GWAS links variants in neuronal development and actin remodeling related loci with pseudoexfoliation syndrome without glaucoma

Pseudoexfoliation syndrome (PEXS) is an age-related elastosis, strongly associated with the development of secondary glaucoma. It is clearly suggested that PEXS has a genetic component, but this has not been extensively studied. Here, a genome-wide association study (GWAS) using a DNA-pooling approach was conducted to explore the potential association of genetic variants with PEXS in a Polish population, including 103 PEXS patients without glaucoma and 106 perfectly (age- and gender-) matched controls. Individual sample TaqMan genotyping was used to validate GWAS-selected single-nucleotide polymorphism (SNP) associations. Multivariate binary logistic regression analysis was applied to develop a prediction model for PEXS. In total, 15 SNPs representing independent PEXS susceptibility loci were selected for further validation in individual samples. For 14 of these variants, significant differences in the allele and genotype frequencies between cases and controls were identified, of which 12 remained significant after Benjamini-Hochberg adjustment. The minor allele of five SNPs was associated with an increased risk of PEXS development, while for nine SNPs, it showed a protective effect. Beyond the known LOXL1 variant rs2165241, nine other SNPs were located within gene regions, including in OR11L1, CD80, TNIK, CADM2, SORBS2, RNF180, FGF14, FMN1, and RBFOX1 genes. None of these associations with PEXS has previously been reported. Selected SNPs were found to explain nearly 69% of the total risk of PEXS development. The overall risk prediction accuracy for PEXS, expressed by the area under the ROC curve (AUC) value, increased by 0.218, from 0.672 for LOXL1 rs2165241 alone to 0.89 when seven additional SNPs were included in the proposed 8-SNP prediction model. In conclusion, several new susceptibility loci for PEXS without glaucoma suggested that neuronal development and actin remodeling are potentially involved in either PEXS onset or inhibition or delay of its conversion to glaucoma

New recurrent BRCA1/2 mutations in Polish patients with familial breast/ovarian cancer detected by next generation sequencing

BACKGROUND: Targeted PCR-based genetic testing for BRCA1 and BRCA2 can be performed at a lower cost than full gene testing; however, it may overlook mutations responsible for familial breast and/or ovarian cancers. In the present study, we report the utility of next generation sequencing (NGS) to identify new pathogenic variants of BRCA1/2. METHODS: BRCA1 and BRCA2 exons were amplified using the Ion AmpliSeq BRCA1/2 Panel and sequenced on the Ion Torrent PGM sequencer in 512 women with familial and/or only early onset breast and/or ovarian cancers who were negative for selected BRCA1/2 mutations. RESULTS: 146 single nucleotide variants (SNVs) and 32 indels were identified. Of them, 14 SNVs and 17 indels were considered as pathogenic or likely pathogenic. One and 18 pathogenic mutations had been detected previously in the Polish and other populations, respectively, and 12 deleterious mutations were previously unknown. Eight mutations were recurrent; Q563X (BRCA1), N3124I (BRCA2) and c.4516delG (BRCA1) were found in eight, six and four patients, respectively, and two other mutations (c.9118-2A > G and c.7249delCA in BRCA2) were detected in three patients each. Altogether, BRCA1/2 pathogenic mutations were identified in 52 out of 512 (10%) patients. CONCLUSIONS: NGS substantially improved the detection rates of a wide spectrum of mutations in Polish patients with familial breast and/or ovarian cancer. Although targeted screening for specific BRCA1 mutations can be offered to all Polish breast or ovarian cancer patients, NGS-based testing is justified in patients with breast or ovarian cancer likely related to BRCA1/2 who test negative for the selected BRCA1/2 pathogenic mutations. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12920-015-0092-2) contains supplementary material, which is available to authorized users

A Strong Neutrophil Elastase Proteolytic Fingerprint Marks the Carcinoma Tumor Proteome

Proteolytic cascades are deeply involved in critical stages of cancer progression. During the course of peptide-wise analysis of shotgun proteomic data sets representative of colon adenocarcinoma (AC) and ulcerative colitis (UC), we detected a cancer-specific proteolytic fingerprint com- posed of a set of numerous protein fragments cleaved C-terminally to V, I, A, T, or C residues, significantly over-represented in AC. A peptide set linked by a common VIATC cleavage consensus was the only prominent can- cer-specific proteolytic fingerprint detected. This se- quence consensus indicated neutrophil elastase as a source of the fingerprint. We also found that a large frac- tion of affected proteins are RNA processing proteins associated with the nuclear fraction and mostly cleaved within their functionally important RNA-binding domains. Thus, we detected a new class of cancer-specific pep- tides that are possible markers of tumor-infiltrating neu- trophil activity, which often correlates with the clinical outcome. Data are available via ProteomeXchange with identifiers: PXD005274 (Data set 1) and PXD004249 (Data set 2). Our results indicate the value of peptide-wise anal- ysis of large global proteomic analysis data sets as op- posed to protein-wise analysis, in which outlier differen- tial peptides are usually neglected

Limited predictive value of achieving beneficial plasma (Z)-endoxifen threshold level by CYP2D6 genotyping in tamoxifen-treated Polish women with breast cancer

Background Tamoxifen, the most frequently used drug for treating estrogen receptor-positive breast cancer, must be converted into active metabolites to exert its therapeutic efficacy, mainly through CYP2D6 enzymes. The objective of this study was to investigate the impact of CYP2D6 polymorphisms on (Z)-endoxifen-directed tamoxifen metabolism and to assess the usefulness of CYP2D6 genotyping for identifying patients who are likely to have insufficient (Z)-endoxifen concentrations to benefit from standard therapy. Methods Blood samples from 279 Polish women with breast cancer receiving tamoxifen 20 mg daily were analyzed for CYP2D6 genotype and drug metabolite concentration. Steady-state plasma levels of tamoxifen and its 14 metabolites were measured by using the ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method. Results In nearly 60 % of patients, including over 30 % of patients with fully functional CYP2D6, (Z)-endoxifen concentration was below the predefined threshold of therapeutic efficacy. The most frequently observed CYP2D6 genotype was EM/PM (34.8 %), among which 83.5 % of patients had a combination of wild-type and *4 alleles. Plasma concentration of five metabolites was significantly correlated with CYP2D6 genotype. For the first time, we identified an association between decreased (E/Z)-4-OH-N-desmethyl-tamoxifen-β-D-glucuronide levels (r 2  = 0.23; p < 10 −16 ) and increased CYP2D6 functional impairment. The strongest correlation was observed for (Z)-endoxifen, whose concentration was significantly lower in groups of patients carrying at least one CYP2D6 null allele, compared with EM/EM patients. The CYP2D6 genotype accounted for plasma level variability of (Z)-endoxifen by 27 % (p < 10 −16 ) and for the variability of metabolic ratio indicating (Z)-endoxifen-directed metabolism of tamoxifen by 51 % (p < 10 −43 ). Conclusions The majority of breast cancer patients in Poland may not achieve a therapeutic level of (Z)-endoxifen upon receiving a standard dose of tamoxifen. This finding emphasizes the limited value of CYP2D6 genotyping in routine clinical practice for identifying patients who might not benefit from the therapy. In its place, direct monitoring of plasma steady-state (Z)-endoxifen concentration should be performed to personalize and optimize the treatment

Evaluation of a short RNA within Prostate Cancer Gene 3 in the predictive role for future cancer using non-malignant prostate biopsies.

BACKGROUND: Prostate Cancer 3 (PCA3) is a long non-coding RNA (ncRNA) upregulated in prostate cancer (PCa). We recently identified a short ncRNA expressed from intron 1 of PCA3. Here we test the ability of this ncRNA to predict the presence of cancer in men with a biopsy without PCa. METHODS: We selected men whose initial biopsy did not identify PCa and selected matched cohorts whose subsequent biopsies revealed PCa or benign tissue. We extracted RNA from the initial biopsy and measured PCA3-shRNA2, PCA3 and PSA (qRT-PCR). RESULTS: We identified 116 men with and 94 men without an eventual diagnosis of PCa in 2-5 biopsies (mean 26 months), collected from 2002-2008. The cohorts were similar for age, PSA and surveillance period. We detected PSA and PCA3-shRNA2 RNA in all samples, and PCA3 RNA in 90% of biopsies. The expression of PCA3 and PCA3-shRNA2 were correlated (Pearson's r = 0.37, p<0.01). There was upregulation of PCA3 (2.1-fold, t-test p = 0.02) and PCA3-shRNA2 (1.5-fold) in men with PCa on subsequent biopsy, although this was not significant for the latter RNA (p = 0.2). PCA3 was associated with the future detection of PCa (C-index 0.61, p = 0.01). This was not the case for PCA3-shRNA2 (C-index 0.55, p = 0.2). CONCLUSIONS: PCA3 and PCA3-shRNA2 expression are detectable in historic biopsies and their expression is correlated suggesting co-expression. PCA3 expression was upregulated in men with PCa diagnosed at a future date, the same did not hold for PCA3-shRNA2. Futures studies should explore expression in urine and look at a time course between biopsy and PCa detection

Påvirkning av Covid-19 på kunderelasjoner

I denne oppgaven ble det gjennomført en undersøkelse der formålet var å finne ut hvordan kunderelasjonene til KTM Shipping har blitt påvirket av den pågående covid-19 pandemien. For å kunne besvare dette spørsmålet ble det gjennomført en kvalitativ undersøkelse, der en var i kontakt med kundene. Funnene fra undersøkelsen ble drøftet sammen med teorien som er valgt for denne oppgaven. Det som kom fra undersøkelsen, var at en av relasjonene som ble undersøkt opplevde en negativ påvirkning og svekkelse av relasjonen. De andre relasjonene som var undersøkt viste seg til å ikke være påvirket i større grad enn at det måtte skje en tilpasning på hvordan møtene var holdt. Det vil si fra fysiske, til digitale. I tillegg til dette, kom det fram at relasjonene kunne bli påvirket av konsekvensene av en potensiell smitte utbrudd.The title of this thesis is “The impact of Covid-19 on customer relations” and this thesis had the purpose of finding out how the customer relationships with KTM Shipping have been affected by the ongoing Covid-19 pandemic. To answer this question, qualitative research has been completed by interviewing both customers of KTM Shipping and employees at KTM Shipping. The findings of this research were discussed alongside the relevant literature which was chosen for this thesis. The results of this research show that while there was one relationship that was negatively impacted by the measurements implemented by governments to control the spread of covid-19, most of the other relations were not influenced to a greater extent than that there had to be adjustments on meeting digital instead of meeting physically. Besides that, it appeared that customer relations could be affected by the consequences of a potential covid-19 outbreak

The role of Tai Chi in managing Parkinson's disease: A review of therapeutic mechanisms and clinical outcomes

Tai Chi is a traditional Chinese martial art characterized by maintaining postures and performing slow, fluid movements. This exercise involves actions like extending the knees and hips, shifting weight, flexing, rotating the trunk, and coordinating arm movements. All of this improves balance, motor coordination, and also mental stability. In this review, we explore the relationship between practicing Tai Chi and the improvement of physical abilities in individuals with Parkinson's Disease. We will also compare Tai Chi to other alternative methods for improving physical abilities

miRNA signature of urine extracellular vesicles shows the involvement of inflammatory and apoptotic processes in diabetic chronic kidney disease

Background: The aim of this study was to investigate the role of urine-derived extracellular vesicles (uEVs) in diabetic kidney disease (DKD) in patients diagnosed with type 2 diabetes mellitus (T2DM). Methods: UEVs were characterized by size distribution and microRNA content by next-generation small RNA sequencing and quantitative reverse transcription PCR. Results: A subset of sixteen miRNAs enriched in T2DM patients with DKD, including hsa-miR-514a-5p, hsa-miR‑451a, hsa-miR-126-3p, hsa-miR-214, or hsa-miR‑503 was identified. Eight miRNAs as hsa-miR-21-3p, hsa-miR-4792, hsa-miR‑375, hsa-miR-1268a, hsa-miR-501-5p, or hsa-miR-582 were downregulated. Prediction of potential target genes and pathway enrichment analysis of the Kyoto Encyclopedia of Genes and Genomes (KEGG) confirmed possible functions related to cellular processes such as apoptosis, inflammation, and tissue remodeling, that promote diabetic complications, such as DKD. Among them, hsa-miR-375, hsa-miR-503, and hsa-miR-451a make important contribution. Additionally, downregulated hsa-miR-582-5p has not been reported so far in any diabetes-related pathways. Conclusions: This study revealed the most significant miRNAs in uEVs of patients with T2DM. However, as this is a bioinformatic prediction that we performed based on the putative targets of the identified miRNAs. Thus, further in vitro functional studies are needed to confirm our findings. Knowing the fact that EVs are crucial in transferring miRNAs, there is a great need toto discover their involvement in the pathomechanism of T2DM-related kidney disease

Halogenated imidazole derivatives block RNA polymerase II elongation along mitogen inducible genes

<p>Abstract</p> <p>Background</p> <p>Aberrant activation of protein kinases is one of the essential oncogenic driving forces inherent to the process of tumorigenesis. The protein kinase CK2 plays an important role in diverse biological processes, including cell growth and proliferation as well as in the governing and transduction of prosurvival signals. Increased expression of CK2 is a hallmark of some cancers, hence its antiapoptotic properties may be relevant to cancer onset. Thus, the designing and synthesis of the CK2 inhibitors has become an important pursuit in the search for cancer therapies.</p> <p>Results</p> <p>Using a high-throughput microarray approach, we demonstrate that two potent inhibitors of CK2, 4,5,6,7-tetrabromo-benzimidazole (TBBz) and 2-Dimethyloamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT), blocked mitogen induced mRNA expression of immediate early genes. Given the impact of these inhibitors on the process of transcription, we investigated their effects on RNA Polymerase II (RNAPII) elongation along the mitogen inducible gene, <it>EGR1 </it>(early growth response 1), using chromatin immunoprecipitation (ChIP) assay. ChIP analysis demonstrated that both drugs arrest RNAPII elongation. Finally, we show that CDK9 kinase activity, essential for the triggering of RNAPII elongation, was blocked by TBBz and to lesser degree by DMAT.</p> <p>Conclusions</p> <p>Our approach revealed that small molecules derived from halogenated imidazole compounds may decrease cell proliferation, in part, by inhibiting pathways that regulate transcription elongation.</p

Factors associated with diversity, quantity and zoonotic potential of ectoparasites on urban mice and voles

Wild rodents are important hosts for tick larvae but co-infestations with other mites and insects are largely neglected. Small rodents were trapped at four study sites in Berlin, Germany, to quantify their ectoparasite diversity. Host-specific, spatial and temporal occurrence of ectoparasites was determined to assess their influence on direct and indirect zoonotic risk due to mice and voles in an urban agglomeration. Rodent-associated arthropods were diverse, including 63 species observed on six host species with an overall prevalence of 99%. The tick Ixodes ricinus was the most prevalent species, found on 56% of the rodents. The trapping location clearly affected the presence of different rodent species and, therefore, the occurrence of particular host-specific parasites. In Berlin, fewer temporary and periodic parasite species as well as non-parasitic species (fleas, chiggers and nidicolous Gamasina) were detected than reported from rural areas. In addition, abundance of parasites with low host-specificity (ticks, fleas and chiggers) apparently decreased with increasing landscape fragmentation associated with a gradient of urbanisation. In contrast, stationary ectoparasites, closely adapted to the rodent host, such as the fur mites Myobiidae and Listrophoridae, were most abundant at the two urban sites. A direct zoonotic risk of infection for people may only be posed by Nosopsyllus fasciatus fleas, which were prevalent even in the city centre. More importantly, peridomestic rodents clearly supported the life cycle of ticks in the city as hosts for their subadult stages. In addition to trapping location, season, host species, body condition and host sex, infestation with fleas, gamasid Laelapidae mites and prostigmatic Myobiidae mites were associated with significantly altered abundance of I. ricinus larvae on mice and voles. Whether this is caused by predation, grooming behaviour or interaction with the host immune system is unclear. The present study constitutes a basis to identify interactions and vector function of rodent-associated arthropods and their potential impact on zoonotic diseases