tbuckley/cabot-search huggingface dataset:
Prognostic Significance of POLE Proofreading Mutations in Endometrial Cancer
Authors: David N. Church, Ellen Stelloo, Remi A. Nout, Nadejda Valtcheva, Jeroen Depreeuw, Natalja ter Haar, Aurelia Noske, Frederic Amant, Ian P. M. Tomlinson, Peter J. Wild, Diether Lambrechts, Ina M. Jürgenliemk-Schulz, Jan J. Jobsen, Vincent T. H. B. M. Smit, Carien L. Creutzberg, Tjalling Bosse
Journal: JNCI Journal of the National Cancer Institute (2014)

Background:Current risk stratification in endometrial cancer (EC) results in frequent over- and underuse of adjuvant therapy, and may be improved by novel biomarkers. We examined whether POLE proofreading mutations, recently reported in about 7% of ECs, predict prognosis.
YKL-40, a Marker of Inflammation and Endothelial Dysfunction, Is Elevated in Patients With Type 1 Diabetes and Increases With Levels of Albuminuria
Authors: Camilla Noelle Rathcke, Frederik Persson, Lise Tarnow, Peter Rossing, Henrik Vestergaard
Journal: Diabetes Care (2008)

The inflammation marker YKL-40 is elevated in patients with type 2 diabetes and is associated with atherosclerosis and increased cardiovascular mortality. In the present study, YKL-40 levels were examined in patients with type 1 diabetes with increasing levels of albuminuria, known to be associated with an increased risk of cardiovascular disease.A total of 149 patients with type 1 diabetes attending Steno Diabetes Center were examined: 58 had normoalbuminuria (urinary albumin excretion rate <30 mg/24 h), 46 had persistent microalbuminuria (urinary albumin excretion rate 30-300 mg/24 h), and 45 had persistent macroalbuminuria/diabetic nephropathy (urinary albumin excretion rate >300 mg/24 h). The control group consisted of 55 healthy individuals. Groups were matched according to sex and duration of diabetes (>30 years).Median levels [interquartile range] of serum YKL-40 were significantly higher in normoalbuminuria versus control (37 [29-52] vs. 53 [32-105] ng/ml, P < 0.01) and were increasing with increasing levels of albuminuria (microalbuminuria 74 [45-160] ng/ml and diabetic nephropathy 117 [68-215] ng/ml; P < 0.001 for all comparisons). YKL-40 levels correlated with the urinary albumin-to-creatinine ratio in the total group of participants (r2 = 0.25, P < 0.001). Significant but weak intercorrelations of YKL-40 were found with age, diastolic blood pressure, A1C, and serum creatinine. After adjustment for significant covariates, albuminuria was significantly associated with YKL-40 levels (P < 0.001).YKL-40 levels are elevated in patients with type 1 diabetes with an independent association between increasing YKL-40 levels and increasing levels of albuminuria. The present study is the first to suggest a role of YKL-40 in the gradually progressing vascular complications in patients with type 1 diabetes.
Erratum: IL-4 inhibits TGF-β-induced Foxp3+ T cells and, together with TGF-β, generates IL-9+ Foxp3− effector T cells
Authors: Valérie Dardalhon, Amit Awasthi, Hyoung Kwon, George Galileos, Wenda Gao, Raymond A Sobel, Meike Mitsdoerffer, Terry B Strom, Wassim Elyaman, I-Cheng Ho, Samia Khoury, Mohamed Oukka, Vijay K Kuchroo
Journal: Nature Immunology (2009)
The Annals, EULAR and the future of rheumatology
Authors: L. VAN DE PUTTE
Journal: Annals of the Rheumatic Diseases (2000)

The Annals of the Rheumatic Diseases is now the official journal of the European League against Rheumatism (EULAR). This is a hallmark for both EULAR and the Annals . EULAR, the umbrella organisation of the European professional societies dealing with rheumatic diseases is of growing importance for European rheumatology. This certainly relates to the continuing integration process between European countries, which has far reaching consequences for national health care systems and therefore for patients and doctors. It also …
Burden of comorbidity in individuals with asthma
Authors: A. S. Gershon, C. Wang, J. Guan, T. To
Journal: Thorax (2010)

<h3>Background and aims</h3> Asthma comorbidity, such as depression and obesity, has been associated with greater healthcare use, decreased quality of life and poor asthma control. Treating this comorbidity has been shown to improve asthma outcomes as well as overall health. Despite this, asthma comorbidity remains relatively under-recognised and understudied—perhaps because most asthma occurs in young people who are believed to be healthy and relatively free of comorbidity. The aim of this study was to quantify empirically the amount of comorbidity associated with asthma. <h3>Methods</h3> A population-based cohort study was conducted using the health administrative data of the 12 million residents of Ontario, Canada in 2005. A validated health administrative algorithm was used to identify individuals with asthma. <h3>Results</h3> The amount of comorbidity among individuals with asthma, as reflected in rates of hospitalisations, emergency department visits and ambulatory care claims, was found to be substantial and much greater than that observed among individuals without asthma. Together, asthma and asthma comorbidity (the extra comorbidity found in individuals with asthma compared with those without asthma) were associated with 6% of all hospitalisations, 9% of all emergency room visits and 6% of all ambulatory care visits that occurred in Ontario. <h3>Conclusions</h3> Asthma comorbidity places a significant burden on individuals and the healthcare system and should be considered in the management of asthma. Further research should focus on which types of asthma comorbidity are responsible for the greatest burden and how such comorbidity should be prevented and managed.
Imaging and Other Biomarkers in Early Clinical Studies: One Step at a Time or Re-Engineering Drug Development?
Authors: Jerry M. Collins
Journal: Journal of Clinical Oncology (2005)

In this issue of the Journal of Clinical Oncology, the clinical and imaging aspects are described for the first-in-human study of AG-013736, an oral inhibitor of angiogenesis. As for all initial human studies, there are some interesting twists, such as unexpected toxicity at low doses. However, perhaps the most important finding was that magnetic resonance imaging technology for blood-flow measurement can be standardized to yield consistent results in an early clinical trial at three separate institutions. This consistency is a key requirement for the adoption of imaging technology by drug developers.
Inhibition of PI3Kδ Restores Glucocorticoid Function in Smoking-induced Airway Inflammation in Mice
Authors: John A. Marwick, Gaetano Caramori, Christopher S. Stevenson, Paolo Casolari, Elen Jazrawi, Peter J. Barnes, Kazuhiro Ito, Ian M. Adcock, Paul A. Kirkham, Alberto Papi
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Rationale: There is an increasing prevalence of reduced responsiveness to glucocorticoid therapy in severe asthma and chronic obstructive pulmonary disease (COPD). The molecular mechanism of this remains unknown. Recent studies have shown that histone deacetylase activity, which is critical to glucocorticoid function, is altered by oxidant stress and may be involved in the development of glucocorticoid insensitivity.Objectives: To determine the role of phosphoinositol-3-kinase (PI3K) in the development of cigarette smoke–induced glucocorticoid insensitivity.Methods: Wild-type, PI3Kγ knock-out and PI3Kδ kinase dead knock-in transgenic mice were used in a model of cigarette smoke–induced glucocorticoid insensitivity. Peripheral lung tissue was obtained from six healthy nonsmokers, nine smokers with normal lung function, and eight patients with COPD.Measurements and Main Results: In vitro oxidative stress activates PI3K and induced a relative glucocorticoid resistance, which is restored by PI3K inhibition. In vivo, cigarette smoke exposure in mice increased tyrosine nitration of histone deacetylase 2 in the lung, correlating with reduced histone deacetylase 2 activity and reduced glucocorticoid function. Histone deacetylase 2 activity and the antiinflammatory effects of glucocorticoids were restored in PI3Kδ kinase dead knock-in but not PI3Kγ knock-out smoke-exposed mice compared with wild type mice, correlating with reduced histone deacetylase 2 tyrosine nitration. Glucocorticoid receptor expression was significantly reduced in smoke-exposed mice, in smokers with normal lung function, and in patients with COPD.Conclusions: These data show that therapeutic inhibition of PI3Kδ may restore glucocorticoid function in oxidative stress–induced glucocorticoid insensitivity.
AMPA/kainate glutamate receptors contribute to inflammation, degeneration and pain related behaviour in inflammatory stages of arthritis
Authors: Cleo S Bonnet, Anwen S Williams, Sophie J Gilbert, Ann K Harvey, Bronwen A Evans, Deborah J Mason
Journal: Annals of the Rheumatic Diseases (2013)

Objectives Synovial fluid glutamate concentrations increase in arthritis. Activation of kainate (KA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors (GluRs) increase interleukin-6 (IL-6) release and cause arthritic pain, respectively. We hypothesised that AMPA and KA GluRs are expressed in human arthritis, and that intra-articular NBQX (AMPA/KA GluR antagonist) prevents pain and pathology in antigen-induced arthritis (AIA). Methods GluR immunohistochemistry was related to synovial inflammation and degradation in osteoarthritis (OA) and rheumatoid arthritis (RA). A single intra-articular NBQX injection was given at induction, and knee swelling and gait of AIA and AIA+NBQX rats compared over 21 days, before imaging, RT-qPCR, histology and immunohistochemistry of joints. Effects of NBQX on human primary osteoblast (HOB) activity were determined. Results AMPAR2 and KA1 immunolocalised to remodelling bone, cartilage and synovial cells in human OA and RA, and rat AIA. All arthritic tissues showed degradation and synovial inflammation. NBQX reduced GluR abundance, knee swelling (p&lt;0.001, days 1–21), gait abnormalities (days 1–2), end-stage joint destruction (p&lt;0.001), synovial inflammation (p&lt;0.001), and messenger RNA expression of meniscal IL-6 (p&lt;0.05) and whole joint cathepsin K (p&lt;0.01). X-ray and MRI revealed fewer cartilage and bone erosions, and less inflammation after NBQX treatment. NBQX reduced HOB number and prevented mineralisation. Conclusions AMPA/KA GluRs are expressed in human OA and RA, and in AIA, where a single intra-articular injection of NBQX reduced swelling by 33%, and inflammation and degeneration scores by 34% and 27%, respectively, exceeding the efficacy of approved drugs in the same model. AMPA/KA GluR antagonists represent a potential treatment for arthritis.
Helicobacter pylori Cytotoxin-Associated Genotype and Gastric Precancerous Lesions
Authors: M. Plummer, L.-J. van Doorn, S. Franceschi, B. Kleter, F. Canzian, J. Vivas, G. Lopez, D. Colin, N. Munoz, I. Kato
Journal: JNCI Journal of the National Cancer Institute (2007)

BackgroundHelicobacter pylori infection is associated with the development of gastric cancer. Although infection with an H. pylori strain containing the cytotoxin-associated (cag A) gene (a marker for a pathogenicity island) may increase the risk of atrophic gastritis and gastric cancer, the relationship of variants in pathogenic H. pylori genes to the severity and progression of precancerous lesions is not well defined.
Effects of Aerosolized Interferon- α in Patients with Pulmonary Tuberculosis
Authors: SANDRO GIOSUÈ, MASSIMO CASARINI, LUCILLA ALEMANNO, GIANNI GALLUCCIO, PAOLO MATTIA, GIOACCHINO PEDICELLI, LIONELLO REBEK, ALBERTO BISETTI, FRANCO AMEGLIO
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

Interferon- α (IFN- α ) is a cytokine exerting pleiotropic activities, including antimicrobial effects, especially directed against intracellular infectious bacteria. It may be administered by aerosol to reach the lower respiratory tract without systemic side effects. The aim of the study reported here was the evaluation of aerosolized IFN- α treatment (3 MU/dose, given three times a week; total study dose: 72 MU/2 mo) in combination with conventional antimycobacterial therapy in patients with pulmonary tuberculosis. Two groups of 10 patients each were compared before and after 2 mo of conventional antituberculous chemotherapy with or without inhaled IFN- α . Several biologic (bronchoalveolar lavage fluid [BALF] cellularity, Mycobacterium tuberculosis [MT] number in sputum), biochemical (BALF concentrations of 10 cytokines, BALF IFN- α receptor levels), and clinical (fever, vital signs, high-resolution computed tomography [HRCT] images) measures were made in these patients at the time of their enrollment and at the end of the observation period of the study. Fever, MT number in sputum, and abnormalities in HRCT images showed significantly earlier resolution in the IFN- α -treated group, together with a more significant decrease in BALF interleukin-1 β (IL-1 β ), IL-6, and tumor necrosis factor- α (TNF- α ) concentrations and significantly greater pre- versus posttreatment variations in IL-2 and IFN- γ . These data, taken together, suggest that IFN- α administration may favorably affect the evolution of pulmonary tuberculosis when combined with antimycobacterial therapy.
OBSERVATIONS ON THE AGGLUTINATION OF POLYSACCHARIDE-TREATED ERYTHROCYTES BY TULAREMIA ANTISERA
Authors: Mary M. Alexander, George G. Wright, Agnes C. Baldwin
Journal: The Journal of Experimental Medicine (1950)

Erythrocytes treated with polysaccharide from Past. tularensis are specifically agglutinated by the sera of persons recovered from tularemia or vaccinated against it, and by the sera of animals immunized with living cultures. The serum hemagglutination titer is correlated with the amount of antibody as measured by the quantitative precipitin method with polysaccharide, but not with the bacterial agglutination titer. The meaning of the results is discussed.
Cerebrospinal Fever treated by Chemotherapy
Authors: G. E. Harries
Journal: BMJ (1942)

Bacterial DNA containing motifs of unmethylated CpG dinucleotides (CpG-DNA) triggers innate immune cells through the pattern recognition receptor Toll-like receptor 9 (TLR-9). CpG-DNA possesses potent immunostimulatory effects on macrophages, dendritic cells, and B lymphocytes. Therefore, CpG-DNA contributes to inflammation during the course of bacterial infections. In contrast to other TLR-dependent microbial patterns, CpG-DNA is a strong inductor of IL-12. Thus, it acts as a Th1-polarizing agent that can be utilized as potent vaccine adjuvant. To assess the role of CpG-DNA in immune reactions in the CNS, we analyzed the effects of CpG-DNA on microglial cells in vitro and in vivo. Primary microglial cells as well as microglial cell lines express TLR-9 mRNA. Consequently, CpG-DNA activated microglial cells in vitro and induced TNF-α, IL-12p40, IL-12p70, and NO. Furthermore, MHC class II, B7-1, B7-2, and CD40 molecules were up-regulated. In addition, phagocytic activity of microglia was enhanced. After intracerebroventricular injection of CpG-DNA, microglial cells were activated and produced TNF-α and IL-12p40 transcripts, as shown by in situ hybridization. These results indicate that microglia is sensitive to CpG-DNA. Thus, bacterial DNA containing CpG motifs could not only play an important role during infections of the CNS, but also might trigger and sustain Th1-dominated immunopathogenic reactions.
Ototoxicity in Children Receiving Platinum Chemotherapy: Underestimating a Commonly Occurring Toxicity That May Influence Academic and Social Development
Authors: Kristin R. Gilmer Knight, Dale F. Kraemer, Edward A. Neuwelt
Journal: Journal of Clinical Oncology (2005)

To describe the frequency and severity of ototoxicity in a series of pediatric patients treated with platinum-based chemotherapy.Serial audiologic evaluations were conducted for 67 patients aged 8 months to 23 years who received platinum-based chemotherapy. Audiologic data was analyzed to determine time to hearing-loss using American Speech-Language-Hearing Association (ASHA) criteria, and the effects of treatment and patient characteristics on the incidence and severity of ototoxicity.Bilateral decreases in hearing were seen in 61% of patients (median time to hearing loss, 135 days). Children treated for medulloblastoma, osteosarcoma, and neuroblastoma had greater incidence and severity of hearing loss. Agreement between the usually reported National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) and ASHA criteria was inadequate.Traditional reporting of toxicity data (CTCAE) has under-reported ototoxicity and minimized the significance of hearing loss in children. As pediatric patients experience improved survival, the effects and implications of high-frequency hearing loss with regard to academic achievement and speech and language development are important considerations, especially in patients younger than 5 years.
Comparision of procalcitonin and CURB-65 in pneumonia
Authors: Savas Ozsu, Ismail Yilmaz, Yasin Abul, Funda Öztuna, Yilmaz Bulbul, Tevfik Ozlu
Journal: European Respiratory Journal (2012)

CURB-65 score, pneumonia and hospital admission decision as well as useful and simple clinical scoring method for prognosis. CURB-65 score, >= 2 is recommended for patients with inpatient treatment. The other hand, procalcitonin (PCT), a marker for determining prognosis of pneumonia. CURB-65 score and PCT levels were compared in this study.  In this study 58 patients were admitted to our clinic due to common acquired pneumonia. Patients, the clinical and laboratory findings were recorded. CURB-65 score was calculated. CURB-65 score in patients with Group-1 (score,  = 2) as divided into 2 groups. (Normal value: Procalcitonin  In our study, median age 68 (18-96) was found. The most frequent clinical symptoms were cough (83%), dyspnea (71%) and fever (67%), respectively. In group-I, mean PCT level was 3.6 ± 7.7, in Group-II PCT was 9 ± 20 (p = 0.028). The average white blood cell was 12.9 ± 6.6 and was 13.3 ± 6.2 2. (p > 0.05), CRP level of 18.2 ± 1.0, and 19.8 ± 1.4 (p> 0.05), respectively. Total 11 (19%) patients died. The median value of PCT was significantly higher in patients who died (2.2 vs. 0.45, p = 0.012). Similarly, CRP was significantly higher in patients who died (33 vs. 14, p = 0.016). PCT levels were positively correlated with the CURB-65 score (r = 0,296, p = 0.024).  As a result, PCT levels correlated with a CURB-65 score in pneumonia. Initial PCT level may be considered in patients with pneumonia.
Peroxisome Proliferator-Activated Receptor-δ Upregulates 14-3-3ε in Human Endothelial Cells via CCAAT/Enhancer Binding Protein-β
Authors: Luca Brunelli, Katarzyna A. Cieslik, Joseph L. Alcorn, Matteo Vatta, Antonio Baldini
Journal: Circulation Research (2007)

Peroxisome proliferator-activated receptor delta (PPARdelta) agonists are promising new agents for treatment of the metabolic syndrome. Although they possess antiatherosclerotic properties in vivo and promote endothelial cell survival, their mechanism of action is incompletely understood. 14-3-3epsilon is a critical component of the endothelial cell antiapoptotic machinery, which is essential to maintain homeostasis of the vascular wall. To test the hypothesis that PPARdelta targets 14-3-3epsilon in endothelial cells, we studied the response of the gene that encodes 14-3-3epsilon in humans, YWHAE, to PPARdelta ligands (L-165,041 and GW501516). We found that PPARdelta activates YWHAE promoter in a concentration and time-dependent manner. Consistent with these findings, L-165,041 increased 14-3-3epsilon mRNA and protein level, whereas PPARdelta small interfering RNA suppressed both basal and L-165,041-dependent YWHAE transcription and 14-3-3epsilon protein expression. Surprisingly, PPAR response elements in YWHAE promoter were not required for upregulation by PPARdelta, whereas a CCAAT/enhancer binding protein (C/EBP) site located at -160/-151 bp regulated both basal and PPARdelta-dependent promoter activity. Intriguingly, activation or knock down of endogenous PPARdelta regulated C/EBPbeta protein expression. Chromatin immunoprecipitation assays demonstrated that L-165,041 determines the localization of C/EBPbeta to the region spanning this C/EBP response element, whereas sequential chromatin immunoprecipitation analysis revealed that C/EBPbeta and PPARdelta form a transcriptional activating complex on this C/EBP site. Our work uncovers a novel role for C/EBPbeta as a mediator of PPARdelta-dependent 14-3-3epsilon gene regulation in human endothelial cells and provides insight into the mechanism by which PPARdelta agonists may be beneficial in atherosclerosis.
A reluctant start and a premature finish
Authors: D HEARSE
Journal: Cardiovascular Research (2007)

In 1992, the lab was thriving and in order to guarantee sufficient time to continue doing hands-on research I had declined an invitation to edit a well-known cardiology journal. It was then that I received a telephone call from a senior and much respected member of the British ‘cardiological establishment’ suggesting that I should take on the editorship of Cardiovascular Research . It should have been simple to say no thanks and terminate the discussion, but in true British fashion certain ‘pressures’ were applied. The liberal use of the words ‘duty’ and ‘career’ and ‘future’ made it increasingly difficult to escape the challenge and so it came to pass ’ the establishment had its way. … again!

As a still-active researcher and fairly prolific author of papers, I, like the research community at large, was often irritated by what can only be described as the cavalier attitude of journals to the importance of timely publication of new research findings ’ generally, manuscripts were processed by editorial offices at only one speed ’ very, very slow. It usually took weeks or months to get referees' reports and even longer to get a decision from any journal. On top of this publishers took an inordinate time to complete the process. Such delays often threatened the success of grant applications from young investigators surviving on 3-year grants or shorter.

Although Harvey's De Motu Cordis took 12 years to publish in 1543 and Darwin's Origin of the Species took 23 years to publish in 1858, Hook's classical study of lung function when submitted to the … 

* Tel.: +44 20 7188 1101; fax: +44 20 7928 0658. david.hearse{at}kcl.ac.uk
Stimulation of the neurotrophin receptor TrkB on astrocytes drives nitric oxide production and neurodegeneration
Authors: Emanuela Colombo, Chiara Cordiglieri, Giorgia Melli, Jia Newcombe, Markus Krumbholz, Luis F. Parada, Enzo Medico, Reinhard Hohlfeld, Edgar Meinl, Cinthia Farina
Journal: The Journal of Experimental Medicine (2012)

Neurotrophin growth factors support neuronal survival and function. In this study, we show that the expression of the neurotrophin receptor TrkB is induced on astrocytes in white matter lesions in multiple sclerosis (MS) patients and mice with experimental autoimmune encephalomyelitis (EAE). Surprisingly, mice lacking TrkB specifically in astrocytes were protected from EAE-induced neurodegeneration. In an in vitro assay, astrocytes stimulated with the TrkB agonist brain-derived neurotrophic factor (BDNF) released nitric oxide (NO), and conditioned medium from activated astrocytes had detrimental effects on the morphology and survival of neurons. This neurodegenerative process was amplified by NO produced by neurons. NO synthesis in the central nervous system during EAE depended on astrocyte TrkB. Together, these findings suggest that TrkB expression on astrocytes may represent a new target for neuroprotective therapies in MS.