Characterization of a splice-site mutation in the tumor suppressor gene FLCN associated with renal cancer.

BMC Med Genet. 2017 May 12;18(1):53

Authors: Bartram MP, Mishra T, Reintjes N, Fabretti F, Gharbi H, Adam AC, Göbel H, Franke M, Schermer B, Haneder S, Benzing T, Beck BB, Müller RU

Abstract
BACKGROUND: Renal cell carcinoma is among the most prevalent malignancies. It is generally sporadic. However, genetic studies of rare familial forms have led to the identification of mutations in causative genes such as VHL and FLCN. Mutations in the FLCN gene are the cause of Birt-Hogg-Dubé syndrome, a rare tumor syndrome which is characterized by the combination of renal cell carcinoma, pneumothorax and skin tumors.
METHODS: Using Sanger sequencing we identify a heterozygous splice-site mutation in FLCN in lymphocyte DNA of a patient suffering from renal cell carcinoma. Furthermore, both tumor DNA and DNA from a metastasis are analyzed regarding this mutation. The pathogenic effect of the sequence alteration is confirmed by minigene assays and the biochemical consequences on the protein are examined using TALEN-mediated transgenesis in cultured cells.
RESULTS: Here we describe an FLCN mutation in a 55-year-old patient who presented himself with progressive weight loss, bilateral kidney cysts and renal tumors. He and members of his family had a history of recurrent pneumothorax during the last few decades. Histology after tumor nephrectomy showed a mixed kidney cancer consisting of elements of a chromophobe renal cell carcinoma and dedifferentiated small cell carcinoma component. Subsequent FLCN sequencing identified an intronic c.1177-5_-3delCTC alteration that most likely affected the correct splicing of exon 11 of the FLCN gene. We demonstrate skipping of exon 11 to be the consequence of this mutation leading to a shift in the reading frame and the insertion of a premature stop codon. Interestingly, the truncated protein was still expressed both in cell culture and in tumor tissue, though it was strongly destabilized and its subcellular localization differed from wild-type FLCN. Both, altered protein stability and subcellular localization could be partly reversed by blocking proteasomal and lysosomal degradation.
CONCLUSIONS: Identification of disease-causing mutations in BHD syndrome requires the analysis of intronic sequences. However, biochemical validation of the consecutive alterations of the resulting protein is especially important in these cases. Functional characterization of the disease-causing mutations in BHD syndrome may guide further research for the development of novel diagnostic and therapeutic strategies.

PMID: 28499369 [PubMed - in process]

The dynamics of early-state transcriptional changes and aggregate formation in a Huntington's disease cell model.

BMC Genomics. 2017 May 12;18(1):373

Authors: van Hagen M, Piebes DGE, de Leeuw WC, Vuist IM, van Roon-Mom WMC, Moerland PD, Verschure PJ

Abstract
BACKGROUND: Huntington's disease (HD) is a fatal neurodegenerative disorder caused by a CAG expansion in the Huntingtin (HTT) gene. Proteolytic cleavage of mutant huntingtin (Htt) protein with an expanded polyglutamine (polyQ) stretch results in production of Htt fragments that aggregate and induce impaired ubiquitin proteasome, mitochondrial functioning and transcriptional dysregulation. To understand the time-resolved relationship between aggregate formation and transcriptional changes at early disease stages, we performed temporal transcriptome profiling and quantification of aggregate formation in living cells in an inducible HD cell model.
RESULTS: Rat pheochromocytoma (PC12) cells containing a stably integrated, doxycycline-inducible, eGFP-tagged N-terminal human Htt fragment with an expanded polyQ domain were used to analyse gene expression changes at different stages of mutant Htt aggregation. At earliest time points after doxycycline induction no detectable aggregates and few changes in gene expression were observed. Aggregates started to appear at intermediate time points. Aggregate formation and subsequent enlargement of aggregates coincided with a rapid increase in the number of differentially expressed (DE) genes. The increase in number of large aggregates coincided with a decrease in the number of smaller aggregates whereas the transcription profile reverted towards the profile observed before mutant Htt induction. Cluster-based analysis of the 2,176 differentially expressed genes revealed fourteen distinct clusters responding differently over time. Functional enrichment analysis of the two major gene clusters revealed that genes in the up-regulated cluster were mainly involved in metabolic (antioxidant activity and cellular ketone metabolic processes) and genes in the down-regulated cluster in developmental processes, respectively. Promoter-based analysis of the identified gene clusters resulted in identification of a transcription factor network of which several previously have been linked to HD.
CONCLUSIONS: We demonstrate a time-resolved relationship between Htt aggregation and changes in the transcriptional profile. We identified two major gene clusters showing involvement of (i) mitochondrial dysfunction and (ii) developmental processes implying cellular homeostasis defects. We identified novel and known HD-linked transcription factors and show their interaction with known and predicted regulatory proteins. Our data provide a novel resource for hypothesis building on the role of transcriptional key regulators in early stages of HD and possibly other polyQ-dependent diseases.

PMID: 28499347 [PubMed - in process]

A New Algorithm for Identifying Cis-Regulatory Modules Based on Hidden Markov Model.

Biomed Res Int. 2017;2017:6274513

Authors: Guo H, Huo H

Abstract
The discovery of cis-regulatory modules (CRMs) is the key to understanding mechanisms of transcription regulation. Since CRMs have specific regulatory structures that are the basis for the regulation of gene expression, how to model the regulatory structure of CRMs has a considerable impact on the performance of CRM identification. The paper proposes a CRM discovery algorithm called ComSPS. ComSPS builds a regulatory structure model of CRMs based on HMM by exploring the rules of CRM transcriptional grammar that governs the internal motif site arrangement of CRMs. We test ComSPS on three benchmark datasets and compare it with five existing methods. Experimental results show that ComSPS performs better than them.

PMID: 28497059 [PubMed - in process]

Structure based discovery of clomifene as a potent inhibitor of cancer-associated mutant IDH1.

Oncotarget. 2017 Apr 27;:

Authors: Zheng M, Sun W, Gao S, Luan S, Li D, Chen R, Zhang Q, Chen L, Huang J, Li H

Abstract
Isocitrate dehydrogenase (IDH) plays an indispensable role in the tricarboxylic acid cycle, and IDH mutations are present in nearly 75% of glioma and 20% of acute myeloid leukemia. One IDH1R132H inhibitor (clomifene citrate) was found by virtual screening method, which can selectively suppress mutant enzyme activities in vitro and in vivo with a dose-dependent manner. The molecular docking indicated that clomifene occupied the allosteric site of the mutant IDH1. Enzymatic kinetics also demonstrated that clomifene inhibited mutant enzyme in a non-competitive manner. Moreover, knockdown of mutant IDH1 in HT1080 cells decreased the sensitivity to clomifene. In vivo studies indicated that clomifene significantly suppressed the tumor growth of HT1080-bearing CB-17/Icr-scid mice with oral administration of 100 mg/kg and 50 mg/kg per day. In short, our findings highlight clomifene may have clinical potential in tumor therapies as a safe and effective inhibitor of mutant IDH1.

PMID: 28498812 [PubMed - as supplied by publisher]

Fundamentals of Clinical Pharmacology With Application for Pregnant Women.

J Midwifery Womens Health. 2017 May 12;:

Authors: Patil AS, Sheng J, Dotters-Katz SK, Schmoll MS, Onslow M, Pierson RC

Abstract
Medication use is common in pregnancy, yet for most medications the optimal formulation and dosage have not been described specifically for pregnant women. Often, adverse effects are only discovered anecdotally or after extensive off-label use occurs. Since pharmacologic research that includes pregnant women is sparse and animal studies are often not applicable to the human fetus, providers must use knowledge of drug behavior and normal physiologic changes of pregnancy to personalize treatment for pregnant women. In this review, we present an overview of the basic concepts of clinical pharmacology: pharmacokinetics, pharmacodynamics, and pharmacogenomics. The normal physiologic changes of pregnancy are presented as a framework to understand alterations in drug behavior. A clinical vignette that addresses 4 pregnancy scenarios involving medications-preterm birth, vaccination, herpes simplex virus infection, and codeine toxicity-is provided to illustrate application of core clinical pharmacologic concepts. Discussion of relevant literature illustrates the challenges of offering individualized pharmacologic therapy in pregnancy.

PMID: 28498553 [PubMed - as supplied by publisher]

Application of metabolomics: Focus on the quantification of organic acids in healthy adults.

Int J Mol Med. 2017 May 10;:

Authors: Tsoukalas D, Alegakis A, Fragkiadaki P, Papakonstantinou E, Nikitovic D, Karataraki A, Nosyrev AE, Papadakis EG, Spandidos DA, Drakoulis N, Tsatsakis AM

Abstract
Metabolomics, a 'budding' discipline, may accurately reflect a specific phenotype which is sensitive to genetic and epigenetic interactions. This rapidly evolving field in science has been proposed as a tool for the evaluation of the effects of epigenetic factors, such as nutrition, environment, drug and lifestyle on phenotype. Urine, being sterile, is easy to obtain and as it contains metabolized or non‑metabolized products, is a favored study material in the field of metabolomics. Urine organic acids (OAs) reflect the activity of main metabolic pathways and have been used to assess health status, nutritional status, vitamin deficiencies and response to xenobiotics. To date, a limited number of studies have been performed which actually define reference OA values in a healthy population and as reference range for epigenetic influences, and not as a reference to congenital metabolic diseases. The aim of the present study was thus the determination of reference values (RVs) for urine OA in a healthy adult population. Targeted metabolomics analysis of 22 OAs in the urine of 122 healthy adults by gas chromatography‑mass spectrometry, was conducted. Percentile distributions of the OA concentrations in urine, as a base for determining the RVs in the respective population sample, were used. No significant differences were detected between female and male individuals. These findings can facilitate the more sensitive determination of OAs in pathological conditions. Therefore, the findings of this study may contribute or add to the information already available on urine metabolite databases, and may thus promote the use of targeted metabolomics for the evaluation of OAs in a clinical setting and for pathophysiological evaluation. However, further studies with well‑defined patients groups exhibiting specific symptoms or diseases are warranted in order to discern between normal and pathological values.

PMID: 28498405 [PubMed - as supplied by publisher]

Association of NPR3 polymorphism with risk of essential hypertension in a Chinese population.

J Clin Pharm Ther. 2017 May 11;:

Authors: Kuang DB, Zhou JP, Li MP, Tang J, Chen XP

Abstract
WHAT IS KNOWN AND OBJECTIVE: Essential hypertension (EH) is a common disease exhibiting large individual difference in occurrence, development and treatment response. Genetic factors are implicated in the development and progression of EH. This study aimed to explore the association between NPR3 single nucleotide polymorphism rs2270915 (A/G, Asn521Asp) and the risk of EH in a Chinese Han population by a case-control study.
METHODS: The study was a single-centre, case-control trial, in which a total of 287 EH patients and 289 age- and sex-matched healthy controls were enrolled. The inclusion criteria were as follows: Han Chinese origin, male or female patients, systolic blood pressure (SBP) ≥140 mm Hg and/or diastolic blood pressure (DBP) ≥90 mm Hg. The healthy controls were subjects without histories of cardiovascular or cerebrovascular diseases. NPR3 rs2270915 polymorphism was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). In addition, primary human umbilical vein endothelial cells (HUVECs) were isolated from 19 fresh human umbilical cords and cultured. Atrial natriuretic peptide (ANP) concentration in cell medium was determined by enzyme-linked immunosorbent assay (ELISA). NPR3 mRNA expression was determined by real-time semi-quantitative PCR.
RESULTS AND DISCUSSION: No significant difference in genotype distribution of NPR3 rs2270915 polymorphism was observed between cases and controls (P>.05). Patients carrying the rs2270915 G allele showed decreased SBP, and the difference was marginal. As compared with cells carrying the rs2270915 AA genotype, those with the AG genotype showed significantly lower NPR3 mRNA expression levels (P<.05) and lower medium ANP concentration (P<.001).
WHAT IS NEW AND CONCLUSION: This study suggested that NPR3 rs2270915 polymorphism was associated with decreased SBP level marginally in EH patients in a Chinese Han population, and the polymorphism may function through decreasing NPR3 mRNA expression and ANP level.

PMID: 28497617 [PubMed - as supplied by publisher]

A computational algorithm for personalized medicine in schizophrenia.

Schizophr Res. 2017 May 08;:

Authors: Lee BS, McIntyre RS, Gentle JE, Park NS, Chiriboga DA, Lee Y, Singh S, McPherson MA

Abstract
Despite advances in sequencing candidate genes and whole genomes, no method has accurately predicted who will or will not benefit from a specific antipsychotic medication among patients with schizophrenia. We propose a computational algorithm that utilizes a person-centered approach that directly identifies individual patients who will respond to a specific antipsychotic medication. The algorithm was applied to the data obtained from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study. The predictors were either (1) 13 single-nucleotide polymorphisms (SNPs) and 53 baseline variables or (2) 25 SNPs and the same 53 baseline variables, depending on the existing findings and data availability. The outcome variables were either (1) improvement in the Positive and Negative Syndrome Scale (PANSS) (Yes/No) or (2) completion of phase 1/1A (Yes/No). Each of those four predictor-outcome combinations was tried for each of the five antipsychotic medications (Perphenazine, Olanzapine, Quetiapine, Risperidone, and Ziprasidone), leading to 20 prediction experiments. For 18 out of 20 experiments, all three performance measures were greater than 0.50 (sensitivity 0.51-0.79, specificity 0.52-0.79, accuracy 0.52-0.74). Notably, the model provided a promising prediction for Ziprasidone for the case involving completion of phase 1/1A (Yes/No) predicted by 13 SNPs and 53 baseline variables (sensitivity 0.75, specificity 0.74, accuracy 0.74). The proposed algorithm simultaneously used both genetic information and clinical profiles to predict individual patients' response to antipsychotic medications. As the method is not disease-specific but a general algorithm, it can be easily adopted in many other clinical practices for personalized medicine.

PMID: 28495491 [PubMed - as supplied by publisher]

Comprehensive analysis of treatment response phenotypes in rheumatoid arthritis for pharmacogenetic studies.

Arthritis Res Ther. 2017 May 12;19(1):90

Authors: Standish KA, Huang CC, Curran ME, Schork NJ

Abstract
BACKGROUND: An individual patient's response to a particular drug is influenced by multiple factors, which may include genetic predisposition. Pharmacogenetic studies attempt to discover and estimate the contributions of genetic variants to the variability in response to a drug treatment. The task of identifying the genetic contribution is often complicated by response phenotypes that are based on imprecise or subjective clinical observations. Because the success of a pharmacogenetic study depends on the analysis of a heritable phenotype, it is important to identify phenotypes with a significant heritable component to ensure reliable and reproducible results in subsequent genetic association studies.
METHODS: We retrospectively analyzed data collected from 436 rheumatoid arthritis patients treated with golimumab during the phase III GO-FURTHER study. We investigated the reliability of several potential response outcomes after golimumab treatment. Using whole-genome sequencing of the clinical trial cohort, we estimated the heritability of each potential outcome measure. We further performed a longitudinal analysis of the clinical data to estimate variability of outcome measures over time and the degree to which each response metric could be confounded by placebo response.
RESULTS: We determined that the high degree of within-patient variation over time makes a single follow-up visit insufficient to assess an individual patient's response to golimumab treatment. We found that different potential response outcomes had varying degrees of heritability and that averaging across multiple follow-up visits yielded higher heritability estimates than single follow-up estimates. Importantly, we found that the change in swollen and tender joint counts were the most heritable outcome metrics we tested; however, we showed that they are also more likely to be confounded by a placebo response than objective phenotypes like the change in C-reactive protein levels.
CONCLUSIONS: Our rigorous approach to finding robust and heritable response phenotypes could be beneficial to all pharmacogenetic studies and may lead to more reliable and reproducible results.
TRIAL REGISTRATION: Clinicaltrials.gov NCT00973479 . Registered 4 September 2009.

PMID: 28494788 [PubMed - in process]

ABCB1 2677G>T/A variant enhances chemosensitivity to anti-cancer agents acting on microtubule dynamics through LAMP1 inhibition.

Biochem Pharmacol. 2017 Jan 01;123:73-84

Authors: Kwon WS, Rha SY, Jeung HC, Ahn JB, Jung JJ, Ki DH, Kim TS, Chung HC

Abstract
Overexpression of ABCB1 associated with single nucleotide variants in cancers was reported to encode a protein responsible for drug resistance. We studied chemosensitivity-related genes associated with ABCB1 2677G>T/A variant. The associated genes were identified based on the results of the significance analysis of microarray, and then prediction accuracy was evaluated using the prediction analysis of microarray. Functional assay of the selected gene was performed by using siRNA and drug accumulation study. A higher frequency of chemoresistance to microtubule-modulating agents was found in cell lines with wild-type ABCB1 compared to cell lines with 2677G>T/A ABCB1 variant. Based on the pharmacogenetic association study with 2677 variant, we identified seven genes that could predict chemosensitivity to microtubule dynamics modulators. The classification accuracy with these seven genes was 90.0%, and the predicted probability was 0.73. LAMP1 was the only gene that was commonly related to chemosensitivity. LAMP1 expression levels were relatively higher in chemoresistant ABCB1 wild-type compared to chemosensitive polymorphic cells. But, there was no difference in ABCB1 expression levels between the two groups. Following LAMP1 siRNA, chemosensitivity was restored due to increased intracellular drug accumulation in wild type cell line. In conclusion, ABCB1 2677G>T/A variant enhances chemosensitivity on microtubule dynamics through LAMP1 inhibition.

PMID: 27832934 [PubMed - indexed for MEDLINE]

The intestinal microbiome and paediatric liver disease.

Lancet Gastroenterol Hepatol. 2017 Jun;2(6):446-455

Authors: Leung DH, Yimlamai D

Abstract
The intestinal microbiome has been the intense focus of recent study, but how the microbiota affects connected organs, such as the liver, has not been fully elucidated. The microbiome regulates intestinal permeability and helps to metabolise the human diet into small molecules, thus directly affecting liver health. Several studies have linked intestinal dysbiosis to the severity and progression of liver diseases, such as non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, primary sclerosing cholangitis, total parenteral nutrition-associated liver disease, and cystic fibrosis-associated liver disease. However, there is limited information and interpretation with regard to how the microbiome could contribute to liver disease in the paediatric population. Notably, the gut microbiota is distinct at birth and does not establish an adult profile until the third year of life. Clinical research suggests that paediatric liver disease differs in both severity and rate of progression compared with adult forms, suggesting independent mechanisms of pathogenesis. We discuss data linking the intestinal microbiome to liver disease development and therapeutic efforts to modify the microbiome in children.

PMID: 28497760 [PubMed - in process]

[XBP1 and inflammation in cystic fibrosis alveolar macrophages].

Med Sci (Paris). 2017 Apr;33(4):380-382

Authors: Lubamba BA

PMID: 28497731 [PubMed - in process]

Cystic fibrosis transmembrane conductance regulator mediates tenogenic differentiation of tendon-derived stem cells and tendon repair: accelerating tendon injury healing by intervening in its downstream signaling.

FASEB J. 2017 May 11;:

Authors: Liu Y, Xu J, Xu L, Wu T, Sun Y, Lee YW, Wang B, Chan HC, Jiang X, Zhang J, Li G

Abstract
Tendons are a mechanosensitive tissue, which enables them to transmit to bone forces that are derived from muscle. Patients with tendon injuries, such as tendinopathy or tendon rupture, were often observed with matrix degeneration, and the healing of tendon injuries remains a challenge as a result of the limited understanding of tendon biology. Our study demonstrates that the stretch-mediated activation channel, cystic fibrosis transmembrane conductance regulator (CFTR), was up-regulated in tendon-derived stem cells (TDSCs) during tenogenic differentiation under mechanical stretching. Tendon tissues in CFTR dysfunctional mice (DF508) exhibited irregular cell arrangement, uneven fibril diameter distribution, weak mechanical properties, and less matrix formation in a tendon defect model. Moreover, both tendon tissues and TDSCs isolated from DF508 mice showed significantly decreased levels of tendon markers, such as scleraxis, tenomodulin, Col1A1 (collagen type I α 1 chain), and decorin Furthermore, by RNA sequencing analysis, we demonstrated that Wnt/β-catenin signaling was abnormally activated in TDSCs from DF508 mice, thereby further activating the pERK1/2 signaling pathway. Of most importance, we found that intervention in pERK1/2 signaling could promote tenogenic differentiation and tendon regeneration both in vitro and in vivo Taken together, our study demonstrates that CFTR plays an important role in tenogenic differentiation and tendon regeneration by inhibiting the β-catinin/pERK1/2 signaling pathway. The therapeutic strategy of intervening in the CFTR/β-catenin/pERK1/2 regulatory axis may be helpful for accelerating tendon injury healing, which has implications for tendon injury management.-Liu, Y., Xu, J., Xu, L., Wu, T., Sun, Y., Lee, Y.-W., Wang, B., Chan, H.-C., Jiang, X., Zhang, J., Li, G. Cystic fibrosis transmembrane conductance regulator mediates tenogenic differentiation of tendon-derived stem cells and tendon repair: accelerating tendon injury healing by intervening in its downstream signaling.

PMID: 28495756 [PubMed - as supplied by publisher]

Tropical Australia is a potential reservoir of non-tuberculous mycobacteria in cystic fibrosis.

Eur Respir J. 2017 May;49(5):

Authors: Sherrard LJ, Tay GT, Butler CA, Wood ME, Yerkovich S, Ramsay KA, Reid DW, Moore VL, Kidd TJ, Bell SC

PMID: 28495693 [PubMed - in process]

The RESPIRE trials: Two phase III, randomized, multicentre, placebo-controlled trials of Ciprofloxacin Dry Powder for Inhalation (Ciprofloxacin DPI) in non-cystic fibrosis bronchiectasis.

Contemp Clin Trials. 2017 May 08;:

Authors: Aksamit T, Bandel TJ, Criollo M, De Soyza A, Stuart Elborn J, Operschall E, Polverino E, Roth K, Winthrop KL, Wilson R

Abstract
The primary goals of long-term disease management in non-cystic fibrosis bronchiectasis (NCFB) are to reduce the number of exacerbations, and improve quality of life. However, currently no therapies are licensed for this. Ciprofloxacin Dry Powder for Inhalation (Ciprofloxacin DPI) has potential to be the first long-term intermittent therapy approved to reduce exacerbations in NCFB patients. The RESPIRE programme consists of two international phase III prospective, parallel-group, randomized, double-blinded, multicentre, placebo-controlled trials of the same design. Adult patients with idiopathic or post-infectious NCFB, a history of ≥2 exacerbations in the previous 12months, and positive sputum culture for one of seven pre-specified pathogens, undergo stratified randomization 2:1 to receive twice-daily Ciprofloxacin DPI 32.5mg or placebo using a pocket-sized inhaler in one of two regimens: 28-days on/off treatment or 14-days on/off treatment. The treatment period is 48weeks plus an 8-week follow-up after the last dose. The primary efficacy endpoints are time to first exacerbation after treatment initiation and frequency of exacerbations using a stringent definition of exacerbation. Secondary endpoints, including frequency of events using different exacerbation definitions, microbiology, quality of life and lung function will also be evaluated. The RESPIRE trials will determine the efficacy and safety of Ciprofloxacin DPI. The strict entry criteria and stratified randomization, the inclusion of two treatment regimens and a stringent definition of exacerbation should clarify the patient population best positioned to benefit from long-term inhaled antibiotic therapy. Additionally RESPIRE will increase understanding of NCFB treatment and could lead to an important new therapy for sufferers.
TRIAL REGISTRATION: The RESPIRE trials are registered in ClinicalTrials.gov, ID number NCT01764841 (RESPIRE 1; date of registration January 8, 2013) and NCT02106832 (RESPIRE 2; date of registration April 4, 2014).

PMID: 28495619 [PubMed - as supplied by publisher]

Role of iron in the pathogenesis of respiratory disease.

Int J Biochem Cell Biol. 2017 May 07;:

Authors: Ali MK, Kim RY, Karim R, Mayall JR, Martin KL, Shahandeh A, Abbasian F, Starkey MR, Loustaud-Ratti V, Johnstone D, Milward EA, Hansbro PM, Horvat JC

Abstract
Iron is essential for many biological processes, however, too much or too little iron can result in a wide variety of pathological consequences, depending on the organ system, tissue or cell type affected. In order to reduce pathogenesis, iron levels are tightly controlled in throughout the body by regulatory systems that control iron absorption, systemic transport and cellular uptake and storage. Altered iron levels and/or dysregulated homeostasis have been associated with several lung diseases, including chronic obstructive pulmonary disease, lung cancer, cystic fibrosis, idiopathic pulmonary fibrosis and asthma. However, the mechanisms that underpin these associations and whether iron plays a key role in the pathogenesis of lung disease are yet to be fully elucidated. Furthermore, in order to survive and replicate, pathogenic micro-organisms have evolved strategies to source host iron, including freeing iron from cells and proteins that store and transport iron. To counter these microbial strategies, mammals have evolved immune-mediated defence mechanisms that reduce iron availability to pathogens. This interplay between iron, infection and immunity has important ramifications for the pathogenesis and management of human respiratory infections and diseases. An increased understanding of the role that iron plays in the pathogenesis of lung disease and respiratory infections may help inform novel therapeutic strategies. Here we review the clinical and experimental evidence that highlights the potential importance of iron in respiratory diseases and infections.

PMID: 28495571 [PubMed - as supplied by publisher]

Outcomes associated with antibiotic regimens for treatment of Mycobacterium abscessus in cystic fibrosis patients.

J Cyst Fibros. 2017 May 08;:

Authors: DaCosta A, Jordan CL, Giddings O, Lin FC, Gilligan P, Esther CR

Abstract
BACKGROUND: Mycobacterium abscessus infection is associated with declining lung function in cystic fibrosis (CF), but there is little evidence on clinical efficacy to guide treatment.
METHODS: Retrospective review of 37 CF patients treated for M. abscessus respiratory infection at a single center from 2006 to 2014. Outcomes included change in FEV1 at 30, 60, 90, 180, and 365days after treatment and clearance of M. abscessus from sputum cultures.
RESULTS: Lung function was significantly improved after 30 and 60days of treatment, but not at later time points. Gains were inversely related to starting lung function. Antibiotic choices did not influence outcomes except for greater clearance with clarithromycin.
CONCLUSIONS: Treatment of M. abscessus resulted in short term improvement in lung function that is inversely related to pre-treatment FEV1.

PMID: 28495380 [PubMed - as supplied by publisher]

Compositionally and functionally distinct sinus microbiota in chronic rhinosinusitis patients have immunological and clinically divergent consequences.

Microbiome. 2017 May 12;5(1):53

Authors: Cope EK, Goldberg AN, Pletcher SD, Lynch SV

Abstract
BACKGROUND: Chronic rhinosinusitis (CRS) is a heterogeneous disease characterized by persistent sinonasal inflammation and sinus microbiome dysbiosis. The basis of this heterogeneity is poorly understood. We sought to address the hypothesis that a limited number of compositionally distinct pathogenic bacterial microbiota exist in CRS patients and invoke discrete immune responses and clinical phenotypes in CRS patients.
RESULTS: Sinus brushings from patients with CRS (n = 59) and healthy individuals (n = 10) collected during endoscopic sinus surgery were analyzed using 16S rRNA gene sequencing, predicted metagenomics, and RNA profiling of the mucosal immune response. We show that CRS patients cluster into distinct sub-groups (DSI-III), each defined by specific pattern of bacterial co-colonization (permutational multivariate analysis of variance (PERMANOVA); p = 0.001, r (2) = 0.318). Each sub-group was typically dominated by a pathogenic family: Streptococcaceae (DSI), Pseudomonadaceae (DSII), Corynebacteriaceae [DSIII(a)], or Staphylococcaceae [DSIII(b)]. Each pathogenic microbiota was predicted to be functionally distinct (PERMANOVA; p = 0.005, r (2) = 0.217) and encode uniquely enriched gene pathways including ansamycin biosynthesis (DSI), tryptophan metabolism (DSII), two-component response [DSIII(b)], and the PPAR-γ signaling pathway [DSIII(a)]. Each is also associated with significantly distinct host immune responses; DSI, II, and III(b) invoked a variety of pro-inflammatory, TH1 responses, while DSIII(a), which exhibited significantly increased incidence of nasal polyps (Fisher's exact; p = 0.034, relative risk = 2.16), primarily induced IL-5 expression (Kruskal Wallis; q = 0.045).
CONCLUSIONS: A large proportion of CRS patient heterogeneity may be explained by the composition of their sinus bacterial microbiota and related host immune response-features which may inform strategies for tailored therapy in this patient population.

PMID: 28494786 [PubMed - in process]

Academic, Foundation, and Industry Collaboration in Finding New Therapies.

N Engl J Med. 2017 May 04;376(18):1762-1769

Authors: Ramsey BW, Nepom GT, Lonial S

PMID: 28467868 [PubMed - indexed for MEDLINE]

Allergic Bronchopulmonary Aspergillosis: AllA Radiologist Needs To Know.

Curr Pediatr Rev. 2016;12(3):179-189

Authors: Garg MK, Sharma M, Agarwal R, Aggarwal AN, Gupta P, Sodhi KS, Chakrabarty A, Khandelwal N

Abstract
BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is an immunological lung disorder occurring due to hypersensitivity to fungus Aspergillus fumigatus. Early diagnosis of ABPA is desirable as the disease can cause irreversible damage and end stage lung disease. Diagnosis of ABPA is based upon a set of clinical, serological and radiological criteria. Radiology plays an important role in the diagnosis of ABPA. However a radiologist should also be familiar with various clinical and serological criteria, so as to have a complete understanding of the disease process and to give a confident diagnosis.
OBJECTIVE: To describe various clinical, laboratory and radiological findings in ABPA with a comprehensive review of various diagnostic criteria.
METHOD: We searched the literature for various criteria that have been used for diagnosis of ABPA. We also extensively reviewed the radiology literature to look for various imaging findings described in ABPA. We searched the role of various imaging modalities used in evaluation of ABPA starting with conventional radiography to computed tomography to magnetic resonance imaging.
RESULTS: In this article, we have reviewed clinical, serological and radiological aspects of ABPA, with emphasis on the radiological findings. We have also described the various diagnostic criteria of ABPA.
CONCLUSION: In recent years, role of radiology in ABPA has evolved. Radiology plays an important role not only in diagnosis but also classification and prognostication of the disease. A radiologist should also be familiar with the clinical spectrum and laboratory findings of the disease.

PMID: 27585455 [PubMed - indexed for MEDLINE]