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"systems biology"

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Sex combs reduced (Scr) regulatory region of Drosophila revisited.

Mol Genet Genomics. 2017 Mar 22;:

Authors: Calvo-Martín JM, Papaceit M, Segarra C

Abstract
The Hox gene Sex combs reduced (Scr) is responsible for the differentiation of the labial and prothoracic segments in Drosophila. Scr is expressed in several specific tissues throughout embryonic development, following a complex path that must be coordinated by an equally complex regulatory region. Although some cis-regulatory modules (CRMs) have been identified in the Scr regulatory region (~75 kb), there has been no detailed and systematic study of the distinct regulatory elements present within this region. In this study, the Scr regulatory region was revisited with the aim of filling this gap. We focused on the identification of Initiator elements (IEs) that bind segmentation factors, Polycomb response elements (PREs) that are recognized by the Polycomb and Trithorax complexes, as well as insulators and tethering elements. To this end, we summarized all currently available information, mainly obtained from high throughput ChIP data projects. In addition, a bioinformatic analysis based on the evolutionary conservation of regulatory sequences using the software MOTEVO was performed to identify IE and PRE candidates in the Scr region. The results obtained by this combined strategy are largely consistent with the CRMs previously identified in the Scr region and help to: (i) delimit them more accurately, (ii) subdivide two of them into different independent elements, (iii) identify a new CRM, (iv) identify the composition of their binding sites and (v) better define some of their characteristics. These positive results indicate that an approach that integrates functional and bioinformatic data might be useful to characterize other regulatory regions.

PMID: 28331962 [PubMed - as supplied by publisher]

A review of network-based approaches to drug repositioning.

Brief Bioinform. 2017 Feb 27;:

Authors: Lotfi Shahreza M, Ghadiri N, Mousavi SR, Varshosaz J, Green JR

Abstract
Experimental drug development is time-consuming, expensive and limited to a relatively small number of targets. However, recent studies show that repositioning of existing drugs can function more efficiently than de novo experimental drug development to minimize costs and risks. Previous studies have proven that network analysis is a versatile platform for this purpose, as the biological networks are used to model interactions between many different biological concepts. The present study is an attempt to review network-based methods in predicting drug targets for drug repositioning. For each method, the preferred type of data set is described, and their advantages and limitations are discussed. For each method, we seek to provide a brief description, as well as an evaluation based on its performance metrics.We conclude that integrating distinct and complementary data should be used because each type of data set reveals a unique aspect of information about an organism. We also suggest that applying a standard set of evaluation metrics and data sets would be essential in this fast-growing research domain.

PMID: 28334136 [PubMed - as supplied by publisher]

ZNHIT3 is defective in PEHO syndrome, a severe encephalopathy with cerebellar granule neuron loss.

Brain. 2017 Mar 01;:

Authors: Anttonen AK, Laari A, Kousi M, Yang YJ, Jääskeläinen T, Somer M, Siintola E, Jakkula E, Muona M, Tegelberg S, Lönnqvist T, Pihko H, Valanne L, Paetau A, Lun MP, Hästbacka J, Kopra O, Joensuu T, Katsanis N, Lehtinen MK, Palvimo JJ, Lehesjoki AE

Abstract
Progressive encephalopathy with oedema, hypsarrhythmia, and optic atrophy (PEHO) syndrome is an early childhood onset, severe autosomal recessive encephalopathy characterized by extreme cerebellar atrophy due to almost total granule neuron loss. By combining homozygosity mapping in Finnish families with Sanger sequencing of positional candidate genes and with exome sequencing a homozygous missense substitution of leucine for serine at codon 31 in ZNHIT3 was identified as the primary cause of PEHO syndrome. ZNHIT3 encodes a nuclear zinc finger protein previously implicated in transcriptional regulation and in small nucleolar ribonucleoprotein particle assembly and thus possibly to pre-ribosomal RNA processing. The identified mutation affects a highly conserved amino acid residue in the zinc finger domain of ZNHIT3. Both knockdown and genome editing of znhit3 in zebrafish embryos recapitulate the patients' cerebellar defects, microcephaly and oedema. These phenotypes are rescued by wild-type, but not mutant human ZNHIT3 mRNA, suggesting that the patient missense substitution causes disease through a loss-of-function mechanism. Transfection of cell lines with ZNHIT3 expression vectors showed that the PEHO syndrome mutant protein is unstable. Immunohistochemical analysis of mouse cerebellar tissue demonstrated ZNHIT3 to be expressed in proliferating granule cell precursors, in proliferating and post-mitotic granule cells, and in Purkinje cells. Knockdown of Znhit3 in cultured mouse granule neurons and ex vivo cerebellar slices indicate that ZNHIT3 is indispensable for granule neuron survival and migration, consistent with the zebrafish findings and patient neuropathology. These results suggest that loss-of-function of a nuclear regulator protein underlies PEHO syndrome and imply that establishment of its spatiotemporal interaction targets will be the basis for developing therapeutic approaches and for improved understanding of cerebellar development.

PMID: 28335020 [PubMed - as supplied by publisher]

A Rare Congenital Pulmonary Anomaly of a Young Adult: Pseudosequestration.

Ann Thorac Surg. 2016 Aug;102(2):e163

Authors: Özdil A, Akçam Tİ, Çağırıcı U, Savaş R

PMID: 27449457 [PubMed - indexed for MEDLINE]

A review of connectivity map and computational approaches in pharmacogenomics.

Brief Bioinform. 2017 Feb 23;:

Authors:

PMID: 28334173 [PubMed - as supplied by publisher]

rs7968606 polymorphism of ANKS1B is associated with improvement in the PANSS general score of schizophrenia caused by amisulpride.

Hum Psychopharmacol. 2017 Mar 23;:

Authors: Kang SG, Chee IS, Lee K, Lee J

Abstract
A recent genome-wide pharmacogenomics study showed that the rs7968606 single-nucleotide polymorphism (SNP) of the ankyrin repeat and sterile alpha motif domain-containing protein 1B (ANKS1B) gene approached the threshold of statistical significance. The aim of this study was to determine the association between the rs7968606 SNP of ANKS1B and the treatment response to amisulpride in schizophrenia patients. In total, 154 participants were enrolled from six university hospitals in Korea. All the subjects were interviewed before and after 6 weeks of amisulpride treatment with the aid of the positive and negative syndrome scale and the clinical global impression-severity scale. Genotyping for the rs7968606 SNP of ANKS1B was performed in 101 subjects. Both the decrease (t = -2.067, p = 0.041) and improvement rate (t = -1.990, p = 0.049) in the positive and negative syndrome scale general score differed significantly between T-allele carriers and noncarriers of this polymorphism after 6 weeks of amisulpride treatment. To the best of our knowledge, this is the first genetic association study of the relationship between the rs7968606 SNP of ANKS1B and the response of schizophrenia patients to treatment with amisulpride. Future larger-scale studies involving more SNPs of ANKS1B will improve the understanding of the pharmacogenetics underlying the treatment responses to amisulpride.

PMID: 28332719 [PubMed - as supplied by publisher]

Risk of acute myocardial infarction after discontinuation of antihypertensive agents: a case-control study.

J Hum Hypertens. 2017 Mar 23;:

Authors: Alharbi FF, Souverein PC, de Groot MC, Maitland-van der Zee AH, de Boer A, Klungel OH

Abstract
We performed a nested case-control study in a cohort of antihypertensive drug users to assess the association between discontinuation of different antihypertensive agents and the risk of acute myocardial infarction (AMI). Cases and controls were drawn from the Utrecht Cardiovascular Pharmacogenetics database. Patients who were hospitalised for their first AMI were considered cases and controls were not hospitalised for AMI. Antihypertensive users were defined as current users if the index date (date of AMI) fell within the prescribed duration or as discontinuers if this date fell outside the prescribed duration. According to the recency of discontinuation, discontinuers were divided into the following: recent discontinuers (⩽90 days), intermediate-term discontinuers (91-180 days) and long-term discontinuers (>180 days). We found that the risk of AMI was significantly increased in discontinuers, regardless of time since discontinuation, of beta-blockers (adjusted odds ratio (OR) 1.54; 95% confidence interval (CI; 1.25-1.91), P-value<0.0005), calcium channel blockers (CCBs; adjusted OR 2.25; 95% CI (1.53-3.30), P-value<0.0005) and diuretics (adjusted OR 1.76; 95% CI (1.24-2.48), P-value=0.002) compared to current users of these drugs. Moreover, the risk of AMI was significantly increased in long-term discontinuers (beta-blockers, CCBs, angiotensin-converting enzyme inhibitors and diuretics) and intermediate-term discontinuers (beta-blockers and CCBs) versus current users of these drugs. There was no difference in AMI risk between recent discontinuers of antihypertensive drugs versus current users of these drugs. In conclusion, discontinuation of antihypertensive drugs increases the risk of AMI after >90 days of discontinuation. This further underlines the importance of persistence to antihypertensive drug therapy to reduce the risk of AMI in patients with hypertension.Journal of Human Hypertension advance online publication, 23 March 2017; doi:10.1038/jhh.2017.1.

PMID: 28332511 [PubMed - as supplied by publisher]

Effects of FMO3 Polymorphisms on Pharmacokinetics of Sulindac in Chinese Healthy Male Volunteers.

Biomed Res Int. 2017;2017:4189678

Authors: Tang YJ, Hu K, Huang WH, Wang CZ, Liu Z, Chen Y, Ouyang DS, Tan ZR, Zhou HH, Yuan CS

Abstract
Sulindac is a nonsteroidal anti-inflammatory drug, which is clinically used for the ailments of various inflammations. This study investigated the allele frequencies of FMO3 E158K and E308G and evaluated the influences of these two genetic polymorphisms on the pharmacokinetics of sulindac and its metabolites in Chinese healthy male volunteers. Eight FMO3 wild-type (FMO3 HHDD) subjects and seven FMO3 homozygotes E158K and E308G mutant (FMO3 hhdd) subjects were recruited from 247 healthy male volunteers genotyped by PCR-RFLP method. The plasma concentrations of sulindac, sulindac sulfide, and sulindac sulfone were determined by UPLC, while the pharmacokinetic parameters of the two different FMO3 genotypes were compared with each other. The frequencies of FMO3 E158K and E308G were 20.3% and 20.1%, respectively, which were in line with Hardy-Weinberg equilibrium (D' = 0.977, r(2) = 0.944). The mean values of Cmax, AUC0-24, and AUC0-∞ of sulindac were significantly higher in FMO3 hhdd group than those of FMO3 HHDD group (P < 0.05), while the pharmacokinetic parameters except Tmax of sulindac sulfide and sulindac sulfone showed no statistical difference between the two groups. The two FMO3 mutants were in close linkage disequilibrium and might play an important role in the pharmacokinetics of sulindac in Chinese healthy male volunteers.

PMID: 28331852 [PubMed - in process]

Germline Genetic Biomarkers of Sunitinib Efficacy in Advanced Renal Cell Carcinoma: Results From the RENAL EFFECT Trial.

Clin Genitourin Cancer. 2017 Feb 27;:

Authors: Motzer RJ, Figlin RA, Martini JF, Hariharan S, Agarwal N, Li CX, Williams JA, Hutson TE

Abstract
BACKGROUND: Sunitinib, the vascular endothelial growth factor pathway inhibitor, is an established standard-of-care for advanced renal cell carcinoma (RCC). This study aimed to assess correlations between candidate germline single nucleotide polymorphisms (SNPs) and sunitinib efficacy in patients from the RENAL EFFECT trial (NCT00267748), a randomized phase II study in patients with metastatic RCC comparing the 4-weeks-on/2-weeks-off schedule and a continuous daily dosing schedule.
PATIENTS AND METHODS: Informed consent for pharmacogenetics research was obtained from 202 out of 289 treated patients in the trial. Associations between 9 SNP variants (CXCL8, LOXL2, CCDC26, SH3GL2, CLLU1, IL2RA, AURKB, and 2 SNPs on Chromosomes 7 and 12) and progression-free survival (PFS), objective response rate, and overall survival were assessed using Kaplan-Meier analysis, Cox proportional hazard model, and the Fisher exact test.
RESULTS: CXCL8 rs1126647 A/A versus A/T (P = .004) or T/T (P < .0001) and SH3GL2 rs10963287 C/C versus C/T (P = .005) or T/T (P = .018) were associated with improved overall survival in all patients. CLLU1 rs525810 A/A genotype versus A/G (P = .014) or G/G (P = .048) was associated with improved PFS in the continuous daily dosing arm. IL2RA rs7893467 T/G versus T/T was associated with improved PFS (P = .034) in the 4-weeks-on/2-weeks-off arm and objective response rate (P = .034) in all patients. No significant associations between improved efficacy and genotype were found for other SNPs.
CONCLUSION: Germline variants in CLLU1, IL2RA, CXCL8, and SH3GL2 warrant further retrospective study in independent cohorts of patients with metastatic RCC treated with vascular endothelial growth factor-class inhibitors, to test their biological significance and potential clinical fitness as biomarkers to guide treatment.

PMID: 28330808 [PubMed - as supplied by publisher]

Influence of MDR1 CYP3A5 genetic polymorphisms on trough levels and therapeutic response of imatinib in newly diagnosed patients with chronic myeloid leukemia.

Pharmacol Res. 2017 Mar 18;:

Authors: Harivenkatesh N, Kumar L, Bakhshi S, Sharma A, Kabra M, Velpandian T, Gogia A, Shastri SS, Biswas NR, Gupta YK

Abstract
Polymorphisms in genes coding for imatinib transporters and metabolizing enzymes may affect imatinib pharmacokinetics and clinical response. Aim of this study was to assess the influence of polymorphisms in MDR1 and CYP3A5 genes on imatinib trough levels, cytogenetic and molecular response in patients with CML. Newly diagnosed patients with chronic-phase CML started on imatinib therapy were enrolled and followed up prospectively for 24 months. The following single nucleotide polymorphisms were genotyped; C1236T, C3435T, G2677T/A in MDR1 gene and A6986G in CYP3A5 gene. Genotyping was done using PCR-RFLP method and validated by direct gene sequencing. Trough levels of imatinib were measured using LC-MS/MS. Cytogenetic response was assessed by conventional bone-marrow cytogenetics. Molecular response was assessed by qRTPCR using international scale. A total of 173 patients were included, out of which 71 patients were imatinib responders, while 102 were non-responders. Marked inter-individual variability in trough levels of imatinib was seen. Patients with GG genotype for CYP3A5-A6986G (P=0.016) and TT genotype for MDR1-C3435T (P=0.013) polymorphisms had significantly higher trough levels of imatinib. Patients with AA genotype for CYP3A5-A6986G [RR=1.448, 95%CI(1.126, 1.860), P=0.029] and CC genotype for MDR1-C1236T [RR=1.397, 95%CI(1.066, 1.831), P=0.06] &MDR1-C3435T [RR=1.508, 95%CI(1.186, 1.917), P=0.018] polymorphisms were at high risk for failure of imatinib therapy. Patients with CGC haplotype for MDR1 polymorphisms had significantly lower imatinib trough levels and were at a higher risk of imatinib failure [RR=1.547, 95%CI(1.324, 1.808), P<0.001]. GG vs. non-GG genotype for CYP3A5-A6986G [adjusted OR: 0.246; 95%CI (0.116, 0.519); P<0.001] and TT vs. non-TT genotype for MDR1-C1236T [adjusted OR: 0.270; 95%CI(0.110, 0.659); P=0.004] &MDR1-C3435T [adjusted OR: 0.289; 95%CI(0.135, 0.615); P=0.001] polymorphisms were independent factors predicting imatinib response in multivariate analysis. To conclude, MDR1 and CYP3A5 genetic polymorphisms significantly influence plasma trough levels and therapeutic response of imatinib in patients with CML. Genotyping of these polymorphisms could be of value to individualize the therapy and optimize the clinical outcomes.

PMID: 28330783 [PubMed - as supplied by publisher]

A Long Noncoding RNA ZEB1-AS1 Promotes Tumorigenesis and Predicts Poor Prognosis in Glioma.

Int J Mol Sci. 2016 Aug 30;17(9):

Authors: Lv QL, Hu L, Chen SH, Sun B, Fu ML, Qin CZ, Qu Q, Wang GH, He CJ, Zhou HH

Abstract
Emerging studies show that long noncoding RNAs (lncRNAs) have important roles in carcinogenesis. lncRNA ZEB1 antisense 1 (ZEB1-AS1) is a novel lncRNA, whose clinical significance, biological function, and underlying mechanism remains unclear in glioma. Here, we found that ZEB1-AS1 was highly expressed in glioma tissues, being closely related to clinical stage of glioma. Moreover, patients with high ZEB1-AS1 levels had poor prognoses, with the evidence provided by multivariate Cox regression analysis indicating that ZEB1-AS1 expression could serve as an independent prognostic factor in glioma patients. Functionally, silencing of ZEB1-AS1 could significantly inhibit cell proliferation, migration, and invasion, as well as promote apoptosis. Knockdown of ZEB1-AS1 significantly induced the G0/G1 phase arrest and correspondingly decreased the percentage of S phase cells. Further analysis indicated that ZEB1-AS1 could regulate the cell cycle by inhibiting the expression of G1/S transition key regulators, such as Cyclin D1 and CDK2. Furthermore, ZEB1-AS1 functioned as an important regulator of migration and invasion via activating epithelial to mesenchymal transition (EMT) through up-regulating the expression of ZEB1, MMP2, MMP9, N-cadherin, and Integrin-β1 as well as decreasing E-cadherin levels in the metastatic progression of glioma. Additionally, forced down-regulation of ZEB1-AS1 could dramatically promote apoptosis by increasing the expression level of Bax and reducing Bcl-2 expression in glioma. Taken together, our data suggest that ZEB1-AS1 may serve as a new prognostic biomarker and therapeutic target of glioma.

PMID: 27589728 [PubMed - indexed for MEDLINE]

Is deafness mutation screening required in cystic fibrosis patients?

Paediatr Respir Rev. 2016 Aug;20 Suppl:24-6

Authors: Abusamra R, McShane D

Abstract
Aminoglycosides are widely used in cystic fibrosis management. The m.1555A>G mutation predisposes to aminoglycoside ototoxicity. It may cause later onset hearing loss in the absence of aminoglycosides use and gradual hearing loss may be an inevitable consequence of the mutation. Given that aminoglycoside therapy forms the backbone of IV protocols in CF, this article recommends screening for this mutation to allow informed decision-making prior to aminoglycoside administration, to avoid preventable deafness.

PMID: 27427311 [PubMed - indexed for MEDLINE]

Polyphenols from Chilean Propolis and Pinocembrin Reduce MMP-9 Gene Expression and Activity in Activated Macrophages.

Biomed Res Int. 2016;2016:6505383

Authors: Saavedra N, Cuevas A, Cavalcante MF, Dörr FA, Saavedra K, Zambrano T, Abdalla DS, Salazar LA

Abstract
Polyphenols from diverse sources have shown anti-inflammatory activity. In the context of atherosclerosis, macrophages play important roles including matrix metalloproteinases synthesis involved in degradation of matrix extracellular components affecting the atherosclerotic plaque stability. We prepared a propolis extract and pinocembrin in ethanol solution. Propolis extract was chemically characterized using LC-MS. The effect of treatments on gene expression and proteolytic activity was measured in vitro using murine macrophages activated with LPS. Cellular toxicity associated with both treatments and the vehicle was determined using MTT and apoptosis/necrosis detection assays. MMP-9 gene expression and proteolytic activity were measured using qPCR and zymography, respectively. Thirty-two compounds were identified in the propolis extract, including pinocembrin among its major components. Treatment with either ethanolic extract of propolis or pinocembrin inhibits MMP-9 gene expression in a dose-dependent manner. Similarly, an inhibitory effect was observed in proteolytic activity. However, the effect showed by ethanolic extract of propolis was higher than the effect of pinocembrin, suggesting that MMP-9 inhibition results from a joint contribution between the components of the extract. These data suggest a potential role of polyphenols from Chilean propolis in the control of extracellular matrix degradation in atherosclerotic plaques.

PMID: 27119082 [PubMed - indexed for MEDLINE]

Infantile Tremor Syndrome and Subdural Hemorrhage in an Infant with Cystic Fibrosis.

J Trop Pediatr. 2017 Feb 23;:

Authors: Mandal A, Priyadarshi M, Jat K, Kabra SK

Abstract
Cystic fibrosis (CF), an autosomal recessive disease with multi-system involvement, may present with bleeding in infancy owing to vitamin K malabsorption. Infantile tremor syndrome (ITS) is an obscure condition associated with vitamin B12 and other micronutrient deficiencies, described predominantly in Indian subcontinent. We describe an infant presenting with ITS and chronic subdural hemorrhage. He was subsequently diagnosed to have CF. The ITS and subdural hemorrhage is rarely reported in children with CF. In the background of increasing recognition of CF in Indian children, this case demonstrates a new association of this disease.

PMID: 28334845 [PubMed - as supplied by publisher]

Complex Relation Between Diet and Phospholipid Fatty Acids in Children With Cystic Fibrosis.

J Pediatr Gastroenterol Nutr. 2017 Apr;64(4):598-604

Authors: Moukarzel S, Dyer RA, Innis SM

Abstract
OBJECTIVES: Altered total plasma n-6 and n-3 fatty acids are common in cystic fibrosis (CF). Whether alterations extend to plasma phosphatidylcholine (PC) and phosphatidylethanolamine (PE) and are explained by diet is unclear. The present study was to describe the dietary intake of a large group of children with CF and to determine whether dietary fat composition explains differences in plasma PC and PE fatty acids between children with and without CF.
METHODS: Dietary intake was assessed using a food frequency questionnaire. Venous blood was collected. Plasma PC and PE were separately analyzed for fatty acids.
RESULTS: Children with CF, n = 74, consumed more calories and fat (g/day and % energy), with significantly more saturates mainly from dairy foods and less polyunsaturates including linoleic acid (LA), arachidonic acid (ARA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) (% fat) than reference children, n = 71. A subset of children with CF, not differing in dietary intake from the larger group, had significantly lower LA and DHA, but higher EPA in plasma PC and had higher LA and lower ARA and DHA in plasma PE, compared to a subset of reference children. In both groups, LA intake and LA in plasma PC and PE were not associated. EPA and DHA intakes were positively associated with EPA and DHA, respectively, in plasma PC, but not PE, in reference children only.
CONCLUSIONS: The fatty acid composition of plasma PC and PE is altered in CF. Fatty acid differences between children with and without CF are inconsistent between PC and PE and are not explained by dietary fat.

PMID: 28333826 [PubMed - in process]

Qualitative Assessment of the Symptoms and Impact of Pancreatic Exocrine Insufficiency (PEI) to Inform the Development of a Patient-Reported Outcome (PRO) Instrument.

Patient. 2017 Mar 22;:

Authors: Johnson CD, Arbuckle R, Bonner N, Connett G, Dominguez-Munoz E, Levy P, Staab D, Williamson N, Lerch MM

Abstract
BACKGROUND: Pancreatic exocrine insufficiency (PEI) affects patients with chronic pancreatitis (CP) and cystic fibrosis (CF) who produce insufficient digestive pancreatic enzymes. Common symptoms include steatorrhoea, diarrhea, and abdominal pain.
OBJECTIVE: The objective of the study was to develop and test the content validity of a patient-reported outcome (PRO) instrument assessing PEI symptoms and their impact on health-related quality of life.
METHODS: Instrument development was supported by a literature review, expert physician interviews (n = 10: Germany 4, UK 3, France 3), and exploratory, qualitative, concept-elicitation interviews with patients with CF and CP with PEI (n = 61: UK 29, Germany 18, France 14) and expert physicians (n = 10). Cognitive debriefing of the draft instrument was then performed with patients with PEI (n = 37: UK 24, Germany 8, France 5), and feasibility was assessed with physicians (n = 3). For all interviews, verbatim transcripts were qualitatively analysed using thematic analysis methods and Atlas.ti computerized qualitative software. All themes were data driven rather than a priori.
RESULTS: Patient interviews elicited symptoms and impacts not reported in the literature. Six symptom concepts emerged: pain, bloating, bowel symptoms, nausea/vomiting, eating problems, and tiredness/fatigue. Six impact domains were also identified. A 45-item instrument was developed in English, French, and German for testing in cognitive debriefing patient interviews. Following cognitive debriefing, 18 items were deleted.
CONCLUSION: Rigorous qualitative patient research and expert clinical input supported development of a PEI-specific PRO with the potential to aid management and monitoring of unmet needs among patients with PEI. The next step is to perform psychometric evaluation of the resulting instrument.

PMID: 28332032 [PubMed - as supplied by publisher]

A 3-year prognostic score for adults with cystic fibrosis.

J Cyst Fibros. 2017 Mar 18;:

Authors: Nkam L, Lambert J, Latouche A, Bellis G, Burgel PR, Hocine MN

Abstract
BACKGROUND: Therapeutic progress in patients with cystic fibrosis (CF) has resulted in improved prognosis over the past decades. We aim to reevaluate prognostic factors of CF and provide a prognostic score to predict the risk of death or lung transplantation (LT) within a 3-year period in adult patients.
METHODS: We developed a logistic model using data from the French CF Registry and combined the coefficients into a prognostic score. The discriminative abilities of the model and the prognostic score were assessed by c-statistic. The prognostic score was validated using a 10-fold cross-validation.
RESULTS: The risk of death or LT within 3years was related to eight characteristics. The development and the validation provided excellent results for the prognostic score; the c-statistic was 0.91 and 0.90 respectively.
CONCLUSION: The score developed to predict 3-year death or LT in adults with CF might be useful for clinicians to identify patients requiring specialized evaluation for LT.

PMID: 28330773 [PubMed - as supplied by publisher]

ZNHIT3 is defective in PEHO syndrome, a severe encephalopathy with cerebellar granule neuron loss.

Brain. 2017 Mar 01;:

Authors: Anttonen AK, Laari A, Kousi M, Yang YJ, Jääskeläinen T, Somer M, Siintola E, Jakkula E, Muona M, Tegelberg S, Lönnqvist T, Pihko H, Valanne L, Paetau A, Lun MP, Hästbacka J, Kopra O, Joensuu T, Katsanis N, Lehtinen MK, Palvimo JJ, Lehesjoki AE

Abstract
Progressive encephalopathy with oedema, hypsarrhythmia, and optic atrophy (PEHO) syndrome is an early childhood onset, severe autosomal recessive encephalopathy characterized by extreme cerebellar atrophy due to almost total granule neuron loss. By combining homozygosity mapping in Finnish families with Sanger sequencing of positional candidate genes and with exome sequencing a homozygous missense substitution of leucine for serine at codon 31 in ZNHIT3 was identified as the primary cause of PEHO syndrome. ZNHIT3 encodes a nuclear zinc finger protein previously implicated in transcriptional regulation and in small nucleolar ribonucleoprotein particle assembly and thus possibly to pre-ribosomal RNA processing. The identified mutation affects a highly conserved amino acid residue in the zinc finger domain of ZNHIT3. Both knockdown and genome editing of znhit3 in zebrafish embryos recapitulate the patients' cerebellar defects, microcephaly and oedema. These phenotypes are rescued by wild-type, but not mutant human ZNHIT3 mRNA, suggesting that the patient missense substitution causes disease through a loss-of-function mechanism. Transfection of cell lines with ZNHIT3 expression vectors showed that the PEHO syndrome mutant protein is unstable. Immunohistochemical analysis of mouse cerebellar tissue demonstrated ZNHIT3 to be expressed in proliferating granule cell precursors, in proliferating and post-mitotic granule cells, and in Purkinje cells. Knockdown of Znhit3 in cultured mouse granule neurons and ex vivo cerebellar slices indicate that ZNHIT3 is indispensable for granule neuron survival and migration, consistent with the zebrafish findings and patient neuropathology. These results suggest that loss-of-function of a nuclear regulator protein underlies PEHO syndrome and imply that establishment of its spatiotemporal interaction targets will be the basis for developing therapeutic approaches and for improved understanding of cerebellar development.

PMID: 28335020 [PubMed - as supplied by publisher]

Mutations in the leukemia inhibitory factor receptor (LIFR) gene and Lifr deficiency cause urinary tract malformations.

Hum Mol Genet. 2017 Mar 08;:

Authors: Kosfeld A, Brand F, Weiss AC, Kreuzer M, Goerk M, Martens H, Schubert S, Schäfer AK, Riehmer V, Hennies I, Bräsen JH, Pape L, Amann K, Krogvold L, Bjerre A, Daniel C, Kispert A, Haffner D, Weber RG

Abstract
Congenital anomalies of the kidneys and urinary tract (CAKUT) are the most common cause of chronic kidney disease in children. As CAKUT is a genetically heterogeneous disorder and most cases are genetically unexplained, we aimed to identify new CAKUT causing genes. Using whole-exome sequencing and trio-based de novo analysis, we identified a novel heterozygous de novo frameshift variant in the leukemia inhibitory factor receptor (LIFR) gene causing instability of the mRNA in a patient presenting with bilateral CAKUT and requiring kidney transplantation at one year of age. LIFR encodes a transmembrane receptor utilized by IL-6 family cytokines, mainly by the leukemia inhibitory factor (LIF). Mutational analysis of 121 further patients with severe CAKUT yielded two rare heterozygous LIFR missense variants predicted to be pathogenic in three unrelated patients. LIFR mutants showed decreased half-life and cell membrane localization resulting in reduced LIF-stimulated STAT3 phosphorylation. LIFR showed high expression in human fetal kidney and the human ureter, and was also expressed in the developing murine urogenital system. Lifr knockout mice displayed urinary tract malformations including hydronephrosis, hydroureter, ureter ectopia, and, consistently, reduced ureteral lumen and muscular hypertrophy, similar to the phenotypes observed in patients carrying LIFR variants. Additionally, a form of cryptorchidism was detected in all Lifr-/- mice and the patient carrying the LIFR frameshift mutation. Altogether, we demonstrate heterozygous novel or rare LIFR mutations in 3.3% of CAKUT patients, and provide evidence that Lifr deficiency and deactivating LIFR mutations cause highly similar anomalies of the urogenital tract in mice and humans.

PMID: 28334964 [PubMed - as supplied by publisher]