tbuckley/cabot-search huggingface dataset:
Uncovering the Footprint of Positive Selection on the X Chromosome of Drosophila melanogaster
Authors: D. J. Orengo, M. Aguade
Journal: Molecular Biology and Evolution (2009)

A usual approach to detect the spatial footprint left by recent adaptive events has been to follow up putative candidates emerging from multilocus scans of variation by sequencing additional fragments. We have used a similar experimental and analytical approach to study variation at 15 independently evolving and randomly chosen regions of the X chromosome of Drosophila melanogaster. These incompletely sequenced regions, each extending over approximately 40 kb, were subjected to two tests of positive selection that take into account the spatial distribution of nucleotide variation. Our analysis of variation at these genomic regions in a European population of D. melanogaster has allowed us to uncover a candidate region for positive selection and to empirically evaluate the comparative performance of the two tests of selection under a bottleneck scenario. Moreover, the boundaries here estimated for both the rate of adaptive substitution (delta) and the average selection coefficient (s) would support previous estimates obtained by maximum likelihood that suggest rather strong but uncommon positive selection.
The influence of hospital volume and surgical treatment delay on long-term survival after cancer surgery
Authors: Y.H. Yun, Y.A. Kim, Y.H. Min, S. Park, Y.J. Won, D.Y. Kim, I.J. Choi, Y.W. Kim, S.J. Park, J.H. Kim, D.H. Lee, S.J. Yoon, S.Y. Jeong, D.Y. Noh, D.S. Heo
Journal: Annals of Oncology (2012)

We conducted a population-based retrospective cohort study to investigate the influence of hospital volume, delay of surgery, and both together on the long-term survival of postoperative cancer patients.Using information from the Korea Central Cancer Registry from 2001 through 2005 and the National Health Insurance claim database, we determined survival for 147 682 patients who underwent definitive surgery for any of six cancers.Regardless of cancer site, surgical patients in low- to medium-volume hospitals showed significantly worse survival [adjusted hazard ratio (aHR) = 1.36-1.86] than those in high-volume hospitals in multivariable analyses. Among the latter, treatment delays > 1 month were not associated with worse survival for stomach, colon, pancreatic, or lung cancer but were for rectal [aHR = 1.28; 95% confidence interval (CI), 1.17-1.40] and breast (aHR = 1.59; 95% CI, 1.37-1.84) cancer. For patients in low- to medium-volume hospitals, treatment delay was associated with worse survival for all types of cancer (aHR = 1.78-3.81).Our findings suggest that the effect of hospital volume and surgical treatment delay on overall survival of cancer patients should be considered in formulating or revising national health policy.
Emerging and re-emerging infectious diseases: a continuous challenge for Europe
Authors: GianLuca Quaglio, Jacques Demotes-Mainard, Robert Loddenkemper
Journal: European Respiratory Journal (2012)

It is estimated that infectious diseases represent roughly 10% of the total burden of disease in the European Union (EU) [1, 2]. This figure, however, might be underestimated because it does not fully take into account the whole spectrum of long-term sequelae caused by infections [3].

The growing problem of antibiotic resistance represents a major health burden for the EU. For example, carbapenems are the major last-line class of antibiotics to treat infections with multidrug-resistant (MDR) Gram-negative bacteria such as Klebsiella pneumoniae (a frequent cause of pneumonia and urinary tract infections in hospitals). 15–50% of K. pneumoniae from bloodstream infections are resistant to carbapenems in the EU [4]. Another example is Staphylococcus aureus , a bacterium that can cause a variety of infections (from minor skin infections to severe pneumonia). Its adaptation has led to an MDR pathogen, methicillin-resistant S. aureus (MRSA). MRSA is associated with severe invasive disease. Initially, MRSA was only a nosocomial pathogen, but in the last 20 yrs it has been identified in the community (community-associated (CA)-MRSA) [5]. The incidence of CA-MRSA pneumonia is estimated at 0.51–0.64 cases per 100,000 population. Since the incidence of community-acquired pneumonia (CAP) is between 100 and 1,000 per 100,000 population [6], the frequency of CA-MRSA pneumonia can be estimated to be between one in 200 and one in 2,000 cases of CAP [5]. CA-MRSA pneumonia is a severe disease with 75–85% of affected patients being admitted to the intensive care unit and 20–60% dying [7].

Antibiotic resistance also represents a major problem from an economic perspective. In 2009, the European Centre for Diseases and Control (ECDC) and the European Medicines Agency estimated that each year 25,000 Europeans die as a direct consequence of an MDR …
Function and Activation of NF-kappaB in the Immune System
Authors: P A Baeuerle, T Henkel
Journal: Annual Review of Immunology (1994)

NF-kappa B is a ubiquitous transcription factor. Nevertheless, its properties seem to be most extensively exploited in cells of the immune system. Among these properties are NF-kappa B's rapid posttranslational activation in response to many pathogenic signals, its direct participation in cytoplasmic/nuclear signaling, and its potency to activate transcription of a great variety of genes encoding immunologically relevant proteins. In vertebrates, five distinct DNA binding subunits are currently known which might extensively heterodimerize, thereby forming complexes with distinct transcriptional activity, DNA sequence specificity, and cell type- and cell stage-specific distribution. The activity of DNA binding NF-kappa B dimers is tightly controlled by accessory proteins called I kappa B subunits of which there are also five different species currently known in vertebrates. I kappa B proteins inhibit DNA binding and prevent nuclear uptake of NF-kappa B complexes. An exception is the Bcl-3 protein which in addition can function as a transcription activating subunit in th nucleus. Other I kappa B proteins are rather involved in terminating NF-kappa B's activity in the nucleus. The intracellular events that lead to the inactivation of I kappa B, i.e. the activation of NF-kappa B, are complex. They involve phosphorylation and proteolytic reactions and seem to be controlled by the cells' redox status. Interference with the activation or activity of NF-kappa B may be beneficial in suppressing toxic/septic shock, graft-vs-host reactions, acute inflammatory reactions, acute phase response, and radiation damage. The inhibition of NF-kappa B activation by antioxidants and specific protease inhibitors may provide a pharmacological basis for interfering with these acute processes.
Anakinra treatment of SAPHO syndrome: short-term results of an open study
Authors: Daniel Wendling, Clément Prati, François Aubin
Journal: Annals of the Rheumatic Diseases (2012)

SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome comprises many features, but has no specific treatment.1 2 According to the target symptom (synovitis, skin, bone) non-steroidal anti-inflammatory drugs (NSAIDs), disease-modifying anti-rheumatic drugs (DMARDs), bisphosphonates3 and tumour necrosis factor (TNF) blockers4 may be proposed, but with variable results. Some patients do not exhibit improvement of symptoms despite use of several, sometimes combined, lines of treatment. An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist has recently been described5 under the name DIRA. It associates sterile multifocal osteomyelitis, periostitis and pustulosis, which looks like SAPHO, with good response to anakinra, an interleukin 1 (IL-1) receptor antagonist. We describe the …
Aberrant Lipid Metabolism in Hepatocellular Carcinoma Revealed by Plasma Metabolomics and Lipid Profiling
Authors: Andrew D. Patterson, Olivier Maurhofer, Diren Beyoğlu, Christian Lanz, Kristopher W. Krausz, Thomas Pabst, Frank J. Gonzalez, Jean-François Dufour, Jeffrey R. Idle
Journal: Cancer Research (2011)

There has been limited analysis of the effects of hepatocellular carcinoma (HCC) on liver metabolism and circulating endogenous metabolites. Here, we report the findings of a plasma metabolomic investigation of HCC patients by ultraperformance liquid chromatography-electrospray ionization-quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOFMS), random forests machine learning algorithm, and multivariate data analysis. Control subjects included healthy individuals as well as patients with liver cirrhosis or acute myeloid leukemia. We found that HCC was associated with increased plasma levels of glycodeoxycholate, deoxycholate 3-sulfate, and bilirubin. Accurate mass measurement also indicated upregulation of biliverdin and the fetal bile acids 7α-hydroxy-3-oxochol-4-en-24-oic acid and 3-oxochol-4,6-dien-24-oic acid in HCC patients. A quantitative lipid profiling of patient plasma was also conducted by ultraperformance liquid chromatography-electrospray ionization-triple quadrupole mass spectrometry (UPLC-ESI-TQMS). By this method, we found that HCC was also associated with reduced levels of lysophosphocholines and in 4 of 20 patients with increased levels of lysophosphatidic acid [LPA(16:0)], where it correlated with plasma α-fetoprotein levels. Interestingly, when fatty acids were quantitatively profiled by gas chromatography-mass spectrometry (GC-MS), we found that lignoceric acid (24:0) and nervonic acid (24:1) were virtually absent from HCC plasma. Overall, this investigation illustrates the power of the new discovery technologies represented in the UPLC-ESI-QTOFMS platform combined with the targeted, quantitative platforms of UPLC-ESI-TQMS and GC-MS for conducting metabolomic investigations that can engender new insights into cancer pathobiology.
S65 Urinary Prostaglandins As Inflammatory Markers For Childhood Asthma Exacerbations
Authors: R. Brugha, N. Mushtaq, I. Dundas, M. Sanak, J. Grigg
Journal: Thorax (2014)

<h3>Background</h3> Measuring inflammation (inflammometry) may assist decisions regarding preventative anti-inflammatory therapies in asthma.<sup>1</sup> Prostaglandin metabolites, which reflect airway inflammation, may be measured in urine samples.<sup>2</sup> We sought to prospectively assess associations between urine prostaglandins and subsequent asthma exacerbations in children, and to compare these markers to current markers that aim to predict future risk. <h3>Methods</h3> Children with asthma aged 7–15 underwent spirometry, sputum inductions, completed the childhood asthma control test (C-ACT) and provided urine samples at baseline. Urine was also provided by healthy (non-atopic) controls. Urine PGD, PGE and PGJ metabolites were measured using HPLC-MS. At 3 months, sampling was repeated, data was collected on exacerbations (unscheduled medical attendance or day missed from school due to asthma symptoms) and the receiver operator characteristic was calculated for the baseline assessment. <h3>Results</h3> 73 children (asthma n = 25, controls n = 48) were included. Urine PGD<sub>2</sub>, PGE<sub>2</sub> and PGJ<sub>2</sub> metabolites were increased in asthma in comparison to controls, and 15-dPGJ<sub>2</sub> predicted subsequent asthma exacerbation (PPV=75%, NPV=90%, ROC AUC 0.858, p = 0.005). Sputum eosinophils, spirometry and C-ACT did not predict subsequent exacerbations after correction for multiple comparisons, and sputum phenotypes were unstable. Change in C-ACT score was associated with interim control (p = 0.04). <h3>Conclusions</h3> Urinary prostaglandin metabolites are increased in children with asthma in comparison to controls. Urine 15-dPGJ<sub>2</sub> is a biologically plausible, non-invasive marker for inflammometry in childhood asthma, and is superior to assessment of sputum eosinophils, C-ACT, or spirometry. <h3>References</h3> <i>American journal of respiratory and critical care medicine</i> 2005;171:1077–1082 <i>Thorax</i> 2008;63:27–34
The pattern recognition receptor PTX3 is recruited at the synapse between dying and dendritic cells, and edits the cross-presentation of self, viral, and tumor antigens
Authors: Paramita Baruah, Antonella Propato, Ingrid E. Dumitriu, Patrizia Rovere-Querini, Vincenzo Russo, Raffaella Fontana, Daniele Accapezzato, Giuseppe Peri, Alberto Mantovani, Vincenzo Barnaba, Angelo A. Manfredi
Journal: Blood (2005)
Gene expression profile, pathways, and transcriptional system regulation in indolent systemic mastocytosis
Authors: M. Niedoszytko, J. N. G. Oude Elberink, M. Bruinenberg, B. Nedoszytko, J. G. R. de Monchy, G. J. te Meerman, R. K. Weersma, A. B. Mulder, E. Jassem, J. J. van Doormaal
Journal: Allergy (2010)

To cite this article: Niedoszytko M, Oude Elberink JNG, Bruinenberg M, Nedoszytko B, de Monchy JGR, te Meerman GJ, Weersma RK, Mulder AB, Jassem E, van Doormaal JJ. Gene expression profile, pathways, and transcriptional system regulation in indolent systemic mastocytosis. Allergy 2011; 66: 229–237. Background: Mastocytosis is an uncommon disease resulting from proliferation of abnormal mast cells infiltrating skin, bone marrow, liver, and other tissues. The aim of this study was to find differences in gene expression in peripheral blood cells of patients with indolent systemic mastocytosis compared to healthy controls. The second aim was to define a specific gene expression profile in patients with mastocytosis. Methods: Twenty-two patients with indolent systemic mastocytosis and 43 healthy controls were studied. Whole genome gene expression analysis was performed on RNA samples isolated from the peripheral blood. For amplification and labelling of the RNA, the Illumina TotalPrep 96 RNA Amplification Kit was used. Human HT-12_V3_expression arrays were processed. Data analysis was performed using GeneSpring, Genecodis, and Transcriptional System Regulators. Results: Comparison of gene expression between patients and controls revealed a significant difference (P < 0.05 corrected for multiple testing) and the fold change difference >2 in gene expression in 2303 of the 48.794 analysed transcripts. Functional annotation indicated that the main pathways in which the differently expressed genes were involved are ubiquitin-mediated proteolysis, MAPK signalling pathway, pathways in cancer, and Jak-STAT signalling. The expression distributions for both groups did not overlap at all, indicating that many genes are highly differentially expressed in both groups. Conclusion: We were able to find abnormalities in gene expression in peripheral blood cells of patients with indolent systemic mastocytosis and to construct a gene expression profile which may be useful in clinical practice to predict the presence of mastocytosis and in further research of novel drugs.
Nosocomial Pneumonia in the Intensive Care Unit Acquired by Mechanically Ventilated versus Nonventilated Patients
Authors: Mariano Esperatti, Miquel Ferrer, Anna Theessen, Adamantia Liapikou, Mauricio Valencia, Lina Maria Saucedo, Elisabeth Zavala, Tobias Welte, Antoni Torres
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Most current information on hospital-acquired pneumonia (HAP) is extrapolated from patients with ventilator-associated pneumonia (VAP). No studies have evaluated HAP in the intensive care unit (ICU) in nonventilated patients.To compare pneumonia acquired in the ICU by mechanically ventilated versus nonventilated patients.We prospectively collected 315 episodes of ICU-acquired pneumonia. We compared clinical and microbiologic characteristics of patients with VAP (n = 164; 52%) and nonventilator ICU-acquired pneumonia (NV-ICUAP; n = 151; 48%). Among NV-ICUAP patients, 79 (52%) needed subsequent intubation.Compared with NV-ICUAP, patients with VAP were more severe (APACHE-II 17 ± 6 vs. 15 ± 5; P < 0.001) and pneumonia occurred later in the ICU (8 ± 8 vs. 5 ± 6 d; P < 0.001). Etiologic diagnosis (117, 71% vs. 64, 42%; P < 0.001), nonfermenting (28% vs. 15%; P = 0.009) and enteric gram-negative bacilli (26% vs. 13%; P = 0.006), and methicillin-sensitive Staphylococcus aureus (14% vs. 6%; P = 0.031) were more frequent in VAP, likely caused by more patients with lower respiratory tract samples cultured (100% vs. 84%; P < 0.001). However, in patients with defined etiology only, the proportion of pathogens was similar between groups, except for a higher proportion of Streptococcus pneumoniae in NV-ICUAP (P = 0.045). The hospital mortality also was similar.Despite a lower proportion of pathogens in NV-ICUAP compared with VAP, the type of isolates and outcomes are similar regardless of whether pneumonia is acquired or not during ventilation, indicating they may depend on patients' underlying severity rather than previous intubation. With the diagnostic techniques currently recommended by guidelines, both types of patients might receive similar empiric antibiotic treatment.
A Factor Analysis of Tic Symptoms in Gilles de la Tourette’s Syndrome
Authors: John P Alsobrook, David L Pauls
Journal: American Journal of Psychiatry (2002)

Gilles de la Tourette's syndrome is a well-characterized disorder with clear DSM-IV criteria. However, the great deal of clinical variability across patients may represent an underlying etiologic complexity. Issues of phenotypic heterogeneity are particularly critical to current efforts at mapping genes involved in this syndrome.Lifetime tic symptom data were obtained from direct structured interviews of 85 Tourette's disorder probands. Information on 29 tic symptoms was elicited. The probands' tic symptoms were grouped by using agglomerative hierarchical clustering, with no a priori assumptions concerning the relatedness of symptoms. Scores for the probands' symptom clusters were used as variables in a principal-component factor analysis. The relationships of the resulting factor scores to comorbidity in probands and recurrence risks in relatives were examined. In addition, intraclass correlations were calculated for within-family factor scores of 36 families.Four significant factors were identified: 1) aggressive phenomena (e.g., kicking, temper fits, argumentativeness), 2) purely motor and phonic tic symptoms, 3) compulsive phenomena (e.g., touching of others or objects, repetitive speech, throat clearing), and 4) tapping and absence of grunting. Analysis of the symptom loadings, comorbidity, recurrence risks, and within-family correlations indicate that these factors represent a valid structure with clinical and biological relevance.In this symptom-based factor analysis of Tourette's disorder, four factors accounted for 61% of the phenotypic symptom variance in Tourette's disorder probands and their first-degree relatives. Three of these factors may indicate the presence of heritable components of the Tourette's disorder phenotype.
Inhibition of heat shock protein (molecular weight 90 kDa) attenuates proinflammatory cytokines and prevents lipopolysaccharide-induced liver injury in mice
Authors: Aditya Ambade, Donna Catalano, Arlene Lim, Pranoti Mandrekar
Journal: Hepatology (2011)

Abstract Endotoxin-mediated proinflammatory cytokines play a significant role in the pathogenesis of acute and chronic liver diseases. Heat shock protein 90 (molecular weight, 90 kDa) (hsp90) functions as an important chaperone of lipopolysaccharide (LPS) signaling and is required for the production of proinflammatory cytokines. We hypothesized that inhibition of hsp90 would prevent LPS-induced liver injury by decreasing proinflammatory cytokines. C57BL/6 mice were injected intraperitoneally with an hsp90 inhibitor, 17-dimethylamino-ethylamino-17-demethoxygeldanamycin (17-DMAG), and LPS. Parameters of liver injury, proinflammatory cytokines, and associated mechanisms were studied by in vivo and in vitro experiments. Inhibition of hsp90 by 17-DMAG prevented LPS-induced increases in serum alanine aminotransferase activity and significantly reduced serum tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6) protein as well as messenger RNA (mRNA) in liver. Enhanced DNA-binding activity of heat shock transcription factor 1 (HSF1) and induction of target gene heat shock protein 70 (molecular weight, 70 kDa) confirmed hsp90 inhibition in liver. 17-DMAG treatment decreased cluster of differentiation 14 mRNA and LPS-induced nuclear factor kappa light-chain enhancer of activated B cells (NFκB) DNA binding without affecting Toll-like receptor 4 mRNA in liver. Mechanistic studies revealed that 17-DMAG-mediated inhibition of TNFα showed no effect on LPS-induced NFκB promoter-driven reporter activity, but significantly decreased TNFα promoter-driven reporter activity. Chromatin immunoprecipitation assays showed that 17-DMAG enhanced HSF1 binding to the TNFα promoter, but not the IL-6 promoter, suggesting HSF1 mediated direct inhibition of TNFα, but not IL-6. We show that HSF1 indirectly regulates IL-6 by the induction of another transcription factor, activating transcription factor 3. Inhibition of HSF1, using small interfering RNA, prevented 17-DMAG-mediated down-regulation of NFκB-binding activity, TNFα, and IL-6 induction, supporting a repressive role for HSF1 on proinflammatory cytokine genes during hsp90 inhibition. Conclusion: Hsp90 inhibition in vivo reduces proinflammatory cytokines and prevents LPS-induced liver injury likely through repressive action of HSF1. Our results suggest a novel application for 17-DMAG in alleviating LPS-induced liver injury. (Hepatology 2011)
Differential effects of ureteral obstruction on rat kininogen gene family.
Authors: S S el-Dahr, S Dipp
Journal: Journal of the American Society of Nephrology (1994)

The precursors of kinins, K-kininogens and T-kininogens (KG), are encoded by separate genes that display 90% nucleotide sequence homology. Despite their homology, K-KG and T-KG genes are differentially regulated. The K-KG gene is expressed constitutively and encodes high- and low-molecular-weight KG, the precursors of the vasoactive nonapeptide bradykinin. In contrast, the T-KG gene is inducible, and its protein is a potent thiol-protease inhibitor. Given their potential role in the regulation of blood pressure, renal hemodynamics, and the response to inflammation and tissue injury, K-KG and T-KG gene expression in rats subjected to chronic (1 or 5 wk) unilateral ureteral obstruction (UUO), a maneuver that suppresses renal kallikrein synthesis to 25% of controls, has been examined. Northern and slot blots of total liver and kidney RNA were probed with oligonucleotides complementary to either T-KG or K-KG mRNA under high-stringency conditions. Steady-state levels of hepatic T-KG mRNA were increased in the UUO compared with sham-operated rats--2.7-fold at 1 wk and 4.1-fold at 5 wk (P < 0.05). Western blot analysis revealed that the 68-kd T-KG protein was up-regulated 2.5- to 3-fold in the liver of UUO rats (P < 0.05). In marked contrast, the abundance of high (2.3-kb)- and low (1.6-kb)-molecular-weight splicing transcripts of hepatic pre-K-KG mRNA was not altered at either time after UUO.(ABSTRACT TRUNCATED AT 250 WORDS)