| 91871. |
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| 91872. |
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| 91873. |
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| 91874. |
- Larne, Olivia, et al.
(författare)
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miQ - a novel microRNA based diagnostic and prognostic tool for prostate cancer.
- 2013
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136. ; 132:12, s. 2867-2875
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Tidskriftsartikel (refereegranskat)abstract
- Today, the majority of prostate tumours are detected at early stages with uncertain prognosis. Therefore, we set out to identify early predictive markers of prostate cancer with aggressive progression characteristics. We measured the expression of microRNAs (miRNA) using qRT-PCR in FFPE prostatic tissue samples from a Swedish cohort of 49 patients with prostate cancer and 25 without cancer and found eight of 14 preselected miRNAs to discriminate between the two groups. Subsequently four discriminatory miRNAs were combined to a quota, denoted the miRNA index quote (miQ); ((miR-96-5p x miR-183-5p)/(miR-145-5p x miR221-5p)). The advantage using a quote is increased discrimination, no need for house-keepings, and most important it may be an advantage considering the heterogeneity of the disease. miQ was found to successfully predict diagnosis (p<0.0001) with high accuracy (AUC=0.931) that was verified in an independent Dutch cohort and three external cohorts, and significantly outperforming PSA. Importantly, miQ also has prognostic power to predict aggressiveness of tumours (AUC=0.895), metastatic statues (AUC=0.827), and overall survival (p=0.0013, Wilcoxon test HR=6.5, median survival 2 versus 5 years), verified in the Dutch cohort. In this preliminary study we propose that miQ has potential to be used as a clinical tool for prostate cancer diagnosis and as a prognostic marker of disease progression. © 2012 Wiley Periodicals, Inc.
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| 91875. |
- Larne, Olivia, et al.
(författare)
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miR-145 suppress the androgen receptor in prostate cancer cells and correlates to prostate cancer prognosis
- 2015
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Ingår i: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 36:8, s. 858-866
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Tidskriftsartikel (refereegranskat)abstract
- Androgen signalling through the androgen receptor (AR) is essential for prostate cancer initiation, progression and transformation to the lethal castration-resistant state. The aim of this study was to characterize the mechanisms by which miR-145 deregulation contribute to prostate cancer progression. The miR-145 levels, measured by quantitative reverse transcription-polymerase chain reaction, were found to inversely correlate with occurrence of metastases, survival and androgen deprivation therapy response in a well-characterized prostate cancer cohort. Introduction of ectopic miR-145 in prostate cancer cells generated an inhibitory effect on the AR at both transcript and protein levels as well as its activity and downstream targets prostate-specific antigen (PSA), kallikrein-related peptidase 2 and TMPRSS2. The regulation was shown to be mediated by direct binding using Ago2-specific immunoprecipitation, but there was also indication of synergetic AR activation. These findings were verified in clinical prostate specimens by demonstrating inverse correlations between miR-145 and AR expression as well as serum PSA levels. In addition, miR-145 was found to regulate androgen-dependent cell growth in vitro. Our findings put forward novel possibilities of therapeutic intervention, as miR-145 potentially could decrease both the stem cells and the AR expressing bulk of the tumour and hence reduce the transformation to the deadly castration-resistant form of prostate cancer. © The Author 2015. Published by Oxford University Press. All rights reserved.
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| 91876. |
- Larne, Olivia, et al.
(författare)
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MIR-183 in prostate cancer cells positively regulates synthesis and serum levels of prostate-specific antigen
- 2015
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Ingår i: European Urology. - : Elsevier. - 0302-2838 .- 1873-7560. ; 68:4, s. 581-588
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Tidskriftsartikel (refereegranskat)abstract
- Background Factors affecting serum prostate-specific antigen (PSA) levels in men are clinically important, but apart from effects mediated through the androgen receptor, they are poorly understood. Objective To investigate whether microRNA (miRNA) affects the synthesis and serum levels of PSA. Design, setting, and participants Reporter assays with PSA and KLK2 3′ untranslated regions (UTRs) to confirm posttranscriptional regulation was followed by high-throughput screening of the effect of 1129 miRNAs on PSA levels using reverse phase protein arrays (RPPAs) to identify individual regulatory miRNAs. The candidate miRNAs were investigated further in vitro by Western blot, immunofluorometrics, activity assays, quantitative reverse transcriptase polymerase chain reaction, reporter assays, and growth assays. Prostate levels of miR-183 were compared with PSA transcript and serum PSA levels in prostate cancer cohorts. Outcome measurements and statistical analysis RankProd was used to evaluate the RPPAs, and the Student t test was used for the in vitro experiments. The Spearman and Cuzick tests were used in the patient material, and overall survival was analysed by Kaplan-Meier and log-rank analysis. Results and limitations Gain-of-function screenings identified 32 miRNAs that increase PSA levels. One of these, miR-183, was found to bind the 3′ UTR of PSA directly and increase both protein and messenger RNA levels. Prostatic levels of miR-183 and serum PSA showed correlation in a cohort of 74 men. In addition, miR-183 promotes cellular growth in vitro and correlates to clinical parameters such as World Health Organisation grade and clinical progression. Conclusions The synthesis and serum levels of PSA are directly affected by miR-183 and may be a factor to consider when PSA values are evaluated in clinical settings. Patient summary These findings offer novel insights into the regulation of prostate-specific antigen and may eventually affect clinical decision making in prostate cancer. © 2014 European Association of Urology.
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| 91877. |
- Larne, Olivia
(författare)
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Translational and functional analyses of microRNAs in prostate cancer
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aims of this thesis were to identify microRNAs (miRNAs) with prostate cancer prognostic and diagnostic potential, to discover miRNAs with therapeutic capacity against prostate cancer, and to investigate if prostate specific antigen (PSA) is miRNA regulated. Prostate cancer is a globally spread disease with low mortality, but some patients develop an aggressive lethal form of prostate cancer with severe morbidity. In the early nineties the PSA test was introduced as a blood based test that has high sensitivity for prostate cancer. The possibility to set prognosis by this test is however limited. For men that may develop incurable aggressive prostate cancer, there is therefore an urgent need for novel biomarkers and therapeutics, so that these are detected and more correctly treated at an early stage. miRNAs are molecules that have post-transcriptional regulatory capacity, by binding their target transcripts. The miRNA profile has been shown to be deregulated in cancer cells, which can lead to elevated or inhibited expression of their targets. The effect can be increased or decreased expression of oncogenes or tumour suppressors respectively. By analysing prostatic tissues from men with and without prostate cancer, we found that the levels of four miRNAs (miR-96, -145, -183, and -221), in an algorithm denoted miQ, can in addition to set the correct diagnosis, predominantly of PSA, predict metastases and tumour aggressiveness. Further, patients with high miQ levels lived three years longer after surgery compared to patients with low miQ. The miQ profile is highly translational to the clinic. The biological function of miR-145 was investigated and found to inhibit androgen induced cell growth and to regulate the androgen receptor; therefore it is a good therapeutic candidate. Exploring functionality of miR-96 in prostate cancer, we found that it has good potential to be targeted therapeutically. The antiproliferative protein FOXO1 was found to be a direct target of miR-96, explaining the cell growth promoting effect of miR-96. By an extensive screening for miRNAs that affect PSA levels, we found that miR-183 increases its expression. This implies that miR-183 has an effect on the PSA test, today used for detection of prostate cancer. All three functionally studied miRNAs have individually diagnostic and prognostic properties, but combined into miQ the individual qualities enhances each other. To conclude, we found a miRNA profile that is associated with both prostate cancer prognosis and diagnosis, miRNAs have therapeutic potential, and can influence the PSA detection method.
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| 91878. |
- Larnert, G, et al.
(författare)
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Positioning improves the oral and pharyngeal swallowing function in children with cerebral palsy
- 1995
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Ingår i: Acta Pædiatrica. - : Wiley. - 1651-2227 .- 0803-5253. ; 84:6, s. 689-693
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Tidskriftsartikel (refereegranskat)abstract
- Many children with cerebral palsy have feeding difficulties. The aim of this study was to investigate if trunk and neck positioning influenced oral and pharyngeal swallow. Five children with feeding problem aged 3-10 years with cerebral palsy were examined using videofluoroscopy. All children had tetraplegia with dystonia, i.e. poor head control and poor trunk stability. All children had gross aspiration and posterior oral leak. The pharyngeal phase was delayed in relation to the oral phase. Two children had pharyngeal retention. The children were positioned with both an extended and flexed neck. The flexed neck position was combined with a 30 degrees reclined sitting position. In both positions they were given puree with barium and liquid barium during video recording. In the reclined position with the neck flexed, aspiration decreased in all five children, oral leak diminished in two children and retention improved in one child.
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| 91879. |
- Larnert, Per, et al.
(författare)
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Hip displacement in relation to age and gross motor function in children with cerebral palsy
- 2014
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Ingår i: Journal of Children's Orthopaedics. - : SAGE Publications. - 1863-2521 .- 1863-2548. ; 8:2, s. 129-134
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Hip dislocation in cerebral palsy (CP) is a serious complication. By radiographic screening and prophylactic surgery of children at risk most dislocations can be prevented. CPUP, the Swedish CP registry and follow-up program, includes annual radiographic examinations of children at Gross Motor Function Classification System (GMFCS) levels III-V. Data from CPUP were analysed to assess the risk of hip displacement in relation to GMFCS levels and age. Methods: All children at GMFCS levels III-V (N = 353) whose first radiographic screening occurred before 3 years of age were followed between the ages 2-7 years. Migration percentages (MPs) were recorded annually (1,664 pelvic radiographs) and analysed using discrete time survival analysis. Results: The risk of hip displacement between 2 years and 7 years of age was significantly (p < 0.05) higher for children at GMFCS level V during the entire study period. The risk was highest at 2-3 years of age and decreased significantly (p < 0.001) with each year of age (OR = 0.71, 95 % CI 0.60-0.83). The cumulative risk at age 7 years for those at GMFCS V for MP ≥ 40 % was 47 % (95 % CI 37-58). The corresponding risk at GMFCS IV was 24 % (16-34) and at GMFCS III 23 % (12-42). Conclusions: Children at GMFCS V have a significantly higher risk of hip displacement compared with children at GMFCS III-IV. The risk is highest at 2-3 years of age. The results support a surveillance program including radiographic hip examinations as soon as the diagnosis of severe CP is suspected.
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| 91880. |
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