tbuckley/cabot-search huggingface dataset:
Complex host genetics influence the microbiome in inflammatory bowel disease
Authors: Dan Knights, Mark S Silverberg, Rinse K Weersma, Dirk Gevers, Gerard Dijkstra, Hailiang Huang, Andrea D Tyler, Suzanne van Sommeren, Floris Imhann, Joanne M Stempak, Hu Huang, Pajau Vangay, Gabriel A Al-Ghalith, Caitlin Russell, Jenny Sauk, Jo Knight, Mark J Daly, Curtis Huttenhower, Ramnik J Xavier
Journal: Genome Medicine (2014)

Abstract Background Human genetics and host-associated microbial communities have been associated independently with a wide range of chronic diseases. One of the strongest associations in each case is inflammatory bowel disease (IBD), but disease risk cannot be explained fully by either factor individually. Recent findings point to interactions between host genetics and microbial exposures as important contributors to disease risk in IBD. These include evidence of the partial heritability of the gut microbiota and the conferral of gut mucosal inflammation by microbiome transplant even when the dysbiosis was initially genetically derived. Although there have been several tests for association of individual genetic loci with bacterial taxa, there has been no direct comparison of complex genome-microbiome associations in large cohorts of patients with an immunity-related disease. Methods We obtained 16S ribosomal RNA (rRNA) gene sequences from intestinal biopsies as well as host genotype via Immunochip in three independent cohorts totaling 474 individuals. We tested for correlation between relative abundance of bacterial taxa and number of minor alleles at known IBD risk loci, including fine mapping of multiple risk alleles in the Nucleotide-binding oligomerization domain-containing protein 2 ( NOD2 ) gene exon. We identified host polymorphisms whose associations with bacterial taxa were conserved across two or more cohorts, and we tested related genes for enrichment of host functional pathways. Results We identified and confirmed in two cohorts a significant association between NOD2 risk allele count and increased relative abundance of Enterobacteriaceae, with directionality of the effect conserved in the third cohort. Forty-eight additional IBD-related SNPs have directionality of their associations with bacterial taxa significantly conserved across two or three cohorts, implicating genes enriched for regulation of innate immune response, the JAK-STAT cascade, and other immunity-related pathways. Conclusions These results suggest complex interactions between genetically altered host functional pathways and the structure of the microbiome. Our findings demonstrate the ability to uncover novel associations from paired genome-microbiome data, and they suggest a complex link between host genetics and microbial dysbiosis in subjects with IBD across independent cohorts.
Phase I Study of the Novel Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (MLN4924) in Patients with Relapsed/Refractory Multiple Myeloma or Lymphoma
Authors: Jatin J. Shah, Andrzej J. Jakubowiak, Owen A. O'Connor, Robert Z. Orlowski, R. Donald Harvey, Mitchell R. Smith, Daniel Lebovic, Catherine Diefenbach, Kevin Kelly, Zhaowei Hua, Allison J. Berger, George Mulligan, Hélène M. Faessel, Stephen Tirrell, Bruce J. Dezube, Sagar Lonial
Journal: Clinical Cancer Research (2015)

Evaluate the safety, pharmacokinetic profile, pharmacodynamic effects, and antitumor activity of the first-in-class investigational NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924) in patients with relapsed/refractory lymphoma or multiple myeloma.Patients with relapsed/refractory myeloma (n = 17) or lymphoma (n = 27) received intravenous pevonedistat 25 to 147 mg/m(2) on days 1, 2, 8, 9 (schedule A; n = 27) or 100 to 261 mg/m(2) on days 1, 4, 8, 11 (schedule B; n = 17) of 21-day cycles.Maximum tolerated doses were 110 mg/m(2) (schedule A) and 196 mg/m(2) (schedule B). Dose-limiting toxicities included febrile neutropenia, transaminase elevations, muscle cramps (schedule A), and thrombocytopenia (schedule B). Common adverse events included fatigue and nausea. Common grade ≥3 events were anemia (19%; schedule A), and neutropenia and pneumonia (12%; schedule B). Clinically significant myelosuppression was uncommon. There were no treatment-related deaths. Pevonedistat pharmacokinetics exhibited a biphasic disposition phase and approximate dose-proportional increases in systemic exposure. Consistent with the short mean elimination half-life of approximately 8.5 hours, little-to-no drug accumulation in plasma was seen after multiple dosing. Pharmacodynamic evidence of NAE inhibition included increased skin levels of CDT-1 and NRF-2 (substrates of NAE-dependent ubiquitin ligases), and increased NRF-2-regulated gene transcript levels in whole blood. Pevonedistat-NEDD8 adduct was detected in bone marrow aspirates, indicating pevonedistat target engagement in the bone marrow compartment. Three lymphoma patients had partial responses; 30 patients achieved stable disease.Pevonedistat demonstrated anticipated pharmacodynamic effects in the clinical setting, a tolerable safety profile, and some preliminary evidence that may be suggestive of the potential for activity in relapsed/refractory lymphoma.
DNA Editing of LTR Retrotransposons Reveals the Impact of APOBECs on Vertebrate Genomes
Authors: Binyamin A Knisbacher, Erez Y Levanon
Journal: Molecular Biology and Evolution (2015)

Long terminal repeat retrotransposons (LTR) are widespread in vertebrates and their dynamism facilitates genome evolution. However, these endogenous retroviruses (ERVs) must be restricted to maintain genomic stability. The APOBECs, a protein family that can edit C-to-U in DNA, do so by interfering with reverse transcription and hypermutating retrotransposon DNA. In some cases, a retrotransposon may integrate into the genome despite being hypermutated. Such an event introduces a unique sequence into the genome, increasing retrotransposon diversity and the probability of developing new function at the locus of insertion. The prevalence of this phenomenon and its effects on vertebrate genomes are still unclear. In this study, we screened ERV sequences in the genomes of 123 diverse species and identified hundreds of thousands of edited sites in multiple vertebrate lineages, including placental mammals, marsupials, and birds. Numerous edited ERVs carry high mutation loads, some with greater than 350 edited sites, profoundly damaging their open-reading frames. For many of the species studied, this is the first evidence that APOBECs are active players in their innate immune system. Unexpectedly, some birds and especially zebra finch and medium ground-finch (one of Darwin's finches) are exceptionally enriched in DNA editing. We demonstrate that edited retrotransposons may be preferentially retained in active genomic regions, as reflected from their enrichment in genes, exons, promoters, and transcription start sites, thereby raising the probability of their exaptation for novel function. In conclusion, DNA editing of retrotransposons by APOBECs has a substantial role in vertebrate innate immunity and may boost genome evolution.
Quality of Care
Authors: W. David Holloway
Journal: JAMA (1992)

<h3>To the Editor.</h3> —The statement by Chassin<sup>1</sup>that "about half the hospitals were above average in their performance" damages the credibility of his subsequent comments.<i>Of course</i>about half the hospitals should be above average (and half below). This is no more than the definition of average. Let's not fall into the same trap as the reformers in education, looking for what is wrong with the below-average schools in America. We should remember that any process results in variation: that variation will follow a bell curve, the variation that is not in statistical control needs our immediate attention, and almost all processes can benefit from continuous improvement.
An open, randomized, controlled, phase II, single centre, two-period cross-over study to compare the quality of life and toxicity experienced on PEG interferon with interferon-α2b in patients with multiple myeloma maintained on a steady dose of interferon-α2b
Authors: B Sirohi, R Powles, D Lawrence, J Treleaven, S Kulkarni, A Leary, C Rudin, C Horton, G Morgan
Journal: Annals of Oncology (2007)
Role of Respiratory Motor Output in Within-Breath Modulation of Muscle Sympathetic Nerve Activity in Humans
Authors: Claudette M. St. Croix, Makoto Satoh, Barbara J. Morgan, James B. Skatrud, Jerome A. Dempsey
Journal: Circulation Research (1999)

Abstract —We measured muscle sympathetic nerve activity (MSNA, peroneal microneurography) in 5 healthy humans under conditions of matched tidal volume, breathing frequency, and end-tidal CO 2 , but varying respiratory motor output as follows: (1) passive positive pressure mechanical ventilation, (2) voluntary hyperventilation, (3) assisted mechanical ventilation that required the subject to generate –2.5 cm H 2 O to trigger each positive pressure breath, and (4) added inspiratory resistance. Spectral analyses showed marked respiratory periodicities in MSNA; however, the amplitude of the peak power was not changed with changing inspiratory effort. Time domain analyses showed that maximum MSNA always occurred at end expiration (25% to 30% of total activity) and minimum activity at end inspiration (2% to 3% of total activity), and the amplitude of the variation was not different among conditions despite marked changes in respiratory motor output. Furthermore, qualitative changes in intrathoracic pressure were without influence on the respiratory modulation of MSNA. In all conditions, within-breath changes in MSNA were inversely related to small changes in diastolic pressure (1 to 3 mm Hg), suggesting that respiratory rhythmicity in MSNA was secondary to loading/unloading of carotid sinus baroreceptors. Furthermore, at any given diastolic pressure, within-breath MSNA varied inversely with lung volume, demonstrating an additional influence of lung inflation feedback on sympathetic discharge. Our data provide evidence against a significant effect of respiratory motor output on the within-breath modulation of MSNA and suggest that feedback from baroreceptors and pulmonary stretch receptors are the dominant determinants of the respiratory modulation of MSNA in the intact human.
Increased mortality in COPD among construction workers exposed to inorganic dust
Authors: I.A. Bergdahl, K. Torén, K. Eriksson, U. Hedlund, T. Nilsson, R. Flodin, B. Järvholm
Journal: European Respiratory Journal (2004)

The aim of this study was to find out if occupational exposure to dust, fumes or gases, especially among never-smokers, increased the mortality from chronic obstructive pulmonary disease (COPD). A cohort of 317,629 Swedish male construction workers was followed from 1971 to 1999. Exposure to inorganic dust (asbestos, man-made mineral fibres, dust from cement, concrete and quartz), gases and irritants (epoxy resins, isocyanates and organic solvents), fumes (asphalt fumes, diesel exhaust and metal fumes), and wood dust was based on a job-exposure matrix. An internal control group with “unexposed” construction workers was used, and the analyses were adjusted for age and smoking. When all subjects were analysed, there was an increased mortality from COPD among those with any airborne exposure (relative risk 1.12 (95% confidence interval (CI) 1.03–1.22)). In a Poisson regression model, including smoking, age and the major exposure groups, exposure to inorganic dust was associated with an increased risk (hazard ratio (HR) 1.10 (95% CI 1.06–1.14)), especially among never-smokers (HR 2.30 (95% CI 1.07–4.96)). The fraction of COPD among the exposed attributable to any airborne exposure was estimated as 10.7% overall and 52.6% among never-smokers. In conclusion, occupational exposure among construction workers increases mortality due to chronic obstructive pulmonary disease, even among never-smokers.
Human Mesenchymal Stem Cell–Derived Matrices for Enhanced Osteoregeneration
Authors: Suzanne Zeitouni, Ulf Krause, Bret H. Clough, Hillary Halderman, Alexander Falster, Darryl T. Blalock, Christopher D. Chaput, H. Wayne Sampson, Carl A. Gregory
Journal: Science Translational Medicine (2012)

The methodology for the repair of critical-sized or non-union bone lesions has unpredictable efficacy due in part to our incomplete knowledge of bone repair and the biocompatibility of bone substitutes. Although human mesenchymal stem cells (hMSCs) differentiate into osteoblasts, which promote bone growth, their ability to repair bone in vivo has been variable. We hypothesized that given the multistage process of osteogenesis, hMSC-mediated repair might be maximal at a specific time point of healing. Using a mouse model of calvarial healing, we demonstrate that the osteo-repair capacity of hMSCs can be substantially augmented by treatment with an inhibitor of peroxisome proliferator-activated receptor γ, but efficacy is confined to the rapid osteogenic phase. Upon entry into the bone-remodeling phase, hMSC retention signals are lost, resulting in truncation of healing. To solve this limitation, we prepared a scaffold consisting of hMSC-derived extracellular matrix (ECM) containing the necessary biomolecules for extended site-specific hMSC retention. When inhibitor-treated hMSCs were coadministered with ECM, they remained at the injury, well into the remodeling phase of healing, which resulted in reproducible and complete repair of critical-sized bone defects in mice in 3 weeks. These data suggest that hMSC-derived ECM and inhibitor-treated hMSCs could be used at optimal times to substantially and reproducibly improve bone repair.
Hepatitis C Virus NS3/NS4A DNA Vaccine Induces Multiepitope T Cell Responses in Rhesus Macaques Mimicking Human Immune Responses
Authors: Krystle A Lang Kuhs, Arielle A Ginsberg, Jian Yan, Roger W Wiseman, Amir S Khan, Niranjan Y Sardesai, David H O'Connor, David B Weiner
Journal: Molecular Therapy (2011)

Numerous studies have suggested that an effective hepatitis C virus (HCV) vaccine must induce a strong T helper 1 (Th1) T cell response. While several therapeutic vaccine candidates have shown promise in clinical trials, response rates have been low suggesting that further optimization is important. However, such optimization has been hindered by a lack of a benchmark animal model in which to test vaccine-induced immune responses before clinical evaluation. The goal of this study was to analyze the utility of the rhesus macaque vaccination model in assessing HCV vaccine-induced T cell responses. To test this, we employed the use of a novel HCV genotype 1a/1b consensus DNA vaccine encoding both HCV nonstructural protein 3 (NS3) and nonstructural protein 4A (NS4A) proteins. Following immunization, rhesus macaques mounted HCV-specific responses strikingly similar to those reported in resolving patients, including strong NS3-specific interferon-γ (IFN-γ) responses, robust CD4(+) and CD8(+) T cell proliferation, and induction of polyfunctional T cells. Additionally, fine epitope mapping revealed one animal that mounted a T cell response against a known HCV NS3 human leukocyte antigen A2 (HLA-A2) epitope previously identified in humans. Taken together our findings suggest that the rhesus macaque vaccination model is a useful tool in the evaluation of immune responses induced by HCV immunogens.
Hg- and Cu-induced hepatocellular changes in the mummichog, Fundulus heteroclitus.
Authors: P Weis, J D Bogden, E C Enslee
Journal: Environmental Health Perspectives (1986)

To investigate mechanisms by which the mummichog (F. heteroclitus) successfully withstands heavy metal pollution, fish were treated with Hg2+ at up to 0.10 mg/L, Cu2+ at up to 1.0 mg/L, or combinations of Hg2+ and Cu2+. In earlier work, protein analysis of liver indicated that most of the cytosolic Cu is bound to the sulfhydryl-rich metallothionein, but that Hg is not associated with cytosolic proteins. Morphometric analysis indicates the Hg-treatment increases the lipid compartment of hepatocytes (ANOVA, F = 10.73, p less than 0.01). This lipid increase is correlated with the Hg content (analyzed by atomic absorption spectrophotometry) of individual liver samples (Spearman rank correlation, rs = 0.621, p less than 0.01). Cu treatment causes a reduction in the lipid compartment (F = 10.38, p less than 0.01), reduced cytoplasm in general (F = 18.55, p less than 0.001) and an increased lysosome count (F = 14.21, p less than 0.001). X-Ray microanalysis locates Cu in secondary lysosomes, but not in other organelles. Results of treatment with both Hg2+ and Cu2+ are similar to those of Hg2+ alone. Concentrations of Cu in liver varied too much to allow assessment of correlations with cytoplasmic changes. Usual mechanisms for handling toxic heavy metals include binding to metallothionein and sequestering in lysosomes. Our findings for Cu are in agreement with this. Fish, however, can methylate Hg. (We have found greater than 75% of killifish hepatic Hg to be methylated.) Increased cellular lipid may be a mechanism for sequestering the lipid-soluble methylmercury.
TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand
Authors: Tomoki Ito, Yui-Hsi Wang, Omar Duramad, Toshiyuki Hori, Guy J. Delespesse, Norihiko Watanabe, F. Xiao-Feng Qin, Zhengbin Yao, Wei Cao, Yong-Jun Liu
Journal: The Journal of Experimental Medicine (2005)

We recently showed that dendritic cells (DCs) activated by thymic stromal lymphopoietin (TSLP) prime naive CD4+ T cells to differentiate into T helper type 2 (Th2) cells that produced high amounts of tumor necrosis factor-α (TNF-α), but no interleukin (IL)-10. Here we report that TSLP induced human DCs to express OX40 ligand (OX40L) but not IL-12. TSLP-induced OX40L on DCs was required for triggering naive CD4+ T cells to produce IL-4, -5, and -13. We further revealed the following three novel functional properties of OX40L: (a) OX40L selectively promoted TNF-α, but inhibited IL-10 production in developing Th2 cells; (b) OX40L lost the ability to polarize Th2 cells in the presence of IL-12; and (c) OX40L exacerbated IL-12–induced Th1 cell inflammation by promoting TNF-α, while inhibiting IL-10. We conclude that OX40L on TSLP-activated DCs triggers Th2 cell polarization in the absence of IL-12, and propose that OX40L can switch IL-10–producing regulatory Th cell responses into TNF-α–producing inflammatory Th cell responses.
In-vitro T cell mediated function in patients with active rheumatoid arthritis.
Authors: S Slavin, S Strober
Journal: Annals of the Rheumatic Diseases (1981)

In-vitro synthesis of peripheral blood lymphocytes from patients with rheumatoid arthritis was measured after stimulation with phytohaemagglutinin (PHA) in a short-term, serum-free culture system. Diminished responses were found in 16 out of 17 consecutive patients with active disease. Normal PHA responsiveness was recovered by assaying Ficoll-Hypaque isolated E rosette forming cells in serum-free medium, indicating basically normal T cell function in RA. Preincubation of normal peripheral blood lymphocytes (or isolated E rosette forming cells) with sera obtained from patients with active RA for 30 minutes at 4 degrees C or 37 degrees C blocked PHA responsiveness in 34 out of 43 tests. This suggests that serum blocking factors may be responsible for reduced T cell reactivity in RA.
In vivo Monitoring of microRNA Biogenesis Using Reporter Gene Imaging
Authors: So Won Oh, Do Won Hwang, Dong Soo Lee
Journal: Theranostics (2013)

MicroRNAs are small noncoding RNAs regulating gene expression, through base paring with their target mRNAs, which have been actively investigated as key regulators in a wide range of biological processes.Conventional methods such as Northern blot are generally time-consuming, non-repeatable, and cannot be applied in vivo due to the requirement for cell fixation.Therefore, a noninvasive imaging system is required for the monitoring of microRNA biogenesis to understand the versatile functions of microRNAs in vivo as well as in vitro and to accelerate the clinical application of microRNA-based therapy.In this paper, we reviewed noninvasive molecular imaging systems for the monitoring of the biogenesis of microRNAs and post-transcriptional regulation of genes by microRNAs and the roles of microRNAs in various biological processes.
Antisynthetase syndrome positive for anti-threonyl-tRNA synthetase (anti-PL7) antibodies
Authors: B. Hervier, Y. Uzunhan, E. Hachulla, O. Benveniste, H. Nunes, P. Delaval, L. Musset, S. Dubucquoi, B. Wallaert, M. Hamidou
Journal: European Respiratory Journal (2011)

To the Editors:

Antisynthetase syndrome (ASS) is characterised by an inflammatory myositis associated with interstitial lung disease (ILD) and antisynthetase antibodies. Other symptoms, including arthritis, Raynaud's phenomenon and mechanic's hands, are also associated with ASS. Several antisynthetase antibodies 1 have been described, with anti-Jo1 being the most common. Little is known about the clinical manifestations of ASS associated with anti-threonyl-tRNA synthetase antibodies (anti-PL7) 2–4, most probably because anti-PL7 antibodies are particularly rare (5% of myositis 5) and have not been routinely researched in the past.

We conducted this retrospective multicentric study to describe the clinical, radiographic and biological manifestations of ASS in 12 patients.

This retrospective study was conducted in five university hospitals. The patients were followed from 2000–2010 in the Depts of Pneumology (n = 7) and Internal Medicine (n = 5). 16 anti-PL7 positive patients were identified due to immunological laboratory databases. To exclude false-positive patients, we only included patients who successively tested positive for anti-PL7 twice (n = 13): the three patients tested only once did not disclose any symptoms in accordance with ASS. We excluded one patient for whom clinical data were missing. The 12 included patients tested positive for anti-PL7 antibodies at least twice by immunodot (immuno-DOT D-tek; Diasorin, Antony, France) and/or Western blot using protein extracts from Hep2 cells (n = 7 and n = 5, respectively). They presented with one or more ASS symptoms, including ILD and/or myositis. A search for anti-DNA and anti-extractable nuclear antigen antibodies was systematically performed, whereas rheumatoid factor and anti-citrullinated peptide were available in four and two patients, respectively.

The characterisation of the ILD pattern was made by several radiologists who were all experienced in ILD and were based on the American Thoracic Society/European Respiratory Society 2002 consensus 6.

Pulmonary hypertension was suspected by …
<i>Horror Autoinflammaticus</i>: The Molecular Pathophysiology of Autoinflammatory Disease
Authors: Seth L. Masters, Anna Simon, Ivona Aksentijevich, Daniel L. Kastner
Journal: Annual Review of Immunology (2009)

The autoinflammatory diseases are characterized by seemingly unprovoked episodes of inflammation, without high-titer autoantibodies or antigen-specific T cells. The concept was proposed ten years ago with the identification of the genes underlying hereditary periodic fever syndromes. This nosology has taken root because of the dramatic advances in our knowledge of the genetic basis of both mendelian and complex autoinflammatory diseases, and with the recognition that these illnesses derive from genetic variants of the innate immune system. Herein we propose an updated classification scheme based on the molecular insights garnered over the past decade, supplanting a clinical classification that has served well but is opaque to the genetic, immunologic, and therapeutic interrelationships now before us. We define six categories of autoinflammatory disease: IL-1beta activation disorders (inflammasomopathies), NF-kappaB activation syndromes, protein misfolding disorders, complement regulatory diseases, disturbances in cytokine signaling, and macrophage activation syndromes. A system based on molecular pathophysiology will bring greater clarity to our discourse while catalyzing new hypotheses both at the bench and at the bedside.