Pathological Hyaluronan Matrices in Cystic Fibrosis Airways and Secretions.

Am J Respir Cell Mol Biol. 2016 May 31;

Authors: Matuska B, Comhair S, Farver C, Chmiel J, Midura RJ, Bonfield T, Lauer ME

Abstract
RATIONALE: Hyaluronan (HA) has been used in treatment of CF via a nebulizer and has demonstrated success in clinical outcomes. HA is an important glycosaminoglycan that is crosslinked by heavy chains (HCs) from inter-alpha-inhibitor during inflammation. HC-HA becomes significantly more adhesive for leukocytes than non-cross-linked HA, which can enhance inflammation. Our studies tested the hypothesis that HC-HA is present in cystic fibrosis (CF) airways and that altered ratios of HC-HA to its degradation into relatively lower molecular weight HA contribute to the pathophysiology of chronic inflammation in CF.
METHODS: We evaluated the distribution, levels and size of HC-HA within CF, healthy and diseased control lung, bronchus, and sputum tissues by histological and biochemical approaches.
RESULTS: HC-HA was significantly elevated in CF, with deposits around the pulmonary vasculature, airway submucosa, and in the stroma of the submucosal glands. The increased infiltration of leukocyte populations correlated with the distribution of HC-HA matrices in the airways. Elevated lung tissue HC-HA correlated with decreased HA levels in CF mucus and sputum compared to controls, suggesting that aberrant degradation and cross-linking of HA in lung tissue is a unique feature of CF.
CONCLUSIONS: The accumulation and degradation of pro-inflammatory HC-HA in CF lung tissue suggests that aberrant HA catabolism and cross-linking may contribute to chronic inflammation in airway tissues and impact on mucus viscosity in CF airways.

PMID: 27243106 [PubMed - as supplied by publisher]

Cyanide Toxicity to Burkholderia cenocepacia Is Modulated by Polymicrobial Communities and Environmental Factors.

Front Microbiol. 2016;7:725

Authors: Bernier SP, Workentine ML, Li X, Magarvey NA, O'Toole GA, Surette MG

Abstract
Microbes within polymicrobial communities can establish positive and negative interactions that have the potential to influence the overall behavior of the community. Pseudomonas aeruginosa and species of the Burkholderia cepacia complex (Bcc) can co-exist in the lower airways, however several studies have shown that P. aeruginosa can effectively kill the Bcc in vitro, for which hydrogen cyanide (HCN) was recently proposed to play a critical role. Here we show that modification of the environment (i.e., culture medium), long-term genetic adaptation of P. aeruginosa to the cystic fibrosis (CF) lung, or the addition of another bacterial species to the community can alter the sensitivity of Burkholderia cenocepacia to P. aeruginosa toxins. We specifically demonstrate that undefined rich media leads to higher susceptibility of B. cenocepacia to P. aeruginosa toxins like cyanide as compared to a synthetic medium (SCFM), that mimics the CF lung nutritional content. Overall, our study shows that the polymicrobial environment can have profound effects on negative interactions mediated by P. aeruginosa against B. cenocepacia. In fact, evolved P. aeruginosa or the presence of other species such as Staphylococcus aureus can directly abolish the direct competition mediated by cyanide and consequently maintaining a higher level of species diversity within the community.

PMID: 27242743 [PubMed]

Pandoraea pnomenusa Isolated from an Australian Patient with Cystic Fibrosis.

Front Microbiol. 2016;7:692

Authors: Ambrose M, Malley RC, Warren SJ, Beggs SA, Swallow OF, McEwan B, Stock D, Roddam LF

Abstract
Pandoraea species are considered as emerging pathogens in people with cystic fibrosis (CF). The contribution of these organisms to disease progression in CF patients is not fully understood owing in large measure to the scant reports in clinical and research literature describing their colonization of CF patients and their associated virulence determinants. In an effort to increase awareness and evidence for Pandoraea spp. infection in people with CF, and to stimulate research aimed at unraveling the pathogenic properties of Pandoraea, we report a case of a 26-year-old Australian (Tasmanian) man with CF who was chronically infected with Pandoraea pnomenusa for at least one year prior to his death from respiratory failure. In addition, we describe for the first time evidence suggesting that this bacterium is a facultative anaerobe and report on the availability of a whole genome sequence for this organism. To the best of our knowledge, this report represents only the second clinical case study of P. pnomenusa infection in the world, and the first in an Australian CF patient.

PMID: 27242717 [PubMed]

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"Systems Biology"[Title/Abstract] AND ("2005/01/01"[PDAT] : "3000"[PDAT])

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PubMed comprises more than 24 million 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.

Drug combination therapy increases successful drug repositioning.

Drug Discov Today. 2016 May 27;

Authors: Sun W, Sanderson P, Zheng W

Abstract
Repositioning of approved drugs has recently gained new momentum for rapid identification and development of new therapeutics for diseases that lack effective drug treatment. Reported repurposing screens have increased dramatically in number in the past five years. However, many newly identified compounds have low potency; this limits their immediate clinical applications because the known, tolerated plasma drug concentrations are lower than the required therapeutic drug concentrations. Drug combinations of two or more compounds with different mechanisms of action are an alternative approach to increase the success rate of drug repositioning.

PMID: 27240777 [PubMed - as supplied by publisher]

Building the Ferretome.

Front Neuroinform. 2016;10:16

Authors: Sukhinin DI, Engel AK, Manger P, Hilgetag CC

Abstract
Databases of structural connections of the mammalian brain, such as CoCoMac (cocomac.g-node.org) or BAMS (https://bams1.org), are valuable resources for the analysis of brain connectivity and the modeling of brain dynamics in species such as the non-human primate or the rodent, and have also contributed to the computational modeling of the human brain. Another animal model that is widely used in electrophysiological or developmental studies is the ferret; however, no systematic compilation of brain connectivity is currently available for this species. Thus, we have started developing a database of anatomical connections and architectonic features of the ferret brain, the Ferret(connect)ome, www.Ferretome.org. The Ferretome database has adapted essential features of the CoCoMac methodology and legacy, such as the CoCoMac data model. This data model was simplified and extended in order to accommodate new data modalities that were not represented previously, such as the cytoarchitecture of brain areas. The Ferretome uses a semantic parcellation of brain regions as well as a logical brain map transformation algorithm (objective relational transformation, ORT). The ORT algorithm was also adopted for the transformation of architecture data. The database is being developed in MySQL and has been populated with literature reports on tract-tracing observations in the ferret brain using a custom-designed web interface that allows efficient and validated simultaneous input and proofreading by multiple curators. The database is equipped with a non-specialist web interface. This interface can be extended to produce connectivity matrices in several formats, including a graphical representation superimposed on established ferret brain maps. An important feature of the Ferretome database is the possibility to trace back entries in connectivity matrices to the original studies archived in the system. Currently, the Ferretome contains 50 reports on connections comprising 20 injection reports with more than 150 labeled source and target areas, the majority reflecting connectivity of subcortical nuclei and 15 descriptions of regional brain architecture. We hope that the Ferretome database will become a useful resource for neuroinformatics and neural modeling, and will support studies of the ferret brain as well as facilitate advances in comparative studies of mesoscopic brain connectivity.

PMID: 27242503 [PubMed]

The pharmacogenomics of osteosarcoma.

Pharmacogenomics J. 2016 May 31;

Authors: Serra M, Hattinger CM

Abstract
Osteosarcoma (OS), the most common malignant tumor of bone, is presently treated with multidrug neoadjuvant chemotherapy protocols, which allow to cure 60-65% of patients but also induce toxicity events that cannot be predicted or efficiently prevented. The identification and validation of pharmacogenomic biomarkers is, therefore, absolutely warranted to provide the bases for planning personalized treatments with the aim to increase the therapeutic benefits and to avoid or limit unnecessary toxicities. As several targeted therapies against molecular and immunological markers in OS are presently under clinical investigation, it may be speculated that some new agents for innovative treatments may emerge in the next years. However, the real improvement of therapeutic perspectives for OS is strictly connected to the identification of pharmacogenomic biomarkers that may stratify patients in responders or non-responders and identify those individuals with higher susceptibility to treatment-associated toxicity. This review provides an overview of the pharmacogenomic biomarkers identified so far in OS, which appear to be promising candidates for a translation to clinical practice, after further investigation and/or prospective validation.The Pharmacogenomics Journal advance online publication, 31 May 2016; doi:10.1038/tpj.2016.45.

PMID: 27241064 [PubMed - as supplied by publisher]

Influence of ABCB1 and ABCG2 polymorphisms on the antiemetic efficacy in patients with cancer receiving cisplatin-based chemotherapy: a TRIPLE pharmacogenomics study.

Pharmacogenomics J. 2016 May 31;

Authors: Tsuji D, Yokoi M, Suzuki K, Daimon T, Nakao M, Ayuhara H, Kogure Y, Shibata K, Hayashi T, Hirai K, Inoue K, Hama T, Takeda K, Nishio M, Itoh K

Abstract
Resistance to antiemetic treatment with 5-hydroxytryptamine-3 receptor antagonist is an issue. This study evaluated the potential roles of ABCB1 and ABCG2 polymorphisms in antiemetic treatment resistance in patients with cancer previously enrolled in a randomized controlled trial. A total of 156 patients were evaluated for their responses to antiemetic therapy and then subdivided into granisetron or palonosetron groups. The genotypes were evaluated for their association with antiemetic efficacy in each treatment groups. Additional risk factors associated with complete response (CR) were examined using a multivariate regression analysis. No significant associations were identified for genetic polymorphisms in the palonosetron group. In the granisetron group, patients with ABCB1 2677TT and 3435TT genotypes had higher proportion of CR. In addition to ABCB1 polymorphisms, gender and cisplatin dose were associated with granisetron response by univariate analysis. Multivariate logistic regression analysis revealed that the ABCB1 3435C>T polymorphism and cisplatin dose were significant predictors of CR.The Pharmacogenomics Journal advance online publication, 31 May 2016; doi:10.1038/tpj.2016.38.

PMID: 27241063 [PubMed - as supplied by publisher]

Genetic variations in immunomodulatory pathways to predict survival in patients with locoregional gastric cancer.

Pharmacogenomics J. 2016 May 31;

Authors: Sunakawa Y, Cao S, Volz NB, Berger MD, Yang D, Parekh A, Zhang W, Matsusaka S, Ning Y, Stremitzer S, Stintzing S, Sebio A, Okazaki S, Wakatsuki T, Azuma M, Watanabe M, Koizumi W, Wu AH, Lenz HJ

Abstract
Immunomodulator-targeting therapies are under development in gastric cancer (GC). However, the role of genes modulating anti-tumor immunity in GC remains poorly understood. We investigated the association of variations in genes involved in immunomodulatory pathways with overall survival (OS) in locoregional GC patients. Extracted genomic DNA was analyzed for 35 functional single-nucleotide polymorphisms in genes, PDCD1, CD274, CTLA4, FOXP3, LAG3, ADORA2A, NT5E and IDO1, in 162 Japanese patients as discovery set and 277 US patients as validation set. The C allele of PDCD1 rs10204525 had univariate and multivariable associations with shorter OS in Japanese cohort (P=0.015, P=0.043, respectively). In US cohort the C allele predicted worse OS (P=0.007). Univariate and multivariable analyses revealed IDO1 rs9657182 associated with OS in the Japanese cohort; moreover, the association was confirmed in the US cohort. Genetic predisposition of the host in the immunomodulators may serve as a prognostic biomarker in patients with locoregional GC.The Pharmacogenomics Journal advance online publication, 31 May 2016; doi:10.1038/tpj.2016.46.

PMID: 27241062 [PubMed - as supplied by publisher]

Comparing cytochrome P450 pharmacogenetic information available on United States drug labels and European Union Summaries of Product Characteristics.

Pharmacogenomics J. 2016 May 31;

Authors: Reis-Pardal J, Rodrigues A, Rodrigues E, Fernandez-Llimos F

Abstract
Regulatory agencies are increasing the pharmacogenomic information in their official drug labeling. However, despite the importance of regulatory harmonization, this implementation may not be running in parallel among major agencies. Comparing labeling of medicines approved by different agencies may identify gaps to solve. Our study compared the cytochrome P450 pharmacogenetic information included in the United States (US) Food and Drug Administration (FDA) drug labels and European Union (EU) Summaries of Product Characteristics (SmPCs). US labels presented significantly more specific pharmacogenetic subheadings (51 vs 26%), more prevalence and pharmacokinetic data for each metabolic phenotype (59 vs 25% and 82 vs 48%, respectively) and more applicable information about dose modifications required (25 vs 5%). Approximately 75% of the US labels evaluated scored higher on the overall quality than the analogous EU SmPCs, and this difference was not associated with the time since the EU SmPCs' last review. To enhance harmonization, regulatory agencies should simultaneously introduce the pharmacogenetic information in their drug labeling.The Pharmacogenomics Journal advance online publication, 31 May 2016; doi:10.1038/tpj.2016.40.

PMID: 27241061 [PubMed - as supplied by publisher]

HLA-B18 as a risk factor of short-term progression to severe liver fibrosis in HIV/HCV co-infected patients with absent or minimal fibrosis: implications for timing of therapy.

Pharmacogenomics J. 2016 May 31;

Authors: Frías M, Rodríguez-Cano D, Cuenca-López F, Macías J, Gordon A, Manzanares-Martín B, Pineda JA, Camacho Á, Torre-Cisneros J, Peña J, Rivero-Juárez A, Rivero A

Abstract
Our aim was to analyze the influence of HLA-B haplotypes on liver fibrosis progression in HIV/hepatitis C virus (HCV) co-infected patients. Retrospective longitudinal study including HIV/HCV, non-cirrhotic and HCV treatment-naïve patients. The main outcome variable was liver fibrosis progression of at least one stage. One hundred and four patients constituted the study population (F0-F1: 62 (59.6%); F2: 22 (21.2%); F3: 20 (19.2%)). During a median follow-up of 54.5 months (IQR: 26.2-77), 45 patients (43.3%) showed an increase in the stage of liver fibrosis (time to event: 29 (IQR: 14-49.5) months). HLA-B18(pos) patients more frequently had a higher and faster fibrosis progression rate (73.3%; 24 (IQR: 8-29) months) than HLA-B18(neg) patients (38.2%; 34.5 (IQR: 14.7-51.2) months). This association was also observed in the development of F3-F4 fibrosis among F0-F2 patients (HLA-B18(pos): 69.2%; 18 (6.5-37) months vs HLA-B18(neg): 28.2%; 37 (IQR: 19-52) months). These results could impact the timing of HCV therapy in F0-F2 patients.The Pharmacogenomics Journal advance online publication, 31 May 2016; doi:10.1038/tpj.2016.42.

PMID: 27241060 [PubMed - as supplied by publisher]

Genetic epidemiology of pharmacogenetic variants in South East Asian Malays using whole-genome sequences.

Pharmacogenomics J. 2016 May 31;

Authors: Sivadas A, Salleh MZ, Teh LK, Scaria V

Abstract
Expanding the scope of pharmacogenomic research by including multiple global populations is integral to building robust evidence for its clinical translation. Deep whole-genome sequencing of diverse ethnic populations provides a unique opportunity to study rare and common pharmacogenomic markers that often vary in frequency across populations. In this study, we aim to build a diverse map of pharmacogenetic variants in South East Asian (SEA) Malay population using deep whole-genome sequences of 100 healthy SEA Malay individuals. We investigated the allelic diversity of potentially deleterious pharmacogenomic variants in SEA Malay population. Our analysis revealed 227 common and 466 rare potentially functional single nucleotide variants (SNVs) in 437 pharmacogenomic genes involved in drug metabolism, transport and target genes, including 74 novel variants. This study has created one of the most comprehensive maps of pharmacogenetic markers in any population from whole genomes and will hugely benefit pharmacogenomic investigations and drug dosage recommendations in SEA Malays.The Pharmacogenomics Journal advance online publication, 31 May 2016; doi:10.1038/tpj.2016.39.

PMID: 27241059 [PubMed - as supplied by publisher]

COMT val158met moderation of dopaminergic drug effects on cognitive function: a critical review.

Pharmacogenomics J. 2016 May 31;

Authors: Schacht JP

Abstract
The relationship between dopamine (DA) tone in the prefrontal cortex (PFC) and PFC-dependent cognitive functions (for example, working memory, selective attention, executive function) may be described by an inverted-U-shaped function, in which both excessively high and low DA is associated with impairment. In the PFC, the COMT val158met single nucleotide polymorphism (rs4680) confers differences in catechol-O-methyltransferase (COMT) efficacy and DA tone, and individuals homozygous for the val allele display significantly reduced cortical DA. Many studies have investigated whether val158met genotype moderates the effects of dopaminergic drugs on PFC-dependent cognitive functions. A review of 25 such studies suggests evidence for this pharmacogenetic effect is mixed for stimulants and COMT inhibitors, which have greater effects on D1 receptors, and strong for antipsychotics, which have greater effects on D2 receptors. Overall, COMT val158met genotype represents an enticing target for identifying individuals who are more likely to respond positively to dopaminergic drugs.The Pharmacogenomics Journal advance online publication, 31 May 2016; doi:10.1038/tpj.2016.43.

PMID: 27241058 [PubMed - as supplied by publisher]

Anti-tumor necrosis factor-α therapy in uveitis.

Surv Ophthalmol. 2015 Nov-Dec;60(6):575-89

Authors: Cordero-Coma M, Sobrin L

Abstract
Since the first reported use in 2001 of an anti-tumor necrosis factor-alpha (TNF-α) agent, infliximab, for the treatment of uveitis, several new anti-TNF-α agents have emerged for the treatment of refractory noninfectious uveitides, although their use remains off-label in the US. These agents have demonstrated remarkable clinical antiinflammatory efficacy and a potential immunoregulatory role in selected uveitis patients, but it is currently unclear whether they can modify the natural history of disease. We review the rationale and clinical indications for this therapy, the differences between agents, how to manage dosing and intervals, and how to screen for and identify potential side effects. We also present a summary of the science behind the use of anti-TNF-α agents in ocular inflammation and the evidence for their efficacy.

PMID: 26164735 [PubMed - indexed for MEDLINE]

Detection of Chromosomal Aberrations in Clinical Practice: From Karyotype to Genome Sequence.

Annu Rev Genomics Hum Genet. 2015;16:309-26

Authors: Martin CL, Warburton D

Abstract
Since the inception of clinical cytogenetics in the late 1950s, the field has witnessed the evolution of multiple methodologies for the evaluation of chromosomal imbalances and rearrangements. From the replacement of solidly stained chromosomes by Giemsa banding (G-banding) to in situ hybridization and microarrays, each technique has sought to detect smaller and smaller chromosomal aberrations across the genome. Microarray analysis has revealed that copy-number variants-a class of mutation resulting from the loss (deletion) or gain (duplication) of genomic material that is >1 kb in size-are among the significant contributors to human disease and normal variation. Here, we evaluate the history and utility of various methodologies and their impact on the current practice of clinical cytogenetics.

PMID: 26077817 [PubMed - indexed for MEDLINE]

Genome-wide microarray analysis of gene expression profiling in major depression and antidepressant therapy.

Prog Neuropsychopharmacol Biol Psychiatry. 2016 Jan 4;64:334-40

Authors: Lin E, Tsai SJ

Abstract
Major depressive disorder (MDD) is a serious health concern worldwide. Currently there are no predictive tests for the effectiveness of any particular antidepressant in an individual patient. Thus, doctors must prescribe antidepressants based on educated guesses. With the recent advent of scientific research, genome-wide gene expression microarray studies are widely utilized to analyze hundreds of thousands of biomarkers by high-throughput technologies. In addition to the candidate-gene approach, the genome-wide approach has recently been employed to investigate the determinants of MDD as well as antidepressant response to therapy. In this review, we mainly focused on gene expression studies with genome-wide approaches using RNA derived from peripheral blood cells. Furthermore, we reviewed their limitations and future directions with respect to the genome-wide gene expression profiling in MDD pathogenesis as well as in antidepressant therapy.

PMID: 25708651 [PubMed - indexed for MEDLINE]

MET network in PubMed: a text-mined network visualization and curation system.

Database (Oxford). 2016;2016

Authors: Dai HJ, Su CH, Lai PT, Huang MS, Jonnagaddala J, Rose Jue T, Rao S, Chou HJ, Milacic M, Singh O, Syed-Abdul S, Hsu WL

Abstract
Metastasis is the dissemination of a cancer/tumor from one organ to another, and it is the most dangerous stage during cancer progression, causing more than 90% of cancer deaths. Improving the understanding of the complicated cellular mechanisms underlying metastasis requires investigations of the signaling pathways. To this end, we developed a METastasis (MET) network visualization and curation tool to assist metastasis researchers retrieve network information of interest while browsing through the large volume of studies in PubMed. MET can recognize relations among genes, cancers, tissues and organs of metastasis mentioned in the literature through text-mining techniques, and then produce a visualization of all mined relations in a metastasis network. To facilitate the curation process, MET is developed as a browser extension that allows curators to review and edit concepts and relations related to metastasis directly in PubMed. PubMed users can also view the metastatic networks integrated from the large collection of research papers directly through MET. For the BioCreative 2015 interactive track (IAT), a curation task was proposed to curate metastatic networks among PubMed abstracts. Six curators participated in the proposed task and a post-IAT task, curating 963 unique metastatic relations from 174 PubMed abstracts using MET.Database URL: http://btm.tmu.edu.tw/metastasisway.

PMID: 27242035 [PubMed - in process]

Rapid Identification of Klebsiella pneumoniae by Matrix-Assisted Laser Desorption/Ionization-Time of Flight Mass Spectrometry and Detection of Meropenem Resistance by Flow Cytometric Assay.

J Clin Lab Anal. 2016 May 30;

Authors: Kilic A, Dogan E, Kaya S, Oren S, Tok D, Ardic N, Baysallar M

Abstract
BACKGROUND: The aim of this study was to develop a rapid detection method of carbapenem-resistant Klebsiella pneumoniae (CRKP) strains both MALDI-TOF MS and flow cytometry (FCM).
METHODS: A total of 174 K. pneumoniae strains were included in this study. Molecular characterization of carbapenemase gene was performed by PCR. Bacterial identification was performed by MALDI-TOF-MS. Meropenem susceptibility was tested at the concentrations of breakpoints described by the Clinical and Laboratory Standards Institute (CLSI) guide by FCM.
RESULTS: Sixty-two CRKP were positive for at least one carbapenemase gene. A total of 174 K. pneumoniae isolates obtained from clinically relevant material were correctly identified by Bruker MALDI-TOF MS with log (score) >2.0. These results were 100% concordant with the Phoenix(™) Automated Microbiology System (BD, MD) and conventional identification results. Based on the analysis of the receiver operating characteristic (ROC) curves, the best validity and sensitivity data were obtained with a cut-off value of 18.88% by FCM. The concordance, sensitivity, and specificity for FCM by the selected cut-off values were 99.4%, 98.9%, and 100%, respectively.
CONCLUSIONS: We conclude that reliable results on bacterial identification and meropenem susceptibility test can be obtained within 2 hr combined by MALDI-TOF-MS and FCM.

PMID: 27239799 [PubMed - as supplied by publisher]

Appendicular mucinous adenocarcinoma associated with pseudomyxoma peritonei, a rare and difficult imaging diagnosis.

Med Ultrason. 2016 Jun;18(2):257-9

Authors: Chira RI, Nistor-Ciurba CC, Mociran A, Mircea PA

Abstract
Pseudomyxoma peritonei (PMP) is a rare disease, caused by primary mucinous tumors that arise most frequently from appendix, ovary, or pancreas. Usually diagnosis is made by computed tomography, but ultrasonography can be a very useful imagistic method, if this diagnosis is taken into account by the observer. We present a case of a PMP caused by an appendiceal mucinous carcinoma, in a 34-year-old male patient, with family history of malignancies, diagnosed in our department. He was thereafter surgically treated - appendiceal resection, peritoneal lavage - followed by chemotherapy. We underline the importance of ultrasonography, even though at first encounter, the diagnosis of PMP being generally difficult.

PMID: 27239665 [PubMed - in process]