Lipidomic analysis of patients with microbial invasion of the amniotic cavity reveals upâ regulation of leukotriene B4

Bioactive lipids derived from the metabolism of polyunsaturated fatty acids are important mediators of the inflammatory response. Labor per se is considered a sterile inflammatory process. Intraâ amniotic inflammation (IAI) due to microorganisms (i.e., intraâ amniotic infection) or danger signals (i.e., sterile IAI) has been implicated in the pathogenesis of preterm labor and clinical chorioamnionitis at term. Early and accurate diagnosis of microbial invasion of the amniotic cavity (MIAC) requires analysis of amniotic fluid (AF). It is possible that IAI caused by microorganisms is associated with a stereotypic lipidomic profile, and that analysis of AF may help in the identification of patients with this condition. To test this hypothesis, we analyzed the fatty acyl lipidome of AF by liquid chromatographyâ mass spectrometry from patients in spontaneous labor at term and preterm gestations. We report that the AF concentrations of proinflammatory lipid mediators of the 5â lipoxygenase pathway are significantly higher in MIAC than in cases of sterile IAI. These results suggest that the concentrations of 5â lipoxygenase metabolites of arachidonic acid, 5â hydroxyeicosatetraenoic acid, and leukotriene B4 in particular could serve as potential biomarkers of MIAC. This finding could have important implications for the rapid identification of patients who may benefit from antimicrobial treatment.â Maddipati, K. R., Romero, R., Chaiworapongsa, T., Chaemsaithong, P., Zhou, S.â L., Xu, Z., Tarca, A. L., Kusanovic, J. P., Gomez, R., Chaiyasit, N., Honn, K. V. Lipidomic analysis of patients with microbial invasion of the amniotic cavity reveals upâ regulation of leukotriene B4. FASEBJ. 30, 3296â 3307 (2016). www.fasebj.orgPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154488/1/fsb2fasebj30100583.pd

Low Serum Glutathione Peroxidase Activity Is Associated with Increased Cardiovascular Mortality in Individuals with Low HDLc’s

Background Since oxidized LDL is thought to initiate atherosclerosis and the serum glutathione peroxidase (GPx3) reduces oxidized lipids, we investigated whether high GPx3 activity reduces cardiovascular disease (CVD) mortality. Methods We determined GPx3 in stored samples from the Minnesota Heart Survey of 130 participants who after 5 to 12 years of follow-up had died of CVD and 240 controls. Participants were 26 to 85 years old and predominantly white. In a nested case-control, study we performed logistic regressions to calculate odds ratios (OR) adjusted for age, sex, baseline year, body mass index, smoking, alcohol intake, physical activity, total and HDL cholesterols, systolic blood pressure, serum glucose and gamma glutamyltransferase (GTT) activity. The referent was the quartile with the highest GPx3 activity (quartile 4). Results OR’s for CVD mortality for increasing quartiles of GPx3 were 2.37, 2.14, 1.83 and 1.00 (P for trend 0.02). This inverse correlation was confined to those with HDLc’s below the median (P for interaction, 0.006). The OR’s for increasing quartiles of GPx3 in this group were 6.08, 5.00, 3.64 and 1.00 (P for trend, 0.002). Conclusions Individuals with both low HDLc and GPx3 activity are at markedly increased risk for death from CVD

MFSD2A Promotes Endothelial Generation of Inflammation-resolving Lipid Mediators and Reduces Colitis in Mice

Alterations in signaling pathways that regulate resolution of inflammation (resolving pathways) contribute to pathogenesis of ulcerative colitis (UC). The resolution process is regulated by lipid mediators, such as those derived from the \u3c9-3 docosahexaenoic acid (DHA), whose esterified form is transported by the major facilitator superfamily domain containing 2A (MFSD2A) through the endothelium of brain, retina, and placenta. We investigated if and how MFSD2A regulates lipid metabolism of gut endothelial cells to promote resolution of intestinal inflammation

Adrenal function recovery after durable oral corticosteroid sparing with benralizumab in the PONENTE study

Background Oral corticosteroid (OCS) dependence among patients with severe eosinophilic asthma can cause adverse outcomes, including adrenal insufficiency. PONENTE's OCS reduction phase showed that, following benralizumab initiation, 91.5% of patients eliminated corticosteroids or achieved a final dosage ≤5 mg·day-1 (median (range) 0.0 (0.0-40.0) mg). Methods The maintenance phase assessed the durability of corticosteroid reduction and further adrenal function recovery. For ~6 months, patients continued benralizumab 30 mg every 8 weeks without corticosteroids or with the final dosage achieved during the reduction phase. Investigators could prescribe corticosteroids for asthma exacerbations or increase daily dosages for asthma control deteriorations. Outcomes included changes in daily OCS dosage, Asthma Control Questionnaire (ACQ)-6 and St George's Respiratory Questionnaire (SGRQ), as well as adrenal status, asthma exacerbations and adverse events. Results 598 patients entered PONENTE; 563 (94.1%) completed the reduction phase and entered the maintenance phase. From the end of reduction to the end of maintenance, the median (range) OCS dosage was unchanged (0.0 (0.0-40.0) mg), 3.2% (n=18/563) of patients experienced daily dosage increases, the mean ACQ-6 score decreased from 1.26 to 1.18 and 84.5% (n=476/563) of patients were exacerbation free. The mean SGRQ improvement (-19.65 points) from baseline to the end of maintenance indicated substantial quality-of-life improvements. Of patients entering the maintenance phase with adrenal insufficiency, 32.4% (n=104/321) demonstrated an improvement in adrenal function. Adverse events were consistent with previous reports. Conclusions Most patients successfully maintained maximal OCS reduction while achieving improved asthma control with few exacerbations and maintaining or recovering adrenal function

Collective cell migration and metastases induced by an epithelial-to-mesenchymal transition in Drosophila intestinal tumors.

Metastasis underlies the majority of cancer-related deaths yet remains poorly understood due, in part, to the lack of models in vivo. Here we show that expression of the EMT master inducer Snail in primary adult Drosophila intestinal tumors leads to the dissemination of tumor cells and formation of macrometastases. Snail drives an EMT in tumor cells, which, although retaining some epithelial markers, subsequently break through the basal lamina of the midgut, undergo a collective migration and seed polyclonal metastases. While metastases re-epithelialize over time, we found that early metastases are remarkably mesenchymal, discarding the requirement for a mesenchymal-to-epithelial transition for early stages of metastatic growth. Our results demonstrate the formation of metastases in adult flies, and identify a key role for partial-EMTs in driving it. This model opens the door to investigate the basic mechanisms underlying metastasis, in a powerful in vivo system suited for rapid genetic and drug screens

Rare variant analysis of 4241 pulmonary arterial hypertension cases from an international consortium implicates FBLN2, PDGFD, and rare de novo variants in PAH

Abstract: Background: Pulmonary arterial hypertension (PAH) is a lethal vasculopathy characterized by pathogenic remodeling of pulmonary arterioles leading to increased pulmonary pressures, right ventricular hypertrophy, and heart failure. PAH can be associated with other diseases (APAH: connective tissue diseases, congenital heart disease, and others) but often the etiology is idiopathic (IPAH). Mutations in bone morphogenetic protein receptor 2 (BMPR2) are the cause of most heritable cases but the vast majority of other cases are genetically undefined. Methods: To identify new risk genes, we utilized an international consortium of 4241 PAH cases with exome or genome sequencing data from the National Biological Sample and Data Repository for PAH, Columbia University Irving Medical Center, and the UK NIHR BioResource – Rare Diseases Study. The strength of this combined cohort is a doubling of the number of IPAH cases compared to either national cohort alone. We identified protein-coding variants and performed rare variant association analyses in unrelated participants of European ancestry, including 1647 IPAH cases and 18,819 controls. We also analyzed de novo variants in 124 pediatric trios enriched for IPAH and APAH-CHD. Results: Seven genes with rare deleterious variants were associated with IPAH with false discovery rate smaller than 0.1: three known genes (BMPR2, GDF2, and TBX4), two recently identified candidate genes (SOX17, KDR), and two new candidate genes (fibulin 2, FBLN2; platelet-derived growth factor D, PDGFD). The new genes were identified based solely on rare deleterious missense variants, a variant type that could not be adequately assessed in either cohort alone. The candidate genes exhibit expression patterns in lung and heart similar to that of known PAH risk genes, and most variants occur in conserved protein domains. For pediatric PAH, predicted deleterious de novo variants exhibited a significant burden compared to the background mutation rate (2.45×, p = 2.5e−5). At least eight novel pediatric candidate genes carrying de novo variants have plausible roles in lung/heart development. Conclusions: Rare variant analysis of a large international consortium identified two new candidate genes—FBLN2 and PDGFD. The new genes have known functions in vasculogenesis and remodeling. Trio analysis predicted that ~ 15% of pediatric IPAH may be explained by de novo variants

Advanced computational and machine learning tools in pharmaceutical informatics

Computational and informatics approaches are of immediate necessity in the drug discovery research to analyze the possible side effects of the drugs a priori and also to leverage and integrate vast amounts of the disparate data that is being generated by the high throughput screening experiments and the ‘omic’ technologies. In this work, computational methods are proposed for two problems: (1) A priori prediction of side effects of cancer therapeutic drugs: Protein kinases are central targets for drug-based treatment of diseases such as cancer, diabetes and arthritis. However, recent high throughput screening data reveal that most kinase inhibitors of pharmacological relevance exhibit high cross reactivity, frequently leading to toxic side effects since kinases play a critical role in many cell signaling events. In this work, the recently proposed theory of dehydrons is first illustrated by molecular dynamics simulations and is then used to develop a structure-based predictor of cross reactivity, which is validated against affinity fingerprinting of the kinases. It is shown that pharmacological distances are highly correlated to the patterns of dehydrons. (2) Analysis of the high throughput data on recombinant proteins: Recombinant proteins find several applications in biotechnology and pharmaceutical industries. Recent high throughput experiments can measure the properties of several of these artificial proteins. However, experiments spanning the entire combinatorial library of such proteins are quite expensive and hence building statistical models based on the limited experimental data is of utmost importance. In this work, a statistical classification model built using Support Vector Machines is used to analyze the folding patterns in recombinants of Cytochrome P450. This model can further be used in formulating a design problem to find the optimal recombinants. The methods (kernels) developed in this work can be generalized to arrive at new kernels called ‘categorical kernels’ and are found to be applicable in general pattern recognition problems like hand written digit recognition. Since the kernel methods can be applied to categorical, numerical and even continuous attributes, they can potentially be employed to make cross reactivity predictions for other protein families, for which only few crystal structures are available. These kernels could bridge the high throughput experimental data with sequence and structure information

Eicosanomic profiling reveals dominance of the epoxygenase pathway in human amniotic fluid at term in spontaneous labor

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154414/1/fsb2028011021.pd