tbuckley/cabot-search huggingface dataset:
Cardiac Tissue Engineering
Authors: Marc N. Hirt, Arne Hansen, Thomas Eschenhagen
Journal: Circulation Research (2014)

The engineering of 3-dimensional (3D) heart muscles has undergone exciting progress for the past decade. Profound advances in human stem cell biology and technology, tissue engineering and material sciences, as well as prevascularization and in vitro assay technologies make the first clinical application of engineered cardiac tissues a realistic option and predict that cardiac tissue engineering techniques will find widespread use in the preclinical research and drug development in the near future. Tasks that need to be solved for this purpose include standardization of human myocyte production protocols, establishment of simple methods for the in vitro vascularization of 3D constructs and better maturation of myocytes, and, finally, thorough definition of the predictive value of these methods for preclinical safety pharmacology. The present article gives an overview of the present state of the art, bottlenecks, and perspectives of cardiac tissue engineering for cardiac repair and in vitro testing.
Targeting Akt and Heat Shock Protein 90 Produces Synergistic Multiple Myeloma Cell Cytotoxicity in the Bone Marrow Microenvironment
Authors: Alissa Huston, Xavier Leleu, Xiaoying Jia, Anne-Sophie Moreau, Hai T. Ngo, Judith Runnels, Judy Anderson, Yazan Alsayed, Aldo Roccaro, Sonia Vallet, Evdoxia Hatjiharissi, Yu-Tsu Tai, Peter Sportelli, Nikhil Munshi, Paul Richardson, Teru Hideshima, David G. Roodman, Kenneth C. Anderson, Irene M. Ghobrial
Journal: Clinical Cancer Research (2008)

Abstract Purpose: We hypothesized that targeting both Akt and heat shock protein (HSP) 90 would induce cytotoxic activity against multiple myeloma (MM) cells and target the bone marrow (BM) microenvironment to inhibit angiogenesis, osteoclast formation, as well as migration and adhesion of MM cells. Experimental Design: MM cell lines were incubated with perifosine (5 and 10 μmol/L) and 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG; 50 and 100 nmol/L) alone and in combination. Results: The combination of Akt inhibitor perifosine and HSP90 inhibitor 17-DMAG was synergistic in inducing MM cell cytotoxicity, evidenced by inhibition of DNA synthesis and induction of apoptosis. In addition, perifosine and 17-DMAG almost completely inhibited osteoclast formation: perifosine interfered with both early and late stages of osteoclast progenitor development, whereas 17-DMAG targeted only early stages. We next showed that combined therapy overcomes tumor growth and resistance induced by BM stromal cells and endothelial cells as well as the proliferative effect of exogenous interleukin-6, insulin-like growth factor-I, and vascular endothelial growth factor. Moreover, the combination also induced apoptosis and growth inhibition in endothelial cells and inhibited angiogenesis. Finally, we showed that the two agents prevented migration of MM cells toward stromal-derived factor-1 and vascular endothelial growth factor, which are present in the BM milieu, and also prevented adhesion of MM cells to fibronectin. Conclusions: This study provides the preclinical framework for treatment protocols targeting both the Akt and HSP pathways in MM.
International Staging System for Multiple Myeloma
Authors: Philip R. Greipp, Jesus San Miguel, Brian G.M. Durie, John J. Crowley, Bart Barlogie, Joan Bladé, Mario Boccadoro, J. Anthony Child, Hervé Avet-Loiseau, Robert A. Kyle, Juan J. Lahuerta, Heinz Ludwig, Gareth Morgan, Raymond Powles, Kazuyuki Shimizu, Chaim Shustik, Pieter Sonneveld, Patrizia Tosi, Ingemar Turesson, Jan Westin
Journal: Journal of Clinical Oncology (2005)

Purpose There is a need for a simple, reliable staging system for multiple myeloma that can be applied internationally for patient classification and stratification. Patients and Methods Clinical and laboratory data were gathered on 10,750 previously untreated symptomatic myeloma patients from 17 institutions, including sites in North America, Europe, and Asia. Potential prognostic factors were evaluated by univariate and multivariate techniques. Three modeling approaches were then explored to develop a staging system including two nontree and one tree survival assessment methodologies. Results Serum beta 2 -microglobulin (Sβ 2 M), serum albumin, platelet count, serum creatinine, and age emerged as powerful predictors of survival and were then used in the tree analysis approach. A combination of Sβ 2 M and serum albumin provided the simplest, most powerful and reproducible three-stage classification. This new International Staging System (ISS) was validated in the remaining patients and consists of the following stages: stage I, Sβ 2 M less than 3.5 mg/L plus serum albumin ≥ 3.5 g/dL (median survival, 62 months); stage II, neither stage I nor III (median survival, 44 months); and stage III, Sβ 2 M ≥ 5.5 mg/L (median survival, 29 months). The ISS system was further validated by demonstrating effectiveness in patients in North America, Europe, and Asia; in patients less than and ≥ 65 years of age; in patients with standard therapy or autotransplantation; and in comparison with the Durie/Salmon staging system. Conclusion The new ISS is simple, based on easy to use variables (Sβ 2 M and serum albumin), and recommended for early adoption and widespread use.
Comorbidity and Course of Psychiatric Disorders in a Community Sample of Former Prisoners of War
Authors: Brian Engdahl, Thomas N. Dikel, Raina Eberly, Arthur Blank
Journal: American Journal of Psychiatry (1998)

Objective:The authors assessed DSM-III-R disorders among American former prisoners of war. Comorbidity, time of onset, and the relationship of trauma severity to complicated versus uncomplicated posttraumatic stress disorder (PTSD) were examined. Method:A community sample (N=262) of men exposed to combat and imprisonment was assessed by clinicians using the Structured Clinical Interview for DSM-III-R.Results:The rates of comorbidity among the men with PTSD were lower than rates from community samples assessed by lay interviewers. Over one-third of the cases of lifetime PTSD were uncomplicated by another axis I disorder; over one-half of the cases of current PTSD were uncomplicated. PTSD almost always emerged soon after exposure to trauma. Lifetime PTSD was associated with increased risk of lifetime panic disorder, major depression, alcohol abuse/dependence, and social phobia. Current PTSD was associated with increased risk of current panic disorder, dysthymia, social phobia, major depression, and generalized anxiety disorder. Relative to PTSD, the onset of the comorbid disorders was as follows: major depression, predominantly secondary; alcohol abuse/dependence and agoraphobia, predominantly concurrent (same year); social phobia, equal proportions primary and concurrent; and panic disorder, equal proportions concurrent and secondary. Trauma exposure was comparable in the subjects with complicated and uncomplicated PTSD.Conclusions:The types of comorbid diagnoses and their patterns of onset were comparable to the diagnoses and patterns observed in other community samples. The findings support the validity of the PTSD construct; PTSD can be distinguished from comorbid disorders. Uncomplicated PTSD may be more common than previous studies suggest, particularly in clinician-assessed subjects exposed to severe trauma. Am J Psychiatry 1998; 155: 1740-1745
Homozygous Deficiency of Heparin Cofactor II
Authors: Javier Corral, Justo Aznar, Rocio Gonzalez-Conejero, Piedad Villa, Antonia Miñano, Amparo Vayá, Robin W. Carrell, James A. Huntington, Vicente Vicente
Journal: Circulation (2004)

Background— Heparin cofactor II (HCII) is a hepatic serpin with significant antithrombin activity that has been implicated in coagulation, inflammation, atherosclerosis, and wound repair. Recent data obtained in mice lacking HCII suggest that this serpin might inhibit thrombosis in the arterial circulation. However, the clinical relevance and molecular mechanisms associated with deficiency of HCII in humans are unclear. Methods and Results— We studied the first family with homozygous HCII deficiency, identifying a Glu428Lys mutation affecting a conserved glutamate at the hinge (P17) of the reactive loop. No carrier reported arterial thrombosis, and only 1 homozygous HCII-deficient patient developed severe deep venous thrombosis, but she also had a de novo Glu100Stop nonsense truncation in the antithrombin gene. Conclusions— Our results confirm the key structural role of the P17 glutamate in serpins. The same mutation causes conformational instability and polymerization in 3 serpins: Drosophila necrotic, human α1-antitrypsin, and human HCII, which explains their plasma deficiency. In the family under study here, however, plasma HCII deficiency was not associated with a significant clinical phenotype.
The T-Helper Cell Type 1 Immune Response to Gram-Negative Bacterial Infections Is Impaired in COPD
Authors: Jürgen Knobloch, Katharina Schild, David Jungck, Katja Urban, Katja Müller, Elke K. H. Schweda, Jan Rupp, Andrea Koch
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

The increased susceptibility to bacterial infections in chronic obstructive pulmonary disease (COPD) is critical for exacerbations. Toll-like receptor-4 (TLR4) detects bacteria via LPS and induces IFN-γ-based immune responses. The direct responsiveness of Th1 lymphocytes to LPS is disputed because they lack surface expression of the TLR4 coreceptor CD14.We hypothesized that the Th1-mediated adaptive immune response to bacterial infections is impaired in COPD.LPS-induced TLR4 expression and IFN-γ release in and from ex vivo-generated Th1 cells was compared among nonsmokers (n = 14), smokers without COPD (n = 13), and smokers with COPD (n = 25) via quantitative reverse transcription polymerase chain reaction, Western blot, and ELISA. TLR4 transfection experiments were performed to functionally link receptor to IFN-γ dysregulation in COPD.Short-chain LPS from Salmonella species and nontypeable Haemophilus influenzae and nontypeable Haemophilus influenzae whole-cell extract all induced TLR4 expression via TLR4/MyD88/IRAK/mitogen-activated protein-kinase signaling and IFN-γ release via TLR4/TRIF/IKKε/TBK1 signaling in Th1 cells of nonsmokers. These effects were all impaired in smokers with and without COPD. The LPS responses were partially dependent on soluble CD14 and correlated positively to lung-function parameters but negatively to cigarette smoking (pack-years). Endogenous MyD88/IRAK signaling antagonists were up-regulated in Th1 cells of smokers and COPD, and TLR4 overexpression in Th1 cells of COPD restored LPS-dependent IFN-γ release.Th1 cells directly respond to short-chain LPS. Cigarette smoking suppresses Th1-mediated immune responses to gram-negative bacterial infections by interfering with MyD88/IRAK signaling thereby reducing LPS-induced TLR4 expression. This can explain the increased susceptibility to bacterial infections in COPD. Targeting TLR signaling might be useful to reduce exacerbation rates.
Hygiene, Sanitation, and Water: Forgotten Foundations of Health
Authors: Jamie Bartram, Sandy Cairncross
Journal: PLoS Medicine (2010)

As the first article in a four-part PLoS Medicine series on water and sanitation, Jamie Bartram and Sandy Cairncross argue that the massive burden of ill health associated with poor hygiene, sanitation, and water supply demands more attention from health professionals and policymakers.
Pulmonary vasorelaxant activity of atrial natriuretic peptide and brain natriuretic peptide in humans.
Authors: R I Cargill, B J Lipworth
Journal: Thorax (1995)

BACKGROUND--Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) exhibit in vitro pulmonary vasodilator activity, but little information is available regarding their effects in the human pulmonary vasculature. Their effects in the human pulmonary circulation and their ability to modulate the pulmonary pressor effects of angiotensin II have therefore been evaluated. METHODS--Eight healthy volunteers were studied on three separate occasions. Infusions of either ANP, BNP, or placebo were given for 60 minutes with a concomitant infusion of angiotensin II given for the final 30 minutes. Pulmonary haemodynamics were measured by pulsed wave Doppler echocardiography at baseline (T0), before commencing angiotensin II (T30), and at the end of the infusion period (T60). RESULTS--Mean pulmonary artery pressure (MPAP) showed a fall with ANP and BNP infusion at T30 compared with placebo. Although angiotensin II infusion had significant pulmonary pressor effects on all three study days, MPAP at T60 was lower when ANP (18.3 (2.0) mm Hg) and BNP (16.1 (1.5) mm Hg) were given concomitantly compared with placebo (21.8 (1.6) mm Hg). CONCLUSIONS--These findings indicate that both ANP and BNP exhibit pulmonary vasorelaxant activity in humans in terms of antagonism of the pulmonary pressor effects of angiotensin II. This would support the hypothesis that ANP and BNP act as circulating counter-regulatory hormones in states of pathological pulmonary vasoconstriction.
Potential Role of Hepatocyte Growth Factor, a Novel Angiogenic Growth Factor, in Peripheral Arterial Disease : Downregulation of HGF in Response to Hypoxia in Vascular Cells
Authors: S.-i. Hayashi, R. Morishita, S. Nakamura, K. Yamamoto, A. Moriguchi, T. Nagano, M. Taiji, H. Noguchi, K. Matsumoto, T. Nakamura, J. Higaki, T. Ogihara
Journal: Circulation (1999)

Although hepatocyte growth factor (HGF), a novel angiogenic growth factor, plays an important role in angiogenesis, regulation of local HGF production under hypoxia has not yet been clarified in vascular smooth muscle cells (VSMC) and endothelial cells (EC). Thus, we have studied the role of HGF in hypoxia-induced endothelial injury and the regulation of local vascular HGF expression in response to hypoxia.
Involvement of tachykinin NK&lt;SUB&gt;1&lt;/SUB&gt; and NK&lt;SUB&gt;2&lt;/SUB&gt; receptors in substance P-induced microvascular leakage hypersensitivity and airway hyperresponsiveness in guinea-pigs
Authors: E. Boichot, K. Biyah, N. Germain, X. Emonds-Alt, V. Lagente, C. Advenier
Journal: European Respiratory Journal (1996)

Tachykinins, such as substance P, might be involved in the development of airway hyperresponsiveness (AHR) and airway inflammation. However, it is unknown which tachykinin receptors mediate these biological activities. The effects of two antagonists of tachykinin neurokinin-1 (NK1) and tachykinin neurokinin-2 (NK2) receptors, SR 140333 and SR 48968, respectively, were investigated on substance P (SP)-induced airway hyperresponsiveness and potentiation of the histamine-induced increase in microvascular leakage, in phosphoramidon-pretreated guinea-pigs. Guinea-pigs were pretreated with phosphoramidon (0.1 mM aerosol for 15 min) and exposed 15 min later to saline solution alone or to saline solution containing SP (0.1 mg.mL-1 for 30 min). Twenty four hours later, the animals were anaesthetized and prepared for the recording of the pulmonary inflation pressure (PIP) to acetylcholine or for the investigation of microvascular leakage to histamine. Pretreatment of the guinea-pigs with a single dose of SR 48968 (1 mg.kg-1, i.p.) 30 min before SP exposure, significantly prevented the development of AHR, whereas SR 140333 (1 mg.kg-1, i.p.) did not. In a second set of experiments, phosphoramidon-pretreated guinea-pigs exposed to SP presented a significant potentiation of the histamine-induced increase in microvascular leakage in pulmonary airways. When the guinea-pigs were pretreated with SR 140333, an inhibition of the increased microvascular leakage to histamine was observed. In contrast, no significant inhibitory activity was noted when the guinea-pigs were pretreated with SR 48968. The present data demonstrate the importance of tachykinin NK2 receptor stimulation in the development of airway hyperresponsiveness and that of tachykinin NK1 receptor stimulation in microvascular leakage hypersensitivity in phosphoramidon-pretreated and substance P-exposed guinea-pigs. The results also suggest a dissociation between the presence of microvascular leakage and the occurrence of airway hyperresponsiveness.
Genetic Modifiers of Liver Disease in Cystic Fibrosis
Authors: Jaclyn R. Bartlett, Kenneth J. Friedman, Simon C. Ling, Rhonda G. Pace, Scott C. Bell, Billy Bourke, Giuseppe Castaldo, Carlo Castellani, Marco Cipolli, Carla Colombo, John L. Colombo, Dominique Debray, Adriana Fernandez, Florence Lacaille, Milan Macek, Marion Rowland, Francesco Salvatore, Christopher J. Taylor, Claire Wainwright, Michael Wilschanski, Dana Zemková, William B. Hannah, M. James Phillips, Mary Corey, Julian Zielenski, Ruslan Dorfman, Yunfei Wang, Fei Zou, Lawrence M. Silverman, Mitchell L. Drumm, Fred A. Wright, Ethan M. Lange, Peter R. Durie, Michael R. Knowles
Journal: JAMA (2009)

<h3>Context</h3>A subset (≈ 3%-5%) of patients with cystic fibrosis (CF) develops severe liver disease with portal hypertension.<h3>Objective</h3>To assess whether any of 9 polymorphisms in 5 candidate genes (α<sub>1</sub>-antitrypsin or α<sub>1</sub>-antiprotease [SERPINA1], angiotensin-converting enzyme [ACE], glutathione S-transferase [GSTP1], mannose-binding lectin 2 [MBL2], and transforming growth factor β1 [TGFB1]) are associated with severe liver disease in patients with CF.<h3>Design, Setting, and Participants</h3>Two-stage case-control study enrolling patients with CF and severe liver disease with portal hypertension (CFLD) from 63 CF centers in the United States as well as 32 in Canada and 18 outside of North America, with the University of North Carolina at Chapel Hill as the coordinating site. In the initial study, 124 patients with CFLD (enrolled January 1999-December 2004) and 843 control patients without CFLD were studied by genotyping 9 polymorphisms in 5 genes previously studied as modifiers of liver disease in CF. In the second stage, the SERPINA1 Z allele and TGFB1 codon 10 genotype were tested in an additional 136 patients with CFLD (enrolled January 2005-February 2007) and 1088 with no CFLD.<h3>Main Outcome Measures</h3>Differences in distribution of genotypes in patients with CFLD vs patients without CFLD.<h3>Results</h3>The initial study showed CFLD to be associated with the SERPINA1 Z allele (odds ratio [OR], 4.72; 95% confidence interval [CI], 2.31-9.61; P = 3.3 × 10<sup>−6</sup>) and with TGFB1 codon 10 CC genotype (OR, 1.53; 95% CI, 1.16-2.03; P = 2.8 × 10<sup>−3</sup>). In the replication study, CFLD was associated with the SERPINA1 Z allele (OR, 3.42; 95% CI, 1.54-7.59; P = 1.4 × 10<sup>−3</sup>) but not with TGFB1 codon 10. A combined analysis of the initial and replication studies by logistic regression showed CFLD to be associated with SERPINA1 Z allele (OR, 5.04; 95% CI, 2.88-8.83; P = 1.5 × 10<sup>−8</sup>).<h3>Conclusions</h3>The SERPINA1 Z allele is a risk factor for liver disease in CF. Patients who carry the Z allele are at greater risk (OR, ≈ 5) of developing severe liver disease with portal hypertension.
<i>In vitro</i> studies of the interaction between heparin and eosinophil cationic protein
Authors: K. Fredens, R. Dahl, P. Venge
Journal: Allergy (1991)

Eosinophil cationic protein (ECP) is a protein specific to the granules of human eosinophil granulocytes, ECP is highly cationic and may damage tissue if not inactivated. Heparin is a highly anionic substance present in mast cells and basophil granulocytes. The present in vitro study shows that ECP can inactivate the anticoagulant activity of heparin probably by the formation of a complex between the two molecules. This function may be of importance for the microenvironment of allergic diseases where secretion of heparin may promote penetration of mast cell products through tissues. Also this may constitute one mechanism whereby the cytotoxic action of ECP is neutralized.
Oral liarozole in the treatment of palmoplantar pustular psoriasis: a randomized, double-blind, placebo-controlled study
Authors: M. Bhushan, A.D. Burden, K. MCelhone, R. James, F.P. Vanhoutte, C.E.M. Griffiths
Journal: British Journal of Dermatology (2001)

Journal Article Oral liarozole in the treatment of palmoplantar pustular psoriasis: a randomized, double‐blind, placebo‐controlled study Get access M. Bhushan, M. Bhushan Dermatology Centre, University of Manchester School of Medicine, Hope Hospital, Salford, Manchester M6 8HD, U.K. Search for other works by this author on: Oxford Academic Google Scholar A.D. Burden, A.D. Burden Department of Dermatology, Western Infirmary, Glasgow G11 6NT, U.K. Search for other works by this author on: Oxford Academic Google Scholar K. MCelhone, K. MCelhone Dermatology Centre, University of Manchester School of Medicine, Hope Hospital, Salford, Manchester M6 8HD, U.K. Search for other works by this author on: Oxford Academic Google Scholar R. James, R. James Janssen‐Cilag Limited, High Wycombe, U.K. Search for other works by this author on: Oxford Academic Google Scholar F.P. Vanhoutte, F.P. Vanhoutte Janssen Research Foundation, Beerse, Belgium Search for other works by this author on: Oxford Academic Google Scholar C.E.M. Griffiths C.E.M. Griffiths Dermatology Centre, University of Manchester School of Medicine, Hope Hospital, Salford, Manchester M6 8HD, U.K. Professor C.E.M.Griffiths.E‐mail: christopher.griffiths@man.ac.uk Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 145, Issue 4, 1 October 2001, Pages 546–553, https://doi.org/10.1046/j.1365-2133.2001.04411.x Published: 01 October 2001
Effect of nitric oxide inhalation on respiratory system resistance in chronic obstructive pulmonary disease
Authors: N Roger, JA Barbera, R Farre, A Cobos, J Roca, R Rodriguez-Roisin
Journal: European Respiratory Journal (1996)

Nitric oxide (NO) has been identified as a neurotransmitter of nonadrenergic noncholinergic bronchodilator nerves. To investigate whether inhaled NO exerts a bronchodilator effect in patients with chronic obstructive pulmonary disease (COPD), we measured the resistance of the respiratory system, using the forced oscillation technique, while breathing NO. Eight patients with COPD (7 men and 1 woman; aged 66 +/- 7 yrs (mean +/- SD); forced expiratory volume in one second (FEV1) 37 +/- 17% of predicted) and eight healthy subjects (7 men and 1 woman; 33 +/- 4 yrs; FEV1 108 +/- 14% pred) were studied. Nitric oxide, at a concentration of 40 parts per million (ppm) in air, was inhaled for 20 min. Total resistance (Rrs) and reactance (Xrs) of the respiratory system, arterial oxygen saturation, heart rate, tidal volume, and breathing frequency were continuously recorded at baseline, and during and after ceasing NO inhalation. Methaemoglobin levels were additionally measured in healthy subjects. At baseline, patients with COPD showed higher Rrs than healthy subjects (Rrs at 10 Hz (Rrs,10) 4.97 +/- 2.19 vs 2.29 +/- 0.65 hPa.L-1.s). During NO inhalation, no significant change in Rrs or in Xrs was observed. Mean variation in Rrs,10 while breathing NO was negligible and similar in the two groups (-0.10 +/- 0.13 hPa.L-1.s in COPD patients and -0.02 +/- 0.13 hPa.L-1.s in healthy subjects). Moreover, there were no differences in oxygen saturation, heart rate, tidal volume and breathing frequency during NO inhalation. Methaemoglobinaemia increased at the end of NO inhalation (from 0.48 +/- 0.18 to 0.81 +/- 0.16%), and this increment remained 10 min later (0.86 +/- 0.31%). From these results, we conclude that inhaled nitric oxide, at a concentration of 40 ppm, exerts no effect on respiratory system resistance in patients with chronic obstructive pulmonary disease or in healthy subjects.