Fusion genes result from genomic structural changes, which can lead to alterations in gene expression that supports tumor development. The aim of the study was to use fusion genes as a tool to ...identify new breast cancer (BC) genes with a role in BC progression.
Fusion genes from breast tumors and BC cell lines were collected from publications. RNA-Seq data from tumors and cell lines were retrieved from databanks and analyzed for fusions with SOAPfuse or the analysis was purchased. Fusion genes identified in both tumors (n = 1724) and cell lines (n = 45) were confirmed by qRT-PCR and sequencing. Their individual genes were ranked by selection criteria that included correlation of their mRNA level with copy number. The expression of the top ranked gene was measured by qRT-PCR in normal tissue and in breast tumors from an exploratory cohort (n = 141) and a validation cohort (n = 277). Expression levels were correlated with clinical and pathological factors as well as the patients' survival. The results were followed up in BC cohorts from TCGA (n = 818) and METABRIC (n = 2509).
Vacuole membrane protein 1 (VMP1) was the most promising candidate based on specific selection criteria. Its expression was higher in breast tumor tissue than normal tissue (p = 1x10-4), and its expression was significantly higher in HER2 positive than HER2 negative breast tumors in all four cohorts analyzed. High expression of VMP1 associated with breast cancer specific survival (BCSS) in cohort 1 (hazard ratio (HR) = 2.31, CI 1.27-4.18) and METABRIC (HR = 1.26, CI 1.02-1.57), and also after adjusting for HER2 expression in cohort 1 (HR = 2.03, CI 1.10-3.72). BCSS was not significant in cohort 2 or TCGA cohort, which may be due to differences in treatment regimens.
The results suggest that high VMP1 expression is a potential marker of poor prognosis in HER2 positive BC. Further studies are needed to elucidate how VMP1 could affect pathways supportive of tumorigenesis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose
The microphthalmia‐associated transcription factor (Mitf) gene is crucial for development of the retinal pigment epithelium (RPE) and photoreceptors. Loss of function mutations in this gene ...can cause ocular hypopigmentation, microphthalmia and blindness. Mice heterozygous for the Mitfmi‐wh/+ mutation have been used as a model for Waardenburg and Tietz syndromes in humans. The compound heterozygote Mitfmi‐wh/Mitfmi has two different mutant alleles in the Mitf gene each of which have quite severe effects on the phenotype. The purpose of this study was to examine changes over time in retinal function and structure in these mice, between 1 and 5 months of age, to elucidate the rate of progression of the retinal degenerations.
Methods
B6‐Mitfmi‐wh/+ and B6‐Mitfmi‐wh/Mitfmi mice were examined and compared to C5BL/6J mice as control. Mice were anesthetized by an intraperitoneal injection of 40 mg/kg‐1 Ketamine and 4 mg/kg‐1 Xylazine. Fundus and optical coherence tomography (OCT) images were obtained with a Micron IV. Flash electroretinography (ERG) from mice with a corneal electrode was used to determine retinal function.
Results
Fundus images from all mutant mice show hypopigmentation at 1 month, with large non‐pigmented areas forming at later stages. Mitfmi‐wh/+ mice are either blind or not at 1 month, with the ERG normal in amplitude in some animals and absent in others. The Mitfmi‐wh/+ mice with ERG responses at 1 month show slow retinal degeneration, with reduced responses at 5 months. Mitfmi‐wh/Mitfmi mice show either abnormal ERG responses at 1 month, or a flat ERG. The ERG responses in some of the Mitfmi‐wh/Mitfmi mice decrease with time, and at 4 months is flat. OCT images reveal that retinal layers in animals with flat ERG are thinner than in mice showing reduced ERG, but abnormally thin in both.
Conclusions
We conclude that Mitfmi‐wh/Mitfmi mutant mice show evidence of fast retinal degeneration. The Mitfmi‐wh/+ mutant mice are either blind at 1 month or show evidence of slow degeneration. Mice with these Mitf mutations may serve as models of retinal degenerations progressing at different rates, due to mutations in a gene expressed in the RPE.
We have previously reported suggestive linkage of type 2 diabetes mellitus to chromosome 10q. We genotyped 228 microsatellite markers in Icelandic individuals with type 2 diabetes and controls ...throughout a 10.5-Mb interval on 10q. A microsatellite, DG10S478, within intron 3 of the transcription factor 7-like 2 gene (TCF7L2; formerly TCF4) was associated with type 2 diabetes (P = 2.1 × 10−9). This was replicated in a Danish cohort (P = 4.8 × 10−3) and in a US cohort (P = 3.3 × 10−9). Compared with non-carriers, heterozygous and homozygous carriers of the at-risk alleles (38% and 7% of the population, respectively) have relative risks of 1.45 and 2.41. This corresponds to a population attributable risk of 21%. The TCF7L2 gene product is a high mobility group box-containing transcription factor previously implicated in blood glucose homeostasis. It is thought to act through regulation of proglucagon gene expression in enteroendocrine cells via the Wnt signaling pathway.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
We previously mapped susceptibility to stroke to chromosome 5q12. Here we finely mapped this locus and tested it for association with stroke. We found the strongest association in the gene encoding ...phosphodiesterase 4D (PDE4D), especially for carotid and cardiogenic stroke, the forms of stroke related to atherosclerosis. Notably, we found that haplotypes can be classified into three distinct groups: wild-type, at-risk and protective. We also observed a substantial disregulation of multiple PDE4D isoforms in affected individuals. We propose that PDE4D is involved in the pathogenesis of stroke, possibly through atherosclerosis, which is the primary pathological process underlying ischemic stroke.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The study describes the identification of type VI secretion systems (T6SSs) in Moritella viscosa, the aetiological agent of winter ulcer disease. Despite the availability of commercial vaccines, M. ...viscosa causes significant financial losses in salmonid farming. The T6SS transports bacterial proteins from the cell into the environment or directly into host cells, and has been implicated with bacterial virulence. The aim of the study was to identify potential T6SSs in M. viscosa and to determine whether it possesses active T6S, providing further insight into the biology of the bacterium.
The genome of M. viscosa 06/09/139 was screened for homology with known T6SS encoding genes. Two genetically distinct loci, termed Moritella Type Six Secretion 1 and 2 (mts1 and mts2), were identified as encoding putative T6SSs. Each locus contained known T6S core genes. The mts2 locus contained species specific genes, some of which have not previously been connected with T6S. The mts1 locus showed sequence homology and synteny to T6SSs of the fish pathogen Aliivibrio salmonicida and a non-pathogenic Moritella sp. PE36. The mts2 locus was more similar to a Vibrio parahaemolyticus T6SS. A functional T6SS was confirmed through identification of secreted Mts1-M, a hemolysin coregulated protein (Hcp) which is a part of the secretion system. Both virulent and avirulent M. viscosa isolates expressed two genes encoding Hcp, mts1-M and mts2-M. The results show that M. viscosa has a functional T6S, but the role of the secretion system and possible connections with virulence need further examination.
Stroke is one of the most complex diseases, with several subtypes, as well as secondary risk factors, such as hypertension, hyperlipidemia, and diabetes, which, in turn, have genetic and ...environmental risk factors of their own. Here, we report the results of a genomewide search for susceptibility genes for the common forms of stroke. We cross-matched a population-based list of patients with stroke in Iceland with an extensive computerized genealogy database clustering 476 patients with stroke within 179 extended pedigrees. Linkage to 5q12 was detected, and the LOD score at this locus meets the criteria for genomewide significance (multipoint allele-sharing LOD score of 4.40,
P=3.9×10
−6). A 20-cM region on 5q was physically and genetically mapped to obtain accurate marker order and intermarker distances. This locus on 5q12, which we have designated as “
STRK1,” does not correspond to known susceptibility loci for stroke or for its risk factors and represents the first mapping of a locus for common stroke.
Iceland Gudmundsdottir, Thorunn
The European Company,
01/2006
Book Chapter
Introduction1. Over the decade or so that Iceland has been a member of the European Economic Area (EEA), Icelandic company lawhas been amended on numerous occasions to bring it into line with ...Community law.In the explanatory memorandum to a bill amending Icelandic company law, later adopted by the Althing as Act No. 2/1995 on public limited companies, reference was made to a proposal for a Community regulation on a European company as well as to a proposed directive on employee involvement in such a company. The proposed regulation was intended to simplify and make possible the merger and establishment of holding companies and joint ventures by companies from different Member States. The proposed directive outlined three different ways to guarantee employee involvement in the new European company. The explanatory memorandum stated that although Icelandic law did not (yet) contain any provisions on employee involvement, Iceland should be able to choose one of the three methods described in the proposed directive, if the other EFTA countries and the EU Member States were able to do so. Many organisations and entities were asked to comment on the bill and their comments were submitted to the Althing. However, no particular questions were raised regarding the Statute for a European company (SE).2. Pursuant to a resolution dated 13 December 2002, the Althing authorised the government to adopt two EEA joint committee decisions integrating into the EEA Agreement Council Regulation (EC) No. 2157/2001 of 8 October 2001 on the Statute for a European company (SE) (the ‘Regulation’) and Council Directive 2001/86/EC of 8 October 2001 supplementing the Statute for a European company with regard to the involvement of employees (the ‘Directive’).
Iceland Gudmundsdottir, Thorunn
The European Company,
01/2006
Book Chapter
Introduction1. Over the decade or so that Iceland has been a member of the European Economic Area (EEA), Icelandic company lawhas been amended on numerous occasions to bring it into line with ...Community law.In the explanatory memorandum to a bill amending Icelandic company law, later adopted by the Althing as Act No. 2/1995 on public limited companies, reference was made to a proposal for a Community regulation on a European company as well as to a proposed directive on employee involvement in such a company. The proposed regulation was intended to simplify and make possible the merger and establishment of holding companies and joint ventures by companies from different Member States. The proposed directive outlined three different ways to guarantee employee involvement in the new European company. The explanatory memorandum stated that although Icelandic law did not (yet) contain any provisions on employee involvement, Iceland should be able to choose one of the three methods described in the proposed directive, if the other EFTA countries and the EU Member States were able to do so. Many organisations and entities were asked to comment on the bill and their comments were submitted to the Althing. However, no particular questions were raised regarding the Statute for a European company (SE).2. Pursuant to a resolution dated 13 December 2002, the Althing authorised the government to adopt two EEA joint committee decisions integrating into the EEA Agreement Council Regulation (EC) No. 2157/2001 of 8 October 2001 on the Statute for a European company (SE) (the ‘Regulation’) and Council Directive 2001/86/EC of 8 October 2001 supplementing the Statute for a European company with regard to the involvement of employees (the ‘Directive’).
Increased morbidity and higher prevalence of medication use commonly coexists among the elderly. When managed appropriately, older patients can benefit from drug therapy. However, drug related ...problems are more frequent and more serious in the elderly. The aim of the study was to assess the quality of medication use in older people at hospital admission.
A retrospective medical record review was performed for patients 70 years and older who had an unplanned admission to the internal medicine and geriatric units at Landspitali University Hospital in 2007. Among the sampled medical records, 913 met inclusion criteria. Assessment was carried out using 15 drug-specific quality indicators.
Mean age was 80.9 years and 54.5% were women. Mean number of drugs at admission was 7.0 for women and 6.5 for men (p=0.047). The prevalence of having one or more quality indicators on admission was 48.4%. Women were more likely to have a quality indicator than men (women 56.2%, men 39.9%). The probability also increased with increasing age and number of drugs.
The quality of drug therapy among older patients at hospital admission appears to be suboptimal. A more accurate estimate of the problem could be obtained through a prospective study where drug regimens are correlated with symptoms and reason for admission. Additional studies are also needed in the outpatient setting. Such studies could provide more accurate evidence and assist policy making towards improved quality of drug prescribing for a growing number of older patients.
elderly, quality indicators, hospitalization, drugs, inappropriate prescribing.
PDF
