Molecular Neurodegeneration (2014)

Mouse models are used in the study of human disease. Despite well-known homologies, the difference in immune response between mice and humans impacts the application of data derived from mice to human disease outcomes. Nitric oxide synthase-2 (NOS2) is a key gene that displays species-specific outcomes via altered regulation of the gene promoter and via post-transcriptional mechanisms in humans that are not found in mice. The resulting levels of NO produced by activation of human NOS2 are different from the levels of NO produced by mouse Nos2. Since both tissue redox environment and immune responsiveness are regulated by the level of NO and its interactions, we investigated the significance of mouse and human differences on brain oxidative stress and on immune activation in HuNOS2 tg /mNos2 -/- mice that express the entire human NOS2 gene and that lack a functional mNos2 compared to wild type (WT) mice that express normal mNos2. Similarly to human, brain tissue from HuNOS2 tg /mNos2 -/- mice showed the presence of a NOS2 gene 3′UTR binding site. We also identified miRNA-939, the binding partner for this site, in mouse brain lysates and further demonstrated reduced levels of nitric oxide (NO) typical of the human immune response on injection with lipopolysaccharide (LPS). HuNOS2 tg /mNos2 -/- brain samples were probed for characteristic differences in redox and immune gene profiles compared to WT mice using gene arrays. Selected genes were also compared against mNos2 -/- brain lysates. Reconstitution of the human NOS2 gene significantly altered genes that encode multiple anti-oxidant proteins, oxidases, DNA repair, mitochondrial proteins and redox regulated immune proteins. Expression levels of typical pro-inflammatory, anti-inflammatory and chemokine genes were not significantly different with the exception of increased TNFα and Ccr1 mRNA expression in the HuNOS2 tg /mNos2 -/- mice compared to WT or mNos2 -/- mice. NO is a principle factor in establishing the tissue redox environment and changes in NO levels impact oxidative stress and immunity, both of which are primary characteristics of neurodegenerative diseases. The HuNOS2 tg /mNos2 -/- mice provide a potentially useful mechanism to address critical species- specific immune differences that can impact the study of human diseases.
Role of Nitric Oxide in Ca <sup>2+</sup> Sensitivity of the Slowly Activating Delayed Rectifier K <sup>+</sup> Current in Cardiac Myocytes
Authors: Chang-Xi Bai, Iyuki Namekata, Junko Kurokawa, Hikaru Tanaka, Koki Shigenobu, Tetsushi Furukawa
Journal: Circulation Research (2004)

Sarcolemmal Ca2+ entry is a vital step for contraction of cardiomyocytes, but Ca2+ overload is harmful and may trigger arrhythmias and/or apoptosis. To maintain the amount of Ca2+ entry within an appropriate range, cardiomyocytes have feedback systems that tightly regulate ion channel activities in response to the changes in intracellular Ca2+ concentration ([Ca2+]i), thereby regulating Ca2+ entry. In guinea pig ventricular myocytes, Ca2+ ionophore, A23187, induced suppression of the L-type Ca2+ currents (I(Ca,L)) and enhancement of the slowly activating delayed rectifier K(+) currents (I(Ks)). At a low stimulation rate, I(Ca,L) suppression and I(Ks) enhancement contributed to the A23187-induced APD shortening with a similar magnitude, whereas at a high stimulation rate, I(Ks) enhancement dominantly contributed to APD shortening. I(Ks) enhancement induced by A23187 was attributable to actions of nitric oxide (NO), because they were inhibited by an inhibitor of NO synthase (NOS) and by a NO scavenger. A23187-induced alterations of APD and I(Ks) were strongly suppressed by a NOS3 inhibitor, but barely affected by a NOS1 inhibitor, suggesting that NOS3 was responsible for NO release in this phenomenon. Inhibition of calmodulin (CaM), but not Akt, blocked the enhancement of I(Ks) by A23187. Thus, CaM-dependent NOS3 activation confers the selective Ca2+-sensitivity on I(Ks). Ca2+-induced I(Ks) enhancement and resultant APD shortening potentially act as a physiological regulatory mechanism of Ca2+ recycling, because they were observed at a physiological range of [Ca2+]i in cardiac myocytes and are induced by physiologically relevant Ca2+ loading, such as digitalis application and rise in extracellular Ca2+ concentration.
New combination therapy improves survival in non-small cell lung cancer
Authors: Vinod Aiyappan
Journal: Thorax (2007)

▴ Sandler A, Gray R, Perry MC, et al . Paclitaxel–carboplatin alone or with bevacizumab for non–small-cell lung cancer. N Engl J Med2006;355:2542–50.

[OpenUrl][1][CrossRef][2][PubMed][3][Web of Science][4]



The survival rate of patients with metastatic non-small-cell lung cancer remains poor even with chemotherapy. This randomised-controlled trial looks at the effect of monoclonal antibody against vascular endothelial growth factor (bevacizumab) in the treatment of patients with metastatic non-squamous-cell, non-small-cell-lung cancer.

Eight hundred and seventy- eight patients with recurrent or advanced …

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Interleukin 4 production by CD4+ T cells from allergic individuals is modulated by antigen concentration and antigen-presenting cell type.
Authors: H Secrist, R H DeKruyff, D T Umetsu
Journal: The Journal of Experimental Medicine (1995)

We have previously shown that CD4+ T cells from allergic individuals are predisposed to produce interleukin (IL)-4 in response to allergens, and that allergen immunotherapy greatly reduced IL-4 production in an allergen-specific fashion. The mechanism that results in the reduction of IL-4 synthesis in treated individuals is unknown, but because clinical improvement during immunotherapy is associated with the administration of the highest doses of allergen, we hypothesized that high concentration of allergen results in the downregulation of IL-4 synthesis in CD4+ T cells. In this report, we demonstrated that CD4+ T cells from allergic donors produced high levels of IL-4 when stimulated with low concentrations of allergen (0.003-0.01 micrograms/ml), particularly when B cell-enriched populations presented the antigen. In contrast, the same responding CD4+ T cell population produced little IL-4 when stimulated with high concentrations of allergen (10-30 micrograms/ml), especially when monocytes were used as antigen-presenting cells (APC). The quantity of IL-4 produced was also found to be inversely related to the extent of proliferation of the CD4+ T cells in response to allergen/antigen; maximal proliferation of CD4+ T cells occurred in response to high concentrations of antigen when IL-4 production was minimal. Antigen presentation by B cell-enriched populations, instead of monocytes, induced less CD4+ T cell proliferation, but induced much greater IL-4 synthesis. Moreover, the addition of increasing numbers of APC (either B cells or monocytes) to cultures containing a constant number of responder T cells resulted in increased T cell proliferation and decreased IL-4 production. These results indicate that the circumstances under which memory T cells are activated, as well as the strength of the proliferative signal to T cells, greatly affect the quantity of IL-4 produced. Thus, our observations that the cytokine profile of allergen-specific memory CD4+ T cells can indeed be modulated by the antigen dose and APC type suggest that methods that preferentially enhance allergen uptake by monocytes and that enhance T cell proliferation will improve the clinical efficacy of immunotherapy in the treatment of allergic disease.
Bioinformatics and Multiepitope DNA Immunization to Design Rational Snake Antivenom
Authors: Simon C Wagstaff, Gavin D Laing, R. David G Theakston, Christina Papaspyridis, Robert A Harrison
Journal: PLoS Medicine (2006)

Background Snake venom is a potentially lethal and complex mixture of hundreds of functionally diverse proteins that are difficult to purify and hence difficult to characterize. These difficulties have inhibited the development of toxin-targeted therapy, and conventional antivenom is still generated from the sera of horses or sheep immunized with whole venom. Although life-saving, antivenoms contain an immunoglobulin pool of unknown antigen specificity and known redundancy, which necessitates the delivery of large volumes of heterologous immunoglobulin to the envenomed victim, thus increasing the risk of anaphylactoid and serum sickness adverse effects. Here we exploit recent molecular sequence analysis and DNA immunization tools to design more rational toxin-targeted antivenom. Methods and Findings We developed a novel bioinformatic strategy that identified sequences encoding immunogenic and structurally significant epitopes from an expressed sequence tag database of a venom gland cDNA library of Echis ocellatus, the most medically important viper in Africa. Focusing upon snake venom metalloproteinases (SVMPs) that are responsible for the severe and frequently lethal hemorrhage in envenomed victims, we identified seven epitopes that we predicted would be represented in all isomers of this multimeric toxin and that we engineered into a single synthetic multiepitope DNA immunogen (epitope string). We compared the specificity and toxin-neutralizing efficacy of antiserum raised against the string to antisera raised against a single SVMP toxin (or domains) or antiserum raised by conventional (whole venom) immunization protocols. The SVMP string antiserum, as predicted in silico, contained antibody specificities to numerous SVMPs in E. ocellatus venom and venoms of several other African vipers. More significantly, the antiserum cross-specifically neutralized hemorrhage induced by E. ocellatus and Cerastes cerastes cerastes venoms. Conclusions These data provide valuable sequence and structure/function information of viper venom hemorrhagins but, more importantly, a new opportunity to design toxin-specific antivenoms—the first major conceptual change in antivenom design after more than a century of production. Furthermore, this approach may be adapted to immunotherapy design in other cases where targets are numerous, diverse, and poorly characterized such as those generated by hypermutation or antigenic variation.
Elderly patients with non-Hodgkin’s lymphoma: Population-based results in the Netherlands
Authors: E. Maartense, J. Hermans, J.C. Kluin-Nelemans, P.M. Kluin, W.A. Van Deijk, S. Snijder, P.W. Wijermans, E.M. Noordijk
Journal: Annals of Oncology (1998)