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Serrano-Fernandez P.,University of Rostock | Serrano-Fernandez P.,Pomeranian Academy of Medicine | Moller S.,University of Rostock | Moller S.,University of Lubeck | And 5 more authors.
Autoimmunity | Year: 2010

Despite its generalized use as drug therapy for multiple sclerosis (MS), the molecular mechanisms of action of interferon beta (IFNB) are still poorly understood. IFNB therapy is long-termed and clinical effects are not immediate, therefore reliable early biomarkers for IFNB activity should maintain a differential expression over time, but longitudinal studies at a transcriptional level have been rare. Microarrays were used to monitor 18 IFNB1b treated MS patients at four time points spanning a period of 1 year. Genes showing in the majority of patients the greatest and most consistent changes in their expression levels were studied. Interferon regulated genes were significantly overrepresented. Fifteen markers were differentially expressed during all three time points and followed a consistent time course pattern: EIF2AK2, IFI6, IFI44, IFI44L, IFIH1, IFIT1, IFIT2, IFIT3, ISG15, MX1, OASL, RSAD2, SN, XAF1 and the marker 238704-at. Except for the last one, these biomarkers were all formerly identified as being indicative for IFNB activity. Expression changes were both early detectable and long lasting and could thus be optimal biomarkers for IFNB activity in long-term studies. Other known biomarkers of IFNB activity were found to be differentially expressed just for certain periods after therapy onset: Interleukin-8 was a short lasting marker and changes in STAT1 were detected with delay. © 2010 Informa UK Ltd.


Iwanowski P.S.,Medical University of Bialystok | Panasiuk B.,Medical University of Bialystok | Van Buggenhout G.,University Hospital Leuven | Murdolo M.,University Cattolica Sacro Cuore | And 10 more authors.
American Journal of Medical Genetics, Part A | Year: 2011

The aim of this study was to obtain a quantitative definition of Wolf-Hirschhorn syndrome (WHS) through systematic phenotypic analyses in a group of six children with 4p15.32→pter, 4p15.33→pter, or 4p16.1→pter monosomy (considered together as M4p16.1). These results were used for evaluation of the phenotypic effects of a double chromosome imbalance in one child with 4p16.1→pter monosomy and additional 11q23.3→qter trisomy. Children with pure M4p16.1 presented with a total of 227 clinical and morphological traits, of which 119 were positive in at least two of them. These traits overlap to a great extent with clinical criteria defining the WHS phenotype. Among the 103 traits identified in the child with unbalanced translocation der(4)t(4;11)(p16.1;q23.3), most clinical and developmental traits (but only 11 morphological) were found to be shared by WHS children with pure M4p16.1 and at least one reported patient with pure 11q trisomy. Forty-six traits of this child corresponded solely to those identified in at least one child with pure M4p16.1. Only five traits of the hybrid phenotype were present in at least one child with pure distal 11q trisomy but in none of the present children with pure M4p16.1. In conclusion, most of the morphological traits of the hybrid phenotype in the child with der(4)t(4;11)(p16.1;q23.3) can be attributed to the M4p16.1, whereas their overlap with those associated with pure distal 11q trisomy is less evident. Phenotype analyses based on the same systematic data acquisition may be useful in understanding the phenotypic effects of different chromosome regions in complex rearrangements. © 2011 Wiley-Liss, Inc.


Talseth-Palmer B.A.,University of Newcastle | Wijnen J.T.,Leiden University | Brenne I.S.,University of Newcastle | Brenne I.S.,University of Tromso | And 16 more authors.
International Journal of Cancer | Year: 2013

Two colorectal cancer (CRC) susceptibility loci have been found to be significantly associated with an increased risk of CRC in Dutch Lynch syndrome (LS) patients. Recently, in a combined study of Australian and Polish LS patients, only MLH1 mutation carriers were found to be at increased risk of disease. A combined analysis of the three data-sets was performed to better define this association. This cohort-study includes three sample populations combined totaling 1,352 individuals from 424 families with a molecular diagnosis of LS. Seven SNPs, from six different CRC susceptibility loci, were genotyped by both research groups and the data analyzed collectively. We identified associations at two of the six CRC susceptibility loci in MLH1 mutation carriers from the combined LS cohort: 11q23.1 (rs3802842, HR = 2.68, p ≤ 0.0001) increasing risk of CRC, and rs3802842 in a pair-wise combination with 8q23.3 (rs16892766) affecting age of diagnosis of CRC (log-rank test; p ≤ 0.0001). A significant difference in the age of diagnosis of CRC of 28 years was observed in individuals carrying three risk alleles compared to those with 0 risk alleles for the pair-wise SNP combination. A trend (due to significance threshold of p ≤ 0.0010) was observed in MLH1 mutation carriers towards an increased risk of CRC for the pair-wise combination (p = 0.002). This study confirms the role of modifier loci in LS. We consider that LS patients with MLH1 mutations would greatly benefit from additional genotyping of SNPs rs3802842 and rs16892766 for personalized risk assessment and a tailored surveillance program. What's new? Three independent genetic studies recently examined the role of common colorectal susceptibility loci in the risk for early-onset colorectal cancer in patients with Lynch syndrome, a dominantly inherited cancer syndrome characterized by early-onset epithelial cancers. Here, the authors performed a new analysis of the combined datasets from two of the earlier studies and confirmed associations at two of six colorectal cancer susceptibility loci in this larger dataset. These associations were only observed in carriers of MLH1 mutations, one of several mutations defining Lynch syndrome carriers. One consequence of this study is that MLH1mutation carriers should receive additional genotyping at the two loci to individually tailor tumor surveillance. Copyright © 2012 UICC.


Shroff R.,Great Ormond Street Hospital for Children NHS Foundation Trust | Aitkenhead H.,Great Ormond Street Hospital for Children NHS Foundation Trust | Costa N.,Great Ormond Street Hospital for Children NHS Foundation Trust | Trivelli A.,G Gaslini Institute | And 59 more authors.
Journal of the American Society of Nephrology | Year: 2016

Angiotensin-converting enzyme inhibitors (ACEi) for renin-angiotensin-aldosterone system (RAAS) blockade are routinely used to slow CKD progression. However, Vitamin D may also promote renoprotection by suppressing renin transcription through cross-talk between RAAS and Vitamin D -fibroblast growth factor-23 (FGF-23)-Klotho pathways. To determine whether Vitamin D levels influence proteinuria and CKD progression in children, we performed a post hoc analysis of the Effect of Strict Blood Pressure Control and ACE Inhibition on Progression of CKD in Pediatric Patients (ESCAPE) cohort. In 167 children (median EGFR 51 ml/min per 1.73 m2), serum 25-hydroxyvitaminD(25(OH)D),FGF-23, andKlotho levelsweremeasuredatbaselineandafteramedian8months onACEi.Childrenwith lower 25(OH)D levels had higher urinary protein/creatinine ratios at baseline (P=0.03) and at follow-up (P=0.006). Levels of 25(OH)D and serum Vitamin D -binding protein were not associated, but 25(OH)D #50 nmol/L associated with higher diastolicBP(P=0.004).ACEi therapy alsoassociatedwith increasedKlotho levels (P<0.001). The annualized loss of EGFR was inversely associated with baseline 25(OH)D level (P<0.001, r=0.32). Five-year renal survivalwas 75%in patientswith baseline 25(OH)D$50 nmol/L and 50%in thosewith lower 25(OH) D levels (P<0.001). This renoprotective effect remained significant but attenuated with ACEi therapy (P=0.05). Renal survival increased 8.2% per 10 nmol/L increase in 25(OH)D (P=0.03), independent of EGFR; proteinuria, BP, and FGF-23 levels; and underlying renal diagnosis. In children with CKD, 25(OH)D≥50 nmol/L was associatedwith greater preservation of renal function. This effect was present but attenuated with concomitant ACEi therapy. © 2016 by the American Society of Nephrology.


Talseth-Palmer B.A.,University of Newcastle | Talseth-Palmer B.A.,Hunter Medical Research Institute | Brenne I.S.,Hunter Medical Research Institute | Brenne I.S.,Institute of Pharmacy | And 12 more authors.
Journal of Medical Genetics | Year: 2011

Objective: Recently, six colorectal cancer (CRC) susceptibility loci have been identified, and two single-nucleotide polymorphisms (SNPs)drs16892766 (8q23.3) and rs3802842 (11q23.1)dfrom two of these regions have been found to be significantly associated with an increased CRC risk in patients with Lynch syndrome. The objective of this study was to genotype nine SNPs within these six loci to confirm previous findings and investigate whether they act as modifiers of disease risk in patients with Lynch syndrome. Design: The patient cohort consisted of 684 mutation-positive patients with Lynch syndrome from 298 Australian and Polish families. Nine SNPs were genotyped: rs16892766 (8q23.3), rs7014346 and rs6983267 (8q24.21), rs10795668 (10p14), rs3802842 (11q23.1), rs10318 and rs4779584 (15q13.3), and rs4939827 and rs4464148 (18q21.1). The data were analysed to investigate possible associations between the presence of variant alleles and the risk of developing disease. Results: An association between SNP rs3802842 on chromosome 11q23.1 and rs16892766 on chromosome 8q23.3 and the risk of developing CRC and age of diagnosis was found in MLH1 mutation carriers. Female MLH1 mutation carriers harbouring the homozygous variant genotype for SNP rs3802842 have the highest risk of developing CRC. When the number of risk alleles for the two SNPs combined was analysed, a difference of 24 years was detected between individuals carrying three risk alleles and those carrying no risk alleles. Conclusion: The authors were able to replicate the association between the CRC susceptibility loci on chromosomes 8q23.3 and 11q23 and the risk of developing CRC in patients with Lynch syndrome, but the association could only be detected in MLH1 mutation carriers in this study.

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