bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bortezomib treatment and regulatory T-cell depletion enhance the antitumor effects of adoptively infused NK cells
Authors: Lundqvist Andreas , Yokoyama Hisayuki , Smith Aleah , Berg Maria , Childs Richard 
Published: February 2009

AbstractLigation of inhibitory receptors renders natural killer (NK) cells inactive against autologous tumors. Recently, the proteasome inhibitor bortezomib was shown to sensitize tumors to autologous NK-cell cytotoxicity in vitro. Here, we show bortezomib augments the antitumor effects of syngeneic NK-cell infusions in tumor-bearing animals; this effect is further enhanced in regulatory T cell (Treg cell)–depleted hosts. In vitro, bortezomib-treated tumors had higher tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) and perforin/granzyme-mediated caspase-8 activity, which enhanced their susceptibility to NK-cell lysis. Bioluminescence imaging of mice with established tumors showed treatment with bortezomib and syngeneic NK cells reduced tumor growth and prolonged survival compared with controls receiving bortezomib or NK cells alone. In contrast, tumor progression was not delayed when animals received bortezomib and perforin-deficient NK cells, showing drug-induced augmentation in NK-cell cytotoxicity was mediated through perforin/granzyme. Furthermore, tumor growth was slower in bortezomib-treated recipients when host Treg cells were eradicated with anti-CD25 antibody before infusing NK cells compared with mice without Treg-cell ablation (tumor doubling time, 16.7 vs 4.9 days, respectively; P = .02). These findings suggest that depletion of Treg cells followed by bortezomib-induced tumor sensitization to autologous NK cells could be used as a novel strategy to treat cancer.
Joint effect of obesity andTNFAvariability on asthma: two international cohort studies
Authors: Castro-Giner F. , Kogevinas M. , Imboden M. , de Cid R. , Jarvis D. , Mächler M. , Berger W. , Burney P. , Franklin K. A. , Gonzalez J. R. , Heinrich J. , Janson C. , Omenaas E. , Pin I. , Rochat T. , Sunyer J. , Wjst M. , Antó J-M. , Estivill X. , Probst-Hensch N. M. 
Published: February 2009

Obesity is a risk factor for asthma. Adipose tissue expresses pro-inflammatory molecules including tumour necrosis factor (TNF), and levels of TNF are also related to polymorphisms in the TNF-α (TNFA) gene. The current authors examined the joint effect of obesity andTNFAvariability on asthma in adults by combining two population-based studies.The European Community Respiratory Health Survey and the Swiss Cohort Study on Air Pollution and Lung and Heart Disease in Adults used comparable protocols, questionnaires and measures of lung function and atopy. DNA samples from 9,167 participants were genotyped forTNFA -308and lymphotoxin-α (LTA)+252gene variants.Obesity andTNFAwere associated with asthma when mutually adjusting for their independent effects (odds ratio (OR) for obesity 2.4, 95% confidence interval (CI) 1.7–3.2; OR forTNFA -308polymorphism 1.3, 95% CI 1.1–1.6). The association of obesity with asthma was stronger for subjects carrying theG/AandA/ATNFA -308genotypes compared with the more commonG/Ggenotype, particularly among nonatopics (OR forG/AandA/Agenotypes 6.1, 95% CI 2.5–14.4; OR forG/Ggenotype 1.7, 95% CI 0.8–3.3).The present findings provide, for the first time, evidence for a complex pattern of interaction between obesity, a pro-inflammatory genetic factor and asthma.
COPD prevalence is increased in lung cancer, independent of age, sex and smoking history
Authors: Young R. P. , Hopkins R. J. , Christmas T. , Black P. N. , Metcalf P. , Gamble G. D. 
Published: February 2009

Chronic obstructive pulmonary disease (COPD) is a common comorbid disease in lung cancer, estimated to affect 40–70% of lung cancer patients, depending on diagnostic criteria. As smoking exposure is found in 85–90% of those diagnosed with either COPD or lung cancer, coexisting disease could merely reflect a shared smoking exposure. Potential confounding by age, sex and pack-yr smoking history, and/or by the possible effects of lung cancer on spirometry, may result in over-diagnosis of COPD prevalence.In the present study, the prevalence of COPD (pre-bronchodilator Global Initiative for Chronic Obstructive Lung Disease 2+ criteria) in patients diagnosed with lung cancer was 50% compared with 8% in a randomly recruited community control group, matched for age, sex and pack-yr smoking exposure (n = 602, odds ratio 11.6; p<0.0001).In a subgroup analysis of those with lung cancer and lung function measured prior to the diagnosis of lung cancer (n = 127), we found a nonsignificant increase in COPD prevalence following diagnosis (56–61%; p = 0.45). After controlling for important variables, the prevalence of COPD in newly diagnosed lung cancer cases was six-fold greater than in matched smokers; this is much greater than previously reported.We conclude that COPD is both a common and important independent risk factor for lung cancer.
Effect of low-dose theophylline plus beclometasone on lung function in smokers with asthma: a pilot study
Authors: Spears M. , Donnelly I. , Jolly L. , Brannigan M. , Ito K. , McSharry C. , Lafferty J. , Chaudhuri R. , Braganza G. , Adcock I. M. , Barnes P. J. , Wood S. , Thomson N. C. 
Published: February 2009

Smoking is common in asthma and is associated with worse asthma control and a reduced therapeutic response to corticosteroids. The present authors hypothesised that treating smokers with asthma with low-dose theophylline added to inhaled corticosteroids would enhance steroid sensitivity and thereby improve lung function and symptoms.In a double-blind, parallel group exploratory trial, 68 asthmatic smokers were randomised to one of three treatments for 4 weeks: inhaled beclometasone (200 μg·day−1), theophylline (400 mg·day−1) or both treatments combined. Outcome measures included change in lung function and Asthma Control Questionnaire (ACQ) scores.At 4 weeks, theophylline added to inhaled beclometasone produced an improvement in peak expiratory flow (39.9 L·min−1, 95% confidence intervals (CI) 10.9–68.8) and ACQ score (-0.47, 95% CI -0.91– -0.04) and a borderline improvement in pre-bronchodilator forced expiratory volume in one second (mean difference 165 mL, 95% CI -13–342) relative to inhaled corticosteroid alone. Theophylline alone improved the ACQ score (-0.55, 95% CI -0.99– -0.11), but not lung function.In the present pilot study, the combination of low-dose theophylline and inhaled beclometasone produced improvements in both lung function and symptoms in a group of smokers with asthma. Larger trials are required to extend and confirm these findings.
Exploring the role of CT densitometry: a randomised study of augmentation therapy in α1-antitrypsin deficiency
Authors: Dirksen A. , Piitulainen E. , Parr D. G. , Deng C. , Wencker M. , Shaker S. B. , Stockley R. A. 
Published: February 2009

Assessment of emphysema-modifying therapy is difficult, but newer outcome measures offer advantages over traditional methods. The EXAcerbations and Computed Tomography scan as Lung End-points (EXACTLE) trial explored the use of computed tomography (CT) densitometry and exacerbations for the assessment of the therapeutic effect of augmentation therapy in subjects with α1-antitrypsin (α1-AT) deficiency.In total, 77 subjects (protease inhibitor type Z) were randomised to weekly infusions of 60 mg·kg−1human α1-AT (Prolastin®) or placebo for 2–2.5 yrs. The primary end-point was change in CT lung density, and an exploratory approach was adopted to identify optimal methodology, including two methods of adjustment for lung volume variability and two statistical approaches. Other end-points were exacerbations, health status and physiological indices.CT was more sensitive than other measures of emphysema progression, and the changes in CT and forced expiratory volume in 1 s were correlated. All methods of densitometric analysis concordantly showed a trend suggestive of treatment benefit (p-values for Prolastin®versusplacebo ranged 0.049–0.084). Exacerbation frequency was unaltered by treatment, but a reduction in exacerbation severity was observed.In patients with α1-AT deficiency, CT is a more sensitive outcome measure of emphysema-modifying therapy than physiology and health status, and demonstrates a trend of treatment benefit from α1-AT augmentation.
Analysis of small nucleolar RNAs reveals unique genetic features in malaria parasites
Authors: Mishra Prakash Chandra , Kumar Anuj , Sharma Amit 
Published: February 2009

AbstractBackgroundRibosome biogenesis is an energy consuming and stringently controlled process that involves hundreds of trans-acting factors. Small nucleolar RNAs (snoRNAs), important components of ribosome biogenesis are non-coding guide RNAs involved in rRNA processing, nucleotide modifications like 2'-O-ribose methylation, pseudouridylation and possibly gene regulation. snoRNAs are ubiquitous and are diverse in their genomic organization, mechanism of transcription and process of maturation. In vertebrates, most snoRNAs are present in introns of protein coding genes and are processed by exonucleolytic cleavage, while in plants they are transcribed as polycistronic transcripts.ResultsThis is a comprehensive analysis of malaria parasite snoRNA genes and proteins that have a role in ribosomal biogenesis. Computational and experimental approaches have been used to identify several box C/D snoRNAs from different species ofPlasmodiumand confirm their expression. Our analyses reveal that the gene for endoribonuclease Rnt1 is absent fromPlasmodium falciparumgenome, which indicates the existence of alternative pre-rRNA processing pathways. The structural features of box C/D snoRNAs are highly conserved inPlasmodiumgenus; however, unlike other organisms most parasite snoRNAs are present in single copy. The genomic localization of parasite snoRNAs shows mixed patterns of those observed in plants, yeast and vertebrates. We have localized parasite snoRNAs in untranslated regions (UTR) of mRNAs, and this is an unprecedented and novel genetic feature. Akin to mammalian snoRNAs, those inPlasmodiummay also behave as mobile genetic elements.ConclusionThis study provides a comprehensive overview on trans-acting genes involved in ribosome biogenesis and also a genetic insight into malaria parasite snoRNA genes.
PGC-1alphaas modifier of onset age in Huntington disease
Authors: Taherzadeh-Fard Elahe , Saft Carsten , Andrich Jürgen , Wieczorek Stefan , Arning Larissa 
Published: February 2009

Abstract
Although there is a strong correlation between CAG repeat length and age at onset (AO) of motor symptoms, individual Huntington disease (HD) patients may differ dramatically in onset age and disease manifestations despite similar CAG repeat lengths. This has led to a search for genetic factors that influence AO. In order to identify such a genetic modifier, we analysed polymorphisms in the PGC-1alpha gene. Recent data indicate inhibition of PGC-1alpha function by mutant Htt supporting a link between transcriptional deregulation and mitochondrial dysfunction in HD. In > 400 HD patients, a polymorphism located within intron 2, a potential recombination hot spot, explains a small, but statistically significant, amount of the variability in AO. Our data suggest that PGC-1alpha has modifying effects on the pathogenic process in HD.
Dysregulation of CXCL9 and reduced tumor growth in Egr-1 deficient mice
Authors: Caso Giuseppe , Barry Catherine , Patejunas Gerald 
Published: February 2009

Abstract

Background
Early growth response-1 (Egr-1) is an immediate-early transcription factor inducible in the vasculature in response to injury, shear stress, and other stimuli. Mice lacking Egr-1 have a profound deficit in the ability to recover from femoral artery ligation, suggesting a role in neovascularization. Previous studies have shown that manipulating Egr-1 expression can have either positive or negative effects on tumor growth. We hypothesized that Egr-1 knockout mice might exhibit reduced tumor growth, possibly due to a reduced capacity to respond to angiogenic signals from a growing tumor.

Results
We injected 106 Lewis lung carcinoma (LLC1) cells subcutaneously in the flank of wild type and Egr-1 knockout mice. The average mass of tumors from wild type mice at 12 days after implantation was 413 +/- 128 mg, while those from Egr-1-/- mice was 219 +/- 81 mg (p = 0.001, mean +/- SD). However, sectioning the tumors and staining with anti-CD31 antibodies revealed no difference in the vascularity of the tumors and there was no difference in angiogenic growth factor expression. Expression of the chemokine Mig (CXCL9) was increased 2.8-fold in tumors from knockout mice, but no increase was found in serum levels of Mig. Natural killer cells have a 1.7-fold greater prevalence in the CD45+ cells found in tumors from Egr-1-/- mice compared to those from wild type mice. Immunohistochemical staining suggests that Mig expression in the tumors comes from invading macrophages.

Conclusion
Mice deficient in Egr-1 exhibit reduced growth of LLC1 tumors, and this phenomenon is associated with overexpression of Mig locally within the tumor. There are no obvious differences in tumor vascularity in the knockout mice. Natural killer cells accumulate in the tumors grown in Egr-1-/- mice, providing a potential mechanism for the reduction in growth.
Distinct synovial immunopathology in Behçet disease and psoriatic arthritis
Authors: Cañete Juan D , Celis Raquel , Noordenbos Troy , Moll Conchita , Gómez-Puerta Jose A , Pizcueta Pilar , Palacin Antonio , Tak Paul P , Sanmartí Raimon , Baeten Dominique 
Published: February 2009

Abstract
Introduction
The aim of the study was to investigate synovial immunopathology differences between early Behçet disease (BD) and psoriatic arthritis (PsA).

Methods
Needle arthroscopy of an inflamed knee joint was performed in patients with early untreated BD (n = 8) and PsA (n = 9). Synovial fluid (SF) was collected for cytokines, perforin, and granzyme analysis. Eight synovial biopsies per patient were obtained for immunohistochemical analysis of the cellular infiltrate (T cells, natural killer cells, macrophages, B cells, plasma cells, mast cells, and neutrophils), blood vessels as well as expression of perforin and granzyme. The stained slides were evaluated by digital image analysis.

Results
The global degree of synovial inflammation was similar in the two types of arthritis. In the analysis of the innate immune cell infiltration, there was a striking neutrophilic inflammation in BD synovitis whereas PsA displayed significantly higher numbers of cells positive for c-kit, a marker of mast cells. As for lymphocytes, CD3+ T cells, but neither CD20+ B cells nor CD138+ plasma cells, were significantly increased in BD versus PsA. Further analysis of the T-lymphocyte population showed no clear shift in CD4/CD8 ratio or Th1/Th2/Th17 profile. The SF levels of perforin, an effector molecule of cytotoxic cells, displayed a significant four- to fivefold increase in BD.

Conclusions
This systematic comparative analysis of early untreated synovitis identifies neutrophils and T lymphocytes as important infiltrating cell populations in BD. Increased levels of perforin in BD suggest the relevance of cytotoxicity in this disease.
Impaired vascular responses to parasympathetic nerve stimulation and muscarinic receptor activation in the submandibular gland in nonobese diabetic mice
Authors: Berggreen Ellen , Nyløkken Krister , Delaleu Nicolas , Hajdaragic-Ibricevic Hamijeta , Jonsson Malin V 
Published: February 2009

Abstract
Introduction
Decreased vascular responses to salivary gland stimulation are observed in Sjögren's syndrome patients. We investigate whether impaired vascular responses to parasympathetic stimulation and muscarinic receptor activation in salivary glands parallels hyposalivation in an experimental model for Sjögren's syndrome.

Methods
Blood flow responses in the salivary glands were measured by laser Doppler flowmeter. Muscarinic receptor activation was followed by saliva secretion measurements. Nitric oxide synthesis-mediated blood flow responses were studied after administration of a nitric oxide synthase inhibitor. Glandular autonomic nerves and muscarinic 3 receptor distributions were also investigated.

Results
Maximal blood flow responses to parasympathetic stimulation and muscarinic receptor activation were significantly lower in nonobese diabetic (NOD) mice compared with BALB/c mice, coinciding with impaired saliva secretion in nonobese diabetic mice (P < 0.005). Nitric oxide synthase inhibitor had less effect on blood flow responses after parasympathetic nerve stimulation in nonobese diabetic mice compared with BALB/c mice (P < 0.02). In nonobese diabetic mice, salivary gland parasympathetic nerve fibres were absent in areas of focal infiltrates. Muscarinic 3 receptor might be localized in the blood vessel walls of salivary glands.

Conclusions
Impaired vasodilatation in response to parasympathetic nerve stimulation and muscarinic receptor activation may contribute to hyposalivation observed in nonobese diabetic mice. Reduced nitric oxide signalling after parasympathetic nerve stimulation may contribute in part to the impaired blood flow responses. The possibility of muscarinic 3 receptor in the vasculature supports the notion that muscarinic 3 receptor autoantibodies present in nonobese diabetic mice might impair the fluid transport required for salivation. Parasympathetic nerves were absent in areas of focal infiltrates, whereas a normal distribution was found within glandular epithelium.

Trial registration
The trial registration number for the present study is 79-04/BBB, given by the Norwegian State Commission for Laboratory Animals.
Characteristics and outcomes of cancer patients in European ICUs
Authors: Taccone Fabio Silvio , Artigas Antonio A , Sprung Charles L , Moreno Rui , Sakr Yasser , Vincent Jean-Louis 
Published: February 2009

Abstract
Introduction
Increasing numbers of cancer patients are being admitted to the intensive care unit (ICU), either for cancer-related complications or treatment-associated side effects, yet there are relatively few data concerning the epidemiology and prognosis of cancer patients admitted to general ICUs. The aim of this study was to assess the characteristics of critically ill cancer patients, and to evaluate their prognosis.

Methods
This was a substudy of the Sepsis Occurrence in Acutely Ill Patients (SOAP) study, a cohort, multicentre, observational study that included data from all adult patients admitted to one of 198 participating ICUs from 24 European countries during the study period. Patients were followed up until death, hospital discharge or for 60 days.

Results
Of the 3147 patients enrolled in the SOAP study, 473 (15%) had a malignancy, 404 (85%) had solid tumours and 69 (15%) had haematological cancer. Patients with solid cancers had the same severity of illness as the non-cancer population, but were older, more likely to be a surgical admission and had a higher frequency of sepsis. Patients with haematological cancer were more severely ill and more commonly had sepsis, acute lung injury/acute respiratory distress syndrome, and renal failure than patients with other malignancies; these patients also had the highest hospital mortality rate (58%). The outcome of all cancer patients was comparable with that in the non-cancer population, with a 27% hospital mortality rate. However, in the subset of patients with more than three failing organs, more than 75% of patients with cancer died compared with about 50% of patients without cancer (p = 0.01).

Conclusions
In this large European study, patients with cancer were more often admitted to the ICU for sepsis and respiratory complications than other ICU patients. Overall, the outcome of patients with solid cancer was similar to that of ICU patients without cancer, whereas patients with haematological cancer had a worse outcome.
α-1-Antitrypsin is an endogenous inhibitor of proinflammatory cytokine production in whole blood
Authors: Pott Gregory B , Chan Edward D , Dinarello Charles A , Shapiro Leland 
Published: February 2009

AbstractSeveral observations suggest endogenous suppressors of inflammatory mediators are present in human blood. α-1-Antitrypsin (AAT) is the most abundant serine protease inhibitor in blood, and AAT possesses anti-inflammatory activity in vitro and in vivo. Here, we show that in vitro stimulation of whole blood from persons with a genetic AAT deficiency resulted in enhanced cytokine production compared with blood from healthy subjects. Using whole blood from healthy subjects, dilution of blood with RPMI tissue-culture medium, followed by incubation for 18 h, increased spontaneous production of IL-8, TNF-α, IL-1β, and IL-1R antagonist (IL-1Ra) significantly, compared with undiluted blood. Dilution-induced cytokine production suggested the presence of one or more circulating inhibitors of cytokine synthesis present in blood. Serially diluting blood with tissue-culture medium in the presence of cytokine stimulation with heat-killed Staphylococcus epidermidis (S. epi) resulted in 1.2- to 55-fold increases in cytokine production compared with S. epi stimulation alone. Diluting blood with autologous plasma did not increase the production of IL-8, TNF-α, IL-1β, or IL-1Ra, suggesting that the endogenous, inhibitory activity of blood resided in plasma. In whole blood, diluted and stimulated with S. epi, exogenous AAT inhibited IL-8, IL-6, TNF-α, and IL-1β significantly but did not suppress induction of the anti-inflammatory cytokines IL-1Ra and IL-10. These ex vivo and in vitro observations suggest that endogenous AAT in blood contributes to the suppression of proinflammatory cytokine synthesis.
Pivotal Advance: Up-regulation of acetylcholine synthesis and paracrine cholinergic signaling in intravascular transplant leukocytes during rejection of rat renal allografts
Authors: Hecker Andreas , Mikulski Zbigniew , Lips Katrin S , Pfeil Uwe , Zakrzewicz Anna , Wilker Sigrid , Hartmann Petra , Padberg Winfried , Wessler Ignaz , Kummer Wolfgang , Grau Veronika 
Published: February 2009

AbstractA new role and source of the old mediator acetylcholine is described, which is produced by graft monocytes and attenuates monocytic ATP-signaling.During acute rejection, large numbers of leukocytes accumulate in the blood vessels of experimental renal allografts. About 70% of them are activated, cytotoxic monocytes that appear to be involved in allograft destruction. ACh exerts anti-inflammatory effects upon monocytes/macrophages and has been proposed to be a key player in neuroimmunological interactions. Its short half-life, however, makes it unlikely that neuronal ACh affects blood leukocytes. Renal transplantation was performed in the allogeneic DA to LEW and in the isogeneic LEW to LEW rat strain combination. Intravascular leukocytes were harvested after 4 days, and the expression of CHT1, cChAT, pChAT, and nAChR subunits was investigated by RT-PCR, immunoblotting, and immunohistochemistry. Monocytes were identified by double-labeling with ED1-antibody, directed to a CD68-like antigen. ACh content was measured by HPLC. [Ca2+]i was monitored by Fura-2. Intravascular graft leukocytes express CHT1 and cChAT mRNA and protein and pChAT protein. Their expression is strongly up-regulated in vivo during acute allograft rejection. Immunohistochemistry revealed CHT1, cChAT, and pChAT protein in ED1-positive monocytes. The ACh content of allograft intravascular leukocytes was sixfold higher than that of isografts. Intravascular leukocytes express nAChR subunits, and an ATP-induced increase in [Ca2+]i was augmented in vitro by a nAChR inhibitor in allograft but not isograft leukocytes. Intravascular graft leukocytes, among them monocytes, up-regulate non-neuronal ACh synthesis and develop auto-/paracrine cholinergic attenuation of ATP signaling during acute allograft rejection.