Differences between WHO AND CDC early growth measurements in the assessment of Cystic Fibrosis clinical outcomes.

J Cyst Fibros. 2016 Dec 15;:

Authors: Usatin D, Yen EH, McDonald C, Asfour F, Pohl J, Robson J

Abstract
BACKGROUND: Early childhood growth status has been used to predict long-term clinical outcomes in Cystic Fibrosis (CF) patients. Adulthood CF outcomes based on early weight-for-length (WFL) measurements, using either World Health Organization (WHO) or Centers for Disease Control (CDC) scales, have not been compared.
METHODS: Cystic Fibrosis Foundation registry patients were studied (n=3014). Participants were categorized at age two years as WFL <50th percentile on both WHO and CDC scales, ≥50th percentile on WHO but not CDC, or ≥50th percentile on both. Pulmonary function and overall survival were assessed at age 18years.
RESULTS: Stepwise gains in pulmonary function and lung transplant-free survival were noted across the three increasing WFL categories.
CONCLUSIONS: Children with CF who achieve higher WFL at age two years have improved pulmonary and survival outcomes into adulthood. CF providers should continue to utilize current early growth recommendations, with goal WFL ≥50th percentile on CDC growth charts before age two.

PMID: 27989470 [PubMed - as supplied by publisher]

Increasing sputum levels of gamma-glutamyltransferase may identify cystic fibrosis patients who do not benefit from inhaled glutathione.

J Cyst Fibros. 2016 Dec 14;:

Authors: Corti A, Griese M, Hector A, Pompella A

Abstract
Glutathione (GSH) is decreased in cystic fibrosis (CF) airways, thus its resupply by inhalation has been employed to restore antioxidant defense. CF airways present however increased activity of gamma-glutamyltransferase (GGT), the enzyme specifically capable of degrading GSH, and thus inhaled GSH might be promptly catabolized. In addition, prooxidant reactions are known to originate during GGT-mediated GSH catabolism. We determined levels of GGT in the sputum samples obtained from a previously published trial of GSH inhalation treatment, and analyzed their correlations with inflammatory markers and FEV1% values. Results indicate that differentiating patients with increasing vs. decreasing GGT activity - as measured in sputum before and after the six months duration of the study - may discriminate subjects more likely profiting from inhaled GSH, as opposed to those with increasing GGT in which these treatments might even produce aggravation of the damage.

PMID: 27988297 [PubMed - as supplied by publisher]

Unsupervised Analysis of Array Comparative Genomic Hybridization Data from Early-Onset Colorectal Cancer Reveals Equivalence with Molecular Classification and Phenotypes.

Neoplasia. 2016 Dec 14;19(1):28-34

Authors: Arriba M, García JL, Rueda D, Pérez J, Brandariz L, Nutu OA, Alonso L, Rodríguez Y, Urioste M, González-Sarmiento R, Perea J

Abstract
AIM: To investigate whether chromosomal instability (CIN) is associated with tumor phenotypes and/or with global genomic status based on MSI (microsatellite instability) and CIMP (CpG island methylator phenotype) in early-onset colorectal cancer (EOCRC).
METHODS: Taking as a starting point our previous work in which tumors from 60 EOCRC cases (≤45 years at the time of diagnosis) were analyzed by array comparative genomic hybridization (aCGH), in the present study we performed an unsupervised hierarchical clustering analysis of those aCGH data in order to unveil possible associations between the CIN profile and the clinical features of the tumors. In addition, we evaluated the MSI and the CIMP statuses of the samples with the aim of investigating a possible relationship between copy number alterations (CNAs) and the MSI/CIMP condition in EOCRC.
RESULTS: Based on the similarity of the CNAs detected, the unsupervised analysis stratified samples into two main clusters (A, B) and four secondary clusters (A1, A2, B3, B4). The different subgroups showed a certain correspondence with the molecular classification of colorectal cancer (CRC), which enabled us to outline an algorithm to categorize tumors according to their CIMP status. Interestingly, each subcluster showed some distinctive clinicopathological features. But more interestingly, the CIN of each subcluster mainly affected particular chromosomes, allowing us to define chromosomal regions more specifically affected depending on the CIMP/MSI status of the samples.
CONCLUSIONS: Our findings may provide a basis for a new form of classifying EOCRC according to the genomic status of the tumors.

PMID: 27987438 [PubMed - as supplied by publisher]

Association between AXL, Hippo transducers and survival outcomes in male breast cancer.

J Cell Physiol. 2016 Dec 17;:

Authors: Di Benedetto A, Mottolese M, Sperati F, Ercolani C, Di Lauro L, Pizzuti L, Vici P, Terrenato I, Shaaban AM, Humphries MP, Sundara-Rajan S, Barba M, Speirs V, De Maria R, Maugeri-Saccà M

Abstract
Male breast cancer (MBC) is an uncommon malignancy. We have previously reported that the expression of the Hippo transducers TAZ/YAP and their target CTGF was associated with inferior survival in MBC patients. Preclinical evidence demonstrated that Axl is a transcriptional target of TAZ/YAP. Thus, we herein assessed AXL expression to further investigate the significance of active TAZ/YAP-driven transcription in MBC. For this study, 255 MBC samples represented in tissue microarrays were screened for AXL expression, and 116 patients were included. The association between categorical variables was verified by the Pearson's Chi-squared test of independence (2-tailed) or the Fisher Exact test. The relationship between continuous variables was tested with the Pearson's correlation coefficient. The Kaplan-Meier method was used for estimating survival curves, which were compared by log-rank test. Factors potentially impacting 10-year and overall survival were verified in Cox proportional regression models. AXL was positively associated with the TAZ/CTGF and YAP/CTGF phenotypes (p = 0.001 and p = 0.002, respectively). Patients with TAZ/CTGF/AXL- or YAP/CTGF/AXL-expressing tumors had inferior survival compared with non-triple-positive patients (log rank p = 0.042 and p = 0.048, respectively). The variables TAZ/CTGF/AXL and YAP/CTGF/AXL were adverse factors for 10-year survival in the multivariate Cox models (HR 2.31, 95%CI:1.02-5.22, p = 0.045, and HR 2.27, 95%CI:1.00-5.13, p = 0.050). Nearly comparable results were obtained from multivariate analyses of overall survival. The expression pattern of AXL corroborates the idea of the detrimental role of TAZ/YAP activation in MBC. Overall, Hippo-linked biomarkers deserve increased attention in this rare disease. This article is protected by copyright. All rights reserved.

PMID: 27987320 [PubMed - as supplied by publisher]

Cost-Effectiveness of the Quantification of Enzymatic Activity in Leukocytes in Comparison to Its Nonrealization for a Rare Disease in Latin America: The Case of Mucopolysaccharidosis Type II in Colombia.

Value Health Reg Issues. 2016 Dec;11:42-48

Authors: Parody E, A Guevara C, Aguirre A, M Tello P

Abstract
BACKGROUND: Mucopolysaccharidosis (MPS) type II is produced by a deficiency of iduronate-2-sulfatase (I2S). The quantification of the enzyme activity in leukocytes is used as diagnostic confirmation of MPS.
OBJECTIVE: To determinate the cost-effectiveness of the measurement of I2S enzyme activity in leukocytes compared with not carrying out the enzyme activity measurement for diagnostic confirmation of MPS II from the perspective of the Colombian health system.
METHODS: A cost-effectiveness analysis was conducted on the basis of a decision tree model. The measure of effectiveness was the correct diagnosis of cases of MPS II. The costs of I2S enzymatic quantification in leukocytes, consultation with a geneticist and with other specialists, and costs of diagnostic procedures were included. The time horizon was less than 1 year. A probabilistic sensitivity analysis was performed using Monte-Carlo simulation with 10,000 iterations.
RESULTS: The incremental cost was -US $43,145 with an incremental effectiveness of 42 cases. The probabilistic sensitivity analysis confirms the results of basal data, in which the quantification of I2S enzyme activity was less costly and more effective than the alternative.
CONCLUSIONS: The quantification of I2S enzymatic activity is a dominant technology for the diagnostic confirmation of MPS II, compared with not making the quantification, from the perspective of the Colombian health system.

PMID: 27986197 [PubMed - in process]

Using dendritic cells to evaluate how Burkholderia cenocepacia clonal isolates from a chronically infected cystic fibrosis patient subvert immune functions.

Med Microbiol Immunol. 2016 Dec 16;

Authors: Guadalupe Cabral M, Pereira M, Silva Z, Iria I, Coutinho C, Lopes A, Sá-Correia I, Videira PA

Abstract
Infection with Burkholderia cepacia complex (Bcc) bacteria is a threat to cystic fibrosis (CF) patients, commonly leading to a fatal pneumonia, the cepacia syndrome. It causes a massive production of pro-inflammatory cytokines and leucocyte recruitment to airway epithelium without resolving infection and contributing to tissue lesion. To dissect how Bcc bacteria subvert the immune response, we developed a co-culture model with human dendritic cells (DCs) and B. cenocepacia clonal variants isolated from a chronically infected CF patient, who died with cepacia syndrome. We demonstrated that the two late variants were sevenfold and 17-fold (respectively) more internalized by DCs than the variant that initiated infection. The late variants showed improved survival within DCs (60.29 and 52.82 CFU/DC) compared to the initial variant (0.38 CFU/DC). All clonal isolates induced high expression of inflammatory cytokines IL-8, IL-6, IL-1β, IL-12, IL-23, TNF-α and IL-1β. This pro-inflammatory trait was significantly more pronounced in DCs infected with the late variants than in DCs infected with the variant that initiated patient's infection. All infected DCs failed to upregulate maturation markers, HLA-DR, CD80, CD86 and CD83. Nevertheless, these infected DCs activated approximately twice more T cells than non-infected DCs. Similar T cell activation was observable with respective conditioned media, suggesting a non-antigen-specific activation. Our data indicate that during prolonged infection, B. cenocepacia acquires ability to survive intracellularly, inducing inflammation, while refraining DC's maturation and stimulating non-antigen-specific T cell responses. The co-culture model here developed may be broadly applied to study B. cenocepacia-induced immunomodulation.

PMID: 27987042 [PubMed - as supplied by publisher]

Medical diagnostics for indoor mold exposure.

Int J Hyg Environ Health. 2016 Dec 05;:

Authors: Hurraß J, Heinzow B, Aurbach U, Bergmann KC, Bufe A, Buzina W, Cornely OA, Engelhart S, Fischer G, Gabrio T, Heinz W, Herr CE, Kleine-Tebbe J, Klimek L, Köberle M, Lichtnecker H, Lob-Corzilius T, Merget R, Mülleneisen N, Nowak D, Rabe U, Raulf M, Seidl HP, Steiß JO, Szewszyk R, Thomas P, Valtanen K, Wiesmüller GA

Abstract
In April 2016, the German Society of Hygiene, Environmental Medicine and Preventative Medicine (Gesellschaft für Hygiene, Umweltmedizin und Präventivmedizin (GHUP)) together with other scientific medical societies, German and Austrian medical societies, physician unions and experts has provided an AWMF (Association of the Scientific Medical Societies) guideline 'Medical diagnostics for indoor mold exposure'. This guideline shall help physicians to advise and treat patients exposed indoors to mold. Indoor mold growth is a potential health risk, even without a quantitative and/or causal association between the occurrence of individual mold species and health effects. Apart from the allergic bronchopulmonary aspergillosis (ABPA) and the mycoses caused by mold, there is only sufficient evidence for the following associations between moisture/mold damages and different health effects: Allergic respiratory diseases, asthma (manifestation, progression, exacerbation), allergic rhinitis, exogenous allergic alveolitis and respiratory tract infections/bronchitis. In comparison to other environmental allergens, the sensitizing potential of molds is estimated to be low. Recent studies show a prevalence of sensitization of 3-10% in the total population of Europe. The evidence for associations to mucous membrane irritation and atopic eczema (manifestation, progression, exacerbation) is classified as limited or suspected. Inadequate or insufficient evidence for an association is given for COPD, acute idiopathic pulmonary hemorrhage in children, rheumatism/arthritis, sarcoidosis, and cancer. The risk of infections from indoor molds is low for healthy individuals. Only molds that are capable to form toxins can cause intoxications. The environmental and growth conditions and especially the substrate determine whether toxin formation occurs, but indoor air concentrations are always very low. In the case of indoor moisture/mold damages, everyone can be affected by odor effects and/or impairment of well-being. Predisposing factors for odor effects can be given by genetic and hormonal influences, imprinting, context and adaptation effects. Predisposing factors for impairment of well-being are environmental concerns, anxieties, conditioning and attributions as well as a variety of diseases. Risk groups that must be protected are patients with immunosuppression and with mucoviscidosis (cystic fibrosis) with regard to infections and individuals with mucoviscidosis and asthma with regard to allergies. If an association between mold exposure and health effects is suspected, the medical diagnosis includes medical history, physical examination, conventional allergy diagnosis, and if indicated, provocation tests. For the treatment of mold infections, it is referred to the AWMF guidelines for diagnosis and treatment of invasive Aspergillus infections. Regarding mycotoxins, there are currently no validated test methods that could be used in clinical diagnostics. From the perspective of preventive medicine, it is important that mold damages cannot be tolerated in indoor environments.

PMID: 27986496 [PubMed - as supplied by publisher]

Current strategies for the long-term assessment, monitoring, and management of cystic fibrosis patients treated with CFTR modulator therapy.

J Cyst Fibros. 2016 Dec 13;:

Authors: Elborn JS, Davies J, Mall MA, Flume PA, Plant B

Abstract
The content for this activity is based on the satellite symposium, "Current Strategies for the Long-term Assessment, Monitoring, and Management for Cystic Fibrosis Patients Treated with CFTR Modulator Therapy" that was presented at the 39th European Cystic Fibrosis Society Conference on June 10, 2016 (Online access: http://courses.elseviercme.com/ecfs2016e/619e). The emergence of novel targeted agents, that directly correct CFTR loss function alleles, has created new treatment opportunities for patients with cystic fibrosis with advanced disease. Knowledge of the role of these agents in the clinical setting is quickly evolving and will require physicians to stay acquainted with the latest data as well as evidence-based treatment guidelines in order to achieve optimized cystic fibrosis patient care. Ideally, after diagnosis, a personalized approach would be adapted and tailored to the patient through genome-informed medicine. However, due to the relative recentness of genomic-based therapeutics, physicians may have a limited knowledge base regarding these new treatment options and how to best incorporate these agents into patient management plans. Although cystic fibrosis is still largely regarded as a pediatric disease, the median survival for patients is 35years of age. Consequently, pediatric-to-adult cystic fibrosis care programs would allow suitable preparation time for this transition and develop a standardized group of self-care and management skills.

PMID: 27986495 [PubMed - as supplied by publisher]

The psychometric properties of the Leicester Cough Questionnaire and Respiratory Symptoms in CF tool in cystic fibrosis: A preliminary study.

J Cyst Fibros. 2016 Dec 13;:

Authors: Ward N, Stiller K, Rowe H, Holland AE

Abstract
BACKGROUND: There are few tools to quantify the impact of cough in cystic fibrosis (CF). The psychometric properties of the Leicester Cough Questionnaire (LCQ) and Respiratory Symptoms in CF (ReS-CF) tool were investigated in adults with CF.
METHODS: Validity and reliability were assessed in clinically stable participants who completed the questionnaires twice, along with the Cystic Fibrosis Questionnaire - Revised (CFQ-R). Responsiveness was assessed by change in questionnaires following treatment for an acute respiratory exacerbation.
RESULTS: Correlations between the LCQ and CFQ-R respiratory domain were moderate (n=59, rs=0.78, p<0.001). Correlations between ReS-CF and CFQ-R respiratory domain were fair (rs=-0.50, p<0.001). The LCQ total score was repeatable (ICC 0.92, 95%CI 0.87-0.96, n=50). In those reporting improvement in symptoms following treatment (n=36), LCQ total score had a mean change of 4.6 (SD 3.7) and effect size of 1.2.
CONCLUSIONS: The LCQ and ReS-CF appear to be valid, reliable and responsive in CF.
TRIAL REGISTRATION: www.anzctr.org.au: ACTRN12615000262505.

PMID: 27986494 [PubMed - as supplied by publisher]

Incorporating Pharmacogenomics into Health Information Technology, Electronic Health Record and Decision Support System: An Overview.

J Med Syst. 2017 Feb;41(2):19

Authors: Alanazi A

Abstract
As the adoption of information technology in healthcare is rising, the potentiality of moving Pharmacogenomics from benchside to bedside is aggravated. This paper reviews the current status of Pharmacogenomics (PGx) information and the attempts for incorporating them into the Electronic Health Record (EHR) system through Decision Support Systems (DSSs). Rigorous review strategies of PGx information and providing context-relevant recommendations in form of action plan- dose adjustment, lab tests rather than just information- would be ideal for making clinical recommendations out of PGx information. Lastly, realistic projections of what pharmacogenomics can provide is another important aspect in incorporating Pharmacogenomics into health information technology.

PMID: 27987157 [PubMed - in process]

PGSB/MIPS PlantsDB Database Framework for the Integration and Analysis of Plant Genome Data.

Methods Mol Biol. 2017;1533:33-44

Authors: Spannagl M, Nussbaumer T, Bader K, Gundlach H, Mayer KF

Abstract
Plant Genome and Systems Biology (PGSB), formerly Munich Institute for Protein Sequences (MIPS) PlantsDB, is a database framework for the integration and analysis of plant genome data, developed and maintained for more than a decade now. Major components of that framework are genome databases and analysis resources focusing on individual (reference) genomes providing flexible and intuitive access to data. Another main focus is the integration of genomes from both model and crop plants to form a scaffold for comparative genomics, assisted by specialized tools such as the CrowsNest viewer to explore conserved gene order (synteny). Data exchange and integrated search functionality with/over many plant genome databases is provided within the transPLANT project.

PMID: 27987163 [PubMed - in process]

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

"orphan disease" OR "rare disease" OR "orphan diseases" OR "rare diseases"

These pubmed results were generated on 2016/12/17

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8 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 2016/12/17

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 Repurposing Patent Applications April-June 2016.

Assay Drug Dev Technol. 2016 Dec;14(10):573-576

Authors: Mucke HA

PMID: 27982706 [PubMed - in process]

Drug Repurposing Patent Applications July-September 2016.

Assay Drug Dev Technol. 2016 Dec;14(10):577-582

Authors: Mucke HA

PMID: 27982705 [PubMed - in process]

Revisiting Repurposing.

Assay Drug Dev Technol. 2016 Dec;14(10):554-556

Authors: Sharlow ER

Abstract
Drug repurposing can be a cost-effective strategy to identify new small molecule-based therapies. Thus, drug repurposing significantly influences the discovery of therapeutics, particularly for rare and neglected diseases, which are often constrained by limited research and development funds. The push for translational science and access to drug discovery-associated resources such as high throughput screening instrumentation, assay development expertise, and Food and Drug Administration-approved drug libraries have intensified interest in drug repurposing. However, successful drug repurposing is highly challenging and subject to particular limitations. Despite these challenges, drug repurposing is a critical component to any comprehensive drug discovery strategy and has the capacity to benefit a wide variety of therapeutically underserved diseases.

PMID: 27982703 [PubMed - in process]

The potential role of trimethoprim-sulfamethoxazole in the treatment of drug-resistant tuberculosis.

Future Microbiol. 2016;11(4):539-47

Authors: Palomino JC, Martin A

Abstract
Tuberculosis (TB) remains a serious public health threat worsened by emerging drug resistance. Mycobacterium tuberculosis has become resistant not only to front-line drugs but also to second-line antimicrobials directed at drug-resistant TB. Renewed efforts are devoted for the development of new antibiotics active against TB. Also, repurposing of other antibiotics is being explored to shorten the time to develop new drugs against M. tuberculosis. As a result, trimethoprim-sulfamethoxazole (SXT) has emerged as a potential new option to treat drug-resistant TB. SXT has been found to be surprisingly active against drug-resistant M. tuberculosis, not only in vitro but also in vivo. The potential role of SXT for the treatment of multidrug resistant/extensively drug resistant TB might be explored in further clinical evaluations.

PMID: 27070731 [PubMed - indexed for MEDLINE]

Patient perceptions of care as influenced by a large institutional pharmacogenomic implementation program.

Clin Pharmacol Ther. 2016 Dec 16;:

Authors: McKillip RP, Borden BA, Galecki P, Ham SA, Patrick-Miller L, Hall JP, Hussain S, Danahey K, Siegler M, Sorrentino MJ, Sacro Y, Davis AM, Rubin DT, Lipstreuer K, Polonsky TS, Nanda R, Harper WR, Koyner JL, Burnet DL, Stadler WM, Ratain MJ, Meltzer DO, O'Donnell PH

Abstract
Despite growing clinical use of genomic information, patient perceptions of genomic-based care are poorly understood. We prospectively studied patient-physician pairs who participated in an institutional pharmacogenomic implementation program. Trust/Privacy/Empathy/Medical Decision-Making (MDM)/Personalized Care (PC) dimensions were assessed through patient surveys after clinic visits at which physicians had access to preemptive pharmacogenomic results (Likert scale, 1-minimum/5-maximum; mean [SD]). From 2012-2015, 1,261 surveys were issued to 507 patients, with 792 (62.8%) returned. Privacy, Empathy, MDM and PC scores were significantly higher following visits when physicians considered pharmacogenomic results. Importantly, PC scores were significantly higher after physicians used pharmacogenomic information to guide medication changes (4.0[1.4] vs. 3.0[1.6], P<0.001) compared to prescribing visits without genomic guidance. Multivariable modeling controlling for clinical factors confirmed PC scores were more favorable following visits with genomic-influenced prescribing (OR=3.26 [1.31-8.14], P<0.05). Physicians appear to individualize care when utilizing pharmacogenomic results and this decision-making augmentation is perceived positively by patients. This article is protected by copyright. All rights reserved.

PMID: 27981566 [PubMed - as supplied by publisher]

Pharmacogenomics in the age of personalized medicine.

Drug Discov Today Technol. 2016 Sep - Dec;21-22:11-16

Authors: Dickmann LJ, Ware JA

Abstract
The aim of personalized medicine is to offer the right treatment to the right person at the right dose, thus maximizing efficacy and minimizing toxicity for each individual patient. Pharmacogenomic approaches attempt to refine the aim of personalized medicine by utilizing an individual's germline and somatic DNA signatures to guide treatment. In this review, we highlight the current use of pharmacogenomic based biomarker information in drug labeling. We also present several case studies on the implementation of pharmacogenomic strategies in drug discovery and development. Lastly, we comment on current challenges to implementing pharmacogenomic based testing in the clinic.

PMID: 27978982 [PubMed - in process]

Disease Model of GATA4 Mutation Reveals Transcription Factor Cooperativity in Human Cardiogenesis.

Cell. 2016 Dec 15;167(7):1734-1749.e22

Authors: Ang YS, Rivas RN, Ribeiro AJ, Srivas R, Rivera J, Stone NR, Pratt K, Mohamed TM, Fu JD, Spencer CI, Tippens ND, Li M, Narasimha A, Radzinsky E, Moon-Grady AJ, Yu H, Pruitt BL, Snyder MP, Srivastava D

Abstract
Mutation of highly conserved residues in transcription factors may affect protein-protein or protein-DNA interactions, leading to gene network dysregulation and human disease. Human mutations in GATA4, a cardiogenic transcription factor, cause cardiac septal defects and cardiomyopathy. Here, iPS-derived cardiomyocytes from subjects with a heterozygous GATA4-G296S missense mutation showed impaired contractility, calcium handling, and metabolic activity. In human cardiomyocytes, GATA4 broadly co-occupied cardiac enhancers with TBX5, another transcription factor that causes septal defects when mutated. The GATA4-G296S mutation disrupted TBX5 recruitment, particularly to cardiac super-enhancers, concomitant with dysregulation of genes related to the phenotypic abnormalities, including cardiac septation. Conversely, the GATA4-G296S mutation led to failure of GATA4 and TBX5-mediated repression at non-cardiac genes and enhanced open chromatin states at endothelial/endocardial promoters. These results reveal how disease-causing missense mutations can disrupt transcriptional cooperativity, leading to aberrant chromatin states and cellular dysfunction, including those related to morphogenetic defects.

PMID: 27984724 [PubMed - in process]