tbuckley/cabot-search huggingface dataset:
T cell regulation of polyclonal B cell responsiveness. III. Overt T helper and latent T suppressor activities from distinct subpopulations of unstimulated splenic T cells
Authors: MG Goodman, WO Weigle
Journal: The Journal of Experimental Medicine (1981)

Polyclonal activation of murine splenic B lymphocytes by lipopolysaccharide was found to be subject to regulation by helper and suppressor influences from T lymphocytes. In the normal adult spleen, only helper influences were exercised over polyclonal B cell activation; this influence is a property of Lyt-l(+)23(-) slowly sedimenting T cells. Suppressive influence evidently is latent, for it exists at such a low level (or the cells are so few in number) that its effects are difficult to detect. Suppressor T cell function may be evoked by culturing spleen cells at high ratios of T:B cells, by activating splenic T cells with concanavalin A, or by sonicating unstimulated splenic T cells to liberate a suppressive potential that is not expressed by these unstimulated cells when intact. The soluble fraction of resident splenic T cell sonicates exerts both helper and suppressor regulatory influences. The soluble helper activity is derived from Lyt-l(+)23(-) slowly sedimenting T cells, whereas suppressor activity is generated from a distinct subpopulation of Lyt-l(-)23(+) rapidly sedimenting T cells. The thymus contains cells capable only of helping but not of suppressing polyclonal activation of splenic B cells. Helper and suppressor activities contained in splenic T cell sonicates were separated by gel chromatography; the suppressive activity was found to elute with a molecular weight between 68,000 and 84,000 and the helper activity eluted with a molecular weight between 15,000 and 23,000. The data indicate that helper and suppressor activities are distinct molecular entities derived from distinct splenic T lymphocyte subpopulations. The possibility that these molecules are precursors to or components of antigen- specific or nonspecific helper and suppressor factors described in the literature is discussed.
G-Quadruplex Ligand RHPS4 Potentiates the Antitumor Activity of Camptothecins in Preclinical Models of Solid Tumors
Authors: Carlo Leonetti, Marco Scarsella, Giuseppe Riggio, Angela Rizzo, Erica Salvati, Maurizio D'Incalci, Lidia Staszewsky, Roberta Frapolli, Malcolm F. Stevens, Antonella Stoppacciaro, Marcella Mottolese, Barbara Antoniani, Eric Gilson, Gabriella Zupi, Annamaria Biroccio
Journal: Clinical Cancer Research (2008)

Abstract Purpose: The formation of G-quadruplex structures at telomeric DNA sequences blocks telomerase activity, offering an original strategy to design and develop new antitumor agents. The pentacyclic acridinium salt RHPS4 is one of the most effective and selective G4 ligands able to rapidly disrupt telomere architecture, resulting in apoptosis of cancer cells. Here, we studied the therapeutic index of RHPS4 and its integration with chemotherapeutics in preclinical model of solid tumors. Experimental Design: The antitumoral activity of RHPS4 was evaluated on human xenografts of different histotypes and compared with that of standard antineoplastic agents. Moreover, the effect of RHPS4/chemotherapeutics combinations on cell survival was studied and the most favorable combination was evaluated on tumor-bearing mice. Results: RHPS4 was active in vivo as single agent and showed a high therapeutic efficacy when compared with conventional drugs. Moreover, RHPS4 had antitumoral activity in human melanoma xenografts inherently resistant to chemotherapy and exhibited antimetastatic activity. RHPS4 also showed a strong synergistic interaction with camptothecins and this effect was strictly dependent on the drug sequence employed. Treatment of mice with irinotecan followed by RHPS4 was able to inhibit and delay tumor growth and to increase mice survival. Conclusions: Our data show that RHPS4 has a good pharmacodynamic profile and in combination therapy produces a strong antitumoral activity, identifying this drug as promising agent for clinical development.
Percutaneous replacement of pulmonary valve in a right-ventricle to pulmonary-artery prosthetic conduit with valve dysfunction
Authors: Philipp Bonhoeffer, Younes Boudjemline, Zakhia Saliba, Jacques Merckx, Yacine Aggoun, Damien Bonnet, Philippe Acar, Jérôme Le Bidois, Daniel Sidi, Jean Kachaner
Journal: The Lancet (2000)
Loss of FOXA1/2 Is Essential for the Epithelial-to-Mesenchymal Transition in Pancreatic Cancer
Authors: Yan Song, M. Kay Washington, Howard C. Crawford
Journal: Cancer Research (2010)

FOXA1 and FOXA2, members of the forkhead transcription factor family, are critical for epithelial differentiation in many endoderm-derived organs, including the pancreas. However, their role in tumor progression is largely unknown. Here, we identified FOXA1 and FOXA2 as important antagonists of the epithelial-to-mesenchymal transition (EMT) in pancreatic ductal adenocarcinoma (PDA) through their positive regulation of E-cadherin and maintenance of the epithelial phenotype. In human PDA samples, FOXA1/2 are expressed in all epithelia from normal to well-differentiated cancer cells, but are lost in undifferentiated cancer cells. In PDA cell lines, FOXA1/2 expression is consistently suppressed in experimental EMT models and RNAi silencing of FOXA1/2 alone is sufficient to induce EMT. Conversely, ectopic FOXA1/2 expression can potently neutralize several EMT-related E-cadherin repressive mechanisms. Finally, ectopic FOXA2 expression could reactivate E-cadherin expression in a PDA cell line with extensive promoter hypermethylation. In fact, demethylation-mediated reactivation of E-cadherin expression in these cells required concurrent reactivation of endogenous FOXA2 expression. We conclude that suppression of FOXA1/2 expression is both necessary and sufficient for EMT during PDA malignant progression.
Hemodynamic assessment of patients with pulmonary hypertension due to lung disease and/or hypoxia
Authors: Mario Gerges, Christian Gerges, Marie Lang, Irene Lang
Journal: European Respiratory Journal (2013)

PURPOSE: Current guidelines classify PH due to lung disease and/or hypoxia (group 3) as pre-capillary PH (mean pulmonary artery pressure (mPAP) ≥25mmHg and mean pulmonary capillary wedge pressure (mPCWP) ≤15mmHg). In the setting of lung disease, multiple mechanisms of disease play a role apart from classical pulmonary arteriopathy, hypoxia, hypercapnia, mechanical stress of hyperinflated lungs, emphysematous and fibrotic changes, inflammation and toxic effects of cigarette smoke. We hypothesized that a significant proportion of patients with PH due to lung diseases carries a post-capillary component.  METHODS: A large database (n=3107) of right and left heart catheterizations was interrogated.  RESULTS: Of 291 patients with PH due to lung disease, 96 patients had normal hemodynamics (“Non-PH” mPAP 15mmHg). Multivariate analysis identified stable ischemic heart disease as an independent predictor of survival (p=0.014).  CONCLUSION: The data demonstrate that a significant proportion of patients with PH due to lung disease suffers from post-capillary pulmonary hypertension.
Vitamin D Levels, Lung Function, and Steroid Response in Adult Asthma
Authors: E. Rand Sutherland, Elena Goleva, Leisa P. Jackson, Allen D. Stevens, Donald Y. M. Leung
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Patients with asthma exhibit variable response to inhaled corticosteroids (ICS). Vitamin D is hypothesized to exert effects on phenotype and glucocorticoid (GC) response in asthma.To determine the effect of vitamin D levels on phenotype and GC response in asthma.Nonsmoking adults with asthma were enrolled in a study assessing the relationship between serum 25(OH)D (vitamin D) concentrations and lung function, airway hyperresponsiveness (AHR), and GC response, as measured by dexamethasone-induced expression of mitogen-activated protein kinase phosphatase (MKP)-1 by peripheral blood mononuclear cells.A total of 54 adults with asthma (FEV(1), 82.9 +/- 15.7% predicted [mean +/- SD], serum vitamin D levels of 28.1 +/- 10.2 ng/ml) were enrolled. Higher vitamin D levels were associated with greater lung function, with a 22.7 (+/-9.3) ml (mean +/- SE) increase in FEV(1) for each nanogram per milliliter increase in vitamin D (P = 0.02). Participants with vitamin D insufficiency (<30 ng/ml) demonstrated increased AHR, with a provocative concentration of methacholine inducing a 20% fall in FEV(1) of 1.03 (+/-0.2) mg/ml versus 1.92 (+/-0.2) mg/ml in those with vitamin D of 30 ng/ml or higher (P = 0.01). In ICS-untreated participants, dexamethasone-induced MKP-1 expression increased with higher vitamin D levels, with a 0.05 (+/-0.02)-fold increase (P = 0.02) in MKP-1 expression observed for each nanogram per milliliter increase in vitamin D, a finding that occurred in the absence of a significant increase in IL-10 expression.In asthma, reduced vitamin D levels are associated with impaired lung function, increased AHR, and reduced GC response, suggesting that supplementation of vitamin D levels in patients with asthma may improve multiple parameters of asthma severity and treatment response. Clinical trials registered with www.clinicaltrials.gov (NCT00495157, NCT00565266, and NCT00557180).
The value of residual liver volume as a predictor of hepatic dysfunction and infection after major liver resection
Authors: M J Schindl, D N Redhead, K C H Fearon, O J Garden, S J Wigmore
Journal: Gut (2005)

<b>Background and aims:</b> Major liver resection incurs a risk of postoperative liver dysfunction and infection and there is a lack of objective evidence relating residual liver volume to these complications. <b>Patients and methods:</b> Liver volumetry was performed on computer models derived from computed tomography (CT) angioportograms of 104 patients with normal synthetic liver function scheduled for liver resection. Relative residual liver volume (%RLV) was calculated as the relation of residual to total functional liver volume and related to postoperative hepatic dysfunction and infection. Receiver operator characteristic curve analysis was undertaken to determine the critical %RLV predicting severe hepatic dysfunction and infection. Univariate analysis and multivariate logistic regression analysis were performed to delineate perioperative predictors of severe hepatic dysfunction and infection. <b>Results:</b> The incidence of severe hepatic dysfunction and infection following liver resection increased significantly with smaller %RLV. A critical %RLV of 26.6% was identified as associated with severe hepatic dysfunction (p&lt;0.0001). Additionally, body mass index (BMI), operating time, and intraoperative blood loss were significant prognostic indicators for severe hepatic dysfunction. It was not possible to predict the individual risk of postoperative infection precisely by %RLV. However, in patients undergoing major liver resection, infection was significantly more common in those who developed postoperative severe hepatic dysfunction compared with those who did not (p = 0.030). <b>Conclusions:</b> The likelihood of severe hepatic dysfunction following liver resection can be predicted by a small %RLV and a high BMI whereas postoperative infection is more related to liver dysfunction than precise residual liver volume. Understanding the relationship between liver volume and synthetic and immune function is the key to improving the safety of major liver resection.
Lipotoxicity in type 2 diabetic cardiomyopathy
Authors: Tineke van de Weijer, Vera B. Schrauwen-Hinderling, Patrick Schrauwen
Journal: Cardiovascular Research (2011)

As obesity and type 2 diabetes are becoming an epidemic in westernized countries, the incidence and prevalence of obesity- and diabetes-related co-morbidities are increasing. In type 2 diabetes ectopic lipid accumulation in the heart has been associated with cardiac dysfunction and apoptosis, a process termed lipotoxicity. Since cardiovascular diseases are the main cause of death in diabetic patients, diagnosis and treatment become increasingly important. Although ischaemic heart disease is a major problem in diabetes, non-ischaemic heart disease (better known as diabetic cardiomyopathy) becomes increasingly important with respect to the impairment of cardiac function and mortality in type 2 diabetes. The underlying aetiology of diabetic cardiomyopathy is incompletely understood but is beginning to be elucidated. Various mechanisms have been proposed that may lead to lipotoxicity. Therefore, this review will focus on the mechanisms of cardiac lipid accumulation and its relation to the development of cardiomyopathy.
First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial
Authors: Gareth J Morgan, Faith E Davies, Walter M Gregory, Kim Cocks, Sue E Bell, Alex J Szubert, Nuria Navarro-Coy, Mark T Drayson, Roger G Owen, Sylvia Feyler, A John Ashcroft, Fiona Ross, Jennifer Byrne, Huw Roddie, Claudius Rudin, Gordon Cook, Graham H Jackson, J Anthony Child
Journal: The Lancet (2010)
Gastric Cancer: Apples Will Always Be Apples
Authors: Jaffer A. Ajani, Mariela A. Blum, Jeannelyn S. Estrella, Prajnan Das, Keith F. Fournier
Journal: Journal of Clinical Oncology (2012)

TO THE EDITOR: Macdonald’s editorial 1 is instructive and provides a great deal of depth and breadth on the subject of adjunctive therapy for gastric cancer. The issue raised is a subject of debate in the West and a resolution is not in sight. We want to emphasize three points that we believe are quite pertinent to this issue and need further discussion. The first point is related to the cross-study comparison of outcomes. It is quite likely that patient susceptibility (patient genetics) factors and carcinogenic forces that lead to the development of gastric cancer are different in different regions; however, the literature on this topic remains sparse and inconclusive. In addition to the assumption that Japanese gastric cancer is biologically different than western gastric cancer, the surgical techniques in the two regions are starkly different. This significantly limits the comparisons among studies. It may be safer to assume that western patients (such as those enrolled in the Intergroup 0116 trial 2 ) were simply grossly understaged for nodal stage. The median number of nodes examined in the ACTS-GC trial (Adjuvant Chemotherapy Trial of TS-1 for Gastric Cancer) 3 is likely to be considerably higher than in the Intergroup 0116 trial. There is a well-documented phenomenon of rampant nodal stage up-migration by carrying out a D2 dissection. 4 Finally, as more nodes are examined/removed, the better is the survival of patients with gastric cancer. 5 Thus, we argue that Western patients are understaged (and undertreated surgically) compared with Japanese patients who not only have adequate nodal staging but also potentially derive a survival benefit from the removal of negative nodes. We must consider these differences when comparing results across studies. Could we argue that a D2 dissection is better than D1 dissection? Yes and no. Yes, because you get proper nodal staging and you also remove more negative nodes and this seems to prolong survival. No, because the results of randomized trials in the West do not support D2 dissection, however none of the Western gastric cancer surgical trials was conducted ideally. The second point is regarding D2 dissection and its loose defini
Drug-Eluting Stents vs. Coronary-Artery Bypass Grafting in Multivessel Coronary Disease
Authors: Edward L. Hannan, Chuntao Wu, Gary Walford, Alfred T. Culliford, Jeffrey P. Gold, Craig R. Smith, Robert S.D. Higgins, Russell E. Carlson, Robert H. Jones
Journal: New England Journal of Medicine (2008)

Numerous studies have compared the outcomes of two competing interventions for multivessel coronary artery disease: coronary-artery bypass grafting (CABG) and coronary stenting. However, little information has become available since the introduction of drug-eluting stents.
PARANA HARD-SKIN SYNDROME: STUDY OF SEVEN FAMILIES
Authors: Izrail Cat, NeivaI. Rodrigues Magdalena, Leide Parolin Marinoni, Mei Pu Wong, OrlandoT. Freitas, A. Malfi, Orival Costa, Lucio Esteves, DinarteJ. Giraldi, JohnM. Opitz
Journal: The Lancet (1974)
IL-9 and its receptor are predominantly involved in the pathogenesis of UC
Authors: Nancy Nalleweg, Mircea Teodor Chiriac, Eva Podstawa, Christian Lehmann, Tilman T Rau, Raja Atreya, Ekaterina Krauss, Gheorghe Hundorfean, Stefan Fichtner-Feigl, Arndt Hartmann, Christoph Becker, Jonas Mudter
Journal: Gut (2014)

<h3>Objective</h3> Several pathogenic roles attributed over the past two decades to either T helper (Th)1 or Th2 cells are increasingly becoming associated with interleukin (IL)-17 and most recently IL-9 signalling. However, the implication of IL-9 in IBD has not been addressed so far. <h3>Design</h3> We investigated the expression of IL-9 and IL-9R by using peripheral blood, biopsies and surgical samples. We addressed the functional role of IL-9 signalling by analysis of downstream effector proteins. Using Caco-2 cell monolayers we followed the effect of IL-9 on wound healing. <h3>Results</h3> IL-9 mRNA expression was significantly increased in inflamed samples from patients with UC as compared with controls. CD3<sup>+</sup> T cells were major IL-9-expressing cells and some polymorphonuclear leucocytes (PMN) also expressed IL-9. IL-9 was co-localised with the key Th9 transcription factors interferon regulatory factor 4 and PU.1. Systemically, IL-9 was abundantly produced by activated peripheral blood lymphocytes, whereas its receptor was overexpressed on gut resident and circulating PMN. IL-9 stimulation of the latter induced IL-8 production in a dose-dependent manner and rendered PMN resistant to apoptosis suggesting a functional role for IL-9R signalling in the propagation of gut inflammation. Furthermore, IL-9R was overexpressed on gut epithelial cells and IL-9 induced STAT5 activation in these cells. Moreover, IL-9 inhibited the growth of Caco-2 epithelial cell monolayers in wound healing experiments. <h3>Conclusions</h3> Our results provide evidence that IL-9 is predominantly involved in the pathogenesis of UC suggesting that targeting IL-9 might become a therapeutic option for patients with UC.
Monitoring for Lack of Benefit: A Critical Component of a Randomized Clinical Trial
Authors: Boris Freidlin, Edward L. Korn
Journal: Journal of Clinical Oncology (2008)

To balance patient interests against the need for acquiring evidence, ongoing randomized clinical trials are formally monitored for early convincing indication of benefit or lack of benefit. In lethal diseases like cancer, where new therapies are often toxic and may have limited preliminary efficacy data, monitoring for lack of benefit is particularly important. We review the complex nature of stopping a randomized trial for lack of benefit and argue that many cancer trials could be improved by a more aggressive approach to monitoring. On the other hand, we caution that some commonly used monitoring guidelines may result in stopping for lack of benefit even when a nontrivial beneficial effect is observed.
Inhaled corticosteroids and hospitalisation due to exacerbation of COPD
Authors: J. Bourbeau, P. Ernst, D. Cockcoft, S. Suissa
Journal: European Respiratory Journal (2003)

Previous studies have provided conflicting evidence as to the possible benefits of inhaled corticosteroids in the treatment of chronic obstructive pulmonary disease (COPD). Using the Saskatchewan healthcare databases subjects were identified who were aged ≥55 yrs, initiating regular treatment for COPD but without any prior treatment for asthma. In the current nested case-control analysis, the authors concentrated on 1,742 subjects with a first hospitalisation for COPD after January 1, 1990 and examined whether the use of inhaled corticosteroids was associated with a change in the risk of a subsequent hospitalisation for COPD. The cases consisted of 846 patients with a subsequent hospitalisation for COPD. These were matched on age, time since the prior hospitalisation and use of other respiratory therapy to all possible person moments in the cohort without rehospitalisation. After further adjustment for comorbidity, sex, calendar year and intensity of other drug therapy, inhaled corticosteroids were not significantly associated with risk of a subsequent COPD hospitalisation. Even relatively high doses of inhaled corticosteroids, &gt;800 µg of beclomethasone or the equivalent per day, were not associated with the risk of COPD hospitalisation. No reduction in chronic obstructive pulmonary disease exacerbations requiring hospitalisation, in relation to the use of inhaled corticosteroids, were observed.
Complete absence of the inferior vena cava presenting as a paraspinous mass.
Authors: L B Milner, R Marchan
Journal: Thorax (1980)

Dilatation of the azygos-hemiazygos venous system presenting as paravertebral masses may be seen in intrahepatic and extrahepatic portal vein obstruction, anomalous pulmonary venous return, occlusion of the superior and inferior vena cava, persistence of the left superior vena cava, hepatic vein obstruction, eleva- tion of central venous pressure as in congestive heart failure, pericardial effusion, constrictive pericarditis, pregnancy, and isolated aneurysms of the azygos vein.' a : :Although prominence of the azygos vein is a well- known finding with infrahepatic interruption of the inferior vena cava or persistence of the supracardinal vein, it has not been described to our knowledge in complete absence of the inferior vena cava.-
Modulation of Protective T Cell Immunity by Complement Inhibitor Expression on Tumor Cells
Authors: Juan C. Varela, Masaki Imai, Carl Atkinson, Rieko Ohta, Michelle Rapisardo, Stephen Tomlinson
Journal: Cancer Research (2008)

Abstract Complement-inhibitory proteins expressed on cancer cells can provide protection from antitumor antibodies and may potentially modulate the induction of an immune response to tumor-associated antigens. In the current study, we investigated the consequences of complement inhibitor down-regulation on the effector and inductive phases of an immune response. Stable small interfering RNA–mediated down-regulation of the complement inhibitor Crry on MB49 murine bladder cancer cells increased their susceptibility to monoclonal antibody and complement in vitro. In a syngeneic model of metastatic cancer, the down-regulation of Crry on i.v.-injected MB49 cells was associated with a significant decrease in tumor burden and an increase in the survival of challenged mice. However, monoclonal antibody therapy had no additional benefit. There was an antitumor IgG response, but the response was not effected by Crry down-regulation on inoculated tumor cells. Down-regulation of Crry on MB49 cells resulted in an enhanced antitumor T-cell response in challenged mice (measured by lymphocyte IFN-γ secretion), and CD8+ T cell depletion of mice prior to injection of MB49 cells completely abrogated the effect of Crry down-regulation on tumor burden and survival. Deficiency of C3 also abrogated the effect of Crry down-regulation on the survival of MB49-challenged mice, indicating a complement-dependent mechanism. These data indicate that complement inhibitors expressed on a tumor cell can suppress a T cell response and that enhancing complement activation on a tumor cell surface can promote protective T cell immunity. [Cancer Res 2008;68(16):6734–42]