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Inhibition of Pseudomonas aeruginosa secreted virulence factors reduces lung inflammation in CF mice.

Virulence. 2018 Jun 25;:

Authors: Sandri A, Ortombina A, Boschi F, Cremonini E, Boaretti M, Sorio C, Melotti P, Bergamini G, Lleo MM

Abstract
BACKGROUND: Cystic fibrosis (CF) lung infection is a complex condition where opportunistic pathogens and defective immune system cooperate in developing a constant cycle of infection and inflammation. The major pathogen, Pseudomonas aeruginosa, secretes a multitude of virulence factors involved in host immune response and lung tissue damage. In this study, we examined the possible anti-inflammatory effects of molecules inhibiting P. aeruginosa virulence factors.
METHODS: Pyocyanin, pyoverdine and proteases were measured in bacterial culture supernatant from different P. aeruginosa strains. Inhibition of virulence factors by sub-inhibitory concentrations of clarithromycin and by protease inhibitors was evaluated. Lung inflammatory response was monitored by in vivo bioluminescence imaging in wild-type and CFTR-knockout mice expressing a luciferase gene under the control of a bovine IL-8 promoter.
RESULTS: The amount of proteases, pyocyanin and pyoverdine secreted by P. aeruginosa strains was reduced after growth in the presence of a sub-inhibitory dose of clarithromycin. Intratracheal challenge with culture supernatant containing bacteria-released products induced a strong IL-8-mediated response in mouse lungs while lack of virulence factors corresponded to a reduction in bioluminescence emission. Particularly, sole inactivation of proteases by inhibitors Ilomastat and Marimastat also resulted in decreased lung inflammation.
CONCLUSIONS: Our data support the assumption that virulence factors are involved in P. aeruginosa pro-inflammatory action in CF lungs; particularly, proteases seem to play an important role. Inhibition of virulence factors production and activity resulted in decreased lung inflammation; thus, clarithromycin and protease inhibitors potentially represent additional therapeutic therapies for P. aeruginosa-infected patients.

PMID: 29938577 [PubMed - as supplied by publisher]

Related Articles

AGTR2 absence or antagonism prevents cystic fibrosis pulmonary manifestations.

J Cyst Fibros. 2018 Jun 21;:

Authors: Darrah RJ, Jacono FJ, Joshi N, Mitchell AL, Sattar A, Campanaro CK, Litman P, Frey J, Nethery DE, Barbato ES, Hodges CA, Corvol H, Cutting GR, Knowles MR, Strug LJ, Drumm ML

Abstract
BACKGROUND: Pulmonary disease remains the primary cause of morbidity and mortality for individuals with cystic fibrosis (CF). Variants at a locus on the X-chromosome containing the type 2 angiotensin II receptor gene (AGTR2) were identified by a large GWAS as significantly associating with lung function in CF patients. We hypothesized that manipulating the angiotensin-signaling pathway may yield clinical benefit in CF.
METHODS: Genetic subset analysis was conducted on a local CF cohort to extend the GWAS findings. Next, we evaluated pulmonary function in CF mice with a deleted AGTR2 gene, and in those who were given subcutaneous injections of PD123,319, a selective AGTR2 antagonist for 12 weeks beginning at weaning.
RESULTS: The genetic subset analysis replicated the initial GWAS identified association, and confirmed the association of this locus with additional lung function parameters. Studies in genetically modified mice established that absence of the AGTR2 gene normalized pulmonary function indices in two independent CF mouse models. Further, we determined that pharmacologic antagonism of AGTR2 improved overall pulmonary function in CF mice to near wild-type levels.
CONCLUSIONS: These results identify that reduced AGTR2 signaling is beneficial to CF lung function, and suggest the potential of manipulating the angiotensin-signaling pathway for treatment and/or prevention of CF pulmonary disease. Importantly, the beneficial effects were not CF gene mutation dependent, and were able to be reproduced with pharmacologic antagonism. As there are clinically approved drugs available to target the renin-angiotensin signaling system, these findings may be quickly translated to human clinical trials.

PMID: 29937318 [PubMed - as supplied by publisher]

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Resistin is elevated in cystic fibrosis sputum and correlates negatively with lung function.

J Cyst Fibros. 2018 Jun 21;:

Authors: Forrest OA, Chopyk DM, Gernez Y, Brown MR, Conrad CK, Moss RB, Tangpricha V, Peng L, Tirouvanziam R

Abstract
BACKGROUND: Resistin is an immunometabolic mediator that is elevated in several inflammatory disorders. A ligand for Toll-like receptor 4, resistin modulates the recruitment and activation of myeloid cells, notably neutrophils. Neutrophils are major drivers of cystic fibrosis (CF) lung disease, in part due to the release of human neutrophil elastase- and myeloperoxidase-rich primary granules, leading to tissue damage. Here we assessed the relationship of resistin to CF lung disease.
METHODS: Resistin levels were measured in plasma and sputum from three retrospective CF cohorts spanning a wide range of disease. We also assessed the ability of neutrophils to secrete resistin upon activation in vitro. Finally, we constructed a multivariate model assessing the relationship between resistin levels and lung function.
RESULTS: Plasma resistin levels were only marginally higher in CF than in healthy control subjects. By contrast, sputum resistin levels were very high in CF, reaching 50-100 fold higher levels than in plasma. Among CF patients, higher plasma resistin levels were associated with allergic bronchopulmonary aspergillosis, and higher sputum resistin levels were associated with CF-related diabetes. Mechanistically, in vitro release of neutrophil primary granules was concomitant with resistin secretion. Overall, sputum resistin levels were negatively correlated with CF lung function, independently of other variables (age, sex, and genotype).
CONCLUSIONS: Our data establish relationships between resistin levels in the plasma and sputum of CF patients that correlate with disease status, and identify resistin as a novel mechanistic link between neutrophilic inflammation and lung disease in CF.

PMID: 29937317 [PubMed - as supplied by publisher]

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StatPearls

Book. 2018 01

Authors:

Abstract
Schwachman-Diamond syndrome (SDS) is an autosomal recessive disorder that is the second most common cause of exocrine pancreatic insufficiency after cystic fibrosis. It presents with the common triad of exocrine pancreatic dysfunction, skeletal abnormalities, and bone marrow dysfunction. However, cardiac abnormalities, immune dysfunction, and hematologic disorders are also reported. A mutation in the Shwachman-Bodian-Diamond syndrome (SBDS) gene on chromosome 7 is found in 90% of the cases.

PMID: 29939643

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PRUNE1 Deficiency: Expanding the Clinical and Genetic Spectrum.

Neuropediatrics. 2018 Jun 25;:

Authors: Alhaddad B, Schossig A, Haack TB, Kovács-Nagy R, Braunisch MC, Makowski C, Senderek J, Vill K, Müller-Felber W, Strom TM, Krabichler B, Freisinger P, Deshpande C, Polster T, Wolf NI, Desguerre I, Wörmann F, Rötig A, Ahting U, Kopajtich R, Prokisch H, Meitinger T, Feichtinger RG, Mayr JA, Jungbluth H, Hubmann M, Zschocke J, Distelmaier F, Koch J

Abstract
BACKGROUND:  Primary microcephaly and profound global developmental delay have been considered the core clinical phenotype in patients with bi-allelic PRUNE1 mutations.
METHODS:  Linkage analysis and whole-exome sequencing (WES) in a multiplex family and extraction of further cases from a WES repository containing 571 children with severe developmental disabilities and neurologic symptoms.
RESULTS:  We identified bi-allelic PRUNE1 mutations in twelve children from six unrelated families. All patients who survived beyond the first 6 months of life had early-onset global developmental delay, bilateral spastic paresis, dysphagia and difficult-to-treat seizures, while congenital or later-evolving microcephaly was not a consistent finding. Brain MRI showed variable anomalies with progressive cerebral and cerebellar atrophies and T2-hyperintense brain stem lesions. Peripheral neuropathy was documented in five cases. Disease course was progressive in all patients and eight children died in the first or early second decade of life. In addition to the previously reported missense mutation p.(Asp106Asn), we observed a novel homozygous missense variant p.(Leu172Pro) and a homozygous contiguous gene deletion encompassing most of the PRUNE1 gene and part of the neighboring BNIPL gene.
CONCLUSIONS:  PRUNE1 deficiency causes severe early-onset disease affecting the central and peripheral nervous systems. Microcephaly is probably not a universal feature.

PMID: 29940663 [PubMed - as supplied by publisher]

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Evidence for HNRNPH1 being another gene for Bain type syndromic mental retardation.

Clin Genet. 2018 Jun 25;:

Authors: Pilch J, Koppolu AA, Walczak A, Pienkowski VAM, Biernacka A, Skiba P, Machnik-Broncel J, Gasperowicz P, Kosińska J, Rydzanicz M, Emich-Widera E, Płoski R

Abstract
The HNRNPH2-associated disease (Mental retardation, X-linked, syndromic, Bain type (MRXSB, MIM#300986) is caused by de novo mutations in the X-linked HNRNPH2 gene. MRXSB has been described in 6 female patients with dysmorphy, developmental delay, intellectual disability, autism, hypotonia and seizures. The reported HNRNPH2 mutations were clustered in the small domain encoding nuclear localization signal; in particular, the p.Arg206Trp was found in 4 independent de novo events. HNRNPH1 is a conserved autosomal paralogue of HNRNPH2 with a similar function in regulation of pre-mRNAs splicing but so far it has not been associated with human disease. We describe a boy with a disease similar to MRXSB in whom a novel de novo mutation c.616C>T (p.Arg206Trp) in HNRNPH1 was found (i.e. the exact paralogue of the recurrent HNRNPH2 mutation). We propose that defective function of HNRNPH2 and HNRNPH1 nuclear localization signal has similar clinical consequences. An important difference between the two diseases is that the HNRNPH1 associated syndrome may occur in boys (as in the case of our proband) which is well explained by the autosomal (chr.5q35.3) rather than X-linked localization of the HNRNPH2 gene. This article is protected by copyright. All rights reserved.

PMID: 29938792 [PubMed - as supplied by publisher]

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The landscape of somatic mutation in sporadic Chinese colorectal cancer.

Oncotarget. 2018 Jun 08;9(44):27412-27422

Authors: Liu Z, Yang C, Li X, Luo W, Roy B, Xiong T, Zhang X, Yang H, Wang J, Ye Z, Chen Y, Song J, Ma S, Zhou Y, Yang M, Fang X, Du J

Abstract
Colorectal cancer is the fifth prevalent cancer in China. Nevertheless, a large-scale characterization of Chinese colorectal cancer mutation spectrum has not been carried out. In this study, we have performed whole exome-sequencing analysis of 98 patients' tumor samples with matched pairs of normal colon tissues using Illumina and Complete Genomics high-throughput sequencing platforms. Canonical CRC somatic gene mutations with high prevalence (>10%) have been verified, including TP53, APC, KRAS, SMAD4, FBXW7 and PIK3CA. PEG3 is identified as a novel frequently mutated gene (10.6%). APC and Wnt signaling exhibit significantly lower mutation frequencies than those in TCGA data. Analysis with clinical characteristics indicates that APC gene and Wnt signaling display lower mutation rate in lymph node positive cancer than negative ones, which are not observed in TCGA data. APC gene and Wnt signaling are considered as the key molecule and pathway for colorectal cancer initiation, and these findings greatly undermine their importance in tumor progression for Chinese patients. Taken together, the application of next-generation sequencing has led to the determination of novel somatic mutations and alternative disease mechanisms in colorectal cancer progression, which may be useful for understanding disease mechanism and personalizing treatment for Chinese patients.

PMID: 29937994 [PubMed]

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Circulating Tumour DNA Analysis for Tumour Genome Characterisation and Monitoring Disease Burden in Extramedullary Multiple Myeloma.

Int J Mol Sci. 2018 Jun 24;19(7):

Authors: Mithraprabhu S, Sirdesai S, Chen M, Khong T, Spencer A

Abstract
Mutational characterisation in extramedullary multiple myeloma (EM-MM) patients is challenging due to inaccessible EM plasmacytomas, unsafe nature of multiple biopsies and the spatial and temporal genomic heterogeneity apparent in MM (Graphical abstract). Conventional monitoring of disease burden is through serum markers and PET-CT, however these modalities are sometimes inadequate (serum markers), not performed in a timely manner (PET-CT) and uninformative for identifying mutations driving disease progression. DNA released into the blood by tumour cells (ctDNA) contains the predominant clones derived from the multiple disease foci. Blood-derived ctDNA can, therefore, provide a holistic illustration of the major drivers of disease progression. In this report, the utility of ctDNA, as an adjunct to currently available modalities in EM-MM, is presented for a patient with EM and oligosecretory (OS) disease. Whole exome sequencing of contemporaneously acquired tumour tissue and matched ctDNA samples revealed the presence of spatial and temporal genetic heterogeneity and the identification of pathways associated with drug resistance. Longitudinal monitoring of plasma samples revealed that ctDNA can be utilised to define the dynamic clonal evolution co-existent with disease progression and as an adjunct non-invasive marker of tumour burden.

PMID: 29937522 [PubMed - in process]

18 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2018/06/26

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Funding Opportunity PA-18-838 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement (FOA) is to encourage applications from the scientific community to support outstanding research related to the role of the gut microbiome in regulating metabolism and reproduction, and its impact on the fertility status. The overarching goal is to gain fundamental insight into the possible role of the gut microbiome in regulating reproduction through HPG, HPA, and HPT axes in the brain. The results of the study could lead to development of diagnostic markers (signature microbiomes) for reproductive and metabolic failure. The project is pertinent to multiple portfolios in the Fertility and Infertility Branch, e.g., basic ovarian biology, fertility preservation, assisted reproductive technology, spermatogenesis and sperm function, and therapeutic interventions to infertility. The emphasis on the gut microbiome and its impact on reproduction through its effects on HPG, HPA, and HPT axes leading to obesity, metabolic syndrome, stress disorders, infection and anxiety is also of interest to the Maternal and Pediatric infectious disease Branch, Pediatric Growth and Nutrition Branch and IDDB.

Funding Opportunity PA-18-839 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement (FOA) is to encourage applications from the scientific community to support outstanding research related to the role of the gut microbiome in regulating metabolism and reproduction, and its impact on the fertility status. The overarching goal is to gain fundamental insight into the possible role of the gut microbiome in regulating reproduction through HPG, HPA, and HPT axes in the brain. The results of the study could lead to development of diagnostic markers (signature microbiomes) for reproductive and metabolic failure. The project is pertinent to multiple portfolios in the Fertility and Infertility Branch, e.g., basic ovarian biology, fertility preservation, assisted reproductive technology, spermatogenesis and sperm function, and therapeutic interventions to infertility. The emphasis on the gut microbiome and its impact on reproduction through its effects on HPG, HPA, and HPT axes leading to obesity, metabolic syndrome, stress disorders, infection and anxiety is also of interest to the Maternal and Pediatric infectious disease Branch, Pediatric Growth and Nutrition Branch and IDDB.

Notice NOT-OD-18-196 from the NIH Guide for Grants and Contracts

Notice NOT-CA-18-082 from the NIH Guide for Grants and Contracts

Notice NOT-CA-18-081 from the NIH Guide for Grants and Contracts

6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2018/06/26

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Related Articles

Disease classification: from phenotypic similarity to integrative genomics and beyond.

Brief Bioinform. 2018 Jun 22;:

Authors: Dozmorov MG

Abstract
A fundamental challenge of modern biomedical research is understanding how diseases that are similar on the phenotypic level are similar on the molecular level. Integration of various genomic data sets with the traditionally used phenotypic disease similarity revealed novel genetic and molecular mechanisms and blurred the distinction between monogenic (Mendelian) and complex diseases. Network-based medicine has emerged as a complementary approach for identifying disease-causing genes, genetic mediators, disruptions in the underlying cellular functions and for drug repositioning. The recent development of machine and deep learning methods allow for leveraging real-life information about diseases to refine genetic and phenotypic disease relationships. This review describes the historical development and recent methodological advancements for studying disease classification (nosology).

PMID: 29939197 [PubMed - as supplied by publisher]

Notice NOT-CA-18-085 from the NIH Guide for Grants and Contracts

Notice NOT-CA-18-084 from the NIH Guide for Grants and Contracts

Notice NOT-CA-18-083 from the NIH Guide for Grants and Contracts

Notice NOT-CA-18-086 from the NIH Guide for Grants and Contracts