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"systems biology"

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("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2018/02/23

PubMed comprises more than millions of 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.

Repurposing of Kinase Inhibitors as Broad-Spectrum Antiviral Drugs.

DNA Cell Biol. 2018 Feb;37(2):63-69

Authors: Schor S, Einav S

Abstract
The high cost of drug development and the narrow spectrum of coverage typically provided by direct-acting antivirals limit the scalability of this antiviral approach. This review summarizes progress and challenges in the repurposing of approved kinase inhibitors as host-targeted broad-spectrum antiviral therapies.

PMID: 29148875 [PubMed - indexed for MEDLINE]

Repurposing ospemifene for potentiating an antigen-specific immune response.

Menopause. 2017 Apr;24(4):437-451

Authors: Kao CJ, Wurz GT, Lin YC, Vang DP, Phong B, DeGregorio MW

Abstract
OBJECTIVE: Ospemifene, an estrogen receptor agonist/antagonist approved for the treatment of dyspareunia and vaginal dryness in postmenopausal women, has potential new indications as an immune modulator. The overall objective of the present series of preclinical studies was to evaluate the immunomodulatory activity of ospemifene in combination with a peptide cancer vaccine.
METHODS: Immune regulating effects, mechanism of action and structure activity relationships of ospemifene and related compounds were evaluated by examining expression of T-cell activating cytokines in vitro, and antigen-specific immune response and cytotoxic T-lymphocyte activity in vivo. The effects of ospemifene (OSP) on the immune response to a peptide cancer vaccine (PV) were evaluated after chronic [control (n = 22); OSP 50 mg/kg (n = 16); PV (n = 6); OSP+PV (n = 11)], intermittent [control (n = 10); OSP 10 and 50 mg/kg (n = 11); PV (n = 11); combination treatment (n = 11 each dose)] and pretreatment [control; OSP 100 mg/kg; PV 100 μg; combination treatment (n = 8 all groups)] ospemifene oral dosing schedules in a total of 317 mixed-sex tumor-bearing and nontumor-bearing mice.
RESULTS: The results showed that ospemifene induced expression of the key TH1 cytokines interferon gamma and interleukin-2 in vitro, which may be mediated by stimulating T-cells through phosphoinositide 3-kinase and calmodulin signaling pathways. In combination with an antigen-specific peptide cancer vaccine, ospemifene increased antigen-specific immune response and increased cytotoxic T-lymphocyte activity in tumor-bearing and nontumor-bearing mice. The pretreatment, intermittent, and chronic dosing schedules of ospemifene activate naive T-cells, modulate antigen-induced tolerance and reduce tumor-associated, pro-inflammatory cytokines, respectively.
CONCLUSIONS: Taken together, ospemifene's dose response and schedule-dependent immune modulating activity offers a method of tailoring and augmenting the efficacy of previously failed antigen-specific cancer vaccines for a wide range of malignancies.

PMID: 27922937 [PubMed - indexed for MEDLINE]

[First cases of Pompe's disease in Kazakhstan].

Zh Nevrol Psikhiatr Im S S Korsakova. 2017;117(8):85-87

Authors: Zharkinbekova NA, Mukhambetova GA, Kaishibayeva GS, Zhiyenbayeva BS, Zhumagulova KB, Kaishibayev SN, Iglikova AE, Suleimanova SY

Abstract
The article presents the clinical observations of two newly diagnosed patients with Pompe disease in the Republic of Kazakhstan, confirmed by genetic research.

PMID: 28884723 [PubMed - indexed for MEDLINE]

MULTIMODAL IMAGING OF POSTERIOR POLAR ANNULAR CHOROIDAL DYSTROPHY.

Retin Cases Brief Rep. 2018 Winter;12(1):29-32

Authors: Forte R, Aptel F, Feldmann A, Chiquet C

Abstract
BACKGROUND: Posterior polar annular choroidal dystrophy (PPACD) is a rare disease. Patients with PPACD show loss of retinal pigment epithelium and choriocapillaries surrounding the vascular arcades and optic nerve.
METHODS: Two patients with PPACD were evaluated with multimodal imaging, including fundus autofluorescence (FAF) and adaptive optics (AO).
REPORT OF CASES: One patient (32 year old, one eye) with PPACD was followed up for 3 years. Best-corrected visual acuity (BCVA) was stable at 20/40, whereas a slight enlargement of paravascular atrophy of pigment epithelium was observed at fundus autofluorescence (FAF). Adaptive optics obtained at last examination showed reduced density of foveal cone photoreceptors. The second patient (30 year old, two eyes) with PPACD showed bilateral normal BCVA, associated with reduction in the density of foveal cone photoreceptors.
CONCLUSION: At FAF, longitudinal follow-up of PPACD showed progression of the paravascular atrophy of the pigment epithelium. Foveal cone photoreceptors can be reduced even in the presence of preserved visual acuity.

PMID: 27579567 [PubMed - indexed for MEDLINE]

Pachydermodactyly: A Benign Cutaneous Condition that May Be Misdiagnosed as a Joint Disorder.

J Rheumatol. 2016 08;43(8):1615-6

Authors: Chu H, Song J, Kim do Y

PMID: 27481990 [PubMed - indexed for MEDLINE]

New insights into the evaluation of randomized controlled trials for rare diseases over a long-term research horizon: a simulation study.

Stat Med. 2016 Aug 30;35(19):3245-58

Authors: Bayar MA, Le Teuff G, Michiels S, Sargent DJ, Le Deley MC

Abstract
Large sample sizes are required in randomized clinical trials designed to meet typical one-sided 2.5% α-level and 80% power. This may not be achievable when the disease is rare. We simulated a series of two-arm superiority trials over a 15-year period. The design parameters examined were the α-level and the number of trials conducted over the 15-year period (thus, trial sample size). Different disease severities and accrual rates were considered. The future treatment effect was characterized by its associated hazard rate; different hypotheses of how treatments improve over time were considered. We defined the total survival benefit as the relative difference of the hazard rates at year 15 versus year 0. The optimal design was defined by maximizing the expected total survival benefit, provided that the risk of selecting at year 15 a treatment inferior to the initial control treatment remains below 1%. Compared with two larger trials with typical one-sided 2.5% α-level, performing a series of small trials with relaxed α-levels leads on average to larger survival benefits over a 15-year research horizon, but also to higher risk of selecting a worse treatment at the end of the research period. Under reasonably optimistic assumptions regarding the future treatment effects, optimal designs outperform traditional ones when the disease is severe (baseline median survival ≤ 1 year) and the accrual is ≥100 patients per year, whereas no major improvement is observed in diseases with better prognosis. Trial designs aiming to maximize survival gain over a long research horizon across a series of trials are worth discussing in the context of rare diseases. Copyright © 2016 John Wiley & Sons, Ltd.

PMID: 27027783 [PubMed - indexed for MEDLINE]

Long-term Microevolution of Pseudomonas aeruginosa Differs Between Mildly and Severely Affected Cystic Fibrosis Lungs.

Am J Respir Cell Mol Biol. 2018 Feb 22;:

Authors: Klockgether J, Cramer N, Fischer S, Wiehlmann L, Tümmler B

Abstract
RATIONALE: The chronic airway infections with Pseudomonas aeruginosa determine morbidity in most individuals with cystic fibrosis (CF). P. aeruginosa may persist for decades in CF lungs which provides the rare opportunity to study the long-term within-host evolution of a bacterial airway pathogen.
OBJECTIVES: To resolve the genetic adaptation of P. aeruginosa in CF lungs from the onset of colonization until the patient's death or permanent replacement by another P. aeruginosa clone.
METHODS: We followed the microevolution of the first persisting P. aeruginosa clone by whole genome sequencing of serial isolates from highly divergent clinical courses of airway infection, i.e. a fatal outcome because of respiratory insufficiency within less than 15 years or still a rather normal daily life 25 to 35 years after acquisition of P. aeruginosa.
MEASUREMENTS AND MAIN RESULTS: Non-neutral mutations predominantly emerged in P. aeruginosa genes relevant for the protection against and communication with signals from the lung environment, i.e. antibiotic resistance, cell wall components and two-component systems. Drastic and loss-of-function mutations preferentially happened during the severe courses of infection and the bacterial lineages of the mild courses more proficiently incorporated extra metabolic genes into their accessory genome.
CONCLUSIONS: P. aeruginosa followed different evolutionary paths depending on whether the bacterium had taken residence in a CF patient with normal or already compromised lung function.

PMID: 29470920 [PubMed - as supplied by publisher]

Miniaturized dispersive liquid-liquid microextraction and MALDI MS using ionic liquid matrices for the detection of bacterial communication molecules and virulence factors.

Anal Bioanal Chem. 2018 Feb 22;:

Authors: Leipert J, Bobis I, Schubert S, Fickenscher H, Leippe M, Tholey A

Abstract
The identification and quantification of molecules involved in bacterial communication are major prerequisites for the understanding of interspecies interactions at the molecular level. We developed a procedure allowing the determination of 2-heptyl-4(1H)-quinolone (HHQ) and 2-heptyl-3-hydroxy-4(1H)-quinolone (PQS) and the virulence factor pyocyanin (PYO) formed by the Gram-negative bacterium Pseudomonas aeruginosa. The method is based on dispersive liquid-liquid microextraction from small supernatant volumes (below 10 μL) followed by quantitative matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS). The use of ionic liquid matrix led to a lowered limit of detection for pyocyanin and, due to suppression of matrix background signals, easy to interpret mass spectra compared to crystalline matrices. Using an isotope-labeled pyocyanin standard synthesized in small-scale synthesis, quantitative analysis spanning approximately one order of magnitude (0.5 to 250 fmol) was feasible. The method was successfully applied to the detection of the signaling molecules PQS and HHQ in cultures of P. aeruginosa strains isolated from sputum of cystic fibrosis patients and allowed a highly sensitive quantification of PYO from these cultures. Hence, the developed method bears the potential to be used for screening purposes in clinical settings and will help to decipher the molecular basis of bacterial communication. Graphical abstract Ionic liquid matrices for the detection and quantification of the toxin pyocyanin and other signaling molecules from P. aeruginosa by MALDI MS.

PMID: 29470663 [PubMed - as supplied by publisher]

Management of nontuberculous mycobacterial pulmonary disease.

Curr Opin Pulm Med. 2018 Feb 20;:

Authors: Adelman MH, Addrizzo-Harris DJ

Abstract
PURPOSE OF REVIEW: To highlight recent original research and specialty society guidelines regarding the diagnosis and treatment of nontuberculous mycobacterial (NTM) pulmonary disease.
RECENT FINDINGS: The prevalence of NTM pulmonary disease has risen in recent years. The prevalence of individual NTM species varies geographically, although Mycobacterium avium complex (MAC) and Mycobacterium abscessus complex (MABC) remain among the most commonly encountered in many regions. Diagnosis and treatment of NTM pulmonary disease can be complex but guideline-based recommendations have been published. However, adherence to guideline recommendations is poor. Drug susceptibility testing plays a role with important caveats for treatment. Alternative therapies are being explored with older antimycobacterial drugs like clofazimine, which has demonstrated efficacy and tolerability for treatment-refractory NTM infections, and a novel formulation of amikacin for inhalation which may be better tolerated than parenteral administration. Several studies have shown that patients will have recurrences as high as 48%, and that these are not solely relapses but many cases are reinfections with a new organism. United States and European research registries of patients with non-cystic fibrosis bronchiectasis are expected to provide needed data on clinical characteristics of patients at risk for NTM pulmonary disease.
SUMMARY: The evidence base for optimal management of NTM pulmonary disease is expanding but notable gaps in the literature remain.

PMID: 29470253 [PubMed - as supplied by publisher]

Are children with chronic illnesses requiring dietary therapy at risk for disordered eating or eating disorders? A systematic review.

Int J Eat Disord. 2018 Feb 22;:

Authors: Conviser JH, Fisher SD, McColley SA

Abstract
OBJECTIVE: Pediatric chronic illnesses (CI) can affect a child's mental health. Chronic illnesses with treatment regimens that specify a therapeutic diet may place the child at increased risk for disordered eating and specific eating disorders (ED). The aim of this review is to examine the relation between diet-treated CI and disordered eating and to determine the order of onset to infer directionality. Diet-treated CI is hypothesized to precede and to be associated with disordered eating.
METHOD: A comprehensive search of empirical articles that examine the relation between diet-treated CI (diabetes, cystic fibrosis, celiac disease, gastrointestinal disorders, and inflammatory bowel diseases) and disordered eating was conducted in Medline and PsycINFO using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A table of the sample's characteristics, ED measures, major pertinent findings, and the onset of CI in relation to ED were provided.
RESULTS: Diet-treated CI was associated with disordered eating and ED. Diet-treated CI had onset prior to disordered eating in most studies, except for inflammatory bowel diseases. Disordered eating and unhealthy weight management practices put children at risk for poor medical outcomes.
DISCUSSION: Interventions for diet-treated CI require a focus on diet and weight, but may increase the risk for disordered eating. Future research is needed to elucidate the mechanisms that transform standard treatment practices into pathological eating, including characteristics and behaviors of the child, parents/care providers, family, and treatment providers.

PMID: 29469935 [PubMed - as supplied by publisher]

Association between body composition and pulmonary function in children and young people with cystic fibrosis.

Nutrition. 2017 Dec 05;48:73-76

Authors: Calella P, Valerio G, Thomas M, McCabe H, Taylor J, Brodlie M, Siervo M

Abstract
OBJECTIVES: Body mass index (BMI) has significant limitations when assessing nutritional status in pediatric patients with cystic fibrosis (CF). We evaluated whether measurements of lean body mass (LBM) and fat mass (FM) are more sensitive nutritional parameters by testing their association with pulmonary function in adolescent patients with CF.
METHODS: Sixty-nine male and female adolescents with CF were studied (age: 14.5 ± 2.3, BMI: 19.5 ± 2.3 kg/m2). Dual-energy x-ray absorptiometry (DXA) was used to measure total and segmental (appendicular, truncal) body composition (FM, LBM bone mineral density, and content) as routine care to monitor bone health. Correlation and multiple regression analyses were performed to assess the association among body composition variables and forced expiratory volume in 1 s (FEV1). We also evaluated the influence of the F508del mutation on body composition.
RESULTS: FEV1 was significantly associated with total (r = 0.68, P <0.001), truncal (r = 0.71, P <0.001), and appendicular (r = 0.67, P <0.001) LBM, whereas it was not associated with total (r = 0.02, P = 0.89) and truncal (r = 0.04, P = 0.77) FM. BMI had a significant but weaker correlation with FEV1 (r = 0.52, P <0.001) compared with LBM. LBM was the only significant predictor of FEV1 in fully adjusted regression models.
CONCLUSIONS: LBM is a significant predictor of pulmonary function in CF adolescent patients. DXA scanning performed as part of routine bone health monitoring in CF can provide important body composition data relevant to clinical interventions that optimize nutritional status. DXA reference data for LBM in non-adult populations are needed to enhance diagnostic assessment and monitor clinical progression of CF.

PMID: 29469024 [PubMed - as supplied by publisher]

Lack of cystic fibrosis transmembrane conductance regulator disrupts fetal airway development in pigs.

Lab Invest. 2018 Feb 21;:

Authors: Meyerholz DK, Stoltz DA, Gansemer ND, Ernst SE, Cook DP, Strub MD, LeClair EN, Barker CK, Adam RJ, Leidinger MR, Gibson-Corley KN, Karp PH, Welsh MJ, McCray PB

Abstract
Loss of cystic fibrosis transmembrane conductance regulator (CFTR) function causes cystic fibrosis (CF), predisposing the lungs to chronic infection and inflammation. In young infants with CF, structural airway defects are increasingly recognized before the onset of significant lung disease, which suggests a developmental origin and a possible role in lung disease pathogenesis. The role(s) of CFTR in lung development is unclear and developmental studies in humans with CF are not feasible. Young CF pigs have structural airway changes and develop spontaneous postnatal lung disease similar to humans; therefore, we studied lung development in the pig model (non-CF and CF). CF trachea and proximal airways had structural lesions detectable as early as pseudoglandular development. At this early developmental stage, budding CF airways had smaller, hypo-distended lumens compared to non-CF airways. Non-CF lung explants exhibited airway lumen distension in response to forskolin/IBMX as well as to fibroblast growth factor (FGF)-10, consistent with CFTR-dependent anion transport/secretion, but this was lacking in CF airways. We studied primary pig airway epithelial cell cultures and found that FGF10 increased cellular proliferation (non-CF and CF) and CFTR expression/function (in non-CF only). In pseudoglandular stage lung tissue, CFTR protein was exclusively localized to the leading edges of budding airways in non-CF (but not CF) lungs. This discreet microanatomic localization of CFTR is consistent with the site, during branching morphogenesis, where airway epithelia are responsive to FGF10 regulation. In summary, our results suggest that the CF proximal airway defects originate during branching morphogenesis and that the lack of CFTR-dependent anion transport/liquid secretion likely contributes to these hypo-distended airways.

PMID: 29467455 [PubMed - as supplied by publisher]

Chronic β2AR stimulation limits CFTR activation in human airway epithelia.

JCI Insight. 2018 Feb 22;3(4):

Authors: Brewington JJ, Backstrom J, Feldman A, Kramer EL, Moncivaiz JD, Ostmann AJ, Zhu X, Lu LJ, Clancy JP

Abstract
Traditional pulmonary therapies for cystic fibrosis (CF) target the downstream effects of CF transmembrane conductance regulator (CFTR) dysfunction (the cause of CF). Use of one such therapy, β-adrenergic bronchodilators (such as albuterol), is nearly universal for airway clearance. Conversely, novel modulator therapies restore function to select mutant CFTR proteins, offering a disease-modifying treatment. Recent trials of modulators targeting F508del-CFTR, the most common CFTR mutation, suggest that chronic β-agonist use may undermine clinical modulator benefits. We therefore sought to understand the impact of chronic or excess β-agonist exposure on CFTR activation in human airway epithelium. The present studies demonstrate a greater than 60% reduction in both wild-type and modulator-corrected F508del-CFTR activation following chronic exposure to short- and long-acting β-agonists. This reduction was due to reduced cellular generation of cAMP downstream of the β-2 adrenergic receptor-G protein complex. Our results point towards a posttranscriptional reduction in adenylyl cyclase function as the mechanism of impaired CFTR activation produced by prolonged β-agonist exposure. β-Agonist-induced CFTR dysfunction was sufficient to abrogate VX809/VX770 modulation of F508del-CFTR in vitro. Understanding the clinical relevance of our observations is critical for CF patients using these drugs, and for investigators to inform future CFTR modulator drug trials.

PMID: 29467332 [PubMed - as supplied by publisher]

Analytical parameters and validation of homopolymer detection in a pyrosequencing-based next generation sequencing system.

BMC Genomics. 2018 Feb 21;19(1):158

Authors: Ivády G, Madar L, Dzsudzsák E, Koczok K, Kappelmayer J, Krulisova V, Macek M, Horváth A, Balogh I

Abstract
BACKGROUND: Current technologies in next-generation sequencing are offering high throughput reads at low costs, but still suffer from various sequencing errors. Although pyro- and ion semiconductor sequencing both have the advantage of delivering long and high quality reads, problems might occur when sequencing homopolymer-containing regions, since the repeating identical bases are going to incorporate during the same synthesis cycle, which leads to uncertainty in base calling. The aim of this study was to evaluate the analytical performance of a pyrosequencing-based next-generation sequencing system in detecting homopolymer sequences using homopolymer-preintegrated plasmid constructs and human DNA samples originating from patients with cystic fibrosis.
RESULTS: In the plasmid system average correct genotyping was 95.8% in 4-mers, 87.4% in 5-mers and 72.1% in 6-mers. Despite the experienced low genotyping accuracy in 5- and 6-mers, it was possible to generate amplicons with more than a 90% adequate detection rate in every homopolymer tract. When homopolymers in the CFTR gene were sequenced average accuracy was 89.3%, but varied in a wide range (52.2 - 99.1%). In all but one case, an optimal amplicon-sequencing primer combination could be identified. In that single case (7A tract in exon 14 (c.2046_2052)), none of the tested primer sets produced the required analytical performance.
CONCLUSIONS: Our results show that pyrosequencing is the most reliable in case of 4-mers and as homopolymer length gradually increases, accuracy deteriorates. With careful primer selection, the NGS system was able to correctly genotype all but one of the homopolymers in the CFTR gene. In conclusion, we configured a plasmid test system that can be used to assess genotyping accuracy of NGS devices and developed an accurate NGS assay for the molecular diagnosis of CF using self-designed primers for amplification and sequencing.

PMID: 29466940 [PubMed - in process]

First-Line Cetuximab Monotherapy in KRAS/NRAS/BRAF Mutation-Negative Colorectal Cancer Patients.

Clin Drug Investig. 2018 Feb 22;:

Authors: Moiseyenko VM, Moiseyenko FV, Yanus GA, Kuligina ES, Sokolenko AP, Bizin IV, Kudriavtsev AA, Aleksakhina SN, Volkov NM, Chubenko VA, Kozyreva KS, Kramchaninov MM, Zhuravlev AS, Shelekhova KV, Pashkov DV, Ivantsov AO, Venina AR, Sokolova TN, Preobrazhenskaya EV, Mitiushkina NV, Togo AV, Iyevleva AG, Imyanitov EN

Abstract
BACKGROUND: Colorectal carcinomas (CRCs) are sensitive to treatment by anti-epidermal growth factor receptor (EGFR) antibodies only if they do not carry activating mutations in down-stream EGFR targets (KRAS/NRAS/BRAF). Most clinical trials for chemo-naive CRC patients involved combination of targeted agents and chemotherapy, while single-agent cetuximab or panitumumab studies included either heavily pretreated patients or subjects who were not selected on the basis of molecular tests. We hypothesized that anti-EGFR therapy would have significant efficacy in chemo-naive patients with KRAS/NRAS/BRAF mutation-negative CRC.
METHODS: Nineteen patients were prospectively included in the study.
RESULTS: Two (11%) patients experienced partial response (PR) and 11 (58%) subjects showed stable disease (SD). Median time to progression approached 6.1 months (range 1.6-15.0 months). Cetuximab efficacy did not correlate with RNA expression of EGFR and insulin-like growth factor 2 (IGF2). Only one tumor carried PIK3CA mutation, and this CRC responded to cetuximab. Exome analysis of patients with progressive disease (PD) revealed 1 CRC with high-level microsatellite instability and 1 instance of HER2 oncogene amplification; 3 of 4 remaining patients with PD had allergic reactions to cetuximab, while none of the subjects with PR or SD had this complication. Comparison with 19 retrospective KRAS/NRAS/BRAF mutation-negative patients receiving first-line fluoropyrimidines revealed no advantages or disadvantages of cetuximab therapy.
CONCLUSIONS: Cetuximab demonstrates only modest efficacy when given as a first-line monotherapy to KRAS/NRAS/BRAF mutation-negative CRC patients. It is of question, why meticulous patient selection, which was undertaken in the current study, did not result in the improvement of outcomes of single-agent cetuximab treatment.

PMID: 29470838 [PubMed - as supplied by publisher]

Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants.

Genet Med. 2018 Feb 22;:

Authors: Johnston JJ, van der Smagt JJ, Rosenfeld JA, Pagnamenta AT, Alswaid A, Baker EH, Blair E, Borck G, Brinkmann J, Craigen W, Dung VC, Emrick L, Everman DB, van Gassen KL, Gulsuner S, Harr MH, Jain M, Kuechler A, Leppig KA, McDonald-McGinn DM, Can NTB, Peleg A, Roeder ER, Rogers RC, Sagi-Dain L, Sapp JC, Schäffer AA, Schanze D, Stewart H, Taylor JC, Verbeek NE, Walkiewicz MA, Zackai EH, Zweier C, Members of the Undiagnosed Diseases Network, Zenker M, Lee B, Biesecker LG

Abstract
PurposeTo characterize the molecular genetics of autosomal recessive Noonan syndrome.MethodsFamilies underwent phenotyping for features of Noonan syndrome in children and their parents. Two multiplex families underwent linkage analysis. Exome, genome, or multigene panel sequencing was used to identify variants. The molecular consequences of observed splice variants were evaluated by reverse-transcription polymerase chain reaction.ResultsTwelve families with a total of 23 affected children with features of Noonan syndrome were evaluated. The phenotypic range included mildly affected patients, but it was lethal in some, with cardiac disease and leukemia. All of the parents were unaffected. Linkage analysis using a recessive model supported a candidate region in chromosome 22q11, which includes LZTR1, previously shown to harbor mutations in patients with Noonan syndrome inherited in a dominant pattern. Sequencing analyses of 21 live-born patients and a stillbirth identified biallelic pathogenic variants in LZTR1, including putative loss-of-function, missense, and canonical and noncanonical splicing variants in the affected children, with heterozygous, clinically unaffected parents and heterozygous or normal genotypes in unaffected siblings.ConclusionThese clinical and genetic data confirm the existence of a form of Noonan syndrome that is inherited in an autosomal recessive pattern and identify biallelic mutations in LZTR1.Genet Med advance online publication, 22 February 2018; doi:10.1038/gim.2017.249.

PMID: 29469822 [PubMed - as supplied by publisher]

Characterization of a novel breast cancer cell line derived from a metastatic bone lesion of a breast cancer patient.

Breast Cancer Res Treat. 2018 Feb 21;:

Authors: Johnson J, Bessette DC, Saunus JM, Smart CE, Song S, Johnston RL, Cocciardi S, Rozali EN, Johnstone CN, Vargas AC, Kazakoff SH, BioBank VC, Khanna KK, Lakhani SR, Chenevix-Trench G, Simpson PT, Nones K, Waddell N, Al-Ejeh F

Abstract
PURPOSE: We aimed to generate and characterize a novel cell line from a breast cancer bone metastasis to better study the progression of the disease.
METHODS: The cell line, P7731, was derived from a metastatic bone lesion of a breast cancer patient and assessed for marker expression. P7731 was analyzed for DNA copy number variation, somatic mutations, and gene expression and was compared with the primary tumor.
RESULTS: P7731 cells are negative for estrogen receptor alpha (ERα), progesterone receptor (PR), and HER2 (triple-negative); strongly express vimentin (100% of cells positive) and also express cytokeratins 8/18 and 19 but at lower frequencies. Flow cytometry indicates P7731 cells are predominantly CD44+/CD49f+/EpCAM-, consistent with a primitive, mesenchymal-like phenotype. The cell line is tumorigenic in immunocompromised mice. Exome sequencing identified a total of 45 and 76 somatic mutations in the primary tumor and cell line, respectively, of which 32 were identified in both samples and included mutations in known driver genes PIK3CA, TP53, and ARID1A. P7731 retains the DNA copy number alterations present in the matching primary tumor. Homozygous deletions detected in the cell line and in the primary tumor were found in regions containing three known (CDKN2A, CDKN2B, and CDKN1B) and 23 putative tumor suppressor genes. Cell line-specific gene amplification coupled with mRNA expression analysis revealed genes and pathways with potential pro-metastatic functions.
CONCLUSION: This novel human breast cancer-bone metastasis cell line will be a useful model to study aspects of breast cancer biology, particularly metastasis-related changes from breast to bone.

PMID: 29468485 [PubMed - as supplied by publisher]

Atherosclerosis Is an Inflammatory Disease which Lacks a Common Anti-inflammatory Therapy: How Human Genetics Can Help to This Issue. A Narrative Review.

Front Pharmacol. 2018;9:55

Authors: Fava C, Montagnana M

Abstract
Atherosclerosis is a multifactorial disease triggered and sustained by different risk factors such as dyslipidemia, arterial hypertension, diabetes mellitus, smoke, etc. Since a couple of decades, a pivotal role for inflammation in its pathogenesis has been recognized and proved at molecular levels, and already described in many animal models. Despite all this knowledge, due to the complexity of the specific inflammatory process subtending atherosclerosis and to the fact that inflammation is also a protective response against microorganisms, no anti-inflammatory therapy has been rendered available in the therapeutic armamentarium against atherosclerosis and vascular events till 2017 when canakinumab in the first ad-hoc randomized clinical trial (RCT) proved for the first time that targeting specifically inflammation lowers cardiovascular (CV) events. From the genetic side, in the 90's and early 2000, several genetic markers in inflammatory pathway have been explored searching for an association with athero-thrombosis which gave seldom consistent results. Then, in the genomic era, plenty of genetic markers covering most of the genome have been analyzed at once without a priori information. The results coming from genome wide association studies (GWAS) have pinpointed some loci closed to inflammatory molecules consistently associated with atherosclerosis and CV consequences revamping the strict link between inflammation and atherosclerosis and suggesting some tailored target therapy. Whole-exome and whole-genome sequencing will come soon showing new and old loci associated with atherosclerosis suggesting new molecular targets or underlying which inflammatory pathway could be most attractive to target for blocking atherosclerosis even in its early stages.

PMID: 29467655 [PubMed]