tbuckley/cabot-search huggingface dataset:
Adrenomedullin Regenerates Alveoli and Vasculature in Elastase-induced Pulmonary Emphysema in Mice
Authors: Shinsuke Murakami, Noritoshi Nagaya, Takefumi Itoh, Takashi Iwase, Toshiya Fujisato, Keisuke Nishioka, Kaoru Hamada, Kenji Kangawa, Hiroshi Kimura
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Adrenomedullin, a potent vasodilator peptide, regulates cell growth and survival. However, whether adrenomedullin contributes to lung regeneration remains unknown.To investigate whether adrenomedullin influences the kinetics of bone marrow cells, and whether adrenomedullin promotes regeneration of alveoli and vasculature and thereby improves lung structure and function in elastase-induced emphysema in mice.Adrenomedullin or vehicle was randomly administered to C57BL/6 mice for 5 days. We counted the numbers of mononuclear cells and stem cell antigen-1-positive cells in circulating blood. After intratracheal injection of elastase or saline, mice were randomized to receive continuous infusion of adrenomedullin or vehicle for 14 days. Functional and histologic analyses were performed 28 days after treatment.Twenty-eight days after elastase injection, destruction of the alveolar walls was observed. However, adrenomedullin infusion significantly inhibited the increase in lung volume, static lung compliance, and mean linear intercept in mice given elastase. Adrenomedullin increased the numbers of mononuclear cells and stem cell antigen-1-positive cells in circulating blood. Adrenomedullin significantly increased the number of bone marrow-derived cells incorporated into the elastase-treated lung. Some of these cells were positive for cytokeratin or von Willebrand factor. Infusion of adrenomedullin after the establishment of emphysema also had beneficial effects on lung structure and function. In vitro, addition of adrenomedullin attenuates elastase-induced cell death in alveolar epithelial cells and endothelial cells.Adrenomedullin improved elastase-induced emphysema at least in part through mobilization of bone marrow cells and the direct protective effects on alveolar epithelial cells and endothelial cells.
Effects of IL-2 treatment on different compartments of the irradiated rat lung analysed by bronchoalveolar lavage and lung tissue morphology
Authors: C Yi-Qing, L Bjermer, O Frojd, O Nettelbladt, A Karlsson-Parra, R Henriksson
Journal: European Respiratory Journal (1995)

In recent years, interleukin-2 (IL-2) has been used as an immunomodulatory agent in the treatment of various malignant tumours. However, this treatment has been limited by serious side-effects, including toxic reactions in the lung. The effects of IL-2 treatment on inflammatory cell populations in the normal and irradiated rat lung were investigated in this study. IL-2 was continuously administered as a subcutaneous infusion over a 6 week study period. Irradiation was given in a single dose (25 Gy) the day after starting IL-2 treatment. Evaluation with bronchoalveolar lavage fluid (BALF) analysis and lung tissue morphology was made 6 weeks after irradiation. In nonirradiated rats, IL-2 treatment induced significant increases in the total number of inflammatory cells in the perivascular, interstitial and peribronchial tissues as well as in the alveolar space. These increases were not reflected in BALF; on the contrary, a significant decrease of the total numbers of inflammatory cells was found in BALF. Irradiation alone caused a more pronounced inflammatory response was significant increases of all inflammatory cells in all lung compartments, which was also reflected in BALF. Concomitant treatment with IL-2 and irradiation induced an enhanced accumulation of inflammatory cells in the perivascular and peribronchial tissues compared with irradiation alone. Thus, both irradiation and IL-2 treatment induce inflammatory reactions in the lung, but there were signs of synergistic effects seen in this study. Furthermore, the results also emphasize the difficulties in making sophisticated conclusions from BALF analyses alone.
Ventricular Hypertrophy Plus Neurohumoral Activation Is Necessary to Alter the Cardiac β-Adrenoceptor System in Experimental Heart Failure
Authors: Kirsten Leineweber, Katja Brandt, Beate Wludyka, Anja Beilfuß, Klaus Pönicke, Ingrid Heinroth-Hoffmann, Otto-Erich Brodde
Journal: Circulation Research (2002)

Treatment of rats with monocrotaline (MCT) leads to pulmonary hypertension, right ventricular (RV) hypertrophy, and finally to RV heart failure. This is associated with characteristic changes in right ventricular beta-adrenoceptors (beta-AR), neuronal noradrenaline transporter (NAT) density and activity (uptake1), and G protein-coupled receptor kinase (GRK) activity. This study aimed to find out factors that determine beta-AR, uptake1, and GRK changes. Thus, 6-week-old rats were treated with 50 mg/kg MCT subcutaneous or 0.9% saline. Within 13 to 19 days after MCT application (group A), RV weight (222+/-6 versus 147+/-5 mg) and RV/left ventricular (LV) weight ratio (0.42+/-0.01 versus 0.29+/-0.01) were significantly increased, whereas plasma noradrenaline, RV beta-AR density, RV NAT density and activity, and RV GRK activity were not significantly altered. Twenty-one to twenty-eight days after MCT (group B), however, not only RV weight (316+/-4 versus 148+/-2 mg) and RV/LV weight ratio (0.61+/-0.01 versus 0.3+/-0.01) were markedly increased but also plasma noradrenaline (645+/-63 versus 278+/-18 pg/mL); now, RV beta-AR density (13.4+/-1.3 versus 26.5+/-1.1 fmol/mg protein), RV NAT density (50.9+/-11.3 versus 79.6+/-2.9 fmol/mg protein), and RV NAT activity (65.4+/-7.4 versus 111.8+/-15.9 pmol [3H]-NA/mg tissue slices/15 min) were significantly decreased and RV-membrane GRK activity (100+/-15 versus 67+/-6 [32P]-rhodopsin in cpm) significantly increased. LV parameters of MCT-treated rats were only marginally different from control LV. We conclude that in MCT-treated rats ventricular hypertrophy per se is not sufficient to cause characteristic alterations in the myocardial beta-AR system often seen in heart failure; only if ventricular hypertrophy is associated with neurohumoral activation beta-ARs are downregulated and GRK activity is increased.
A study of abnormal muscular patterns in diverticular disease of the colon using the polysiloxane foam enema
Authors: L. E. Hughes
Journal: Gut (1970)

Three-dimensional, functional studies of the left colon using a polysiloxane foam enema have shown that three types of impressions due to muscular contractions are commonly found in the region of the rectum and sigmoid, and that at least two of these are closely associated with the presence of diverticular disease. Each type of abnormality has been defined and its extent and frequency assessed. A tentative mechanism for the development of the main muscular abnormality through muscle thickening and simple sigmoid curves is put forward, and it is suggested that the third type of abnormality may be associated with sphincteric action at the recto-sigmoid junction. The reproducibility of findings on repeated examinations must mean that there is a local anatomical basis for the muscular impressions seen and that such contractions do not represent evanescent peristaltic type activity. Sigmoid resection and myotomy as practised for diverticular disease should eliminate the first type of abnormality in the majority of cases, but it is necessary to carry the operation well distally to ensure this. Neither operation is likely to correct the type III abnormality, and further work is necessary to determine whether this is responsible for some of the symptoms persisting after surgery.
Transcutaneous electrical nerve stimulation in osteoarthrosis: a therapeutic alternative?
Authors: D Lewis, B Lewis, R D Sturrock
Journal: Annals of the Rheumatic Diseases (1984)

Thirty patients with chronic pain due to osteoarthrosis (OA) of the knee were enrolled in a randomised double-blind cross-over trial of self-administered transcutaneous electrical nerve stimulation (TENS) and placebo TENS. Medication was standardised to paracetamol tablets only. As measured on visual analogue scales for pain relief 46% of patients responded to active therapy and 43% to placebo. The length of pain relief during active therapy was significantly longer than that during placebo. At the end of the trial more patients wanted to continue using active TENS in preference to placebo or their original medication. Although most of the parameters observed favoured active TENS, it was not possible to establish its clear superiority over placebo, because the response rate to placebo TENS was high and sustained for at least 3 weeks. This trial suggests that a longer study is required to establish the role of TENS as a therapeutic agent in the treatment of the pain of chronic arthritis.
Cell Surface Organization of Stress-inducible Proteins ULBP and MICA That Stimulate Human NK Cells and T Cells via NKG2D
Authors: Konstantina Eleme, Sabrina B. Taner, Björn Önfelt, Lucy M. Collinson, Fiona E. McCann, N. Jan Chalupny, David Cosman, Colin Hopkins, Anthony I. Magee, Daniel M. Davis
Journal: The Journal of Experimental Medicine (2004)

Cell surface proteins major histocompatibility complex (MHC) class I–related chain A (MICA) and UL16-binding proteins (ULBP) 1, 2, and 3 are up-regulated upon infection or tumor transformation and can activate human natural killer (NK) cells. Patches of cross-linked raft resident ganglioside GM1 colocalized with ULBP1, 2, 3, or MICA, but not CD45. Thus, ULBPs and MICA are expressed in lipid rafts at the cell surface. Western blotting revealed that glycosylphosphatidylinositol (GPI)-anchored ULBP3 but not transmembrane MICA, MHC class I protein, or transferrin receptor, accumulated in detergent-resistant membranes containing GM1. Thus, MICA may have a weaker association with lipid rafts than ULBP3, yet both proteins accumulate at an activating human NK cell immune synapse. Target cell lipid rafts marked by green fluorescent protein–tagged GPI also accumulate with ULBP3 at some synapses. Electron microscopy reveals constitutive clusters of ULBP at the cell surface. Regarding a specific molecular basis for the organization of these proteins, ULBP1, 2, and 3 and MICA are lipid modified. ULBP1, 2, and 3 are GPI anchored, and we demonstrate here that MICA is S-acylated. Finally, expression of a truncated form of MICA that lacks the putative site for S-acylation and the cytoplasmic tail can be expressed at the cell surface, but is unable to activate NK cells.
Chromosome Instability Modulated by <i>BMI1–AURKA</i> Signaling Drives Progression in Head and Neck Cancer
Authors: Chun-Hung Chou, Neng-Kai Yang, Ting-Yun Liu, Shyh-Kuan Tai, Dennis Shin-Shian Hsu, Ya-Wei Chen, Yann-Jang Chen, Cheng-Chi Chang, Cheng-Hwai Tzeng, Muh-Hwa Yang
Journal: Cancer Research (2012)

Chromosomal instability (CIN) is widely considered a hallmark of cancer, but its precise roles in cancer stem cells (CSC) and malignant progression remain uncertain. BMI1 is a member of the Polycomb group of chromatin-modifier proteins that is essential for stem cell self-renewal. In human cancers, BMI1 overexpression drives stem-like properties associated with induction of epithelial-mesenchymal transition (EMT) that promotes invasion, metastasis, and poor prognosis. Here, we report that BMI1 mediates its diverse effects through upregulation of the mitotic kinase Aurora A, which is encoded by the AURKA gene. Two mechanisms were found to be responsible for BMI1-induced AURKA expression. First, BMI1 activated the Akt pathway, thereby upregulating AURKA expression through activation of the β-catenin/TCF4 transcription factor complex. Second, BMI1 repressed miRNA let-7i through a Polycomb complex-dependent mechanism, thereby relieving AURKA expression from let-7i suppression. AURKA upregulation by BMI1 exerts several effects, including centrosomal amplification and aneuploidy, antiapoptosis, and cell-cycle progression through p53 degradation and EMT through stabilization of Snail. Inhibiting Aurora A kinase activity attenuated BMI1-induced tumor growth in vivo. In clinical specimens of head and neck cancer, we found that coamplification of BMI1 and AURKA correlated with poorer prognosis. Together, our results link CSCs, EMT, and CIN through the BMI1-AURKA axis and suggest therapeutic use from inhibiting Aurora A in head and neck cancers, which overexpress BMI1.
Cardiac-Resynchronization Therapy in Heart Failure with a Narrow QRS Complex
Authors: Frank Ruschitzka, William T. Abraham, Jagmeet P. Singh, Jeroen J. Bax, Jeffrey S. Borer, Josep Brugada, Kenneth Dickstein, Ian Ford, John Gorcsan, Daniel Gras, Henry Krum, Peter Sogaard, Johannes Holzmeister
Journal: New England Journal of Medicine (2013)

Cardiac-resynchronization therapy (CRT) reduces morbidity and mortality in chronic systolic heart failure with a wide QRS complex. Mechanical dyssynchrony also occurs in patients with a narrow QRS complex, which suggests the potential usefulness of CRT in such patients.We conducted a randomized trial involving 115 centers to evaluate the effect of CRT in patients with New York Heart Association class III or IV heart failure, a left ventricular ejection fraction of 35% or less, a QRS duration of less than 130 msec, and echocardiographic evidence of left ventricular dyssynchrony. All patients underwent device implantation and were randomly assigned to have CRT capability turned on or off. The primary efficacy outcome was the composite of death from any cause or first hospitalization for worsening heart failure.On March 13, 2013, the study was stopped for futility on the recommendation of the data and safety monitoring board. At study closure, the 809 patients who had undergone randomization had been followed for a mean of 19.4 months. The primary outcome occurred in 116 of 404 patients in the CRT group, as compared with 102 of 405 in the control group (28.7% vs. 25.2%; hazard ratio, 1.20; 95% confidence interval [CI], 0.92 to 1.57; P=0.15). There were 45 deaths in the CRT group and 26 in the control group (11.1% vs. 6.4%; hazard ratio, 1.81; 95% CI, 1.11 to 2.93; P=0.02).In patients with systolic heart failure and a QRS duration of less than 130 msec, CRT does not reduce the rate of death or hospitalization for heart failure and may increase mortality. (Funded by Biotronik and GE Healthcare; EchoCRT ClinicalTrials.gov number, NCT00683696.).
Diagnosis and management of Raynaud's phenomenon
Authors: B. Goundry, L. Bell, M. Langtree, A. Moorthy
Journal: BMJ (2012)

#### Summary points

Raynaud’s phenomenon is caused by episodic vasospasm and ischaemia of the extremities in response to cold or emotional stimuli, which result in a characteristic triphasic colour change in extremities—usually fingers or toes—from white, to blue, to red. Raynaud’s phenomenon may be primary, in direct response to stimuli, or secondary to an underlying condition. In 10-20% of cases it may be the first presentation of, or may precede the onset of, a connective tissue disease (such as scleroderma or mixed connective tissue disease), so that underlying causes must be ruled out.

#### Sources and selection criteria

We searched the Cochrane Library and PubMed (2001-11) using the term “Raynaud’s”. Recommendations made at the May 2011 conference “Raynaud’s phenomenon: new insights, new treatments” organised by the vascular medicine section of the Royal Society of Medicine were reviewed. We also consulted published guidelines and information from the European League Against Rheumatism, Raynaud’s and Scleroderma Association, and Arthritis Research UK.

Raynaud’s phenomenon is triggered by a change in temperature rather than simply exposure to cold. Patients can have attacks throughout the year—for example, if they move from a warm environment to an air conditioned one, stand in a cold wind (even on a relatively warm day), or hold a cold …
Prognosis of cryptogenic fibrosing alveolitis.
Authors: P Tukiainen, E Taskinen, P Holsti, O Korhola, M Valle
Journal: Thorax (1983)

We have analysed retrospectively 100 consecutive patients with cryptogenic fibrosing alveolitis, who were treated with corticosteroids and followed for at least three years. At the time of diagnosis biopsy specimens were available in 64 cases. The clinical, radiographic, physiological, and histological features and the response to steroid treatment have been correlated with the prognosis. An early objective functional improvement was observed in 30%. Analysis of the survival data (life table and log rank test) showed a longer survival in younger patients and in patients with a shorter duration of symptoms before presentation, less radiographic abnormality, and less impairment of diffusing capacity, but not clearly in patients with more cellular histological appearances. The most favourable prognostic sign seemed to be an early response to steroid treatment.
Caveolin-1 and Cancer Metabolism in the Tumor Microenvironment: Markers, Models, and Mechanisms
Authors: Federica Sotgia, Ubaldo E. Martinez-Outschoorn, Anthony Howell, Richard G. Pestell, Stephanos Pavlides, Michael P. Lisanti
Journal: Annual Review of Pathology Mechanisms of Disease (2011)

Caveolins are a family of membrane-bound scaffolding proteins that compartmentalize and negatively regulate signal transduction. Recent studies have implicated a loss of caveolin-1 (Cav-1) expression in the pathogenesis of human cancers. Loss of Cav-1 expression in cancer-associated fibroblasts results in an activated tumor microenvironment, thereby driving early tumor recurrence, metastasis, and poor clinical outcome in breast and prostate cancers. We describe various paracrine signaling mechanism(s) by which the loss of stromal Cav-1 promotes tumor progression, including fibrosis, extracellular matrix remodeling, and the metabolic/catabolic reprogramming of cancer-associated fibroblast, to fuel the growth of adjacent tumor cells. It appears that oxidative stress is the root cause of initiation of the loss of stromal Cav-1 via autophagy, which provides further impetus for the use of antioxidants in anticancer therapy. Finally, we discuss the functional role of Cav-1 in epithelial cancer cells.
High-dose chemotherapy and autologous stem cell transplantation for primary refractory or relapsed Hodgkin lymphoma: long-term outcome in the first 100 patients treated in Vancouver
Authors: Julye C. Lavoie, Joseph M. Connors, Gordon L. Phillips, Donna E. Reece, Michael J. Barnett, Donna L. Forrest, Randy D. Gascoyne, Donna E. Hogge, Stephen H. Nantel, John D. Shepherd, Clayton A. Smith, Kevin W. Song, Heather J. Sutherland, Cynthia L. Toze, Nicholas J. S. Voss, Thomas J. Nevill
Journal: Blood (2005)
Reactive oxygen species modulate endothelin-I-induced c-fos gene expression in cardiomyocytes
Authors: T Cheng
Journal: Cardiovascular Research (1999)

Objectives: Recent evidence indicates that reactive oxygen species (ROS) may act as second messengers in receptor-mediated signaling pathways. The possible role of ROS during Et-1 stimulation in cardiomyocytes was therefore investigated. Methods: Intracellular ROS levels were measured with fluorescence probe 2′,7′-dichlorofluorescin diacetate by confocal microscopy in cultured neonatal rat cardiomyocytes. The ROS-inducible c-fos expression was analyzed by Northern blotting and promoter activity. Results: Et-1 applied to cardiomyocytes dose-dependently increased intracellular ROS levels. The increase of ROS levels was attenuated by pretreating cardiomyocytes with Et-A receptor antagonist-BQ485, but not with Et-B receptor antagonist. Cardiomyocytes pretreated with catalase or an antioxidant N-acetylcysteine (NAC) reduced Et-1-induced ROS levels. Et-1 or H2O2 treatment of cardiomyocytes rapidly induced the expression of an immediate early gene c-fos. Et-1-treated cardiomyocytes enhanced the c-fos gene expression as revealed by functional analysis using a reporter gene construct containing c-fos promoter region (−2.25 kb) and reporter gene chloramphenicol acetyltransferase. The induction of mRNA levels and the promoter activities of c-fos gene by Et-1 or H2O2 were abolished by pretreating cardiomyocytes with catalase or NAC. Cells transiently transfected with the dominant positive mutant of p21ras (RasL61) led to a significant increase in intracellular ROS. Concomitantly, the mRNA levels and the promoter activities of c-fos were also induced. In contrast, cells transfected with the dominant negative mutant of Ras (RasN17) inhibited Et-1-induced ROS. Consistently, the increase of c-fos mRNA levels and promoter activities by Et-1 were also inhibited. Conclusions: These findings clearly indicate that Et-1 treatment to cardiomyocytes can induce ROS via Ras pathway and the increased ROS are involved in the increase of c-fos expression. Our studies thus emphasize the importance of ROS as second messengers in Et-1-induced responses in cardiomyocytes.
S156 Chloride intracellular channel protein 4 (CLIC4) in the regulation of human pulmonary endothelial responses to hypoxia
Authors: V. B. Abdul-Salam, M. R. Wilkins, B. Wojciak-Stothard
Journal: Thorax (2010)

<h3>Introduction and Objectives</h3> CLIC-4 belongs to the family of chloride intracellular channels, proteins structurally homologous to glutathione transferases. CLIC4 has been implicated in tumour angiogenesis and signalling pathways important in the pathogenesis of pulmonary arterial hypertension (PAH). We have previously demonstrated increased CLIC4 protein expression in whole lung samples from patients with PAH and animals with chronic hypoxia- and monocrotaline-induced PH. CLIC4 is particularly abundant in pulmonary endothelium of patients with PAH. In this project we aimed to establish a role of CLIC4 plays in the regulation of pulmonary endothelial cell responses to hypoxia. <h3>Methods</h3> Human pulmonary artery endothelial cells (HPAECs) were cultured in normoxic conditions or were exposed to hypoxia (2% O<sub>2</sub>, 5% CO<sub>2</sub>, 93% N<sub>2</sub>) for 1–24 h. CLIC4 expression and localisation was studied by Western blotting, immunofluorescence and confocal microscopy. The wildtype and nuclear-targetted CLIC4 were overexpressed via adenoviral gene transfer while chloride channel inhibitor NPPB (5-Nitro-2-(3-phenylpropylamino)benzoic acid) was used to inhibit CLIC4 activity. We studied the effects of CLIC4 on endothelial permeability, angiogenesis and proliferation. <h3>Results</h3> Overexpression of the wildtype CLIC4 in HPAECs increased pulmonary endothelial proliferation, compromised barrier function and increased angiogenic responses to chronic hypoxia in vitro (Abstract S156 Figure 1). These effects were prevented by chloride channel inhibitor NPPB. In normoxic HPAECs CLIC4 was localised predominantly to the cell nucleus and cytoplasm. Upon stimulation with hypoxia, CLIC-4 translocated to the cell periphery, localising in particular to membrane protrusions (filopodia and lamellipodia), the effect mimicked by overexpression of CLIC4. <h3>Conclusions</h3> Hypoxia induces translocation of CLIC-4 to the membrane of HPAECs. This behaviour has been linked to increased motility and malignant phenotype in other cell types. CLIC-4 overexpression in HPAECs also increases endothelial cell responses to hypoxia in vitro. These findings suggest increased CLIC-4 expression in PAECs in PAH may play a role in pathogenesis of PAH and provide novel insights in to disease pathogenesis and treatment strategies.