Genome-wide study links PNPLA3 variant with elevated hepatic transaminase after acute lymphoblastic leukemia therapy.

Clin Pharmacol Ther. 2017 Jan 16;:

Authors: Liu Y, Fernandez CA, Smith C, Yang W, Cheng C, Panetta JC, Kornegay N, Liu C, Ramsey LB, Karol SE, Janke LJ, Larsen EC, Winick N, Carroll WL, Loh ML, Raetz EA, Hunger SP, Devidas M, Yang JJ, Mullighan CG, Zhang J, Evans WE, Jeha S, Pui CH, Relling MV

Abstract
Remission induction therapy for acute lymphoblastic leukemia (ALL) includes medications that may cause hepatotoxicity, including asparaginase. We used a genome-wide association study (GWAS) to identify loci associated with elevated alanine transaminase (ALT) levels after induction therapy in children with ALL enrolled on St. Jude Children's Research Hospital (SJCRH) protocols. Germline DNA was genotyped using arrays and exome sequencing. Adjusting for age, body mass index, ancestry, asparaginase preparation and dosage, the PNPLA3 rs738409 (C>G) I148M variant, previously associated with fatty liver disease risk, had the strongest genetic association with ALT (P = 2.5x10(-8) ). The PNPLA3 rs738409 variant explained 3.8% of the variability in ALT, and partly explained race-related differences in ALT. The PNPLA3 rs738409 association was replicated in an independent cohort of 2,285 patients treated on Children's Oncology Group protocol AALL0232 (P = 0.024). This is an example of a pharmacogenetic variant overlapping with a disease risk variant. This article is protected by copyright. All rights reserved.

PMID: 28090653 [PubMed - as supplied by publisher]

"The Pharmacogenomics Research Network Translational Pharmacogenetics Program: Outcomes and Metrics of Pharmacogenetic Implementations Across Diverse Healthcare Systems".

Clin Pharmacol Ther. 2017 Jan 16;:

Authors: Luzum JA, Pakyz RE, Elsey AR, Haidar CE, Peterson JF, Whirl-Carrillo M, Handelman SK, Palmer K, Pulley JM, Beller M, Schildcrout JS, Field JR, Weitzel KW, Cooper-DeHoff RM, Cavallari LH, O'Donnell PH, Altman RB, Pereira N, Ratain MJ, Roden DM, Embi PJ, Sadee W, Klein TE, Johnson JA, Relling MV, Wang L, Weinshilboum RM, Shuldiner AR, Freimuth RR, Pharmacogenomics Research Network Translational Pharmacogenetics Program

Abstract
Numerous pharmacogenetic clinical guidelines and recommendations have been published, but barriers have hindered the clinical implementation of pharmacogenetics. The Translational Pharmacogenetics Program (TPP) of the NIH Pharmacogenomics Research Network was established in 2011 to catalog and contribute to the development of pharmacogenetic implementations at eight US healthcare systems, with the goal to disseminate real-world solutions for the barriers to clinical pharmacogenetic implementation. The TPP collected and normalized pharmacogenetic implementation metrics through June 2015, including gene-drug pairs implemented, interpretations of alleles and diplotypes, numbers of tests performed and actionable results, and workflow diagrams. TPP participant institutions developed diverse solutions to overcome many barriers, but the use of Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines provided some consistency among the institutions. The TPP also collected some pharmacogenetic implementation outcomes (scientific, educational, financial, and informatics), which may inform healthcare systems seeking to implement their own pharmacogenetic testing programs. This article is protected by copyright. All rights reserved.

PMID: 28090649 [PubMed - as supplied by publisher]

Mechanisms of intrinsic resistance and acquired susceptibility of Pseudomonas aeruginosa isolated from cystic fibrosis patients to temocillin, a revived antibiotic.

Sci Rep. 2017 Jan 16;7:40208

Authors: Chalhoub H, Pletzer D, Weingart H, Braun Y, Tunney MM, Elborn JS, Rodriguez-Villalobos H, Plésiat P, Kahl BC, Denis O, Winterhalter M, Tulkens PM, Van Bambeke F

Abstract
The β-lactam antibiotic temocillin (6-α-methoxy-ticarcillin) shows stability to most extended spectrum β-lactamases, but is considered inactive against Pseudomonas aeruginosa. Mutations in the MexAB-OprM efflux system, naturally occurring in cystic fibrosis (CF) isolates, have been previously shown to reverse this intrinsic resistance. In the present study, we measured temocillin activity in a large collection (n = 333) of P. aeruginosa CF isolates. 29% of the isolates had MICs ≤ 16 mg/L (proposed clinical breakpoint for temocillin). Mutations were observed in mexA or mexB in isolates for which temocillin MIC was ≤512 mg/L (nucleotide insertions or deletions, premature termination, tandem repeat, nonstop, and missense mutations). A correlation was observed between temocillin MICs and efflux rate of N-phenyl-1-naphthylamine (MexAB-OprM fluorescent substrate) and extracellular exopolysaccharide abundance (contributing to a mucoid phenotype). OpdK or OpdF anion-specific porins expression decreased temocillin MIC by ~1 two-fold dilution only. Contrarily to the common assumption that temocillin is inactive on P. aeruginosa, we show here clinically-exploitable MICs on a non-negligible proportion of CF isolates, explained by a wide diversity of mutations in mexA and/or mexB. In a broader context, this work contributes to increase our understanding of MexAB-OprM functionality and help delineating how antibiotics interact with MexA and MexB.

PMID: 28091521 [PubMed - in process]

Prevalence of gastrointestinal dysmotility and complications detected by abdominal plain films after lung transplantation: a single-centre cohort study.

BMJ Open Respir Res. 2016;3(1):e000162

Authors: Heinrich H, Neuenschwander A, Russmann S, Misselwitz B, Benden C, Schuurmans MM

Abstract
INTRODUCTION AND AIMS: Gastrointestinal (GI) complications such as gastric retention (GR) and constipation are common after lung transplantation (LT). Abdominal plain films (APFs) are a low-cost diagnostic tool to detect impaired GI function. The goal of our study was to assess the prevalence of GI pathology seen on APF in lung transplant recipients (LTRs) and to identify associated risk factors.
METHODS: Retrospective analysis of consecutive LTRs followed up between 2001 and 2013. Demographic, radiographic and clinical data were assessed.
RESULTS: 198 patients were included in the study, 166 thereof had more than 1 APF with a mean number of 5 APFs per patient. 163 patients had a detectable radiographic pathology on APF. The proportion of LTR with GR was highest among cystic fibrosis patients (48.5%). Multivariate regression analysis showed a significant association of diabetes with GR with a trend for age and use of opiates as risk factors. Similarly, female sex, advanced age and diabetes showed a trend to be associated with lower GI tract complications. Almost all patients had suffered from at least 1 episode of lower GI dysmotility during a median follow-up of 5.7 years. No clear correlation between GI events and the development of chronic lung allograft dysfunction could be identified.
CONCLUSIONS: We found a statistically significant association of diabetes with GR and a progressive increase in the prevalence of GR over time after LT. Lower GI complications affected >80% of LTR and increased over time. Future studies correlating GI transit with APF findings are needed.

PMID: 28090331 [PubMed]

A mast cell-ILC2-Th9 pathway promotes lung inflammation in cystic fibrosis.

Nat Commun. 2017 Jan 16;8:14017

Authors: Moretti S, Renga G, Oikonomou V, Galosi C, Pariano M, Iannitti RG, Borghi M, Puccetti M, De Zuani M, Pucillo CE, Paolicelli G, Zelante T, Renauld JC, Bereshchenko O, Sportoletti P, Lucidi V, Russo MC, Colombo C, Fiscarelli E, Lass-Flörl C, Majo F, Ricciotti G, Ellemunter H, Ratclif L, Talesa VN, Napolioni V, Romani L

Abstract
T helper 9 (Th9) cells contribute to lung inflammation and allergy as sources of interleukin-9 (IL-9). However, the mechanisms by which IL-9/Th9 mediate immunopathology in the lung are unknown. Here we report an IL-9-driven positive feedback loop that reinforces allergic inflammation. We show that IL-9 increases IL-2 production by mast cells, which leads to expansion of CD25(+) type 2 innate lymphoid cells (ILC2) and subsequent activation of Th9 cells. Blocking IL-9 or inhibiting CD117 (c-Kit) signalling counteracts the pathogenic effect of the described IL-9-mast cell-IL-2 signalling axis. Overproduction of IL-9 is observed in expectorates from cystic fibrosis (CF) patients, and a sex-specific variant of IL-9 is predictive of allergic reactions in female patients. Our results suggest that blocking IL-9 may be a therapeutic strategy to ameliorate inflammation associated with microbial colonization in the lung, and offers a plausible explanation for gender differences in clinical outcomes of patients with CF.

PMID: 28090087 [PubMed - in process]

Aquagenic Palmoplantar Keratoderma as a CFTR-related Disorder.

Acta Derm Venereol. 2016 Aug 23;96(6):848-9

Authors: Cabrol C, Bienvenu T, Ruaud L, Girodon E, Noacco G, Delobeau M, Fanian F, Richaud-Thiriez B, Van Maldergem L, Aubin F

Abstract
is missing (Short communication).

PMID: 27026144 [PubMed - indexed for MEDLINE]

Microwestern Arrays for Systems-Level Analysis of SH2 Domain-Containing Proteins.

Methods Mol Biol. 2017;1555:453-473

Authors: Ciaccio MF, Jones RB

Abstract
The Microwestern Array (MWA) method combines the scalability and miniaturization afforded by the Reverse Phase Lysate Array (RPLA) approach with the electrophoretic separation characteristic of the Western blot. This technology emulates the creation of an array of small Western blots on a single sheet of nitrocellulose allowing for the sensitive and quantitative measurement of hundreds of proteins from hundreds of cell lysates with minimal cost and maximal accuracy, precision, and reproducibility. The MWA is a versatile technology that can be easily configured for purposes such as antibody screening, cell signaling network inference, protein modification/phenotype regression analysis, and genomic/proteomic relationships. Accordingly, configurations for the MWA can be optimized for maximal numbers of proteins analyzed from small numbers of cell lysates, for small numbers of antibodies against large numbers of cell lysates, or for maximal resolution of protein size achieved by increased electrophoretic separation distance. For example, on a single gel, 6 samples can be printed 96 times if a few samples need to be assayed with a large number of antibodies. Alternatively, up to 100 samples can be assayed with four antibodies on a single gel. Intermediate configurations are also discussed.The efficiency of the MWA is orders of magnitude greater in reagents, labor, and time required per data point relative to the standard Western blotting method and orders of magnitude more sensitive than standard mass spectrometry methods. The MWA is therefore a very attractive approach for capturing global changes in protein abundances and modifications including tyrosine phosphorylation and SH2 domain binding sites.

PMID: 28092050 [PubMed - in process]

Introduction: History of SH2 Domains and Their Applications.

Methods Mol Biol. 2017;1555:3-35

Authors: Liu BA, Machida K

Abstract
The Src Homology 2 (SH2) domain is the prototypical protein interaction module that lies at the heart of phosphotyrosine signaling. Since its serendipitous discovery, there has been a tremendous advancement in technologies and an array of techniques available for studying SH2 domains and phosphotyrosine signaling. In this chapter, we provide a glimpse of the history of SH2 domains and describe many of the tools and techniques that have been developed along the way and discuss future directions for SH2 domain studies. We highlight the gist of each chapter in this volume in the context of: the structural biology and phosphotyrosine binding; characterizing SH2 specificity and generating prediction models; systems biology and proteomics; SH2 domains in signal transduction; and SH2 domains in disease, diagnostics, and therapeutics. Many of the individual chapters provide an in-depth approach that will allow scientists to interrogate the function and role of SH2 domains.

PMID: 28092024 [PubMed - in process]

MPLEx: a method for simultaneous pathogen inactivation and extraction of samples for multi-omics profiling.

Analyst. 2017 Jan 16;:

Authors: Burnum-Johnson KE, Kyle JE, Eisfeld AJ, Casey CP, Stratton KG, Gonzalez JF, Habyarimana F, Negretti NM, Sims AC, Chauhan S, Thackray LB, Halfmann PJ, Walters KB, Kim YM, Zink EM, Nicora CD, Weitz KK, Webb-Robertson BM, Nakayasu ES, Ahmer B, Konkel ME, Motin V, Baric RS, Diamond MS, Kawaoka Y, Waters KM, Smith RD, Metz TO

Abstract
The continued emergence and spread of infectious agents is of great concern, and systems biology approaches to infectious disease research can advance our understanding of host-pathogen relationships and facilitate the development of new therapies and vaccines. Molecular characterization of infectious samples outside of appropriate biosafety containment can take place only subsequent to pathogen inactivation. Herein, we describe a modified Folch extraction using chloroform/methanol that facilitates the molecular characterization of infectious samples by enabling simultaneous pathogen inactivation and extraction of proteins, metabolites, and lipids for subsequent mass spectrometry-based multi-omics measurements. This single-sample metabolite, protein and lipid extraction (MPLEx) method resulted in complete inactivation of clinically important bacterial and viral pathogens with exposed lipid membranes, including Yersinia pestis, Salmonella Typhimurium, and Campylobacter jejuni in pure culture, and Yersinia pestis, Campylobacter jejuni, and West Nile, MERS-CoV, Ebola, and influenza H7N9 viruses in infection studies. In addition, >99% inactivation, which increased with solvent exposure time, was also observed for pathogens without exposed lipid membranes including community-associated methicillin-resistant Staphylococcus aureus, Clostridium difficile spores and vegetative cells, and adenovirus type 5. The overall pipeline of inactivation and subsequent proteomic, metabolomic, and lipidomic analyses was evaluated using a human epithelial lung cell line infected with wild-type and mutant influenza H7N9 viruses, thereby demonstrating that MPLEx yields biomaterial of sufficient quality for subsequent multi-omics analyses. Based on these experimental results, we believe that MPLEx will facilitate systems biology studies of infectious samples by enabling simultaneous pathogen inactivation and multi-omics measurements from a single specimen with high success for pathogens with exposed lipid membranes.

PMID: 28091625 [PubMed - as supplied by publisher]

Quantifying the relative contributions of different solute carriers to aggregate substrate transport.

Sci Rep. 2017 Jan 16;7:40628

Authors: Taslimifar M, Oparija L, Verrey F, Kurtcuoglu V, Olgac U, Makrides V

Abstract
Determining the contributions of different transporter species to overall cellular transport is fundamental for understanding the physiological regulation of solutes. We calculated the relative activities of Solute Carrier (SLC) transporters using the Michaelis-Menten equation and global fitting to estimate the normalized maximum transport rate for each transporter (Vmax). Data input were the normalized measured uptake of the essential neutral amino acid (AA) L-leucine (Leu) from concentration-dependence assays performed using Xenopus laevis oocytes. Our methodology was verified by calculating Leu and L-phenylalanine (Phe) data in the presence of competitive substrates and/or inhibitors. Among 9 potentially expressed endogenous X. laevis oocyte Leu transporter species, activities of only the uniporters SLC43A2/LAT4 (and/or SLC43A1/LAT3) and the sodium symporter SLC6A19/B(0)AT1 were required to account for total uptake. Furthermore, Leu and Phe uptake by heterologously expressed human SLC6A14/ATB(0,+) and SLC43A2/LAT4 was accurately calculated. This versatile systems biology approach is useful for analyses where the kinetics of each active protein species can be represented by the Hill equation. Furthermore, its applicable even in the absence of protein expression data. It could potentially be applied, for example, to quantify drug transporter activities in target cells to improve specificity.

PMID: 28091567 [PubMed - in process]

Complementing genomics and transcriptomics: Phosphoproteomics illuminates systems biology in prostate cancer.

Mol Cell Oncol. 2016;3(6):e1246075

Authors: Tan VM, Cheng LC, Drake JM

Abstract
Integration of phosphoproteomics with traditional genomics and transcriptomics provides a more comprehensive overview of the signaling networks in advanced prostate cancer for immediate preclinical and future clinical use. Our recent publication introduces computational approaches for integrating the phosphoproteome, specifically with the intent of identifying important kinase signaling networks in advanced-stage prostate cancer.

PMID: 28090583 [PubMed - in process]

Prospects and problems for standardizing model validation in systems biology.

Prog Biophys Mol Biol. 2017 Jan 12;:

Authors: Gross F, MacLeod M

Abstract
There are currently no widely shared criteria by which to assess the validity of computational models in systems biology. Here we discuss the feasibility and desirability of implementing validation standards for modeling. Having such a standard would facilitate journal review, interdisciplinary collaboration, model exchange, and be especially relevant for applications close to medical practice. However, even though the production of predictively valid models is considered a central goal, in practice modeling in systems biology employs a variety of model structures and model-building practices. These serve a variety of purposes, many of which are heuristic and do not seem to require strict validation criteria and may even be restricted by them. Moreover, given the current situation in systems biology, implementing a validation standard would face serious technical obstacles mostly due to the quality of available empirical data. We advocate a cautious approach to standardization. However even though rigorous standardization seems premature at this point, raising the issue helps us develop better insights into the practices of systems biology and the technical problems modelers face validating models. Further it allows us to identify certain technical validation issues which hold regardless of modeling context and purpose. Informal guidelines could in fact play a role in the field by helping modelers handle these.

PMID: 28089814 [PubMed - as supplied by publisher]

ChemEngine: harvesting 3D chemical structures of supplementary data from PDF files.

J Cheminform. 2016;8:73

Authors: Karthikeyan M, Vyas R

Abstract
Digital access to chemical journals resulted in a vast array of molecular information that is now available in the supplementary material files in PDF format. However, extracting this molecular information, generally from a PDF document format is a daunting task. Here we present an approach to harvest 3D molecular data from the supporting information of scientific research articles that are normally available from publisher's resources. In order to demonstrate the feasibility of extracting truly computable molecules from PDF file formats in a fast and efficient manner, we have developed a Java based application, namely ChemEngine. This program recognizes textual patterns from the supplementary data and generates standard molecular structure data (bond matrix, atomic coordinates) that can be subjected to a multitude of computational processes automatically. The methodology has been demonstrated via several case studies on different formats of coordinates data stored in supplementary information files, wherein ChemEngine selectively harvested the atomic coordinates and interpreted them as molecules with high accuracy. The reusability of extracted molecular coordinate data was demonstrated by computing Single Point Energies that were in close agreement with the original computed data provided with the articles. It is envisaged that the methodology will enable large scale conversion of molecular information from supplementary files available in the PDF format into a collection of ready- to- compute molecular data to create an automated workflow for advanced computational processes. Software along with source codes and instructions available at https://sourceforge.net/projects/chemengine/files/?source=navbar.Graphical abstract.

PMID: 28090216 [PubMed - in process]

Development of medical treatment for eye injuries in the mainland of China over the past decade.

Chin J Traumatol. 2016 Dec 01;19(6):311-316

Authors: Wang CG, Ma ZZ

Abstract
In the article, the development of medical treatment for eye injuries in the mainland of China was reviewed. According to the data provided in Eye Injury Vitrectomy Study (EIVS), 27% of 72 eyes with no light perception (NLP) gained recovery in term of antomy and visual function. Vitrectomy initiated at more than 4 weeks after open eye injury is an independent risk factor for developing PVR. Prognosis of anatomy and visual function of the injured eye with PVR is markedly worse than that without PVR. Serious injuries of ciliary body, choroid and retina are three key parts of the eye with NLP. The concept that the treatment of the eye injury gradually focus on the whole globe is embodied. The data from 13575 in patients with traumatic eyes in 14 hospitals revealed that the rate of immediate enucleation was remarkable reduced with comparison of 20 years ago.

PMID: 28088931 [PubMed - in process]

Nocardiosis in south of France during the last ten years.

Int J Infect Dis. 2017 Jan 11;:

Authors: Haussaire D, Fournier PE, Djiguiba K, Moal V, Legris T, Purgus R, Bismuth J, Elharrar X, Reynaud-Gaubert M, Vacher-Coponat H

Abstract
BACKGROUND: Nocardiosis is a rare disease with polymorphic presentations. Epidemiology and clinical presentation could change with the increasing number of immunocompromised patients.
METHODS: Medical records and microbiologic data for patients affected by nocardiosis and treated in the university hospital of Marseille between 2004 and 2014 were retrospectively analyzed.
RESULTS: We analyzed 34 patients infected by Nocardia spp during this period. The main underlying conditions were: transplantation (15), malignancy (9), cystic fibrosis (4) and immune disease (3). No immunodeficient condition was observed for 3 patients. No AIDS case was observed. At diagnosis, 61.8% had received steroids for over 3 months. Four clinical presentations depending on the underlying condition were identified: disseminated forms (50.0%) and visceral isolated forms (26.5%) in severe immunocompromised patients, bonchial forms (14.7%) in patients with chronic lung disease and cutaneous isolated forms (8.8%) in immunocompetent patients. N.farcinica was the main observed strain (26.5%). Trimethoprim-sulfamethoxazole was prescribed in 68.0% of patients, and 38.0% had surgery. Mortality was 11.7%, concerning patients with disseminated or visceral nocardiosis.
CONCLUSION: Clinical presentation and evolution of nocardiosis depend on initial immune status and pulmonary underlying condition. Severe forms were all iatrogenic, occurring after treatments altering the immune system.

PMID: 28088585 [PubMed - as supplied by publisher]

CFTR impairment upregulates c-Src activity through IL-1β autocrine signaling.

Arch Biochem Biophys. 2017 Jan 11;:

Authors: Massip-Copiz MM, Clauzure M, Valdivieso ÁG, Santa-Coloma TA

Abstract
Cystic Fibrosis (CF) is a disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Previously, we found several genes showing a differential expression in CFDE cells (epithelial cells derived from a CF patient). One corresponded to c-Src; its expression and activity was found increased in CFDE cells, acting as a signaling molecule between the CFTR activity and MUC1 overexpression. Here we report that bronchial IB3-1 cells (CF cells) also showed increased c-Src activity compared to 'CFTR-corrected' S9 cells. In addition, three different Caco-2 cell lines, each stably transfected with a different CFTR-specific shRNAs, displayed increased c-Src activity. The IL-1β receptor antagonist IL1RN reduced the c-Src activity of Caco-2/pRS26 cells (expressing a CFTR-specific shRNA). In addition, increased mitochondrial and cellular ROS levels were detected in Caco-2/pRS26 cells. ROS levels were partially reduced by incubation with PP2 (c-Src inhibitor) or IL1RN, and further reduced by using the NOX1/4 inhibitor GKT137831. Thus, IL-1β→c-Src and IL-1β→NOX signaling pathways appear to be responsible for the production of cellular and mitochondrial ROS in CFTR-KD cells. In conclusion, IL-1β constitutes a new step in the CFTR signaling pathway, located upstream of c-Src, which is stimulated in cells with impaired CFTR activity.

PMID: 28088327 [PubMed - as supplied by publisher]

Vaccine Candidates against Nontypeable Haemophilus influenzae: a Review

Iran Biomed J. 2017 03;21(2):69-76

Authors: Behrouzi A, Vaziri, Rahimi-Jamnani F, Afrough, Rahbar, Satarian, Siadat SD

Abstract
Nonencapsulated, nontypeable Hemophilus influenzae (NTHi) remains an important cause of acute otitis and respiratory diseases in children and adults. NTHi bacteria are one of the major causes of respiratory tract infections, including acute otitis media, cystic fibrosis, and community-acquired pneumonia among children, especially in developing countries. The bacteria can also cause chronic diseases such as chronic bronchitis and chronic obstructive pulmonary disease in the lower respiratory tract of adults. Such bacteria express several outer membrane proteins, some of which have been studied as candidates for vaccine development. Due to the lack of effective vaccines as well as the spread and prevalence of NTHi worldwide, there is an urgent need to design and develop effective vaccine candidates against these strains.

PMID: 28088130 [PubMed - as supplied by publisher]

A current perspective on the oncopreventive and oncolytic properties of selective serotonin reuptake inhibitors.

Biomed Pharmacother. 2017 Jan 11;87:636-639

Authors: Radin DP, Patel P

Abstract
Current cancer research strongly focuses on identifying novel pathways that can be selectively exploited in the clinic and identifying drugs capable of exploiting cancer vulnerabilities. Occasionally, drugs identified to exploit a cancer-specific vulnerability are on the market for clinical indications in another disease area. Rebranding them as anti-cancer drugs is a process commonly referred to as drug repurposing and is typically a faster method than bringing a novel drug to market. Selective serotonin reuptake inhibitors (SSRIs) are primarily used for treating several types of depression, but over the past two decades mounting evidence suggests that drugs in this class have oncolytic properties and reduce the risk of certain cancers. In the current work, we discuss how the secondary mechanisms of action associated with these drugs mediate their oncolytic effect. In particular, sertraline limits tumor growth by abrogating the PI3K/akt signaling pathway, a growth pathway shown to be constitutively active in multiple cancers. Fluoxetine has been shown to activate the AMPA-type glutamate receptor, induce massive calcium influx and mitochondrial calcium overload and induce caspase-9-dependent apoptosis. This receptor being highly overexpressed in cancer stem cells may explain why SSRIs lower the risk of multiple types of cancer. Fluoxetine has also been shown to inhibit multidrug resistance pumps, increasing the efficacy of several standard chemotherapies. Given the vast potential of SSRIs in treating cancer, these drugs should be more heavily used not only in treating cancer-related depression, but in combating cancer and increasing the efficacy of standard of care chemotherapies.

PMID: 28088112 [PubMed - as supplied by publisher]

Two Small Molecules Restore Stability to a Sub-population of the Cystic Fibrosis Transmembrane conductance Regulator with the Predominant Disease-causing Mutation.

J Biol Chem. 2017 Jan 13;:

Authors: Meng X, Wang Y, Wang X, Wrennall JA, Rimington TL, Li H, Cai Z, Ford RC, Sheppard DN

Abstract
Cystic fibrosis (CF) is caused by mutations that disrupt the plasma membrane expression, stability, and function of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel. Two small molecules, the CFTR corrector lumacaftor and the potentiator ivacaftor, are now used clinically to treat CF, although some studies suggest that they have counteracting effects on CFTR stability. Here, we investigated the impact of these compounds on the instability of F508del-CFTR, the most common CF mutation. To study individual CFTR Cl- channels, we performed single-channel recording, whereas to assess entire CFTR populations, we used purified CFTR proteins and macroscopic CFTR Cl- currents. At 37 degC, low temperature-rescued F508del-CFTR more rapidly lost function in cell-free membrane patches, and showed altered channel gating and current flow through open channels. Compared with purified wild-type CFTR, the full-length F508del-CFTR was about 10 degC less thermo-stable. Lumacaftor partially stabilized purified full-length F508del-CFTR and slightly delayed deactivation of individual F508del-CFTR Cl- channels. By contrast, ivacaftor further destabilized full-length F508del-CFTR and accelerated channel deactivation. Chronic (prolonged) co-incubation of F508del-CFTR-expressing cells with lumacaftor and ivacaftor deactivated macroscopic F508del-CFTR Cl- currents. However, at the single-channel level, chronic co-incubation greatly increased F508del-CFTR channel activity and temporal stability in most, but not all, cell-free membrane patches. We conclude that chronic lumacaftor and ivacaftor co-treatment restores stability in a small sub-population of F508del-CFTR Cl- channels, but that the majority remain destabilized. The fuller understanding of these effects and the characterization of the small F508del-CFTR sub-population might be crucial for CF therapy development.

PMID: 28087700 [PubMed - as supplied by publisher]

Six-Minute Walk Test Results Predict Risk of Hospitalization for Youths with Cystic Fibrosis: A 5-Year Follow-Up Study.

J Pediatr. 2017 Jan 10;:

Authors: Donadio MV, Heinzmann-Filho JP, Vendrusculo FM, Frasson PX, Marostica PJ

Abstract
OBJECTIVE: To evaluate the association of 6-minute walk test (6MWT) and other variables (anthropometry, chronic Pseudomonas aeroginosa colonization, pulmonary function, and respiratory muscle strength) with the risk of hospitalization for pulmonary exacerbation in children and adolescents with cystic fibrosis (CF).
STUDY DESIGN: Cohort study that included patients with CF aged 6-18 years. All participants underwent spirometry, manovacuometry, and 6MWT during the 5-year follow-up. Anthropometric and clinical data were collected and the time to first hospitalization, total days of hospitalization, and antibiotic use during follow-up was recorded.
RESULTS: A total of 26 patients with CF, mean age 10.2 ± 2.8 years, were included. The group had mild impairment of lung function with a significant decline in forced expiratory volume in 1 second (P = .019) over the 5 years. Respiratory muscle strength and 6MWT proved to be preserved, although maximum inspiratory pressure increased (P < .001) and maximum expiratory pressure and 6-minute walk distance (6MWD) remained stable. There were inverse associations of 6MWD in meters (r = -0.813, P < .001) and z score (r = -0.417, P = .015) with total days of hospitalization. Moreover, there was a reduction in the risk of a first hospitalization (Cox HR 0.32; P = .037) in patients with a greater 6MWD.
CONCLUSIONS: We found an association between the 6MWT and the risk of hospitalization in children and adolescents with CF. Furthermore, functional capacity apparently does not follow the expected decline in pulmonary function over time, whereas inspiratory muscle strength increases with disease progression.

PMID: 28087053 [PubMed - as supplied by publisher]