Adults with cystic fibrosis in Portugal: A first step towards improvement.

Rev Port Pneumol (2006). 2016 May-Jun;22(3):139-40

Authors: Raja TH, Flume PA

PMID: 27256624 [PubMed - in process]

Evaluation of a New Newborn Screening Model for Cystic Fibrosis.

J Pediatr. 2016 May 30;

Authors: Kharrazi M

PMID: 27255858 [PubMed - as supplied by publisher]

A Handling Study to Assess Use of the Respimat(®) Soft Mist™ Inhaler in Children Under 5 Years Old.

J Aerosol Med Pulm Drug Deliv. 2015 Oct;28(5):372-81

Authors: Kamin W, Frank M, Kattenbeck S, Moroni-Zentgraf P, Wachtel H, Zielen S

Abstract
BACKGROUND: Respimat(®) Soft Mist(™) Inhaler (SMI) is a hand-held device that generates an aerosol with a high, fine-particle fraction, enabling efficient lung deposition. The study objective was to assess inhalation success among children using Respimat SMI, and the requirement for assistance by the parent/caregiver and/or a valved holding chamber (VHC).
METHODS: This open-label study enrolled patients aged <5 years with respiratory disease and history of coughing and/or recurrent wheezing. Patients inhaled from the Respimat SMI (air only; no aerosol) using a stepwise configuration: "1" (dose released by child); "2" (dose released by parent/caregiver), and "3" (Respimat SMI with VHC, facemask, and parent/caregiver help). Co-primary endpoints included the ability to perform successful inhalation as assessed by the investigators using a standardized handling questionnaire and evaluation of the reasons for success. Inhalation profile in the successful handling configuration was verified with a pneumotachograph. Patient satisfaction and preferences were investigated in a questionnaire.
RESULTS: Of the children aged 4 to <5 years (n=27) and 3 to <4 years (n=30), 55.6% and 30.0%, respectively, achieved success without a VHC or help; with assistance, another 29.6% and 10.0%, respectively, achieved success, and the remaining children were successful with VHC. All children aged 2 to <3 years (n=20) achieved success with the Respimat SMI and VHC. Of those aged <2 years (n=22), 95.5% had successful handling of the Respimat SMI with VHC and parent/caregiver help. Inhalation flow profiles generally confirmed the outcome of the handling assessment by the investigators. Most parent/caregiver and/or child respondents were satisfied with operation, instructions for use, handling, and ease of holding the Respimat SMI with or without a VHC.
CONCLUSIONS: The Respimat SMI is suitable for children aged <5 years; however, children aged <5 years are advised to add a VHC to complement its use.

PMID: 25844687 [PubMed - indexed for MEDLINE]

CAR-engineered cytokine-induced killer cells overcome treatment resistance of pre-B-ALL and enhance survival.

Int J Cancer. 2016 Jun 2;

Authors: Oelsner S, Wagner J, Friede ME, Pfirrmann V, Genßler S, Rettinger E, Buchholz CJ, Pfeifer H, Schubert R, Ottmann OG, Ullrich E, Bader P, Wels WS

Abstract
Pre-emptive cancer immunotherapy by donor lymphocyte infusion (DLI) using cytokine-induced killer (CIK) cells may be beneficial to prevent relapse with a reduced risk of causing graft-versus-host-disease (GvHD). CIK cells are a heterogeneous effector cell population including T cells (CD3(+) CD56(-) ), natural killer (NK) cells (CD3(-) CD56(+) ) and natural killer T (T-NK) cells (CD3(+) CD56(+) ) that exhibit non-MHC-restricted cytotoxicity and are generated by ex vivo expansion of peripheral blood mononuclear cells (PBMC) in the presence of interferon (IFN)-γ, anti-CD3 antibody, interleukin-2 (IL-2) and interleukin-15 (IL-15). To facilitate selective target-cell recognition and enhance specific cytotoxicity against B-cell acute lymphoblastic leukemia (B-ALL), we transduced CIK cells with a lentiviral vector encoding a chimeric antigen receptor (CAR) that carries a composite CD28-CD3ζ domain for signaling and a CD19-specific scFv antibody fragment for cell binding (CAR 63.28.z). In vitro analysis revealed high and specific cell killing activity of CD19-targeted CIK/63.28.z cells against otherwise CIK-resistant cancer cell lines and primary B-ALL blasts, which was dependent on CD19 expression and CAR signaling. In a xenograft model in immunodeficient mice, treatment with CIK/63.28.z cells in contrast to therapy with unmodified CIK cells resulted in complete and durable molecular remissions of established primary pre-B-ALL. Our results demonstrate potent anti-leukemic activity of CAR-engineered CIK cells in vitro and in vivo, and suggest this strategy as a promising approach for adoptive immunotherapy of refractory pre-B-ALL. This article is protected by copyright. All rights reserved.

PMID: 27253354 [PubMed - as supplied by publisher]

Modeling and Re-Engineering of Azotobacter vinelandii Alginate Lyase to Enhance Its Catalytic Efficiency for Accelerating Biofilm Degradation.

PLoS One. 2016;11(6):e0156197

Authors: Jang CH, Piao YL, Huang X, Yoon EJ, Park SH, Lee K, Zhan CG, Cho H

Abstract
Alginate is known to prevent elimination of Pseudomonas aeruginosa biofilms. Alginate lyase (AlgL) might therefore facilitate treatment of Pseudomonas aeruginosa-infected cystic fibrosis patients. However, the catalytic activity of wild-type AlgL is not sufficiently high. Therefore, molecular modeling and site-directed mutagenesis of AlgL might assist in enzyme engineering for therapeutic development. AlgL, isolated from Azotobacter vinelandii, catalyzes depolymerization of alginate via a β-elimination reaction. AlgL was modeled based on the crystal structure template of Sphingomonas AlgL species A1-III. Based on this computational analysis, AlgL was subjected to site-directed mutagenesis to improve its catalytic activity. The kcat/Km of the K194E mutant showed a nearly 5-fold increase against the acetylated alginate substrate, as compared to the wild-type. Double and triple mutants (K194E/K245D, K245D/K319A, K194E/K245D/E312D, and K194E/K245D/K319A) were also prepared. The most potent mutant was observed to be K194E/K245D/K319A, which has a 10-fold improved kcat value (against acetylated alginate) compared to the wild-type enzyme. The antibiofilm effect of both AlgL forms was identified in combination with piperacillin/tazobactam (PT) and the disruption effect was significantly higher in mutant AlgL combined with PT than wild-type AlgL. However, for both the wild-type and K194E/K245D/K319A mutant, the use of the AlgL enzyme alone did not show significant antibiofilm effect.

PMID: 27253324 [PubMed - as supplied by publisher]

Lumacaftor/ivacaftor combination for cystic fibrosis patients homozygous for Phe508del-CFTR.

Drugs Today (Barc). 2016 Apr;52(4):229-37

Authors: Zhang W, Zhang X, Zhang YH, Strokes DC, Naren AP

Abstract
Cystic fibrosis (CF) is a life-shortening inherited disease caused by the loss or dysfunction of the CF transmembrane conductance regulator (CFTR) channel activity resulting from mutations in the CFTR gene. Phe508del is the most prevalent mutation, with approximately 90% of all CF patients carrying it on at least one allele. Over the past two or three decades, significant progress has been made in understanding the pathogenesis of CF, and in the development of effective CF therapies. The approval of Orkambi(R) (lumacaftor/ivacaftor) marks another milestone in CF therapeutics development, which, with the advent of personalized medicine, could potentially revolutionize CF care and management. This article reviews the rationale, progress and future direction in the development of lumacaftor/ivacaftor combination to treat CF patients.

PMID: 27252987 [PubMed - in process]

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Provider and Patient Attitudes Regarding Sexual Health in Young Women With Cystic Fibrosis.

Pediatrics. 2016 May 2;

Authors: Kazmerski TM, Borrero S, Tuchman LK, Weiner DJ, Pilewski JM, Orenstein DM, Miller E

Abstract
OBJECTIVE: To explore the attitudes, preferences, and experiences of patients with cystic fibrosis (CF) and CF providers toward sexual and reproductive health (SRH) care for young women with CF.
METHODS: Young women with CF aged 18 to 30 years from a US CF care center and pediatric and adult CF program directors from a national sample participated in qualitative interviews investigating their experiences regarding SRH care and their attitudes and preferences toward SRH care provision in the CF setting. Interviews were audio-recorded, transcribed, and coded by using a thematic analysis approach.
RESULTS: Twenty-two patient participants and 16 CF program directors were interviewed. Themes shared by both groups included the importance of SRH discussion in the CF care setting, patient and provider discomfort as a barrier to SRH care, and the need for SRH educational resources and provider training to improve SRH care. Providers highlighted the lack of standardization around SRH care in the current CF care model. Patients desired SRH educational resources coupled with early SRH discussions initiated by their CF provider.
CONCLUSIONS: Both CF providers and patients agree that the CF provider has a fundamental role in providing CF-specific SRH care. Educational resources coupled with individualized SRH discussions may facilitate improved SRH care for young women with CF. Investigation into the implementation of SRH education and services into pediatric-onset chronic disease care models is needed.

PMID: 27244858 [PubMed - as supplied by publisher]

Pubertal Height Growth and Adult Height in Cystic Fibrosis After Newborn Screening.

Pediatrics. 2016 May;137(5)

Authors: Zhang Z, Lindstrom MJ, Farrell PM, Lai HJ, with the Wisconsin Cystic Fibrosis Neonatal Screening Group

Abstract
BACKGROUND: To examine long-term growth benefit of newborn screening (NBS), adolescent peak height velocity (PHV), and adult height were compared between the screened (diagnosed early via NBS) and the control (identified generally by symptoms) in the Wisconsin Randomized Clinical Trial.
METHODS: Data from 107 children born in 1985-1994 and followed through 2012 were analyzed. PHV was estimated by a semiparametric growth curve model and compared with Tanner reference.
RESULTS: Meconium ileus (MI; n = 25) was associated with the worst pubertal growth and adult height, including 1 child who did not experience apparent PHV; children with pancreatic sufficiency (n = 18) achieved the best growth (normal PHV and adult height). In children with pancreatic insufficiency without meconium ileus (n = 64), the subgroup most likely to benefit from NBS, screened children had similar PHV but better adult height compared with controls. Specifically, in boys, the screened group (n = 22) achieved normal PHV (9.5 cm at 13.5 years); the control group (n = 19) had similar onset age (13.6 years) but 0.6-cm lower magnitude (P = .08). In girls, the screened group (n = 10) had somewhat later (12.5 years vs 11.7 years, P = .12) and lower PHV (7.3 cm vs 7.9 cm, P = .33) than the controls (n = 13), coinciding with later menarche (13.6 years vs 12.2 years, P = .10). Adult height was taller in the screened than the control (50th vs 29th percentile, P = .02), even after adjusted for genetic potential (32nd vs15th percentile, P = .006). Differences in adult height were primarily attributable to NBS and better prepubertal growth.
CONCLUSIONS: Early linear growth benefits of NBS were sustained through puberty, leading to better adult height in cystic fibrosis.

PMID: 27244789 [PubMed - as supplied by publisher]

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]

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]

Fluorescence-based bioassays for the detection and evaluation of food materials.

Sensors (Basel). 2015;15(10):25831-67

Authors: Nishi K, Isobe S, Zhu Y, Kiyama R

Abstract
We summarize here the recent progress in fluorescence-based bioassays for the detection and evaluation of food materials by focusing on fluorescent dyes used in bioassays and applications of these assays for food safety, quality and efficacy. Fluorescent dyes have been used in various bioassays, such as biosensing, cell assay, energy transfer-based assay, probing, protein/immunological assay and microarray/biochip assay. Among the arrays used in microarray/biochip assay, fluorescence-based microarrays/biochips, such as antibody/protein microarrays, bead/suspension arrays, capillary/sensor arrays, DNA microarrays/polymerase chain reaction (PCR)-based arrays, glycan/lectin arrays, immunoassay/enzyme-linked immunosorbent assay (ELISA)-based arrays, microfluidic chips and tissue arrays, have been developed and used for the assessment of allergy/poisoning/toxicity, contamination and efficacy/mechanism, and quality control/safety. DNA microarray assays have been used widely for food safety and quality as well as searches for active components. DNA microarray-based gene expression profiling may be useful for such purposes due to its advantages in the evaluation of pathway-based intracellular signaling in response to food materials.

PMID: 26473869 [PubMed - indexed for MEDLINE]

Recent developments in multiplexing techniques for immunohistochemistry.

Expert Rev Mol Diagn. 2015;15(9):1171-86

Authors: Dixon AR, Bathany C, Tsuei M, White J, Barald KF, Takayama S

Abstract
Methods to detect immunolabeled molecules at increasingly higher resolutions, even when present at low levels, are revolutionizing immunohistochemistry (IHC). These technologies can be valuable for the management and examination of rare patient tissue specimens, and for improved accuracy of early disease detection. The purpose of this article is to highlight recent multiplexing methods that are candidates for more prevalent use in clinical research and potential translation to the clinic. Multiplex IHC methods, which permit identification of at least 3 and up to 30 discrete antigens, have been divided into whole-section staining and spatially-patterned staining categories. Associated signal enhancement technologies that can enhance performance and throughput of multiplex IHC assays are also discussed. Each multiplex IHC technique, detailed herein, is associated with several advantages as well as tradeoffs that must be taken into consideration for proper evaluation and use of the methods.

PMID: 26289603 [PubMed - indexed for MEDLINE]

[Identification of proteomic biomarkers of preeclampsia using protein microarray and tandem mass spectrometry].

Postepy Hig Med Dosw (Online). 2015;69:562-70

Authors: Charkiewicz K, Jasinska E, Laudanski P

Abstract
Preeclampsia (PE) is the leading cause of death of the fetus and the mother. The exact pathomechanism has not so far been clarified. PE coexists with many other diseases, but it is often difficult to explain the association between them and find a clear reason for their occurrence. There are many predictive factors, but none are highly specific in preeclampsia. The diagnosis of preeclampsia seems to be very complex, which is another argument for the exploration of knowledge on this subject. Although many of the discoveries have hitherto been made in the field of proteomics, still no single specific biomarker of preeclampsia has been discovered. Research at the genome level is important because it can help us understand the genetic predisposition of patients affected by this disease. Nevertheless, researchers have recently become more interested in the pathophysiology of PE, and they are trying to answer the question: what is the real, direct cause of preeclampsia? Thus, the discovery of a protein that is a good predictor of preeclampsia development would significantly accelerate the medical care of pregnant women, and consequently reduce the risk of occurrence of HELLP syndrome and fetal death. Apart from the predictive and diagnostic function, such a discovery would help us to better understand the pathogenesis of preeclampsia and to find in the future a medical drug to suppress this disease. In order to make a breakthrough in this field, scientists need to use the most modern methods of proteomics, which allow for the analysis of small amounts of biological material in the shortest possible time, thereby giving a lot of information about existing proteins in the sample. Such optimization allows two methods, most commonly used by researchers: tandem mass spectrometry and protein microarray technique.

PMID: 25983295 [PubMed - indexed for MEDLINE]

[Functional annotation of rice WRKY transcription factors based on their transcriptional features].

Yi Chuan. 2016 Feb;38(2):126-36

Authors: Liyun L, Jianan S, Shuo Y, Caiqiang S, Guozhen L

Abstract
Transcription factors regulate alteration of transcription levels. Recently, huge amount of transcriptomic data are accumulated via the application of high throughput sequencing technology, and it is reasonable to postulate that in-depth analysis of transcription data could be used to enhance gene annotation. In this study, we chose the gene family of rice WRKY transcription factors. Based on literature search, the transcriptional data under different biological processes, including biotic and abiotic stress, development, and nutrient absorption and hormone treatments were analyzed systematically. To the end, we summarize the list of differentially expressed WRKY genes. We also expect that such information will enrich their functional annotation and also provide direct clues for subsequent functional studies.

PMID: 26907776 [PubMed - indexed for MEDLINE]

Autoantigen Microarray for High-throughput Autoantibody Profiling in Systemic Lupus Erythematosus.

Genomics Proteomics Bioinformatics. 2015 Aug;13(4):210-8

Authors: Zhu H, Luo H, Yan M, Zuo X, Li QZ

Abstract
Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by the production of autoantibodies to a broad range of self-antigens. Profiling the autoantibody repertoire using array-based technology has emerged as a powerful tool for the identification of biomarkers in SLE and other autoimmune diseases. Proteomic microarray has the capacity to hold large number of self-antigens on a solid surface and serve as a high-throughput screening method for the determination of autoantibody specificities. The autoantigen arrays carrying a wide variety of self-antigens, such as cell nuclear components (nucleic acids and associated proteins), cytoplasmic proteins, phospholipid proteins, cell matrix proteins, mucosal/secreted proteins, glomeruli, and other tissue-specific proteins, have been used for screening of autoantibody specificities associated with different manifestations of SLE. Arrays containing synthetic peptides and molecular modified proteins are also being utilized for identification of autoantibodies targeting to special antigenic epitopes. Different isotypes of autoantibodies, including IgG, IgM, IgA, and IgE, as well as other Ig subtypes, can be detected simultaneously with multi-color labeled secondary antibodies. Serum and plasma are the most common biologic materials for autoantibody detection, but other body fluids such as cerebrospinal fluid, synovial fluid, and saliva can also be a source of autoantibody detection. Proteomic microarray as a multiplexed high-throughput screening platform is playing an increasingly-important role in autoantibody diagnostics. In this article, we highlight the use of autoantigen microarrays for autoantibody exploration in SLE.

PMID: 26415621 [PubMed - indexed for MEDLINE]

Molecular cytopathology for thyroid nodules: A review of methodology and test performance.

Cancer Cytopathol. 2016 Jan;124(1):14-27

Authors: Nishino M

Abstract
Advances in the molecular characterization of thyroid cancers have fueled the development of genetic and gene expression-based tests for thyroid fine-needle aspirations. Collectively, these tests are designed to improve the diagnostic certainty of thyroid cytology. This review summarizes the early published experience with the commercially available versions of these tests: the Afirma Gene Expression Classifier, ThyGenX (formerly miRInform)/ThyraMIR, and ThyroSeq. Key differences in testing approaches and issues regarding test performance and interpretation are also discussed.

PMID: 26348024 [PubMed - indexed for MEDLINE]