tbuckley/cabot-search huggingface dataset:
Thorax: the teenage years
Authors: Andrew Bush, Ian Pavord
Journal: Thorax (2011)

We have been at the helm for 18 months—where have we got to, where should we aim for (other than staying out of the divorce courts)?

Napoleon preferred lucky generals, and Thorax has lucky Editors in Chief because we have a great team of deputy editors, associate editors, production staff and editorial board. A former Editor in Chief (it is said!) used to write to authors to say either “I am sorry, but the Associate Editor has recommended rejection of your manuscript” or “I am pleased to tell you I that have accepted your paper”. By contrast, we feel our brilliant team take the credit for what has gone right—any mistakes are rightly laid at the door of the undersigned. They have all worked exceedingly hard, and our twice yearly meetings have been full of energy and enthusiasm and great fun. A big thank you to you all.

No process is perfect. Incoming manuscripts are checked by the staff and, if they conform to the journal style, are assigned to the Editors in Chief. Note please: we are toughening up, and if your manuscript is too long or has too many references, it will be returned unrefereed for you to edit; …
The G Protein–Coupled Receptor S1P2 Regulates Rho/Rho Kinase Pathway to Inhibit Tumor Cell Migration
Authors: Denise Lepley, Ji-Hye Paik, Timothy Hla, Fernando Ferrer
Journal: Cancer Research (2005)

Sphingosine 1-phosphate (S1P) is a lysophospholipid that exerts a variety of responses in cells such as proliferation, migration, and survival. These effects are mediated by G protein-coupled receptors on the cell surface (S1P1-5), which activate downstream signaling intermediates such as Rac and Rho GTPases. Mechanisms of S1P action in human glioblastoma cells are not well defined. S1P receptors (1-5) and S1P-metabolizing enzymes were expressed in three human glioblastoma cell lines. S1P had a profound and differential effect on glioblastoma cell migration. U87 cells treated with S1P showed a significant increase in migration, whereas U118 and U138 cell lines were strongly inhibited. S1P-mediated inhibition correlated with S1P2 receptor expression. FTY720-P, an S1P analogue that binds all S1P receptors except S1P2, did not inhibit glioblastoma cell migration. Overexpression of S1P2 further suppressed migration, and blockage of S1P2 mRNA expression by small interfering RNA reversed the inhibitory effect. Contrary to previous reports showing bimodal regulation of Rac activity and migration by S1P2 receptor stimulation, both Rac1 and RhoA GTPases were activated by S1P treatment in native cells and cells overexpressing S1P2. Treatment of U118 cells with the Rho-associated protein kinase (ROCK) inhibitor Y-27632 restored migration suggesting that ROCK-dependent mechanisms are important. Actin staining of S1P stimulated U118 cells overexpressing beta-galactosidase resulted in pronounced stress fiber formation that was exacerbated by S1P2 overexpression, partially blocked by S1P1, or totally abolished by pretreatment with Y-27632. These data provide evidence of a novel mechanism of S1P inhibition of tumor cell migration via Rho kinase-dependent pathway.
Multicenter phase II study of sunitinib in patients with non-clear cell renal cell carcinoma
Authors: J.-L. Lee, J.-H. Ahn, H.Y. Lim, S.H. Park, S.H. Lee, T.M. Kim, D.-H. Lee, Y.M. Cho, C. Song, J.H. Hong, C.-S. Kim, H. Ahn
Journal: Annals of Oncology (2012)
Physiology of IgD. I. Compensatory phenomena in B lymphocyte activation in mice treated with anti-IgD antibodies.
Authors: E B Jacobson, Y Baine, Y W Chen, T Flotte, M J O'Neil, B Pernis, G W Siskind, G J Thorbecke, P Tonda
Journal: The Journal of Experimental Medicine (1981)

The role of delta-positive cells in the immune response was studied by comparing the effects of treatment with allotype-specific IgD hybridoma antibody on homozygous BALB/c or SJL/J and heterozygous (BALB x SJL)F1 mice. Homozygous mice, injected from birth with the relevant anti-delta antibody, made primary or secondary immune responses to intravenously injected trinitrophenyl (TNP)-Brucella abortus, TNP-Ficoll, and TNP-keyhole limpet hemocyanin, which did not differ significantly from those of control mice, despite the fact that IgD+ cells were depleted and Ig+ cells were markedly reduced in the spleens of treated mice. Responses in nodes draining a local injection of TNP-Brucella abortus were, however, significantly suppressed. Heterozygous mice, injected from birth with either anti-Ig-5a or anti-Ig-5b, showed a marked reduction in the number cells producing IgG antibody of linked allotype specificity in the secondary response to intravenously injected sheep erythrocytes. A corresponding decrease in the amount of serum IgG2a of that allotype specificity was also noted. However, in agreement with the results obtained in homozygotes, heterozygotes injected simultaneously with anti-IgD directed against each of the allotypes made normal, if not enhanced, plaque-forming cell responses of both allotype specificities. Similarly, serum IgG2a levels were normal in all but one mouse treated in this fashion. These results indicate that IgD+ cells are not essential for an immune response in vivo. Although the delta-positive cell is used preferentially under normal conditions, it appears that an alternative mechanism exists by which, in the absence of these cells, the animal is able to make a normal immune response.
Sodium Ascorbate induces apoptosis in neuroblastoma cell lines by interfering with iron uptake
Authors: Roberta Carosio, Guendalina Zuccari, Isabella Orienti, Salvatore Mangraviti, Paolo G Montaldo
Journal: Molecular Cancer (2007)

Neuroblastoma (NB) is an extra-cranial solid tumour of childhood. In spite of the good clinical response to first-line therapy, complete eradication of NB cells is rarely achieved. Thus, new therapeutic strategies are needed to eradicate surviving NB cells and prevent relapse. Sodium ascorbate has been recently reported to induce apoptosis of B16 melanoma cells through down-regulation of the transferrin receptor, CD71. Since NB and melanoma share the same embryologic neuroectodermal origin, we used different human NB cell lines to assess whether the same findings occurred. We could observe dose- and time-dependent induction of apoptosis in all NB cell lines. Sodium ascorbate decreased the expression of CD71 and caused cell death within 24 h. An increase in the global and specific caspase activity took place, as well as an early loss of the mitochondrial transmembrane potential. Moreover, intracellular iron was significantly decreased after exposure to sodium ascorbate. Apoptotic markers were reverted when the cells were pretreated with the iron donor ferric ammonium citrate (FAC), further confirming that iron depletion is responsible for the ascorbate-induced cell death in NB cells. Sodium ascorbate is highly toxic to neuroblastoma cell lines and the specific mechanism of vitamin C-induced apoptosis is due to a perturbation of intracellular iron levels ensuing TfR-downregulation.
HRV1B infection and steroid-treatment do not affect the number of dendritic cells in vagal sensory ganglia under allergic conditions
Authors: Ulrike Funck, Duc Dung Le, Sabine Rochlitzer, Sebastian Heck, Robert Bals, Tobias Welte, Armin Braun, Quoc Thai Dinh
Journal: European Respiratory Journal (2014)

Objectives : Dendritic cells (DCs) play a key role as antigen-presenting cells in allergic inflammation. It has been reported, that DCs are connected with nerve fibers in the lungs during an allergic airway inflammation. Viral infections often lead to an exacerbation in bronchial asthma, the underlying mechanism is not clear yet. In this study we investigated the effect of viral respiratory infection and steroid-treatment on the number of DCs in the vagal sensory ganglia (jugular-nodose complex (JNC)) under allergic conditions.

Methods: Using a house dust mite ( HDM) model for allergic airway inflammation BALB/c, mice were exposed to HDM extract intranasally (i.n.) (25µg/50µl) for 5 consecutive days a week over 7 weeks. Humane rhinovirus serotype 1B (HRV1B) was applied i.n. in the last 3 days. Therapeutic treatment with Fluticasone propionate was performed to assess steroid efficacy.

Results: Dendritic cells were found to be closely located to neurons under physiological conditions in JNC. The percentage of DCs in relation to neurons was significantly increased in allergic airway inflammation with and without viral infection in comparison to the controls (MHCII/PGP9.5: HDM 44.1±2.0% vs. control 35.1±2.3%, p= 0.01, HDM+HRV1B 45.2±2.9% vs. control 35.1±2.3%, p= 0.02). The number of DCs in JNC was found unchanged by steroid treated animals.

Conclusion: Allergic airway inflammation causes an increase of DCs in JNC. The infection with HRV1B and the steroid-treatment have no effect on the number of DCs in JNC of HDM treated animals. The increased amount of DCs indicates that intraganglionic DCs may contribute to the pathogenesis of bronchial asthma.
Antioxidant effects of phosphodiesterase-5 inhibitors: reply
Authors: R. Zhang, Z.-C. Jing
Journal: Cardiovascular Research (2013)

We thank Dr. Tanus-Santos for his interest in our study.1 The study by Muniz et al .2 found that erectile dysfunction patients with the lowest levels of endogenous nitric oxide (NO) have the best responses to the phosphodiesterase-5 (PDE5) inhibitor sildenafil. We believe an equivalent situation exists in patients with pulmonary arterial hypertension (PAH). We found impaired NO production in the patients with PAH included in our study, suggesting that these patients are the best candidates to take advantage of the benefits of vardenafil treatment. This may be because vardenafil is a relatively selective pulmonary vasodilator, which …
The nature of antiidiotype molecules induced by antiallotype. Presence of both latent allotype and allotypic internal images.
Authors: D W Metzger
Journal: The Journal of Experimental Medicine (1985)

Previously (9), I found that immunization of rabbits with antibody directed against variable region heavy chain VH polypeptides of a1 allotype induced the production of antiidiotype (anti-Id) molecules that appeared to bear images of the original a1 allotype. I now show that these anti-Id molecules can be fractionated into two populations: one population (a2a3- anti-Id) that lacks the nominal VH a2 or a3 allotype of the rabbit from which it was derived, and another population (a2a3+ anti-Id) that expresses these allotypes. Both anti-Id populations display epitopes that resemble a1 since: (a) they were capable of inhibiting 125I-a1 Ig binding to rabbit anti-a1, goat anti-a1, and mouse anti-a1 mAb; and (b) immunization of normal a2a3 rabbits with either anti-Id fraction led to the formation of specific anti-a1 antibody. Reductive cleavage of the anti-Id molecules showed that the a1 determinants in the a2a3- population were fully displayed on isolated H chains, consistent with the presence of latent a1 Ig. On the other hand, as expected for internal images encoded by the antigen-combining site, the a2a3+ anti-Id population required intact H and L chains for maximal a1 expression. The a1-like images within the a2a3+ anti-Id population do not appear to be identical to nominal or latent a1, however, since a2a3- anti-Id was invariably a more efficient inhibitor of a 1 Ig-anti-a1 binding than a a2a3+ anti-Id. These results indicate that immunization with antiallotype can result in the simultaneous production of both latent allotypes and allotypic internal images.
Reduced migration of MLH1 deficient colon cancer cells depends on SPTAN1
Authors: Inga Hinrichsen, Benjamin Philipp Ernst, Franziska Nuber, Sandra Passmann, Dieter Schäfer, Verena Steinke, Nicolaus Friedrichs, Guido Plotz, Stefan Zeuzem, Angela Brieger
Journal: Molecular Cancer (2014)

Abstract Introduction Defects in the DNA mismatch repair (MMR) protein MLH1 are frequently observed in sporadic and hereditary colorectal cancers (CRC). Affected tumors generate much less metastatic potential than the MLH1 proficient forms. Although MLH1 has been shown to be not only involved in postreplicative MMR but also in several MMR independent processes like cytoskeletal organization, the connection between MLH1 and metastasis remains unclear. We recently identified non-erythroid spectrin αII (SPTAN1), a scaffolding protein involved in cell adhesion and motility, to interact with MLH1. In the current study, the interaction of MLH1 and SPTAN1 and its potential consequences for CRC metastasis was evaluated. Methods Nine cancer cell lines as well as fresh and paraffin embedded colon cancer tissue from 12 patients were used in gene expression studies of SPTAN1 and MLH1. Co-expression of SPTAN1 and MLH1 was analyzed by siRNA knock down of MLH1 in HeLa, HEK293, MLH1 positive HCT116, SW480 and LoVo cells. Effects on cellular motility were determined in MLH1 deficient HCT116 and MLH1 deficient HEK293T compared to their MLH1 proficient sister cells, respectively. Results MLH1 deficiency is clearly associated with SPTAN1 reduction. Moreover, siRNA knock down of MLH1 decreased the mRNA level of SPTAN1 in HeLa, HEK293 as well as in MLH1 positive HCT116 cells, which indicates a co-expression of SPTAN1 by MLH1. In addition, cellular motility of MLH1 deficient HCT116 and MLH1 deficient HEK293T cells was impaired compared to the MLH1 proficient sister clones. Consequently, overexpression of SPTAN1 increased migration of MLH1 deficient cells while knock down of SPTAN1 decreased cellular mobility of MLH1 proficient cells, indicating SPTAN1-dependent migration ability. Conclusions These data suggest that SPTAN1 levels decreased in concordance with MLH1 reduction and impaired cellular mobility in MLH1 deficient colon cancer cells. Therefore, aggressiveness of MLH1-positive CRC might be related to SPTAN1.
Withdrawal of alcohol promotes regression while continued alcohol intake promotes persistence of LPS-induced pancreatic injury in alcohol-fed rats
Authors: A. Vonlaufen, P. A. Phillips, Z. Xu, X. Zhang, L. Yang, R. C. Pirola, J. S. Wilson, M. V. Apte
Journal: Gut (2010)

<h3>Background and aims</h3> Administration of repeated lipopolysaccharide (LPS) injections in alcohol-fed rats leads to significant pancreatic injury including fibrosis. However, it remains unknown whether alcoholic (chronic) pancreatitis has the potential to regress when alcohol is withdrawn. The aims of the study were (1) to compare the effect of alcohol withdrawal/continuation on pancreatic acute injury and fibrosis; and (2) to assess the effects of alcohol ± LPS on pancreatic stellate cell (PSC) apoptosis in vivo and in vitro. <h3>Methods</h3> Rats fed isocaloric Lieber–DeCarli liquid diets ± alcohol for 10 weeks were challenged with LPS (3 mg/kg/week for 3 weeks) and then either switched to control diet or maintained on an alcohol diet for 3 days, 7 days or 3 weeks. Pancreatic sections were assessed for acute tissue injury, fibrosis, PSC apoptosis and activation. Cultured rat PSCs were exposed to 10 mM ethanol ± 1 μg/ml LPS for 48 or 72 h and apoptosis was assessed (Annexin V, caspase-3 and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL)). <h3>Results</h3> Withdrawal of alcohol led to resolution of pancreatic lesions including fibrosis and to increased PSC apoptosis. Continued alcohol administration perpetuated pancreatic injury and prevented PSC apoptosis. Alcohol and LPS significantly inhibited PSC apoptosis in vitro, and the effect of LPS on PSC apoptosis could be blocked by Toll-like receptor 4 small interfering RNA. <h3>Conclusions</h3> Induction of PSC apoptosis upon alcohol withdrawal is a key mechanism mediating the resolution of pancreatic fibrosis. Conversely, continued alcohol intake perpetuates pancreatic injury by inhibiting apoptosis and promoting activation of PSCs. Characterisation of the pathways mediating PSC apoptosis has the potential to yield novel therapeutic strategies for chronic pancreatitis.
Brugada-Like Syndrome in Infancy Presenting With Rapid Ventricular Tachycardia and Intraventricular Conduction Delay
Authors: Ronald J. Kanter, Ryan Pfeiffer, Dan Hu, Héctor Barajas-Martinez, Michael P. Carboni, Charles Antzelevitch
Journal: Circulation (2011)

Brugada syndrome is a potentially serious channelopathy that usually presents in adulthood and has only rarely been described in infancy. In the absence of metabolic or structural cardiac disease, rapid ventricular tachycardia (>200 bpm) and primary cardiac conduction disease are uncommon in infancy. We hypothesized that infants having rapid ventricular tachycardia and conduction abnormalities and not having structural or metabolic pathogeneses were likely to have mutations in depolarizing current channels.A retrospective review of all clinical materials from a single institution over a 9-year period from all infants <2 years old and having a discharge diagnosis of ventricular tachycardia or ventricular fibrillation was performed. Among 32 infants fulfilling inclusion criteria, 12 had a structurally normal heart, and 9 of them had either prolonged QRS duration or Brugada pattern while in sinus rhythm. Of those 5 infants not having a definitive pathogenesis, electrophysiological testing had been performed in 4, and genetic testing had been performed in all 5 of those infants. During electrophysiological testing, a prolonged HV interval was present in 2 of 4, inducible ventricular tachycardia was present in 1 of 4, and a type 1 Brugada pattern was induced by intravenous procainamide in 3 of 4. Genetic testing revealed disease-causing mutations in depolarizing sodium (SCN5A) or calcium (CaCNB2b) channels in all 5 infants.Infants having rapid ventricular tachycardia and conduction abnormalities in the absence of structural or metabolic abnormalities are likely to have disease-causing mutations in cardiac depolarizing channels.
Dual Role of Toll-Like Receptors in Asthma and Chronic Obstructive Pulmonary Disease
Authors: Gillina F. G. Bezemer, Seil Sagar, Jeroen van Bergenhenegouwen, Niki A. Georgiou, Johan Garssen, Aletta D. Kraneveld, Gert Folkerts
Journal: Pharmacological Reviews (2012)

During the last decade, significant research has been focused on Toll-like receptors (TLRs) in the pathogenesis of airway diseases. TLRs are pattern recognition receptors that play pivotal roles in the detection of and response to pathogens. Because of the involvement of TLRs in innate and adaptive immunity, these receptors are currently being exploited as possible targets for drug development. Asthma and chronic obstructive pulmonary disease (COPD) are chronic inflammatory airway diseases in which innate and adaptive immunity play an important role. To date, asthma is the most common chronic disease in children aged 5 years and older. COPD is prevalent amongst the elderly and is currently the fifth-leading cause of death worldwide with still-growing prevalence. Both of these inflammatory diseases result in shortness of breath, which is treated, often ineffectively, with bronchodilators and glucocorticosteroids. Symptomatic treatment approaches are similar for both diseases; however, the underlying immunological mechanisms differ greatly. There is a clear need for improved treatment specific for asthma and for COPD. This review provides an update on the role of TLRs in asthma and in COPD and discusses the merits and difficulties of targeting these proteins as novel treatment strategies for airway diseases. TLR agonist, TLR adjuvant, and TLR antagonist therapies could all be argued to be effective in airway disease management. Because of a possible dual role of TLRs in airway diseases with shared symptoms and risk factors but different immunological mechanisms, caution should be taken while designing pulmonary TLR-based therapies.
Longitudinal Association Between Endothelial Dysfunction, Inflammation, and Clotting Biomarkers With Subclinical Atherosclerosis in Type 1 Diabetes: An Evaluation of the DCCT/EDIC Cohort
Authors: Kelly J. Hunt, Nathaniel L. Baker, Patricia A. Cleary, Richard Klein, Gabriel Virella, Maria F. Lopes-Virella
Journal: Diabetes Care (2015)

There is considerable interest in identifying biomarkers that predict high risk for the development of macrovascular complications in patients with diabetes. Therefore, the longitudinal association between subclinical atherosclerosis as measured by internal carotid artery intima-media thickness (IMT) and acute-phase reactants, cytokines/adipokines, thrombosis, and adhesion molecules was examined.Biomarkers were measured at four time points over 20 years in 886 DCCT/EDIC participants with type 1 diabetes. Four composite scores were created by combining z scores generated from within the data set of individual biomarkers: acute-phase reactants (fibrinogen, C-reactive protein), thrombosis (fibrinogen, active and total plasminogen activator inhibitor [PAI]-1), cytokines/adipokines (tumor necrosis factor receptor-1 and -2, active and total PAI-1, IL-6), and endothelial dysfunction (soluble intracellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, and soluble E-selectin). Internal carotid IMT was measured at EDIC years 1, 6, and 12, with elevated IMT defined at each time point as being in the upper quintile of its distribution.Logistic regression models indicate that while individual biomarkers were not predictive of or associated with subclinical atherosclerosis, composite scores of acute-phase reactants (odds ratio [OR] 2.78 [95% CI 1.42, 5.42]), thrombolytic factors (OR 2.83 [95% CI 1.45, 5.52]), and cytokines/adipokines (OR 2.83 [95% CI 1.48, 5.41]) measured at our final time point EDIC years 8-11 were associated with higher levels of atherosclerosis at EDIC year 12, but findings were not consistent at early time points. The endothelial dysfunction score was not appreciably predictive of or associated with subclinical atherosclerosis at any of the time points measured.The pathophysiologic relationship between higher biomarker levels and progression of subclinical atherosclerosis remains unclear.
Efficacy of sublingual immunotherapy in asthma: systematic review of randomized‐clinical trials using the Cochrane Collaboration method
Authors: Z. Calamita, H. Saconato, A. B. Pelá, Á. N. Atallah
Journal: Allergy (2006)

Background: Sublingual immunotherapy (SLIT) is effective and safe in the treatment of allergic rhinitis. However, there is no meta‐analysis in asthma treatment. Methods: The clinical efficacy of SLIT for asthma was evaluated through a systematic review with meta‐analysis. MEDLINE (1966–2005), EMBASE (1974–2005), LILACS (1982–2005), and the Cochrane Library were searched for related literature in any language. Randomized‐controlled clinical trials (RCT) on SLIT in asthma treatment for adults and children were selected. From 119 citations, 25 studies with 1706 patients were included in this meta‐analysis. For each report, quality scores were assigned and data were extracted in relation to the outcomes analyzed: asthmatic symptoms, use of asthma medications, lung function, and bronchial provocation. Results: According to the Jadad quality method, 64% of the studies were assigned scores of 4 or 5. Immunotherapy was seen to significantly reduce asthma severity when parameter compositions were all analyzed by categorical outcomes. There was a nonsignificant reduction in asthma symptoms when analyzed using standardized mean differences. No severe reactions were observed. Conclusions: This meta‐analysis found that SLIT is beneficial for asthma treatment albeit the magnitude of the effect is not very large. Moreover, it is a safe alternative to the subcutaneous route. More RCT with standardization of symptom scores and medications are needed in order to contribute further to this subject.