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"systems biology"

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Correction to: Realizing drug repositioning by adapting a recommendation system to handle the process.

BMC Bioinformatics. 2018 Jul 02;19(1):250

Authors: Ozsoy MG, Özyer T, Polat F, Alhajj R

Abstract
Following publication of the original article [1], the authors reported that there was an error in the spelling of the name of one of the authors.

PMID: 29966513 [PubMed - in process]

Inhibition of Fosfomycin Resistance Protein FosA by Phosphonoformate (Foscarnet) in Multidrug-Resistant Gram-Negative Pathogens.

Antimicrob Agents Chemother. 2017 Dec;61(12):

Authors: Ito R, Tomich AD, McElheny CL, Mettus RT, Sluis-Cremer N, Doi Y

Abstract
FosA proteins confer fosfomycin resistance to Gram-negative pathogens via glutathione-mediated modification of the antibiotic. In this study, we assessed whether inhibition of FosA by sodium phosphonoformate (PPF) (foscarnet), a clinically approved antiviral agent, would reverse fosfomycin resistance in representative Gram-negative pathogens. The inhibitory activity of PPF against purified recombinant FosA from Escherichia coli (FosA3), Klebsiella pneumoniae (FosAKP), Enterobacter cloacae (FosAEC), and Pseudomonas aeruginosa (FosAPA) was determined by steady-state kinetic measurements. The antibacterial activity of PPF against FosA in clinical strains of these species was evaluated by susceptibility testing and time-kill assays. PPF increased the Michaelis constant (Km ) for fosfomycin in a dose-dependent manner, without affecting the maximum rate (Vmax) of the reaction, for all four FosA enzymes tested, indicating a competitive mechanism of inhibition. Inhibitory constant (Ki ) values were 22.6, 35.8, 24.4, and 56.3 μM for FosAKP, FosAEC, FosAPA, and FosA3, respectively. Addition of clinically achievable concentrations of PPF (∼667 μM) reduced the fosfomycin MICs by ≥4-fold among 52% of the K. pneumoniae, E. cloacae, and P. aeruginosa clinical strains tested and led to a bacteriostatic or bactericidal effect in time-kill assays among representative strains. PPF inhibits FosA activity across Gram-negative species and can potentiate fosfomycin activity against the majority of strains with chromosomally encoded fosA These data suggest that PPF may be repurposed as an adjuvant for fosfomycin to treat infections caused by some FosA-producing, multidrug-resistant, Gram-negative pathogens.

PMID: 28993329 [PubMed - indexed for MEDLINE]

Metformin inhibits Branched Chain Amino Acid (BCAA) derived ketoacidosis and promotes metabolic homeostasis in MSUD.

Sci Rep. 2016 07 04;6:28775

Authors: S Sonnet D, N O'Leary M, A Gutierrez M, M Nguyen S, Mateen S, Hsu Y, P Mitchell K, J Lopez A, Vockley J, K Kennedy B, Ramanathan A

Abstract
Maple Syrup Urine Disease (MSUD) is an inherited disorder caused by the dysfunction in the branched chain keto-acid dehydrogenase (BCKDH) enzyme. This leads to buildup of branched-chain keto-acids (BCKA) and branched-chain amino acids (BCAA) in body fluids (e.g. keto-isocaproic acid from the BCAA leucine), leading to numerous clinical features including a less understood skeletal muscle dysfunction in patients. KIC is an inhibitor of mitochondrial function at disease relevant concentrations. A murine model of intermediate MSUD (iMSUD) shows significant skeletal muscle dysfunction as by judged decreased muscle fiber diameter. MSUD is an orphan disease with a need for novel drug interventions. Here using a 96-well plate (liquid chromatography- mass spectrometry (LC-MS) based drug-screening platform we show that Metformin, a widely used anti-diabetic drug, reduces levels of KIC in patient-derived fibroblasts by 20-50%. This Metformin-mediated effect was conserved in vivo; Metformin-treatment significantly reduced levels of KIC in the muscle (by 69%) and serum (by 56%) isolated from iMSUD mice, and restored levels of mitochondrial metabolites (e.g. AMP and other TCA). The drug also decreased the expression of mitochondrial branched chain amino transferase (BCAT) which produces KIC in skeletal muscle. This suggests that Metformin can restore skeletal muscle homeostasis in MSUD by decreasing mitochondrial KIC production.

PMID: 27373929 [PubMed - indexed for MEDLINE]

G-protein receptor kinases 2, 5 and 6 redundantly modulate Smoothened-GATA transcriptional crosstalk in fetal mouse hearts.

J Mol Cell Cardiol. 2018 Jun 30;:

Authors: Franco A, Zhang L, Matkovich SJ, Kovacs A, Dorn GW

Abstract
G-protein receptor kinases (GRKs) regulate adult hearts by modulating inotropic, chronotropic and hypertrophic signaling of 7-transmembrane spanning neurohormone receptors. GRK-mediated desensitization and downregulation of β-adrenergic receptors has been implicated in adult heart failure; GRKs are therefore a promising therapeutic target. However, germ-line (but not cardiomyocyte-specific) GRK2 deletion provoked lethal fetal heart defects, suggesting an unexplained role for GRKs in heart development. Here we undertook to better understand the consequences of GRK deficiency on fetal heart development by creating mice and cultured murine embryonic fibroblasts (MEFs) having floxed GRK2 and GRK5 alleles on the GRK6 null background; simultaneous conditional deletion of these 3 GRK genes was achieved using Nkx2-5 Cre or adenoviral Cre, respectively. Phenotypes were related to GRK-modulated gene expression using whole-transcriptome RNA sequencing, RT-qPCR, and luciferase reporter assays. In cultured MEFs the atypical 7-transmembrane spanning protein and GRK2 substrate Smoothened (Smo) stimulated Gli-mediated transcriptional activity, which was interrupted by deleting GRK2/5/6. Mice with Nkx2-5 Cre mediated GRK2/5/6 ablation died between E15.5 and E16.5, whereas mice expressing any one of these 3 GRKs (i.e. GRK2/5, GRK2/6 or GRK5/6 deleted) were developmentally normal. GRK2/5/6 triple null mice at E14.5 exhibited left and right heart blood intermixing through single atrioventricular valves or large membranous ventricular septal defects. Hedgehog and GATA pathway gene expression promoted by Smo/Gli was suppressed in GRK2/5/6 deficient fetal hearts and MEFs. These data indicate that GRK2, GRK5 and GRK6 redundantly modulate Smo-GATA crosstalk in fetal mouse hearts, orchestrating transcriptional pathways previously linked to clinical and experimental atrioventricular canal defects. GRK modulation of Smo reflects convergence of conventional neurohormonal signaling and transcriptional regulation pathways, comprising an unanticipated mechanism for spatiotemporal orchestration of developmental gene expression in the heart.

PMID: 29969579 [PubMed - as supplied by publisher]

Pharmacogenomics, a novel section in the European Journal of Human Genetics.

Eur J Hum Genet. 2018 Jul 02;:

Authors: Guchelaar HJ

PMID: 29967335 [PubMed - as supplied by publisher]

Use of French healthcare insurance databases in pediatric pharmacoepidemiology.

Therapie. 2018 Apr;73(2):127-133

Authors: Kaguelidou F, Sommet A, Lapeyre-Mestre M

Abstract
The French healthcare insurance databases have proven to be valuable tools for the conduct of pharmaco-epidemiological studies with regards to the size of the population covered and that of the available information. Their wider use in the field of pediatric pharmacoepidemiology is of paramount importance given the existing gap of knowledge in the use and effects of many drugs in children and adolescents as well as the difficulties to conduct clinical research studies in this age population. However, because of the architectural complexity of these databases and their specificities, specific expertise should be developed in order to ensure the reliability of studies based on these data. To this purpose, it is important to facilitate knowledge sharing through national collaborative projects.

PMID: 29588074 [PubMed - indexed for MEDLINE]

Study of the link between dopamine transporter gene polymorphisms and response to paroxetin and escitalopram in patients with lifelong premature ejaculation.

Int J Impot Res. 2017 Nov;29(6):235-239

Authors: Eltonsi TK, Tawfik TM, Rashed LA, GamalEl Din SF, Mahmoud MA

Abstract
We evaluated the role of dopamine (DA) transporter gene polymorphism in lifelong premature ejaculation (LPE) and its role in determining the response to paroxetine and escitalopram. Eighty consecutive patients and controls were recruited. Sixty of them suffered from LPE. They were divided into two equal groups. One group received paroxetine 20 mg daily for 3 months and the other one received ecistalopram 20 mg daily for 3 months. Their wives were instructed to measure the intra-vaginal ejaculation latency time using stopwatch. Five milliliters of blood was withdrawn from patients and controls for PCR analysis. The present study revealed that the mean ages of the patients and controls were 41.42 and 36.4 years, respectively. The majority of the patients were of (10R/10R) genotypes of the DA transporter gene polymorphism, whereas the controls were of (6R/6R) genotypes and this revealed statistically significant result (P-value=0.001). Both paroxitine and escitalopram significantly delayed ejaculation in the responders (P-values=0.001 and 0.001, respectively). The study revealed significant association between such response and DA transporter gene polymorphism (P-values of fold increase and log FI were 0.019 and 0.010, respectively). To the best of our knowledge, this is the first report to demonstrate a highly significant association between such response and DA transporter gene polymorphism in patients with LPE.

PMID: 28904397 [PubMed - indexed for MEDLINE]

Bioinformatic Analysis of Plasma Apolipoproteins A-I and A-II Revealed Unique Features of A-I/A-II HDL Particles in Human Plasma.

Sci Rep. 2016 08 16;6:31532

Authors: Kido T, Kurata H, Kondo K, Itakura H, Okazaki M, Urata T, Yokoyama S

Abstract
Plasma concentration of apoA-I, apoA-II and apoA-II-unassociated apoA-I was analyzed in 314 Japanese subjects (177 males and 137 females), including one (male) homozygote and 37 (20 males and 17 females) heterozygotes of genetic CETP deficiency. ApoA-I unassociated with apoA-II markedly and linearly increased with HDL-cholesterol, while apoA-II increased only very slightly and the ratio of apoA-II-associated apoA-I to apoA-II stayed constant at 2 in molar ratio throughout the increase of HDL-cholesterol, among the wild type and heterozygous CETP deficiency. Thus, overall HDL concentration almost exclusively depends on HDL with apoA-I without apoA-II (LpAI) while concentration of HDL containing apoA-I and apoA-II (LpAI:AII) is constant having a fixed molar ratio of 2 : 1 regardless of total HDL and apoA-I concentration. Distribution of apoA-I between LpAI and LpAI:AII is consistent with a model of statistical partitioning regardless of sex and CETP genotype. The analysis also indicated that LpA-I accommodates on average 4 apoA-I molecules and has a clearance rate indistinguishable from LpAI:AII. Independent evidence indicated LpAI:A-II has a diameter 20% smaller than LpAI, consistent with a model having two apoA-I and one apoA-II. The functional contribution of these particles is to be investigated.

PMID: 27526664 [PubMed - indexed for MEDLINE]

Evaluation of food allergy candidate loci in the Genetics of Food Allergy Study.

J Allergy Clin Immunol. 2018 Jun 30;:

Authors: Marenholz I, Grosche S, Rüschendorf F, Kalb B, Blumchen K, Schlags R, Harandi N, Price M, Hansen G, Seidenberg J, Yürek S, Homuth G, Schmidt CO, Nöthen MM, Hubner N, Niggemann B, Beyer K, Lee YA

Abstract
A recent genome-wide association study suggested novel candidate loci for food allergy. Apart from the established locus at 11q13, these revealed no association with food allergy in the Genetics Of Food Allergy Study.

PMID: 29969633 [PubMed - as supplied by publisher]

Intergenic evolution during host adaptation increases expression of the metallophore pseudopaline in Pseudomonas aeruginosa.

Microbiology. 2018 Jul 03;:

Authors: Hermansen GMM, Hansen ML, Khademi SMH, Jelsbak L

Abstract
Regulating intracellular levels of biological metal ions is essential for all bacterial species, as they are needed for virulence and a range of metabolic processes. Zinc is the second most abundant metal ion in Pseudomonas aeruginosa, but little is known about its regulation. Recent studies have identified a novel operon, zrmABCD (also called cntOLMI), encoding a metallophore system (pseudopaline) involved in zinc acquisition. Expression of this operon has been implicated in human infections and is regulated by the transcriptional regulator Zur (Zn2+ uptake regulator). In this study, we show that the intergenic promoter region in front of zrmABCD is a target for recurrent adaptive mutations during chronic infection of cystic fibrosis (CF) patients. We characterize the inter- and intraclonal sequence polymorphisms found in the promoter region of the metallophore system and find that most alterations increase promoter activity. One of the evolved promoters displays a more than 10-fold increase compared to the ancestral strain due to the combined effect of an altered binding site of Zur and changes to the RpoD-binding motif. This specific evolved promoter responds differently to changes in metal ion concentrations in chelated medium. We have previously shown that P. aeruginosa evolves toward iron acquisition from haemoglobin during long-term CF infections. We hereby provide the second example of adaptive mutations targeting intergenic regions that affect metal ion uptake systems during CF infections, and the first involving zinc uptake. Our results suggest that the scarcity of metal ions (including iron and zinc) is an important evolutionary driver in CF host adaptation.

PMID: 29969091 [PubMed - as supplied by publisher]

Metabolomic Analysis by Nuclear Magnetic Resonance Spectroscopy as a New Approach to Understanding Inflammation and Monitoring of Pharmacological Therapy in Children and Young Adults With Cystic Fibrosis.

Front Pharmacol. 2018;9:595

Authors: Montuschi P, Lucidi V, Paris D, Montemitro E, Shohreh R, Mores N, Melck D, Santini G, Majo F, Motta A

Abstract
15-F2t-Isoprostane, a reliable biomarker of oxidative stress, has been found elevated in exhaled breath condensate (EBC), a non-invasive technique for sampling of airway secretions, in patients with cystic fibrosis (CF). Azithromycin has antioxidant properties in experimental models of CF, but its effects on oxidative stress in CF patients are largely unknown. Primary objective of this pilot, proof-of-concept, prospective, parallel group, pharmacological study, was investigating the potential antioxidant effects of azithromycin in CF patients as reflected by EBC 15-F2t-isoprostane. Secondary objectives included studying the effect of azithromycin on EBC and serum metabolic profiles, and on serum 15-F2t-isoprostane. In CF patients who were on maintenance treatment with oral vitamin E (200 UI once daily), treatment with oral azithromycin (250 or 500 mg depending on body weight) plus vitamin E (400 UI once daily) (group A) (n = 24) or oral vitamin E alone (400 UI once daily) (group B) (n = 21) was not associated with changes in EBC 15-F2t-isoprostane concentrations compared with baseline values after 8-weeks treatment or 2 weeks after treatment suspension. There was no between-group difference in post-treatment EBC 15-F2t-isoprostane. Likewise, no within- or between-group differences in serum 15-F2t-isoprostane concentrations were observed in either study group. NMR spectroscopy-based metabolomics of EBC shows that suspension of both azithromycin plus vitamin E and vitamin E alone has a striking effect on metabolic profiles in EBC. Between-group comparisons show that EBC metabolite distribution after treatment and 2 weeks after treatment suspension is different. Quantitative differences in ethanol, saturated fatty acids, acetate, acetoin/acetone, and methanol are responsible for these differences. Our study was unable to show antioxidant effect of azithromycin as add-on treatment with doubling the dose of oral vitamin E as reflected by 15-F2t-isoprostane concentrations in EBC. Add-on therapy with azithromycin itself does not induce EBC metabolite changes, but its suspension is associated with EBC metabolic profiles that are different from those observed after vitamin E suspension. The pathophysiological and therapeutic implications of these findings in patients with stable CF are unknown and require further research. Preliminary data suggest that EBC NMR-based metabolomics might be used for assessing the effects of pharmacological treatment suspension in stable CF patients.

PMID: 29967580 [PubMed]

Broad-spectrum adaptive antibiotic resistance associated with Pseudomonas aeruginosa mucin-dependent surfing motility.

Antimicrob Agents Chemother. 2018 Jul 02;:

Authors: Sun E, Gill EE, Falsafi R, Yeung A, Liu S, Hancock REW

Abstract
Surfing motility is a novel form of surface adaptation exhibited by the nosocomial pathogen, Pseudomonas aeruginosa, in the presence of the glycoprotein mucin that is found in high abundance at mucosal surfaces especially the lungs of cystic fibrosis and bronchiectasis patients. Here we investigated the adaptive antibiotic resistance of P. aeruginosa under conditions in which surfing occurs compared to cells undergoing swimming. P. aeruginosa surfing cells were significantly more resistant to several classes of antibiotics including aminoglycosides, carbapenems, polymyxins, and fluroquinolones. This was confirmed by incorporation of antibiotics into growth medium, which revealed a concentration-dependent inhibition of surfing motility that occurred at concentrations much higher than those needed to inhibit swimming. To investigate the basis of resistance, RNA-Seq was performed and revealed that surfing influenced the expression of numerous genes. Included amongst genes dysregulated under surfing conditions were multiple genes from the Pseudomonas resistome, which are known to affect antibiotic resistance when mutated. Screening transposon mutants in these surfing-dysregulated resistome genes revealed that several of these mutants exhibited changes in susceptibility to one or more antibiotics under surfing conditions, consistent with a contribution to the observed adaptive resistance. In particular, several mutants in resistome genes, including armR, recG, atpB, clpS, nuoB, and certain hypothetical genes such as PA5130, PA3576 and PA4292, showed contributions to broad-spectrum resistance under surfing conditions and could be complemented by their respective cloned genes. Therefore, we propose that surfing adaption led to extensive multidrug adaptive resistance as a result of the collective dysregulation of diverse genes.

PMID: 29967020 [PubMed - as supplied by publisher]

Collagen degradation and formation are elevated in exacerbated COPD compared to stable disease.

Chest. 2018 Jun 29;:

Authors: Schumann DM, Leeming D, Papakonstantinou E, Blasi F, Kostikas K, Boersma W, Louis R, Milenkovic B, Aerts J, Sand JMB, Wouters EFM, Rohde G, Prat C, Torres A, Welte T, Tamm M, Karsdal M, Stolz D

Abstract
The role of the extracellular matrix (ECM) structure and remodelling of thereof in lung diseases is gaining importance. Pathology-related changes in the ECM turnover may result in deleterious changes in lung architecture leading to disease in the small airways. Here, degradation fragments of type I (C1M), type IV (α1 chain, C4M2), and type IV (α3 chain, C4Ma3) collagen, all degraded by metalloproteinases (MMPs) and the pro-form of collagen type V (PRO-C5) were investigated and associated with chronic obstructive pulmonary disease (COPD) severity and outcome. In a prospective, observational, multicenter study including 498 patients with COPD GOLD stage 2 to 4, ECM markers were assessed in serum at stable state, exacerbation and at follow up, 4 weeks after exacerbation. At stable state, there was a significant inverse association between FEV1 %predicted and C1M, C4Ma3 and Pro-C5. C1M, C4M2, C4Ma3 and Pro-C5 were associated with body mass index, airflow obstruction, dyspnea and exercise capacity (BODE) index and the modified medical research council (MMRC) score. C1M, C4M2, C4Ma3 and Pro-C5 were significantly increased from stable state to exacerbation and decreased at follow-up. Furthermore, the biomarkers were significantly higher during severe exacerbation compared to moderate exacerbation. Multivariate analysis adjusted for body mass index, MMRC score, unadjusted Charlson score, and FEV1% predicted, showed a significant influence of C1M, C4Ma3 and C4M2 on time to exacerbation. None of the biomarkers were predictors for mortality. Serologically assessed collagen remodelling appears to play a significant role in COPD severity (airflow limitation, dyspnea) and disease outcome (time to exacerbation, and prognosis as assessed by the BODE index).

PMID: 29966667 [PubMed - as supplied by publisher]

Perspectives on Genetic Testing and Return of Results from the First Cohort of Presymptomatically Tested Individuals At Risk of Huntington Disease.

J Genet Couns. 2018 Jul 02;:

Authors: Stuttgen KM, Bollinger JM, Dvoskin RL, McCague A, Shpritz B, Brandt J, Mathews DJH

Abstract
This qualitative study gathered opinions about genetic testing from people who received presymptomatic testing for Huntington's disease (HD) 20-30 years ago and have lived with the implications of that testing for decades. During the last section of a semi-structured interview, participants were asked open-ended questions about their opinions on the importance of autonomy in the decision to be tested for HD, whether a formal HD testing protocol is necessary, whether physician ordering for HD is acceptable without a formal protocol, whether online direct-to-consumer (DTC) genetic testing for HD is acceptable, and whether incidental/secondary findings should be returned in the context of whole exome/genome sequencing. Most-but not all-participants were in favor of an individual's right to decide whether and when to pursue HD testing, use of a formal HD testing protocol, and returning medically actionable secondary findings. However, the majority of participants were opposed not only to physician ordering and DTC HD testing in the absence of a formal protocol but also to returning a secondary finding of an expanded HD allele. This study presents the opinions of a unique and extremely well-informed cohort on issues that need to be taken into careful consideration by genetic counselors and other medical professionals who are developing genetic testing protocols, making decisions about the availability of genetic tests, and making decisions about whether and how to return incidental findings.

PMID: 29967967 [PubMed - as supplied by publisher]

Discordant molecular subtype classification in the basal-squamous subtype of bladder tumors and matched lymph-node metastases.

Mod Pathol. 2018 Jul 02;:

Authors: Sjödahl G, Eriksson P, Lövgren K, Marzouka NA, Bernardo C, Nordentoft I, Dyrskjøt L, Liedberg F, Höglund M

Abstract
Molecular subtypes of muscle-invasive bladder tumors have emerged as a promising research tool with potential to stratify patients for neoadjuvant treatment. Prior to radical cystectomy, the utility of molecular classification and biomarkers depend on concordance between tissue from transurethrally resected specimens and disseminated disease. We assess the concordance of molecular subtypes and a large number of potential biomarkers in 67 pairs of muscle-invasive bladder tumors and synchronous lymph-node metastases. Tissue cores were stained for 29 immunohistochemistry markers and immunohistochemistry-based molecular subtype classification was performed. Molecular subtype was determined by mRNA profiling for 57 bladder tumors and 28 matched lymph-node metastases. Full section immunohistochemistry was performed to assess intra-tumor subtype heterogeneity in discordant cases, and exome sequencing was performed for 20 sample pairs. Discordant subtype classification between the bladder tumor and lymph-node metastasis was generally rare (12/67, 18%), but most (7/12, 58%) involved the Basal/Squamous-like subtype. Discordant Basal/Squamous-like tumors showed either Urothelial-like or Genomically Unstable, luminal-like phenotype in the lymph-node metastasis. Full section immunohistochemistry revealed intra-tumor subtype heterogeneity for six discordant cases including four involving the Basal/Squamous-like subtype. Subtype concordance for non- Basal/Squamous-like tumors was 91%. RNA-based classification agreed with immunohistochemistry classification but quantitative assessment is necessary to avoid false detection of subtype shifts. Most high confidence cancer mutations were shared between samples (n = 93, 78%), and bladder tumor private mutations (n = 20, 17%) were more frequent than those private to the lymph-node metastasis (n = 7, 6%). We conclude that bladder tumors and lymph-node metastases have overall similar molecular subtype, biomarker expression, and cancer mutations. The main exception was tumors of the Basal/Squamous-like subtype where most cases showed discordant classification, some with evidence of intra-tumor heterogeneity. The data are of relevance for neoadjuvant treatment stratification and raises questions on the dynamics of molecular subtypes during bladder cancer progression.

PMID: 29967424 [PubMed - as supplied by publisher]

A high-risk, Double-Hit, group of newly diagnosed myeloma identified by genomic analysis.

Leukemia. 2018 Jul 02;:

Authors: Walker BA, Mavrommatis K, Wardell CP, Ashby TC, Bauer M, Davies F, Rosenthal A, Wang H, Qu P, Hoering A, Samur M, Towfic F, Ortiz M, Flynt E, Yu Z, Yang Z, Rozelle D, Obenauer J, Trotter M, Auclair D, Keats J, Bolli N, Fulciniti M, Szalat R, Moreau P, Durie B, Stewart AK, Goldschmidt H, Raab MS, Einsele H, Sonneveld P, San Miguel J, Lonial S, Jackson GH, Anderson KC, Avet-Loiseau H, Munshi N, Thakurta A, Morgan G

Abstract
Patients with newly diagnosed multiple myeloma (NDMM) with high-risk disease are in need of new treatment strategies to improve the outcomes. Multiple clinical, cytogenetic, or gene expression features have been used to identify high-risk patients, each of which has significant weaknesses. Inclusion of molecular features into risk stratification could resolve the current challenges. In a genome-wide analysis of the largest set of molecular and clinical data established to date from NDMM, as part of the Myeloma Genome Project, we have defined DNA drivers of aggressive clinical behavior. Whole-genome and exome data from 1273 NDMM patients identified genetic factors that contribute significantly to progression free survival (PFS) and overall survival (OS) (cumulative R2 = 18.4% and 25.2%, respectively). Integrating DNA drivers and clinical data into a Cox model using 784 patients with ISS, age, PFS, OS, and genomic data, the model has a cumlative R2 of 34.3% for PFS and 46.5% for OS. A high-risk subgroup was defined by recursive partitioning using either a) bi-allelic TP53 inactivation or b) amplification (≥4 copies) of CKS1B (1q21) on the background of International Staging System III, comprising 6.1% of the population (median PFS = 15.4 months; OS = 20.7 months) that was validated in an independent dataset. Double-Hit patients have a dire prognosis despite modern therapies and should be considered for novel therapeutic approaches.

PMID: 29967379 [PubMed - as supplied by publisher]

Integrative genomic analysis reveals cancer-associated mutations at diagnosis of CML in patients with high risk disease.

Blood. 2018 Jul 02;:

Authors: Branford S, Wang P, Yeung DT, Thomson D, Purins A, Wadham C, Shahrin NH, Marum JE, Nataren N, Parker WT, Geoghegan J, Feng J, Shanmuganathan N, Mueller MC, Dietz C, Stangl D, Donaldson Z, Altamura H, Georgievski J, Braley J, Brown A, Hahn C, Walker I, Kim SH, Choi SY, Park SH, Kim DW, White DL, Yong ASM, Ross DM, Scott HS, Schreiber AW, Hughes TP

Abstract
Genomic events associated with poor outcome in chronic myeloid leukemia (CML) are poorly understood. We performed whole exome sequencing, copy number variation and/or RNA-Seq for 65 patients to discover mutations at diagnosis and blast crisis (BC). Forty-six chronic phase patients with the extremes of outcome were studied at diagnosis. Cancer gene variants were detected in 15/27 patients (56%) with subsequent BC or poor outcome and in 3/19 optimal responders (16%), P=.007. Frequently mutated genes at diagnosis were ASXL1, IKZF1 and RUNX1 The methyltransferase SETD1B was a novel recurrently mutated gene. A novel class of variant associated with the Philadelphia translocation was detected at diagnosis in 11/46 patients (24%) comprising fusions and/or rearrangement of genes on the translocated chromosomes, with evidence of fragmentation, inversion and imperfect sequence reassembly. These were more frequent at diagnosis in patients with poor outcome: 9/27 (33%) versus 2/19 optimal responders (11%), P=.07. Thirty-nine patients were tested at BC and all had cancer gene variants, including ABL1 kinase domain mutations in 58%. However, ABL1 mutations co-occurred with other mutated cancer genes in 89% of cases, and these predated ABL1 mutations in 62% of evaluable patients. Gene fusions not associated with the Philadelphia translocation occurred in 42% of patients at BC and commonly involved fusion partners that were known cancer genes (78%). Genomic analysis revealed numerous relevant variants at diagnosis in patients with poor outcome and all patients at BC. Future refined biomarker testing of specific variants will likely provide prognostic information to facilitate a risk-adapted therapeutic approach.

PMID: 29967129 [PubMed - as supplied by publisher]

Whole Exome Sequencing of a Consanguineous Turkish Family Identifies a Mutation in GTF2H3 in Brothers with Spermatogenic Failure.

Urology. 2018 Jun 29;:

Authors: Clavijo RI, Arora H, Gibbs E, Cohen S, Griswold A, Bakircioglu E, Bademci G, Tekin M, Ramasamy R

Abstract
In this case report we describe our investigation into the genetic cause of infertility due to idiopathic non-obstructive azoospermia in a consanguineous Turkish family. We extracted DNA from blood and applied whole exome sequencing (WES) on four infertile brothers in this family diagnosed with oligo- and azoospermia. Standard bioinformatics analysis pipelines were run including alignment to the reference genome, variant calling, and quality control filtering. Potentially pathogenic variants were identified and prioritized using genetic variant annotation software and public variant frequency databases, followed by validation with Sanger sequencing. A non-synonymous variant in "general transcription factor TFIIH subunit 3" (GTF2H3) was identified in this consanguineous family. This variant in chromosome 12 (12chr: 124144111 T>C, p.Ser222Pro) of GTF2H3 represents a likely a disease-causing mutation as it is predicted to be damaging, rare, segregates with the disease, and is highly evolutionarily conserved. Familial segregation analysis of the variant showed that it was present as a homozygous mutation in the brothers with NOA, and heterozygous mutation in the oligospermic brothers. We propose a mechanism by which this variant leads to deficits in Vitamin A signaling, which is essential for spermatogenesis.

PMID: 29966603 [PubMed - as supplied by publisher]

Novel mutations in Thai patients with glanzmann thrombasthenia.

Eur J Haematol. 2017 Dec;99(6):520-524

Authors: Ittiwut R, Suchartlikitwong P, Kittikalayawong Y, Ittiwut C, Prasopsanti K, Sosothikul D, Shotelersuk V, Suphapeetiporn K

Abstract
OBJECTIVES: Glanzmann thrombasthenia (GT) is an autosomal recessive platelet disorder, caused by defects of the platelet integrin αIIbβ3 (GPIIb/IIIa) resulting from pathogenic mutations in either ITGA2B or ITGB3. It is characterized by spontaneous mucocutaneous bleeding. The molecular features of GT in Thailand have not been identified. This study aimed to determine the clinical and molecular features of unrelated Thai patients with GT.
METHODS: Four patients with clinically suspected GT were recruited at the Division of Pediatric Hematology/Oncology, King Chulalongkorn Memorial Hospital. The diagnosis was based on clinical and hematological parameters as well as genetic analysis. Whole exome sequencing (WES) was performed in all cases.
RESULTS: Of the four patients studied, the median age at first suspicion of GT was 2.5 years. All presented with severe bleeding symptoms (WHO bleeding scale 3). Flow cytometry to assess the surface GPIIb/IIIa complex showed reduced expression. By WES, we successfully identified seven mutant alleles in ITGA2B. One alteration, the c.2915dup (p.Leu973Alafs*63), was detected in two unrelated families. One patient was homozygous for the c.617T>A (p.Val206Asp). Of the five different mutations, three have never been previously described. These include a missense, c.617T>A (p.Val206Asp), a deletion, c.1524_1533del (p.Gln508Hisfs*3), and a nonsense, c.2344C>T (p.Arg782Ter).
CONCLUSION: This study reported three novel mutations expanding the genotypic spectrum of ITGA2B causing GT.

PMID: 28888044 [PubMed - indexed for MEDLINE]