tbuckley/cabot-search huggingface dataset:
CTEN Prolongs Signaling by EGFR through Reducing Its Ligand-Induced Degradation
Authors: Shiao-Ya Hong, Yi-Ping Shih, Tianhong Li, Kermit L. Carraway, Su Hao Lo
Journal: Cancer Research (2013)

Activation of EGF receptor (EGFR) triggers signaling pathways regulating various cellular events that contribute to tissue development and function. Aberrant activation of EGFR contributes to tumor progression as well as therapeutic resistance in patients with cancer. C-terminal tensin-like (CTEN; TNS4) is a focal adhesion molecule that is a member of the tensin family. Its expression is upregulated by EGF and elevated CTEN mediates EGF-induced cell migration. In the presence of CTEN, we found that EGF treatment elevated the level of EGFR protein but not mRNA. The extended half-life of activated EGFR sustained its signaling cascades. CTEN reduced ligand-induced EGFR degradation by binding to the E3 ubiquitin ligase c-Cbl and decreasing the ubiquitination of EGFR. The Src homology 2 domain of CTEN is not only required for binding to the phosphorylated tyrosine residue at codon 774 of c-Cbl, but is also essential for the tumorigenicity observed in the presence of CTEN. Public database analyses indicated that CTEN mRNA levels are elevated in breast, colon, lung, and pancreas cancers, but not correlated with EGFR mRNA levels in these cancers. In contrast, immunohistochemistry analyses of lung cancer specimens showed that CTEN and EGFR protein levels were positively associated, in support of our finding that CTEN regulates EGFR protein levels through a posttranslational mechanism. Overall, this work defines a function for CTEN in prolonging signaling from EGFR by reducing its ligand-induced degradation.
Quantitative reconstruction of leukocyte subsets using DNA methylation
Authors: William P Accomando, John K Wiencke, E Andres Houseman, Heather H Nelson, Karl T Kelsey
Journal: Genome biology (2014)

Abstract Background Cell lineage-specific DNA methylation patterns distinguish normal human leukocyte subsets and can be used to detect and quantify these subsets in peripheral blood. We have developed an approach that uses DNA methylation to simultaneously quantify multiple leukocyte subsets, enabling investigation of immune modulations in virtually any blood sample including archived samples previously precluded from such analysis. Here we assess the performance characteristics and validity of this approach. Results Using Illumina Infinium HumanMethylation27 and VeraCode GoldenGate Methylation Assay microarrays, we measure DNA methylation in leukocyte subsets purified from human whole blood and identify cell lineage-specific DNA methylation signatures that distinguish human T cells, B cells, NK cells, monocytes, eosinophils, basophils and neutrophils. We employ a bioinformatics-based approach to quantify these cell types in complex mixtures, including whole blood, using DNA methylation at as few as 20 CpG loci. A reconstruction experiment confirms that the approach could accurately measure the composition of mixtures of human blood leukocyte subsets. Applying the DNA methylation-based approach to quantify the cellular components of human whole blood, we verify its accuracy by direct comparison to gold standard immune quantification methods that utilize physical, optical and proteomic characteristics of the cells. We also demonstrate that the approach is not affected by storage of blood samples, even under conditions prohibiting the use of gold standard methods. Conclusions Cell mixture distributions within peripheral blood can be assessed accurately and reliably using DNA methylation. Thus, precise immune cell differential estimates can be reconstructed using only DNA rather than whole cells.
The effect of roflumilast in addition to LABA/LAMA/ICS treatment in COPD patients
Authors: Wilfried De Backer, Wim Vos, Cedric Van Holsbeke, Samir Vinchurkar, Rita Claes, Annemie Hufkens, Paul M. Parizel, Lieven Bedert, Jan De Backer
Journal: European Respiratory Journal (2014)

To the Editor: 

Recently, roflumilast has been added as a therapeutic option for chronic obstructive pulmonary disease (COPD). Roflumilast is a selective phosphodiesterase type 4 (PDE4) inhibitor [1]. The main concern of the large-scale studies performed was that they did not assess the effect of roflumilast in addition to a combination product such as long-acting β2-agonists (LABA) or long-acting muscarinic agents (LAMA) combined with inhaled corticosteroids (ICS) [2]. A novel technology called functional respiratory imaging (FRI) defines, in great detail, lung geometry and regional changes in airway volume and resistance [3–5]. By assessing changes close to the site of action of the intervention, the method is more sensitive (higher effect size) compared with standard pulmonary function tests (PFT) [3]. This implies that the mode of action of an intervention can be assessed in a small number of patients, while maintaining sufficient power to have statistically significant results [3, 4]. We performed a study aimed at investigating the mode of action of roflumilast in COPD patients on top of triple therapy (LABA/LAMA/ICS), using PFT, exercise tolerance tests, patient-reported outcomes (PRO) and FRI. The hypothesis was that roflumilast provides a large benefit to a subset of COPD patients and that FRI can assist in phenotyping these responders. Ideally, a PFT parameter could be defined that could identify the responding phenotype.

A …
Airway obstruction in primary Sjögren's syndrome (PSS)
Authors: Nomonde Mafuna, Sandrine Hirschi, Jacques-Eric Gottenberg, Anne Charloux, Guillaume Bierry, Romain Kessler
Journal: European Respiratory Journal (2013)

INTRODUCTION: Airway disease in PSS is reported to be frequent but its severity and clinical relevance remain unclear. We aimed to assess airway obstruction as defined by pulmonary function test (PFT) in patients with PSS.  METHOD: Among 502 patients followed in a reference center for PSS, 81 (78 females) non smokers who underwent PFTs from 1990 to 2012 were retrospectively evaluated. Airway obstruction (AO) was defined by either FEV1/FVC  120% of predicted (hyperinflation). Clinical and chest CT scan characteristics of patients with airway obstruction were compared with normal PFT patients.  RESULTS: Mean age at PSS diagnosis was 53,1 year. Mean disease duration at study was 5.3 year. 73 (90%) patients had respiratory symptoms. 26 patients (32%) had an airway obstruction: 10% a patent obstruction, 15% a small airway obstruction and 7% an isolated hyperinflation whereas 34 patients (42%) had normal PFTs. Clinical impact in AO patients was mild as mean FEV1 was 90% of predicted. Respiratory symptoms had a low positive predictive value for AO (59%). CT scan manifestation in the AO patients was mainly a bronchial thickening. Diffuse sicca syndrome (mostly cutaneous and genital) was significantly more frequent in the AO group vs normal PFT group (61.5% vs 32.4%, p = 0.036).  CONCLUSION: Airway obstruction in PSS is frequent, generally mild and is poorly correlated to respiratory symptoms.
The metastasis-associated protein-1 gene encodes a host permissive factor for schistosomiasis, a leading global cause of inflammation and cancer
Authors: Sujit S. Nair, Anitha Bommana, Jeffrey M. Bethony, Amanda J. Lyon, Kazufumi Ohshiro, Suresh B. Pakala, Gabriel Rinaldi, Brian Keegan, Sutas Suttiprapa, Maria V. Periago, Peter J. Hotez, Paul J. Brindley, Rakesh Kumar
Journal: Hepatology (2011)

Abstract: Schistosoma haematobium is responsible for two-thirds of the world's 200 million to 400 million cases of human schistosomiasis. It is a group 1 carcinogen and a leading cause of bladder cancer that occurs after years of chronic inflammation, fibrosis, and hyperproliferation in the host liver. The coevolution of blood flukes of the genus Schistosoma and their human hosts is paradigmatic of long-term parasite development, survival, and maintenance in mammals. However, the contribution of host genes, especially those discrete from the immune system, necessary for parasite establishment and development remains poorly understood. This study investigated the role of metastasis-associated protein-1 gene ( Mta1 ) product in the survival of S. haematobium and productive infection in the host. Using a Mta−1 null mouse model, here we provide genetic evidence to suggest that MTA1 expression positively influences survival and/or maturation of schistosomes in the host to patency, as we reproducibly recovered significantly fewer S. haematobium worms and eggs from Mta1−/− mice than wild−type mice. In addition, we found a distinct loss of cytokine interdependence and aberrant Th1 and Th2 cytokine responses in the Mta1−/− mice compared to age-matched wild-type mice. Thus, utilizing this Mta1 -null mouse model, we identified a distinct contribution of the mammalian MTA1 in establishing a productive host–parasite interaction and thus revealed a host factor critical for the optimal survival of schistosomes and successful parasitism. Moreover, MTA1 appears to play a significant role in driving inflammatory responses to schistosome egg–induced hepatic granulomata reactions, and thus offers a survival cue for parasitism as well as an obligatory contribution of liver in schistosomiasis. Conclusion : These findings raise the possibility to develop intervention strategies targeting MTA1 to reduce the global burden of schistosomiasis, inflammation, and neoplasia. (HEPATOLOGY 2011;)
Neutrophil airway influx by platelet-activating factor in asthma: role of adhesion molecules and LTB4 expression
Authors: J. Gabrijelcic, A. Acuña, M. Profita, A. Paternò, K.F. Chung, A.M. Vignola, R. Rodríguez-Roisin
Journal: European Respiratory Journal (2003)

Platelet-activating factor (PAF)-induced neutrophil lung sequestration may require cell surface adhesion molecules (macrophage-1 antigen (MAC-1) and lymphocyte function-associated antigen-1 (LFA-1)). In this randomised, double-blinded, crossover study, the neutrophil kinetics after PAF and Lyso-PAF (L-PAF) airway challenge were investigated in nine mild-intermittent asthmatics. Neutrophils were measured in peripheral blood (PB) before and at 5, 15, 45 and 240 min after bronchoprovocation, and in induced sputum before and at 240 min after challenge. MAC-1 and LFA-1 expression were assessed by immunocytochemistry, and leukotriene B4 (LTB4) was measured by enzyme-immunoassay in induced-sputum supernatants. Compared with baseline, neutrophils in PB decreased 5 min after PAF, while at 240 min neutrophils in induced sputum increased. Compared with baseline and L-PAF, PAF decreased the percentages of MAC-1- and LFA-1-positive neutrophils in PB at 5 min, but increased the percentages of MAC-1 and LFA-1 in neutrophil-induced sputum. Moreover, compared with baseline and L-PAF, PAF-induced sputum revealed higher LTB4 levels, a finding that correlated with the elevated number of neutrophils in induced sputum. These findings suggest that macrophage-1 antigen and lymphocyte function-associated antigen-1 are involved in platelet-activating factor-induced neutrophil lung traffic, and that this process is modulated by enhanced leukotriene B4 release within the airways.
Interactive involvement of brain derived neurotrophic factor, nerve growth factor, and calcitonin gene related peptide in colonic hypersensitivity in the rat
Authors: L Delafoy
Journal: Gut (2006)

<b>Background and aims:</b> Neutrophins are involved in somatic and visceral hypersensitivity. The action of nerve growth factor (NGF) on sensory neurones contributes to the development of referred colonic hypersensitivity induced by trinitrobenzene sulfonic acid (TNBS). Based on data on brain derived neurotrophic factor (BDNF) and calcitonin gene related peptide (CGRP) in pain, the aims of the present study were: (1) to investigate the involvement of BDNF and CGRP in this model of referred colonic hypersensitivity, (2) to test the effect of exogenous BDNF and CGRP on the colonic pain threshold, and (3) to investigate the relationship between BDNF, NGF, and CGRP by testing antineurotrophin antibodies or h-CGRP 8–37 (a CGRP antagonist) on bowel hypersensitivity induced by these peptides. <b>Methods:</b> Colonic sensitivity was assessed using a colonic distension procedure. <b>Results:</b> Anti-BDNF antibody and h-CGRP 8–37 reversed the induced decrease in colonic threshold (33.4 (2.1) and 40.3 (4.1) mm Hg, respectively, compared with a vehicle score of approximately 18 mm Hg; p&lt;0.001). BDNF (1–100 ng/rat intraperitoneally) induced a significant dose dependent decrease in colonic reaction threshold in healthy rats. This effect was reversed by an anti-BDNF antibody and an anti-NGF antibody (33.4 (0.6) <i>v</i> 18.7 (0.7) mm Hg (p&lt;0.001), anti-NGF <i>v</i> vehicle). NGF induced colonic hypersensitivity was reversed by h-CGRP 8–37 but not by the anti-BDNF antibody. Finally, antineurotrophin antibody could not reverse CGRP induced colonic hypersensitivity (at a dose of 1 µg/kg intraperitoneally). <b>Conclusion:</b> Systemic BDNF, NGF, and CGRP can induce visceral hypersensitivity alone and interactively. This cascade might be involved in TNBS induced referred colonic hypersensitivity in which each of these peptides is involved.
Mitochondrial connexin43 as a new player in the pathophysiology of myocardial ischaemia-reperfusion injury
Authors: M. Ruiz-Meana, A. Rodriguez-Sinovas, A. Cabestrero, K. Boengler, G. Heusch, D. Garcia-Dorado
Journal: Cardiovascular Research (2007)

Connexins are transmembrane proteins whose best known function is to form gap junction channels. Ventricular cardiomyocytes express the connexin isoform Cx43 and are rich in gap junctions essential for the normal propagation of the action potential. In addition to this physiological role, cardiomyocyte gap junctions contribute to the pathophysiology of ischaemia–reperfusion injury, mainly by synchronizing the onset of rigour contracture during ischaemia and cell-to-cell propagation of hypercontracture during reperfusion. More recently, it has been recognized that Cx43 plays a role in protection during ischaemic and pharmacological preconditioning and that this role is independent from gap junction-mediated communication. It was demonstrated that Cx43 is localized in cardiomyocyte mitochondria, at least in part in the inner mitochondrial membrane, where it is imported by the general mitochondrial membrane translocase system. Interfering with this import system or genetic ablation of Cx43 abolishes diazoxide-induced protection, indicating that mitochondrial Cx43 participates in the preconditioning cascade. The role of mitochondrial Cx43 in preconditioning appears to be related to reactive oxygen species signalling, but its molecular mechanisms have not been elucidated in detail. The present article reviews available evidence on the localization of Cx43 in cardiomyocyte mitochondria, its role in protection by preconditioning, and the potential molecular mechanisms involved. These data may help to understand the pathophysiology of myocardial ischaemia–reperfusion and ischaemic preconditioning and to identify new strategies for cardioprotection, and they may be particularly relevant to situations such as aging in which total and mitochondrial Cx43 contents have been shown to be reduced.
Diet and Kidney Disease in High-Risk Individuals With Type 2 Diabetes Mellitus
Authors: Daniela Dunkler, Mahshid Dehghan, Koon K. Teo, Georg Heinze, Peggy Gao, Maria Kohl, Catherine M. Clase, Johannes F. E. Mann, Salim Yusuf, Rainer Oberbauer
Journal: JAMA Internal Medicine (2013)

<h3>Importance</h3> Type 2 diabetes mellitus and associated chronic kidney disease (CKD) have become major public health problems. Little is known about the influence of diet on the incidence or progression of CKD among individuals with type 2 diabetes. <h3>Objective</h3> To examine the association between (healthy) diet, alcohol, protein, and sodium intake, and incidence or progression of CKD among individuals with type 2 diabetes. <h3>Design, Setting, and Participants</h3> All 6213 individuals with type 2 diabetes without macroalbuminuria from the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) were included in this observational study. Recruitment spanned from January 2002 to July 2003, with prospective follow-up through January 2008. <h3>Main Outcomes and Measures</h3> Chronic kidney disease was defined as new microalbuminuria or macroalbuminuria or glomerular filtration rate decline of more than 5% per year at 5.5 years of follow-up. We assessed diet using the modified Alternate Healthy Eating Index (mAHEI). The analyses were adjusted for known risk factors, and competing risk of death was considered. <h3>Results</h3> After 5.5 years of follow-up, 31.7% of participants had developed CKD and 8.3% had died. Compared with participants in the least healthy tertile of mAHEI score, participants in the healthiest tertile had a lower risk of CKD (adjusted odds ratio [OR], 0.74; 95% CI, 0.64-0.84) and lower risk of mortality (OR, 0.61; 95% CI, 0.48-0.78). Participants consuming more than 3 servings of fruits per week had a lower risk of CKD compared with participants consuming these food items less frequently. Participants in the lowest tertile of total and animal protein intake had an increased risk of CKD compared with participants in the highest tertile (total protein OR, 1.16; 95% CI, 1.05-1.30). Sodium intake was not associated with CKD. Moderate alcohol intake reduced the risk of CKD (OR, 0.75; 95% CI, 0.65-0.87) and mortality (OR, 0.69; 95% CI, 0.53-0.89). <h3>Conclusions and Relevance</h3> A healthy diet and moderate intake of alcohol may decrease the incidence or progression of CKD among individuals with type 2 diabetes. Sodium intake, within a wide range, and normal protein intake are not associated with CKD. <h3>Trial Registration</h3> clinicaltrials.gov Identifier:NCT00153101
Bone Marrow–Derived Antigen-Presenting Cells Are Required for the Generation of Cytotoxic T Lymphocyte Responses to Viruses and Use Transporter Associated with Antigen Presentation (Tap)-Dependent and -Independent Pathways of Antigen Presentation
Authors: Luis J. Sigal, Kenneth L. Rock
Journal: The Journal of Experimental Medicine (2000)

Bone marrow (BM)-derived professional antigen-presenting cells (pAPCs) are required for the generation of cytotoxic T lymphocyte (CTL) responses to vaccinia virus and poliovirus. Furthermore, these BM-derived pAPCs require a functional transporter associated with antigen presentation (TAP). In this report we analyze the requirements for BM-derived pAPCs and TAP in the initiation of CTL responses to lymphocytic choriomeningitis virus (LCMV) and influenza virus (Flu). Our results indicate a requirement for BM-derived pAPCs for the CTL responses to these viruses. However, we found that the generation of CTLs to one LCMV epitope (LCMV nucleoprotein 396–404) was dependent on BM-derived pAPCs but, surprisingly, TAP independent. The study of the CTL response to Flu confirmed the existence of this BM-derived pAPC-dependent/TAP-independent CTL response and indicated that the TAP-independent pathway is ∼10–300-fold less efficient than the TAP-dependent pathway.
Diagnosis of small bowel Crohn's disease: a prospective comparison of capsule endoscopy with magnetic resonance imaging and fluoroscopic enteroclysis
Authors: J G Albert
Journal: Gut (2005)

<b>Background and aims:</b> The diagnostic yield of capsule endoscopy (CE) compared with magnetic resonance imaging (MRI) in small bowel Crohn's disease is not well established. We prospectively investigated CE, MRI, and double contrast fluoroscopy in patients with suspected small bowel Crohn's disease. <b>Methods:</b> Fifty two consecutive patients (39 females, 13 males) were investigated by MRI, fluoroscopy and—if bowel obstruction could be excluded—by CE. In 25, Crohn's disease was newly suspected while the diagnosis of Crohn's disease (non-small bowel) had been previously established in 27. <b>Results:</b> Small bowel Crohn's disease was diagnosed in 41 of 52 patients (79%). CE was not accomplished in 14 patients due to bowel strictures. Of the remaining 27 patients, CE, MRI, and fluoroscopy detected small bowel Crohn's disease in 25 (93%), 21 (78%), and 7 (of 21; 33%) cases, respectively. CE was the only diagnostic tool in four patients. CE was slightly more sensitive than MRI (12 <i>v</i> 10 of 13 in suspected Crohn's disease and 13 <i>v</i> 11 of 14 in established Crohn's disease). MRI detected inflammatory conglomerates and enteric fistulae in three and two cases, respectively. <b>Conclusion:</b> CE and MRI are complementary methods for diagnosing small bowel Crohn's disease. CE is capable of detecting limited mucosal lesions that may be missed by MRI, but awareness of bowel obstruction is mandatory. In contrast, MRI is helpful in identifying transmural Crohn's disease and extraluminal lesions, and may exclude strictures.
Elucidating Mechanisms of Allergic Inflammation in Eosinophilic Esophagitis
Authors: Denise Loizou, Otto Louis-Jacques, Benjamin Enav, Julie Kim, Peter Lee, Catherine Chao, Lynn Duffy, Ian Leibowitz, Suhasini Kaushal, Annu Farwah, Ozlem Goker-Alpan, Oral Alpan
Journal: Journal of Allergy and Clinical Immunology (2013)
Putting noninvasive lung mechanics into context
Authors: Peter M.A. Calverley, Ramon Farre
Journal: European Respiratory Journal (2013)

Anyone who teaches medical students about how the lungs work meets an immediate problem. The best way to describe the mechanics of breathing is in terms of airways resistance and lung compliance but these measurements are not readily available in clinical practice. Instead clinicians focus on the indirect information available from spirometry. The great advantage that spirometry offers is its known immediate reproducibility and limited between test variation in both health and disease [1]. These properties, coupled with its extensive use in clinical decision making, ensure that spirometric measurements are going to be used in managing respiratory disease for the foreseeable future. One particular advantage of spirometry is the availability of age- and height-related normal values against which any recording can be judged [2].

From the 1950s onwards, physiologists realised that applying small multi-frequency pressure oscillations at the mouth would produce changes in volume and flow that provided a direct and noninvasive measurement of respiratory system mechanics. These data were expressed in terms of respiratory system resistance and reactance (the latter a complex concept involving negative numbers that has never appealed to clinicians), and should give an insight into how breathing at rest is related to disease. To make this measurement clinically practical there had to be substantial improvements in the accuracy of the pressure transducers which measured the very small fluctuations in pressure, and hence flow, within the airways and also a considerable increase in the computing power necessary for the complex mathematical manipulations, such as fast Fourier transformations which disentangle the mixture of frequencies applied to describe the behaviour of the respiratory system. By the early 1980s [3] these developments had become a reality and a number of researchers, especially those based in Belgium, made measurements of resistance and reactance in healthy …