Evaluation of buccal swabs for pharmacogenetics.

BMC Res Notes. 2018 Jun 14;11(1):382

Authors: Ang JS, Aloise MN, Dawes D, Dempster MG, Fraser R, Paterson A, Stanley P, Suarez-Gonzalez A, Dawes M, Katzov-Eckert H

Abstract
OBJECTIVE: A simple, non-invasive sample collection method is key for the integration of pharmacogenetics into clinical practice. The aim of this study was to gain samples for pharmacogenetic testing and evaluate the variation between dry-flocked and sponge-tipped buccal swabs in yield and quality of DNA isolated.
RESULTS: Thirty-one participants collected samples using dry-flocked swabs and sponge-tipped swabs. Samples were assessed for DNA yield, quality and genotyping performance on a qPCR OpenArray platform of 28 pharmacogenetic SNPs and a CYP2D6 TaqMan copy number variant. DNA from sponge-tipped swabs had a significantly greater yield compared to DNA collected with dry-flocked swabs (p = 4.4 × 10-7). Moreover, highest genotyping call rates across all assays and highest CNV confidence scores were observed in DNA samples collected from sponge-tipped swabs (97% vs. 54% dry-flocked swabs; 0.99 vs. 0.88 dry-flocked swabs, respectively). Sample collection using sponge-tipped swabs provides a DNA source of sufficient quantity and quality for pharmacogenetic variant detection using qPCR.

PMID: 29898767 [PubMed - in process]

A cost effective RFLP method to genotype Solute carrier organic anion 1B1 (SLCO1B1) c.1929A>C (p.Leu643Phe, rs34671512); a variant with potential effect on rosuvastatin pharmacokinetics.

BMC Res Notes. 2018 Jun 14;11(1):384

Authors: Soko ND, Masimirembwa C, Dandara C

Abstract
OBJECTIVE: This study describes a restriction fragment polymorphism protocol for rapidly screening the polymorphism SLCO1B1 c.1929A>C in genomic DNA samples. The polymorphism SLCO1B1 c.1929A>C has been associated with increased activity resulting in increased hepatic uptake of drugs. Currently SLCO1B1 c.1929A>C is genotyped using direct sequencing techniques and 5' nuclease based assays which can be cost prohibiting in resource limited settings. The aim of this study therefore was to design and validate a cost effective RFLP for genotyping the SLCO1B1 c.1929A>C polymorphism. This study was designed to investigate the effect of the polymorphism SLCO1B1 c.1929A>C on interindividual variability in rosuvastatin pharmacokinetics in healthy volunteers of African descent.
RESULTS: We describe a restriction fragment length polymorphism method to genotype SLCO1B1 c.1929A>C polymorphism using the restriction enzyme Ase1. A student's t test with Welch correction was used to establish association between the SLCO1B1 c.1929A>C variant and rosuvastatin exposure. The frequency of the SLCO1B1 c.1929C allele amongst Zimbabweans was 6%. The SLCO1B1 c.1929C allele was associated with a 75% reduction (P < 0.001) in rosuvastatin exposure when compared to individuals carrying the wild type SLCO1B1 c.1929A allele. Polymorphism c.1929A>C may therefore play a significant role in rosuvastatin response. The RFLP method is quick and cost effective.

PMID: 29898760 [PubMed - in process]

Preventing the exacerbation of health disparities by iatrogenic pharmacogenomic applications: lessons from warfarin.

Pharmacogenomics. 2018 Jun 14;:

Authors: Duconge J, Ruaño G

PMID: 29898627 [PubMed - as supplied by publisher]

Carbamazepine adverse drug reactions.

Expert Rev Clin Pharmacol. 2018 Jun 14;:

Authors: Fricke-Galindo I, LLerena A, Jung-Cook H, López-López M

Abstract
INTRODUCTION: Carbamazepine (CBZ) is used for the treatment of epilepsy and other neurological and psychiatric disorders. The occurrence of adverse reactions (ADRs) to CBZ can negatively impact the quality of life of patients, as well as, increase health care costs. Thus, knowledge of CBZ-induced ADRs is important to achieve safer treatment outcomes. Areas covered. This review describes the clinical features, known mechanisms, and clinical management of the main CBZ-induced ADRs. In addition, pharmacogenetic studies focused on ADRs induced by CBZ are cited. Expert commentary. CBZ-induced ADRs are well known in the literature. The metabolite CBZ-10,11-epoxide plays an important role in the mechanism that underlies the ADRs induced by CBZ. Several factors should be considered for a safer use of CBZ such as monotherapy prescription when possible, an adequate dose titration, knowledge of previous ADRs in the patient, and routine monitoring of CBZ plasma concentrations in symptomatic patients. Pharmacogenetics is a potential tool for CBZ therapy improvement, and the design of multicenter studies focused on the identification of biomarkers for CBZ-induced ADRs could provide useful information for a safer CBZ therapy.

PMID: 29898616 [PubMed - as supplied by publisher]

Airway Basal Cells Are the Key for Cystic Fibrosis Gene Therapy.

Hum Gene Ther. 2018 Jun;29(6):641-642

Authors: Flotte TR

PMID: 29902084 [PubMed - in process]

Decreased susceptibility of Streptococcus anginosus to vancomycin in a multispecies biofilm is due to increased thickness of the cell wall.

J Antimicrob Chemother. 2018 Jun 12;:

Authors: Tavernier S, Sass A, De Bruyne M, Baeke F, De Rycke R, Crabbé A, Vandecandelaere I, Van Nieuwerburgh F, Coenye T

Abstract
Background: Streptococcus anginosus, Pseudomonas aeruginosa and Staphylococcus aureus are often co-isolated from the sputum of cystic fibrosis patients. It was recently shown that S. anginosus is protected from the activity of vancomycin when it grows in a multispecies biofilm with P. aeruginosa and S. aureus.
Objectives: Elucidating the underlying cause of the reduced susceptibility of S. anginosus to vancomycin when growing in a multispecies biofilm with P. aeruginosa and S. aureus.
Methods: The transcriptome of S. anginosus growing in a multispecies biofilm was compared with that of a S. anginosus monospecies biofilm. Subsequently, transmission electron microscopy was performed to investigate changes in cell wall morphology in S. anginosus and S. aureus in response to growth in multispecies biofilm and to vancomycin treatment.
Results: S. anginosus responds to growth in a multispecies biofilm with induction of genes involved in cell envelope biogenesis. Cell walls of S. anginosus cultured in a multispecies biofilm were thicker than in a monospecies biofilm, without antibiotic challenge. S. aureus, when cultured in a multispecies biofilm, does not respond to vancomycin treatment with cell wall thickening.
Conclusions: Growth in multispecies biofilms can have an impact on the expression of genes related to cell wall synthesis and on the cell wall thickness of S. anginosus.

PMID: 29901811 [PubMed - as supplied by publisher]

The importance of data issues when comparing cystic fibrosis registry outcomes between countries: Are annual review FEV1 in the UK only collected when subjects are well?

J Eval Clin Pract. 2018 Jun 14;:

Authors: Hoo ZH, Curley R, Campbell MJ, Walters SJ, Wildman MJ

Abstract
RATIONALE, AIMS AND OBJECTIVE: Cross-country comparisons of cystic fibrosis (CF) outcomes can potentially identify variation in care but are dependent on data quality. An important assumption is that the UK annual review FEV1 is only collected during periods of clinical stability. If this assumption does not hold, results of FEV1 comparisons may be biased in favour of registries with encounter-based FEV1 . We aimed to test the assumption that CF annual reviews in the UK are only performed during periods of clinical stability.
METHOD: Prospective encounter-based data collected in Sheffield (n = 174) was used to establish whether annual review FEV1 were always collected during periods of clinical stability and to determine the group-level discrepancy between annual review vs best FEV1 . We then went on to quantify the group-level discrepancy between annual review and best annual FEV1 readings within the UK registry (n = 2995) to determine if the differences observed in Sheffield also apply to the wider UK data.
RESULTS: Sheffield results showed a group-level discrepancy between best and annual review FEV1 of -2.5% (95% CI -3.95% to -1.2%) for annual reviews performed during periods of clinical stability (n = 50). The group-level discrepancy is larger at -8.0% (95% CI -11.2% to -4.9%) among annual reviews performed during periods of clinical instability (n = 13). Therefore, the magnitude of this group-level discrepancy is a surrogate for the proportion of clinically stable annual reviews-smaller discrepancy indicates a higher proportion of clinically stable annual reviews and vice versa. The overall group-level discrepancy in the UK registry (-5.6%, 95% CI -5.9 to -5.4%) was similar to Sheffield (-6.1%, 95% CI -7.1 to -5.1%). Around 20% of the clinician reviewed, annual reviews in Sheffield were performed during periods of clinically instability.
CONCLUSIONS: Annual review FEV1 underestimates lung health of adults with CF in the UK and may bias cross-country comparisons.

PMID: 29901239 [PubMed - as supplied by publisher]

Antimicrobial effect of dimethyl sulfoxide and N, N-Dimethylformamide on Mycobacterium abscessus: Implications for antimicrobial susceptibility testing.

Int J Mycobacteriol. 2018 Apr-Jun;7(2):134-136

Authors: Kirkwood ZI, Millar BC, Downey DG, Moore JE

Abstract
Background: The emergence of antimicrobial resistance globally has initiated the discovery of novel antibiotics and other antimicrobial substances. Many of these novel compounds may be found in phytochemicals, where these novel compounds are extremely difficult to redissolve for antimicrobial susceptibility testing, following extraction. The aim of this study was to examine the potential antimicrobial effects of the common solvents, dimethyl sulfoxide (DMSO) and N, N-dimethylformamide (DMF), which are commonly employed as solvents of novel antimicrobial substances, with the nontuberculous Mycobacterium and Mycobacterium abscessus.
Methods: : M. abscessus clinical isolates (n = 17 isolates) were examined for the antimicrobial effects of DMSO and DMF. McFarland 0.5 standards of each isolate were prepared individually on Columbia Blood agar onto which DMSO and DMF were added (10 μl) in the range neat (undiluted) - 10,000-fold (10-4) dilution and incubated. Zones of inhibition were recorded in mm.
Results: : DMSO and DMF had an inhibitory effect on M. abscessus (n = 17 clinical isolates). This inhibitory effect was avoided by diluting DMSO 10-fold and DMF 10,000-fold.
Conclusion: : Such data are important when employing these common solvents with molecules which are difficult to dissolve into solution, including conventional antibiotics, as well as novel antimicrobial agents, particularly in antimicrobial susceptibility studies. Investigators should therefore be aware of this inhibition and avoid working with these solvents at high concentration to avoid bacterial growth inhibition. The use of appropriate experimental controls is highly recommended in such circumstances to avoid the reporting of false-positive antimicrobial effects.

PMID: 29900888 [PubMed - in process]

Mycobacterium abscessus complex: Natural history and treatment outcomes at a tertiary adult cystic fibrosis center.

Int J Mycobacteriol. 2018 Apr-Jun;7(2):109-116

Authors: Tippett E, Ellis S, Wilson J, Kotsimbos T, Spelman D

Abstract
Background: Mycobacterium abscessus complex (MAbsC) is a significant management dilemma when taking care of patients with cystic fibrosis (CF).
Methods: We undertook a retrospective cohort analysis of all CF patients in whom MAbsC was isolated from 2005 to 2014. The natural history of MAbsC was determined and clinical factors examined in an attempt to predict transient compared to persistent colonization.
Results: No correlation was found between recurrent MAbsC isolation and clinical factors such as body mass index, respiratory function, or age. Over two-thirds of our cohort cleared MAbsC colonization with no intervention and no consistent effect on lung function was identified. Four CF patients were initiated on treatment with only one successful outcome.
Conclusion: This analysis demonstrates there are no clear predictors of those CF patients who will become persistently colonized with MAbsC and that a significant proportion will spontaneously clear carriage. As treatment success rate is poor, more work is urgently required in improving patient outcomes.

PMID: 29900884 [PubMed - in process]

Acute effects of combined exercise and oscillatory positive expiratory pressure therapy on sputum properties and lung diffusing capacity in cystic fibrosis: a randomized, controlled, crossover trial.

BMC Pulm Med. 2018 Jun 14;18(1):99

Authors: Radtke T, Böni L, Bohnacker P, Maggi-Beba M, Fischer P, Kriemler S, Benden C, Dressel H

Abstract
BACKGROUND: Regular airway clearance by chest physiotherapy and/or exercise is critical to lung health in cystic fibrosis (CF). Combination of cycling exercise and chest physiotherapy using the Flutter® device on sputum properties has not yet been investigated.
METHODS: This prospective, randomized crossover study compared a single bout of continuous cycling exercise at moderate intensity (experiment A, control condition) vs a combination of interval cycling exercise plus Flutter® (experiment B). Sputum properties (viscoelasticity, yield stress, solids content, spinnability, and ease of sputum expectoration), pulmonary diffusing capacity for nitric oxide (DLNO) and carbon monoxide (DLCO) were assessed at rest, directly and 45 min post-exercise (recovery) at 2 consecutive visits. Primary outcome was change in sputum viscoelasticity (G', storage modulus; G", loss modulus) over a broad frequency range (0.1-100 rad.s- 1).
RESULTS: 15 adults with CF (FEV1range 24-94% predicted) completed all experiments. No consistent differences between experiments were observed for G' and G" and other sputum properties, except for ease of sputum expectoration during recovery favoring experiment A. DLNO, DLCO, alveolar volume (VA) and pulmonary capillary blood volume (Vcap) increased during experiment A, while DLCO and Vcap increased during experiment B (all P < 0.05). We found no differences in absolute changes in pulmonary diffusing capacity and its components between experiments, except a higher VA immediately post-exercise favoring experiment A (P = 0.032).
CONCLUSIONS: The additional use of the Flutter® to moderate intensity interval cycling exercise has no measurable effect on the viscoelastic properties of sputum compared to moderate intensity continuous cycling alone. Elevations in diffusing capacity represent an acute exercise-induced effect not sustained post-exercise.
TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT02750722 ; URL: clinical.trials.gov; Registration date: April 25th, 2016.

PMID: 29898704 [PubMed - in process]

A novel deletion downstream of the PAX6 gene identified in a Chinese family with congenital aniridia.

Ophthalmic Genet. 2018 Jun 14;:1-9

Authors: Liu X, Wu Y, Miao Z, Zhang H, Gong B, Zhu X, Huang L, Shi Y, Hao F, Ma S, Lin H, Wang L, Yang Z

Abstract
PURPOSE: Congenital aniridia, a severe bilateral panocular visual disorder, is an autosomal dominantly inherited eye anomaly. Mutations in the paired box 6 gene (PAX6) have been shown to be responsible for congenital aniridia in most patients. The purpose of the present study was to report clinical features of a Chinese family with congenital aniridia and to screen novel genetic mutations for congenital aniridia.
METHODS: All members of a three-generation family underwent comprehensive ophthalmic examination, and 8 of its 25 members were diagnosed with congenital aniridia. The proband was analyzed by exome sequencing and whole genome sequencing, and linkage analysis was performed for the family. The mutation was confirmed by direct DNA sequencing.
RESULTS: Using Illumina's Human Linkage-12 beadchip microarray (including 6090 SNPs) whole genome scan, the LOD score value showed that the interval on chromosome 11 between rs1389423 to rs910090 exhibited a strong linkage. A novel heterozygous 469 kb deletion mutation within the downstream region of PAX6 (chr11:31189937-31659379) was identified in all affected family members, but not in unaffected family members or 2000 ethnically matched controls.
CONCLUSION: A novel deletion mutation was identified within the PAX6 downstream region that results in congenital aniridia.

PMID: 29902091 [PubMed - as supplied by publisher]

Novel intra-genic large deletions of CTNNB1 gene identified in WT desmoid-type fibromatosis.

Genes Chromosomes Cancer. 2018 Jun 14;:

Authors: Colombo C, Urbini M, Astolfi A, Collini P, Indio V, Belfiore A, Paielli N, Perrone F, Tarantino G, Palassini E, Fiore M, Pession A, Stacchiotti S, Pantaleo MA, Gronchi A

Abstract
A wait and see approach for desmoid tumors (DT) has become part of the routine treatment strategy. However, predictive factors to select the risk of progressive disease are still lacking. A translational project was run in order to identify genomic signatures in patients enrolled within an Italian prospective observational study. Among 12 DT patients (ten CTNNB1-mutated and two WT) enrolled from our Institution only two patients (17%) showed a progressive disease. Tumor biopsies were collected for whole exome sequencing. Overall, DT exhibited low somatic sequence mutation rate and no additional recurrent mutation was found. In the two WT cases, two novel alterations were detected: a complex deletion of APC and a pathogenic mutation of LAMTOR2. Focusing on WT DT subtype, deep sequencing of CTNNB1, APC and LAMTOR2 was conducted on a retrospective series of 11 WT DT using a targeted approach. No other mutation of LAMTOR2 was detected, while APC was mutated in two cases. Low-frequency (mean reads of 16%) CTNNB1 mutations were discovered in five samples (45%) and two novel intra-genic deletions in CTNNB1 were detected in two cases. Both deletions and low frequency mutations of CTNNB1 were highly expressed. In conclusion, a minority of DT is WT for either CTNNB1, APC or any other gene involved in the WNT pathway. In this subgroup novel and hard to be detected molecular alterations in APC and CTNNB1 were discovered, contributing to explain a portion of the allegedly WT DT cases. This article is protected by copyright. All rights reserved.

PMID: 29901254 [PubMed - as supplied by publisher]

Targeted resequencing of phosphorus metabolism‑related genes in 86 patients with hypophosphatemic rickets/osteomalacia.

Int J Mol Med. 2018 Jun 13;:

Authors: Gu J, Wang C, Zhang H, Yue H, Hu W, He J, Fu W, Zhang Z

Abstract
Hypophosphatemic rickets/osteomalacia is characterized by defective renal phosphate reabsorption and abnormal bone mineralization. Hypophosphatemic rickets/osteomalacia consists of inherited and acquired forms, many of which have unknown aetiology. In the present study, next‑generation sequencing‑based resequencing was used on samples from Chinese subjects with hypophosphatemic rickets/osteomalacia, aiming to detect the spectrum of pathogenic genes in these patients. A total of 86 hypophosphatemic rickets/osteomalacia patients (ranging from 3 to 70 years old) were recruited. Patients with tumour‑induced osteomalacia (TIO), renal tubular acidosis, renal osteodystrophy, and adefovir‑induced Fanconi syndrome were excluded. Targeted massively parallel resequencing of 196 candidate genes for hypophosphatemic rickets/osteomalacia was performed in the 86 affected unrelated individuals (cases) and in 100 unrelated healthy controls to identify new genes and mutations in known genes that cause hypophosphatemic rickets/osteomalacia. The results identified seven phosphate‑regulating gene with homologies to endopeptidases on the X chromosome (PHEX) mutations (of which two were novel) and one novel dentin matrix protein 1 (DMP1) mutation in eight patients. Following targeted exome sequencing data analysis, 14 candidate disease‑related gene loci were selected, two of which were of most concern regarding disease severity. Further validation of the present results is warranted, with additional sequencing projects and functional tests. To our knowledge, the present study is the largest cohort of cases with hypophosphatemic rickets/osteomalacia to undergo targeted resequencing. The diagnosis and understanding of the molecular aetiologies of these disorders will be improved by this fast and efficient approach.

PMID: 29901142 [PubMed - as supplied by publisher]

Novel HSPG2 mutations causing Schwartz‑Jampel syndrome type 1 in a Chinese family: A case report.

Mol Med Rep. 2018 Jun 06;:

Authors: Yan W, Dai J, Shi D, Xu X, Han X, Xu Z, Chen D, Teng H, Jiang Q

Abstract
Schwartz-Jampel syndrome type 1 (SJS1) is a rare autosomal recessive disease caused by mutations in the gene heparan sulfate proteoglycan 2 (HSPG2; also known as basement membrane‑specific heparin sulfate). In the present study, a 10‑year‑old female SJS1 proband from a Chinese family, who was diagnosed by X‑ray and physical examination, was recruited. The key clinical features of the patient with SJS1 included short stature, joint contractures, pigeon breast, and myotonia that led to progressive stiffness of the face and limbs; barely discernible kyphosis was also noted. Genetic testing using whole exome sequencing and Sanger sequencing was performed for the proband and family members. A total of 2 novel mutations (c.8788G>A; p.Glu2930Lys and c.11671+5G>A) in the HSPG2 gene were identified in the proband. The family members harboring 1 heterozygous mutation in HSPG2 did not exhibit any skeletal abnormalities. The results of the present study suggested that the compound heterozygous mutations in HSPG2 may be responsible the induction of SJS1, and demonstrated the genotype‑phenotype associations between mutations in the HSPG2 gene and clinical characteristics of SJS1.

PMID: 29901129 [PubMed - as supplied by publisher]

Developmental epileptic encephalopathy with hypomyelination and brain atrophy associated with PTPN23 variants affecting the assembly of UsnRNPs.

Eur J Hum Genet. 2018 Jun 13;:

Authors: Smigiel R, Landsberg G, Schilling M, Rydzanicz M, Pollak A, Walczak A, Stodolak A, Stawinski P, Mierzewska H, Sasiadek MM, Gruss OJ, Ploski R

Abstract
PTPN23 encodes a ubiquitously expressed non-receptor type, catalytically inactive protein-tyrosine phosphatase found in all cells including neurons. Recently, we have identified PTPN23 in a cellular screen for the systematic identification of novel regulators of survival motor neuron (SMN) function in the assembly of splicing factors (Uridine-rich small nuclear ribonucleoproteins, UsnRNPs). Based on three families, recessive PTPN23 variants have been associated with human disease tentatively, without functional studies. Here, we describe a pediatric proband with severe developmental delay, epilepsy, cortical blindness, hypomyelination and brain atrophy on MRI. Whole exome sequencing and family study showed two novel PTPN23 variants, c.1902C>G (p.(Asn634Lys)) and c.2974delC (p.(Leu992Tyrfs*168)), in compound heterozygous state, which are predicted in silico to be damaging. When studying patient's fibroblasts we found similar expression of SMN but a dramatic reduction of cells displaying SMN accumulation in Cajal bodies (CB). SMN strongly accumulated in CB in more than 50% of unrelated control cell fibroblasts as well as in fibroblasts from the parent carrying only the c.2974delC (p.(Leu992Tyrfs*168)) variant (predicted to cause loss-of-function). In contrast, only 22% of cells showed respective SMN accumulations in patient fibroblasts (p = 1.9-2.5 × 10-7) while showing a higher level of nucleoplasmic SMN. Furthermore, the remaining accumulations in patient cells displayed weaker SMN signals than control or heterozygous wt/c.2974delC (p.(Leu992Tyrfs*168)) fibroblasts. Our report provides the first description of the clinical phenotype of recessive PTPN23 variants with pathogenicity substantiated by a functional study.

PMID: 29899372 [PubMed - as supplied by publisher]

Calculating the statistical significance of rare variants causal for Mendelian and complex disorders.

BMC Med Genomics. 2018 Jun 13;11(1):53

Authors: Rao AR, Nelson SF

Abstract
BACKGROUND: With the expanding use of next-gen sequencing (NGS) to diagnose the thousands of rare Mendelian genetic diseases, it is critical to be able to interpret individual DNA variation. To calculate the significance of finding a rare protein-altering variant in a given gene, one must know the frequency of seeing a variant in the general population that is at least as damaging as the variant in question.
METHODS: We developed a general method to better interpret the likelihood that a rare variant is disease causing if observed in a given gene or genic region mapping to a described protein domain, using genome-wide information from a large control sample. Based on data from 2504 individuals in the 1000 Genomes Project dataset, we calculated the number of individuals who have a rare variant in a given gene for numerous filtering threshold scenarios, which may be used for calculating the significance of an observed rare variant being causal for disease. Additionally, we calculated mutational burden data on the number of individuals with rare variants in genic regions mapping to protein domains.
RESULTS: We describe methods to use the mutational burden data for calculating the significance of observing rare variants in a given proportion of sequenced individuals. We present SORVA, an implementation of these methods as a web tool, and we demonstrate application to 20 relevant but diverse next-gen sequencing studies. Specifically, we calculate the statistical significance of findings involving multi-family studies with rare Mendelian disease and a large-scale study of a complex disorder, autism spectrum disorder. If we use the frequency counts to rank genes based on intolerance for variation, the ranking correlates well with pLI scores derived from the Exome Aggregation Consortium (ExAC) dataset (ρ = 0.515), with the benefit that the scores are directly interpretable.
CONCLUSIONS: We have presented a strategy that is useful for vetting candidate genes from NGS studies and allows researchers to calculate the significance of seeing a variant in a given gene or protein domain. This approach is an important step towards developing a quantitative, statistics-based approach for presenting clinical findings.

PMID: 29898714 [PubMed - in process]

Novel Aberrations Uncovered in Barrett's Esophagus and Esophageal Adenocarcinoma Using Whole Transcriptome Sequencing.

Mol Cancer Res. 2017 Nov;15(11):1558-1569

Authors: Maag JLV, Fisher OM, Levert-Mignon A, Kaczorowski DC, Thomas ML, Hussey DJ, Watson DI, Wettstein A, Bobryshev YV, Edwards M, Dinger ME, Lord RV

Abstract
Esophageal adenocarcinoma (EAC) has one of the fastest increases in incidence of any cancer, along with poor five-year survival rates. Barrett's esophagus (BE) is the main risk factor for EAC; however, the mechanisms driving EAC development remain poorly understood. Here, transcriptomic profiling was performed using RNA-sequencing (RNA-seq) on premalignant and malignant Barrett's tissues to better understand this disease. Machine-learning and network analysis methods were applied to discover novel driver genes for EAC development. Identified gene expression signatures for the distinction of EAC from BE were validated in separate datasets. An extensive analysis of the noncoding RNA (ncRNA) landscape was performed to determine the involvement of novel transcriptomic elements in Barrett's disease and EAC. Finally, transcriptomic mutational investigation of genes that are recurrently mutated in EAC was performed. Through these approaches, novel driver genes were discovered for EAC, which involved key cell cycle and DNA repair genes, such as BRCA1 and PRKDC. A novel 4-gene signature (CTSL, COL17A1, KLF4, and E2F3) was identified, externally validated, and shown to provide excellent distinction of EAC from BE. Furthermore, expression changes were observed in 685 long noncoding RNAs (lncRNA) and a systematic dysregulation of repeat elements across different stages of Barrett's disease, with wide-ranging downregulation of Alu elements in EAC. Mutational investigation revealed distinct pathways activated between EAC tissues with or without TP53 mutations compared with Barrett's disease. In summary, transcriptome sequencing revealed altered expression of numerous novel elements, processes, and networks in EAC and premalignant BE.Implications: This study identified opportunities to improve early detection and treatment of patients with BE and esophageal adenocarcinoma. Mol Cancer Res; 15(11); 1558-69. ©2017 AACR.

PMID: 28751461 [PubMed - indexed for MEDLINE]

Safety and Efficacy of Budesonide Oral Suspension Maintenance Therapy in Patients With Eosinophilic Esophagitis.

Clin Gastroenterol Hepatol. 2018 Jun 11;:

Authors: Dellon ES, Katzka DA, Collins MH, Gupta SK, Lan L, Williams J, Hirano I

Abstract
BACKGROUND & AIMS: We aimed to determine the safety and efficacy of budesonide oral suspension (BOS) maintenance therapy in patients with eosinophilic esophagitis (EoE).
METHODS: We performed an open-label extension study of a 12-week, multicenter, randomized, double-blind, placebo-controlled trial. Patients with EoE (11-40 years old) who completed double-blind BOS (n=45) or placebo therapy (n=37) received 24 weeks' open-label BOS (2.0 mg once daily for 12 weeks, with optional dose increase [1.5-2.0 mg twice daily] for 12 weeks thereafter). Predefined efficacy outcomes included: proportion of patients with a histologic response (≤6 eosinophils/high-power field [eos/hpf]) and change in mean peak eosinophil counts after 24 weeks. Analyses were stratified by patients who received placebo (placebo/BOS) or BOS (BOS/BOS) during the double-blind trial.
RESULTS: BOS was well tolerated and drug-related adverse events were uncommon (placebo/BOS, 19% [7/37]; BOS/BOS, 4% [2/45]). Incidence of oral candidiasis (1 per group) and esophageal candidiasis (placebo/BOS group, n=4) remained low. Changes in morning serum cortisol levels were not clinically relevant. A histologic response was observed in 49% (16/33) of patients receiving placebo/BOS and 23% (9/39) receiving BOS/BOS. Mean peak eosinophil counts (baseline vs week 24 or early termination) were: placebo/BOS, 118.8 vs 29.1; P<.001 and BOS/BOS, 38.1 vs 72.4; P=.01. Of the patients who responded to double-blind therapy, 42% maintained a histologic response during the open-label extension; 4% of non-responders gained response.
CONCLUSIONS: In an open-label extension study of patients with EoE, BOS was well tolerated and drug-related adverse events were uncommon. BOS maintained a histologic response in some initial responders but few initial non-responders had a response. ClinicalTrials.gov no: NCT01642212.

PMID: 29902649 [PubMed - as supplied by publisher]

Assessing Drug Safety in Children - The Role of Real-World Data.

N Engl J Med. 2018 Jun 07;378(23):2155-2157

Authors: McMahon AW, Dal Pan G

PMID: 29874532 [PubMed - indexed for MEDLINE]

Randomized, Double-Blind, Placebo- and Active Comparator-Controlled Crossover Study Evaluating the Abuse Potential of the Antiepileptic Drug Lacosamide in Healthy Recreational Drug Users.

J Clin Psychopharmacol. 2017 Dec;37(6):675-683

Authors: Schoedel KA, Andreas JO, Doty P, Eckhardt K, Sellers EM

Abstract
PURPOSE: This phase 1, randomized, double-blind, placebo- and active comparator-controlled crossover study assessed the abuse potential of the antiepileptic drug, lacosamide.
METHODS: After a qualification phase, 38 healthy, recreational central nervous system-depressant users were randomized to treatment sequences comprising single oral therapeutic (200 mg) and supratherapeutic (800 mg) doses of lacosamide, alprazolam (1.5 and 3 mg), and placebo. Subjective effects were assessed for 24 hours following each dose using a range of scales, with a 5- to 9-day washout between treatments.
FINDINGS: Mean subjective effects for 200 mg lacosamide were statistically similar to placebo and significantly lower than with alprazolam for most end points. Lacosamide 800 mg elicited transient, statistically significant positive effects compared with placebo, but also persistent Bad Drug Effects including statistically greater maximum effect (Emax) scores for Nausea and Dysphoria compared with other treatments (P < 0.0002). Consistent with this, the 800 mg lacosamide dose showed a significantly lower "at this moment" Drug Liking visual analog scale (VAS) Emax compared with 3 mg alprazolam, but was not different from 1.5 mg alprazolam (73.1/100, 85.4/100, and 78.9/100, respectively, where 50 is neutral). Overall Drug Liking VAS and Take Drug Again VAS Emax for 800 mg lacosamide were not significantly different from placebo and were lower than those for both alprazolam doses (P < 0.0001).
IMPLICATIONS: These results suggest that in recreational central nervous system-depressant users, lacosamide has detectable abuse-related subjective effects, but a relatively low potential for abuse compared with alprazolam. These findings contributed toward placement of lacosamide into Schedule V of the US Controlled Substances Act.

PMID: 28926353 [PubMed - indexed for MEDLINE]