Nanomolar-potency aminophenyl-1,3,5-triazine activators of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel for pro-secretory therapy of dry eye diseases.

J Med Chem. 2017 Jan 18;:

Authors: Lee S, Phuan PW, Felix CM, Tan JA, Levin MH, Verkman AS

Abstract
Dry eye disorders are a significant health problem for which limited therapeutic options are available. CFTR is a major pro-secretory chloride channel at the ocular surface. We previously identified, by high-throughput screening, aminophenyl-1,3,5-triazine CFTRact-K089 (1) that activated CFTR with EC50 ~250 nM, which when delivered topically increased tear fluid secretion in mice and showed efficacy in an experimental dry eye model. Here, functional analysis of aminophenyl-1,3,5-triazine analogs elucidated structure-activity relationships for CFTR activation and identified substantially more potent analogs than 1. The most potent compound, 12, fully activated CFTR chloride conductance with EC50 ~30 nM, without causing cAMP or calcium elevation. 12 was rapidly metabolized by hepatic microsomes, which supports its topical use. Single topical administration of 25 pmol 12 increased tear volume in wildtype mice with sustained action for 8 hours, and was without effect in CFTR-deficient mice. Topically delivered 12 may be efficacious in human dry eye diseases.

PMID: 28099811 [PubMed - as supplied by publisher]

Computed Tomography in Cystic Fibrosis: Combining Low-Dose Techniques and Iterative Reconstruction.

J Comput Assist Tomogr. 2017 Jan 18;:

Authors: Kahn J, Kaul D, Grupp U, Böning G, Renz D, Staab D, Schreiter V, Streitparth F

Abstract
OBJECTIVE: The aim of the study was to evaluate the impact of iterative reconstruction (IR) and low-kilovolt technique on dose reduction and image quality of chest computed tomography scans obtained in patients with cystic fibrosis (CF).
METHODS: A total of 124 CF patients were examined; group A (n = 63) was examined with a dose reduction protocol using IR and group B (n = 61) with a standard protocol using filtered back projection. Further subgroups with tube voltage modulations were established. Quantitative and qualitative image quality was assessed.
RESULTS: The radiation dose in groups with comparable image quality was approximately 40% lower using IR compared with filtered back projection. The IR protocol combined with 80-kV tube voltage showed adequate image quality with a mean effective dose of only 0.47 mSv.
CONCLUSIONS: Iterative reconstruction helps extensively reduce radiation dose by improving image quality. It permits the use of low-kilovolt protocols without significantly degrading image reading ability in the monitoring of the predominantly young patients with CF.

PMID: 28099226 [PubMed - as supplied by publisher]

Applying proteomics to tick vaccine development: where are we?

Expert Rev Proteomics. 2017 Jan 18;:

Authors: Villar M, Marina A, de la Fuente J

Abstract
INTRODUCTION: Ticks are second to mosquitoes as a vector of human diseases and are the first vector of animal diseases with a great impact on livestock farming. Tick vaccines represent a sustainable and effective alternative to chemical acaricides for the control of tick infestations and transmitted pathogens. The application of proteomics to tick vaccine development is a fairly recent area, which has resulted in the characterization of some tick-host-pathogen interactions and the identification of candidate protective antigens. Areas covered: In this article, we review the application and possibilities of various proteomic approaches for the discovery of tick and pathogen derived protective antigens, and the design of effective vaccines for the control of tick infestations and pathogen infection and transmission. Expert commentary: In the near future, the application of reverse proteomics, immunoproteomics, structural proteomics, and interactomics among other proteomics approaches will likely contribute to improve vaccine design to control multiple tick species with the ultimate goal of controlling tick-borne diseases.

PMID: 28099817 [PubMed - as supplied by publisher]

Cell-Based Systems Biology Analysis of Human AS03-Adjuvanted H5N1 Avian Influenza Vaccine Responses: A Phase I Randomized Controlled Trial.

PLoS One. 2017;12(1):e0167488

Authors: Howard LM, Hoek KL, Goll JB, Samir P, Galassie A, Allos TM, Niu X, Gordy LE, Creech CB, Prasad N, Jensen TL, Hill H, Levy SE, Joyce S, Link AJ, Edwards KM

Abstract
BACKGROUND: Vaccine development for influenza A/H5N1 is an important public health priority, but H5N1 vaccines are less immunogenic than seasonal influenza vaccines. Adjuvant System 03 (AS03) markedly enhances immune responses to H5N1 vaccine antigens, but the underlying molecular mechanisms are incompletely understood.
OBJECTIVE AND METHODS: We compared the safety (primary endpoint), immunogenicity (secondary), gene expression (tertiary) and cytokine responses (exploratory) between AS03-adjuvanted and unadjuvanted inactivated split-virus H5N1 influenza vaccines. In a double-blinded clinical trial, we randomized twenty adults aged 18-49 to receive two doses of either AS03-adjuvanted (n = 10) or unadjuvanted (n = 10) H5N1 vaccine 28 days apart. We used a systems biology approach to characterize and correlate changes in serum cytokines, antibody titers, and gene expression levels in six immune cell types at 1, 3, 7, and 28 days after the first vaccination.
RESULTS: Both vaccines were well-tolerated. Nine of 10 subjects in the adjuvanted group and 0/10 in the unadjuvanted group exhibited seroprotection (hemagglutination inhibition antibody titer > 1:40) at day 56. Within 24 hours of AS03-adjuvanted vaccination, increased serum levels of IL-6 and IP-10 were noted. Interferon signaling and antigen processing and presentation-related gene responses were induced in dendritic cells, monocytes, and neutrophils. Upregulation of MHC class II antigen presentation-related genes was seen in neutrophils. Three days after AS03-adjuvanted vaccine, upregulation of genes involved in cell cycle and division was detected in NK cells and correlated with serum levels of IP-10. Early upregulation of interferon signaling-related genes was also found to predict seroprotection 56 days after first vaccination.
CONCLUSIONS: Using this cell-based systems approach, novel mechanisms of action for AS03-adjuvanted pandemic influenza vaccination were observed.
TRIAL REGISTRATION: ClinicalTrials.gov NCT01573312.

PMID: 28099485 [PubMed - in process]

Mitochondrial respiratory gene expression is suppressed in many cancers.

Elife. 2017 Jan 18;6:

Authors: Reznik E, Wang Q, La K, Schultz N, Sander C

Abstract
The fundamental metabolic decision of a cell, the balance between respiration and fermentation, rests in part on expression of the mitochondrial genome (mtDNA) and coordination with expression of the nuclear genome (nuDNA). Previously we described mtDNA copy number depletion across many solid tumor types (Reznik et al., 2016). Here, we use orthogonal RNA-sequencing data to quantify mtDNA expression (mtRNA), and report analogously lower expression of mtRNA in tumors (relative to normal tissue) across a majority of cancer types. Several cancers exhibit a trio of mutually consistent evidence suggesting a drop in respiratory activity: depletion of mtDNA copy number, decreases in mtRNA levels, and decreases in expression of nuDNA-encoded respiratory proteins. Intriguingly, a minority of cancer types exhibit a drop in mtDNA expression but an increase in nuDNA expression of respiratory proteins, with unknown implications for respiratory activity. Our results indicate suppression of respiratory gene expression across many cancer types.

PMID: 28099114 [PubMed - in process]

10 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"

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

"cystic fibrosis"

These pubmed results were generated on 2017/01/18

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.

Link prediction in drug-target interactions network using similarity indices.

BMC Bioinformatics. 2017 Jan 17;18(1):39

Authors: Lu Y, Guo Y, Korhonen A

Abstract
BACKGROUND: In silico drug-target interaction (DTI) prediction plays an integral role in drug repositioning: the discovery of new uses for existing drugs. One popular method of drug repositioning is network-based DTI prediction, which uses complex network theory to predict DTIs from a drug-target network. Currently, most network-based DTI prediction is based on machine learning - methods such as Restricted Boltzmann Machines (RBM) or Support Vector Machines (SVM). These methods require additional information about the characteristics of drugs, targets and DTIs, such as chemical structure, genome sequence, binding types, causes of interactions, etc., and do not perform satisfactorily when such information is unavailable. We propose a new, alternative method for DTI prediction that makes use of only network topology information attempting to solve this problem.
RESULTS: We compare our method for DTI prediction against the well-known RBM approach. We show that when applied to the MATADOR database, our approach based on node neighborhoods yield higher precision for high-ranking predictions than RBM when no information regarding DTI types is available.
CONCLUSION: This demonstrates that approaches purely based on network topology provide a more suitable approach to DTI prediction in the many real-life situations where little or no prior knowledge is available about the characteristics of drugs, targets, or their interactions.

PMID: 28095781 [PubMed - in process]

Emerging strategies for the treatment of pulmonary tuberculosis: promise and limitations?

Korean J Intern Med. 2016 Jan;31(1):15-29

Authors: Yew WW, Koh WJ

Abstract
A worsening scenario of drug-resistant tuberculosis has increased the need for new treatment strategies to tackle this worldwide emergency. There is a pressing need to simplify and shorten the current 6-month treatment regimen for drug-susceptible tuberculosis. Rifamycins and fluoroquinolones, as well as several new drugs, are potential candidates under evaluation. At the same time, treatment outcomes of patients with drug-resistant tuberculosis should be improved through optimizing the use of fluoroquinolones, repurposed agents and newly developed drugs. In this context, the safety and tolerance of new therapeutic approaches must be addressed.

PMID: 26767853 [PubMed - indexed for MEDLINE]

A landscape of synthetic viable interactions in cancer.

Brief Bioinform. 2017 Jan 17;:

Authors: Gu Y, Wang R, Han Y, Zhou W, Zhao Z, Chen T, Zhang Y, Peng F, Liang H, Qi L, Zhao W, Yang D, Guo Z

Abstract
Synthetic viability, which is defined as the combination of gene alterations that can rescue the lethal effects of a single gene alteration, may represent a mechanism by which cancer cells resist targeted drugs. Approaches to detect synthetic viable (SV) interactions in cancer genome to investigate drug resistance are still scarce. Here, we present a computational method to detect synthetic viability-induced drug resistance (SVDR) by integrating the multidimensional data sets, including copy number alteration, whole-exome mutation, expression profile and clinical data. SVDR comprehensively characterized the landscape of SV interactions across 8580 tumors in 32 cancer types by integrating The Cancer Genome Atlas data, small hairpin RNA-based functional experimental data and yeast genetic interaction data. We revealed that the SV interactions are favorable to cells and can predict clinical prognosis for cancer patients, which were robustly observed in an independent data set. By integrating the cancer pharmacogenomics data sets from Cancer Cell Line Encyclopedia (CCLE) and Broad Cancer Therapeutics Response Portal, we have demonstrated that SVDR enables drug resistance prediction and exhibits high reliability between two databases. To our knowledge, SVDR is the first genome-scale data-driven approach for the identification of SV interactions related to drug resistance in cancer cells. This data-driven approach lays the foundation for identifying the genomic markers to predict drug resistance and successfully infers the potential drug combination for anti-cancer therapy.

PMID: 28096076 [PubMed - as supplied by publisher]

Weight of ABCB1 and POR genes on oral tacrolimus exposure in CYP3A5 nonexpressor pediatric patients with stable kidney transplant.

Pharmacogenomics J. 2017 Jan 17;:

Authors: Almeida-Paulo GN, Dapía García I, Lubomirov R, Borobia AM, Alonso-Sánchez NL, Espinosa L, Carcas-Sansuán AJ

Abstract
Tacrolimus (TAC) is highly effective for the prevention of acute organ rejection. However, its clinical use may be challenging due to its large interindividual pharmacokinetic variability, which can be partially explained by genetic variations in TAC-metabolizing enzymes and transporters. The aim of this study was to evaluate the influence of genetic and clinical factors on TAC pharmacokinetic variability in 21 stable pediatric renal transplant patients. This study was nested in a previous Prograf to Advagraf conversion clinical trial. CYP3A5, ABCB1 and two POR genotypes were assessed by real-time PCR. The impact on TAC pharmacokinetics of individual genetic variants on CYP3A5 nonexpressors was evaluated by genetic score. Explicative models for TAC AUC0-24h, Cmax and Cmin after Advagraf were developed by linear regression. The built genetic scores explain 13.7 and 26.5% of the total AUC0-24h and Cmin total variability, respectively. Patients genetic information should be considered to monitorizate and predict TAC exposure.The Pharmacogenomics Journal advance online publication, 17 January 2017; doi:10.1038/tpj.2016.93.

PMID: 28094348 [PubMed - as supplied by publisher]

Reliable and efficient solution of genome-scale models of Metabolism and macromolecular Expression.

Sci Rep. 2017 Jan 18;7:40863

Authors: Ma D, Yang L, Fleming RM, Thiele I, Palsson BO, Saunders MA

Abstract
Constraint-Based Reconstruction and Analysis (COBRA) is currently the only methodology that permits integrated modeling of Metabolism and macromolecular Expression (ME) at genome-scale. Linear optimization computes steady-state flux solutions to ME models, but flux values are spread over many orders of magnitude. Data values also have greatly varying magnitudes. Standard double-precision solvers may return inaccurate solutions or report that no solution exists. Exact simplex solvers based on rational arithmetic require a near-optimal warm start to be practical on large problems (current ME models have 70,000 constraints and variables and will grow larger). We have developed a quadruple-precision version of our linear and nonlinear optimizer MINOS, and a solution procedure (DQQ) involving Double and Quad MINOS that achieves reliability and efficiency for ME models and other challenging problems tested here. DQQ will enable extensive use of large linear and nonlinear models in systems biology and other applications involving multiscale data.

PMID: 28098205 [PubMed - in process]

Notions of similarity for systems biology models.

Brief Bioinform. 2017 Jan 17;:

Authors: Henkel R, Hoehndorf R, Kacprowski T, Knüpfer C, Liebermeister W, Waltemath D

PMID: 28096074 [PubMed - as supplied by publisher]

What we can learn from a tadpole about ciliopathies and airway diseases - Using systems biology in Xenopus to study cilia and mucociliary epithelia.

Genesis. 2017 Jan 17;:

Authors: Walentek P, Quigley IK

Abstract
Over the past years, the Xenopus embryo has emerged as an incredibly useful model organism for studying the formation and function of cilia and ciliated epithelia in vivo. This has led to a variety of findings elucidating the molecular mechanisms of ciliated cell specification, basal body biogenesis, cilia assembly and ciliary motility. These findings also revealed the deep functional conservation of signaling, transcriptional, post-transcriptional and protein networks employed in the formation and function of vertebrate ciliated cells. Therefore, Xenopus research can contribute crucial insights not only into developmental and cell biology, but also into the molecular mechanisms underlying cilia related diseases (ciliopathies) as well as diseases affecting the ciliated epithelium of the respiratory tract in humans (e.g. chronic lung diseases). Additionally, systems biology approaches including transcriptomics, genomics and proteomics have been rapidly adapted for use in Xenopus, and broaden the applications for current and future translational biomedical research. This review aims to present the advantages of using Xenopus for cilia research, highlight some of the evolutionarily conserved key concepts and mechanisms of ciliated cell biology that were elucidated using the Xenopus model, and describe the potential for Xenopus research to address unresolved questions regarding the molecular mechanisms of ciliopathies and airway diseases. This article is protected by copyright. All rights reserved.

PMID: 28095645 [PubMed - as supplied by publisher]

Identifying niche mediated regulatory factors of stem cell phenotypic state: a systems biology approach.

FEBS Lett. 2017 Jan 17;:

Authors: Ravichandran S, Del Sol A

Abstract
Understanding how the cellular niche controls the stem cell phenotype is often hampered due to the complexity of variegated niche composition, its dynamics, and non-linear stem cell-niche interactions. Here, we propose a systems biology view that considers stem cell-niche interactions as a many-body problem amenable to simplification by the concept of mean field approximation. This enables approximation of the niche effect on stem cells as a constant field that induces sustained activation/inhibition of specific stem cell signaling pathways in all stem cells within heterogeneous populations exhibiting the same phenotype (niche determinants). This view offers a new basis for the development of single cell-based computational approaches for identifying niche determinants, which has potential applications in regenerative medicine and tissue engineering. This article is protected by copyright. All rights reserved.

PMID: 28094442 [PubMed - as supplied by publisher]

NK cell phenotypic and functional shifts coincide with specific clinical phases in the natural history of chronic HBV infection.

Antiviral Res. 2017 Jan 13;:

Authors: de Groen RA, Hou J, van Oord GW, Groothuismink ZM, van der Heide M, de Knegt RJ, Boonstra A

Abstract
BACKGROUND: Chronic HBV infection can be divided into 4 distinct clinical phases: immune tolerant, immune active, inactive carrier, and HBeAg-negative hepatitis. Using a systems biology approach, we recently identified innate immune response components, specifically NK cells as a distinctive factor of specific HBV clinical phases. To expand on this study and identify the underlying immunological mechanisms, we performed a comprehensive profiling of NK cells in chronic HBV infection.
METHODS: Peripheral blood from untreated chronic HBV patients was used to analyze phenotypic markers, as well as cytokine production and cytoxicity of NK cells.
RESULTS: The overall composition, phenotype, and cytolytic activity of the NK cells remained constant across all clinical phases, with the exception of a few specific markers (KIRs, NKp46). CD56(bright) NK cells of chronic HBV patients differed in their ability to produce IFN-γ between the clinical phases pre- and post-HBeAg seroconversion.
CONCLUSION: This depicts a shift in NK cell characteristics between the immune active, under heavy viral or immune pressure, and inactive carrier phases, that coincides with HBeAg seroconversion. Although these changes in NK cells do not appear to be completely responsible for differences in liver damage characteristic of specific clinical phases, they could provide a step toward understanding immune dysregulation in chronic HBV infection.

PMID: 28093337 [PubMed - as supplied by publisher]

Assessing occurrence of hypoglycemia and its severity from electronic health records of patients with type 2 diabetes mellitus.

Diabetes Res Clin Pract. 2016 Nov;121:192-203

Authors: Nunes AP, Yang J, Radican L, Engel SS, Kurtyka K, Tunceli K, Yu S, Iglay K, Doherty MC, Dore DD

Abstract
AIMS: Accurate measures of hypoglycemia within electronic health records (EHR) can facilitate clinical population management and research. We quantify the occurrence of serious and mild-to-moderate hypoglycemia in a large EHR database in the US, comparing estimates based only on structured data to those from structured data and natural language processing (NLP) of clinical notes.
METHODS: This cohort study included patients with type 2 diabetes identified from January 2009 through March 2014. We compared estimates of occurrence of hypoglycemia derived from diagnostic codes to those recorded within clinical notes and classified via NLP. Measures of hypoglycemia from only structured data (ICD-9 Algorithm), only note mentions (NLP Algorithm), and either structured data or notes (Combined Algorithm) were compared with estimates of the period prevalence, incidence rate, and event rate of hypoglycemia, overall and by seriousness.
RESULTS: Of the 844,683 eligible patients, 119,695 had at least one recorded hypoglycemic event identified with ICD-9 or NLP. The period prevalence of hypoglycemia was 12.4%, 25.1%, and 32.2% for the ICD-9 Algorithm, NLP Algorithm, and Combined Algorithm, respectively. There were 6128 apparent non-serious events utilizing the ICD-9 Algorithm, which increased to 152,987 non-serious events within the Combined Algorithm.
CONCLUSIONS: Ascertainment of events from clinical notes more than doubled the completeness of hypoglycemia capture overall relative to measures from structured data, and increased capture of non-serious events more than 20-fold. The structured data and clinical notes are complementary within the EHR, and both need to be considered in order to fully assess the occurrence of hypoglycemia.

PMID: 27744128 [PubMed - indexed for MEDLINE]

Postal recruitment and consent obtainment from index cases of narcolepsy.

BMC Med Ethics. 2016 Jan 16;17:6

Authors: Aliyu G, Mahmud SM

Abstract
BACKGROUND: Access to research volunteers may be hampered by low numbers of cases and few eligible participants for rare diseases in clinical settings.
METHODS: We recruited volunteers and obtained informed consent by mail from narcolepsy cases in a case-control study, and here in we report feasibility, response rate, timeliness and cost. We invited index cases into the study by mail through their care-giving physicians then mailed study information and consent forms to cases that indicated interest in the study.
RESULTS: Of the 33 index cases invited, 15 (45.0%) expressed interest in the study, and of those, 14 (93.3%) returned their signed informed consents by mail. The median number of days from invitation to consent return was 39, interquartile range = 45, and the cost per consent obtained from the recruited subjects was $ 23.61.
CONCLUSION: In this setting, postal recruitment for biomedical research on rare conditions is feasible and time and cost effective.

PMID: 26772982 [PubMed - indexed for MEDLINE]

Superficial morphea of the lips and gingiva.

Acta Dermatovenerol Croat. 2015;23(2):152-4

Authors: Vučićević Boras V, Gabrić D, Brailo V, Čikeš N, Velimir Vrdoljak D

PMID: 26228830 [PubMed - indexed for MEDLINE]

Subcutaneous cavernous angiolipoma: a new soft-tissue entity.

Acta Dermatovenerol Croat. 2015;23(2):144-5

Authors: Roncati L, Pusiol T, Piscioli F, Maiorana A

PMID: 26228827 [PubMed - indexed for MEDLINE]