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| 2. |
- Bratt, Ola, et al.
(författare)
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Satsa på MRT för diagnostik av prostatacancer.
- 2015
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Ingår i: Läkartidningen. - : Läkartidningen Förlag. - 1652-7518 .- 0023-7205. ; 112:Apr 20, s. DFZ3-
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 3. |
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| 4. |
- Guan, Jikui, et al.
(författare)
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Anaplastic lymphoma kinase L1198F and G1201E mutations identified in anaplastic thyroid cancer patients are not ligand-independent.
- 2017
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 2017:8, s. 11566-11578
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Tidskriftsartikel (refereegranskat)abstract
- Activating mutations in full length anaplastic lymphoma kinase (ALK) have been reported in neuroblastoma and in anaplastic thyroid cancer. ALK-L1198F and ALK-G1201E mutations were originally identified in anaplastic thyroid cancer (ATC) and characterized as constitutively activating mutations. In this study, we employed in vitro cell culture assays together with biochemical and in vivo Drosophila analyses to characterize their sensitivity to either activation by the FAM150A (AUG-β) and FAM150B (AUG-α) ALK ligands or inhibition by ALK inhibitors. Here we report that neither ALK-L1198F nor ALK-G1201E mutations result in ligand independent gain-of-function (GOF) activity in either in vitro biochemical analysis or the various model systems employed. ALK-L1198F is activated by the FAM150 (AUG) ligands and its ligand-dependant activity is similar to the wild type full length ALK receptor. ALK-G1201E is only very weakly activated by the FAM150 (AUG) ligands, most likely due to impaired protein stability. We conclude that neither ALK-L1198F nor ALK-G1201E displays ligand independent kinase activity, with ALK-L1198F belonging to the class of ligand dependent ALK mutations which are not constitutively active but that responds to ligand activation, while the ALK-G1201E mutation generates an unstable receptor with very low levels of kinase activity.
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| 5. |
- Guan, Jikui, et al.
(författare)
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FAM150A and FAM150B are activating ligands for anaplastic lymphoma kinase
- 2015
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Ingår i: eLIFE. - Cambridge : eLife Sciences Publications. - 2050-084X. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Aberrant activation of anaplastic lymphoma kinase (ALK) has been described in a range of human cancers, including non-small cell lung cancer and neuroblastoma (Hallberg and Palmer, 2013). Vertebrate ALK has been considered to be an orphan receptor and the identity of the ALK ligand(s) is a critical issue. Here we show that FAM150A and FAM150B are potent ligands for human ALK that bind to the extracellular domain of ALK and in addition to activation of wild-type ALK are able to drive 'superactivation' of activated ALK mutants from neuroblastoma. In conclusion, our data show that ALK is robustly activated by the FAM150A/B ligands and provide an opportunity to develop ALK-targeted therapies in situations where ALK is overexpressed/activated or mutated in the context of the full length receptor.
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| 6. |
- Hugosson, Fredrik, 1972-
(författare)
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Deciphering the Alk signaling pathway in Drosophila
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In Drosophila melanogaster the visceral mesoderm (VM) develops during embryogenesis in a process where myoblasts become specified to generate two distinct cell types, the founder cells (FCs) and the fusion competent myoblasts (FCMs) that consequently fuses. The cell specification is dependent on cell signaling mediated by the receptor tyrosine kinase (RTK) Anaplastic lymphoma kinase (Alk) and its ligand Jelly belly (Jeb), how this further sets up different identity programs that drive myoblasts to differentiate into FCs and FCMs is still not well understood.We have analysed whether the Midkine (MDK)/Pleiotrophin (PTN) homologues in Drosophila, Miple1 and Miple2 activate the Alk RTK in vivo. Earlier results from cell culture experiments suggested that vertebrate MDK/PTN is capable of activating ALK, findings that have become controversial with other studies showing contradictory results. We wanted to use Drosophila that have conserved homologues of both MDK/PTN and ALK, to address the question in vivo. We analysed the contribution of Miple in Alk dependent developmental processes such as visceral mesoderm (VM) specification during embryogenesis and in body size regulation of adult flies. Specification of VM as well as body size are not effected by loss of Miple proteins, and over expression of Miple proteins do not effect VM specification or body size. All together we conclude that there is no evidence that Miple1 or Miple2 can activate Alk in vivo. We found that loss of Miple protein effect the median lifespan of the fly which is reduced, interestingly the over expression of Miple proteins can promote an increased median life span in Drosophila.We have also analysed how Alk RTK signaling regulates the Gli-like transcription factor Lame duck (Lmd) in vivo on a post-translational level. It has already been reported that Lmd plays an essential role in specification of FCMs in the somatic mesoderm during embryogenesis. We detect Lmd protein exclusively in FCMs of VM in control embryos, but in Alk mutants Lmd protein is present in all cells of VM and opposite to this when Alk is activated in all cells in VM by over expression of Jeb this results in total loss of Lmd protein. This suggests that Alk signaling is regulating Lmd, and we additionally show that Lmd persist in FCMs in mutants where VM is specified but where myoblast fusion do not occur, supporting that Alk activity in FCs is regulating the downregulation of Lmd in FCMs upon fusion.Finally we have characterised the Rap1GEF C3G in vivo in Drosophila. In cell culture systems, the GTPase Rap1 has been identified to mediate Alk signaling and that this is regulated by the GEF C3G and interestingly the Drosophila C3G is expressed in the FCs of VM. We generated deletion mutants of C3G which exhibit semi-lethality and reduced life span, but no defects in visceral mesoderm development during embryogenesis. Instead we detected distinct phenotypes in somatic muscles of 3rd instar mutant larvae, with detachment and mistargeting of muscles, which effect localisation of integrins. We suggest that Drosophila C3G regulates Rap1 via inside out signaling of integrins which in turn effects cell adhesion in vivo in Drosophila larval muscles.
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| 7. |
- Hugosson, Fredrik, et al.
(författare)
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The Drosophila Midkine/Pleiotrophin Homologues Miple1 and Miple2 Affect Adult Lifespan but Are Dispensable for Alk Signaling during Embryonic Gut Formation
- 2014
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 9:11
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Tidskriftsartikel (refereegranskat)abstract
- Midkine (MDK) and Pleiotrophin (PTN) are small heparin-binding cytokines with closely related structures. The Drosophila genome harbours two genes encoding members of the MDK/PTN family of proteins, known as miple1 and miple2. We have investigated the role of Miple proteins in vivo, in particular with regard to their proposed role as ligands for the Alk receptor tyrosine kinase (RTK). Here we show that Miple proteins are neither required to drive Alk signaling during Drosophila embryogenesis, nor are they essential for development in the fruit fly. Additionally we show that neither MDK nor PTN can activate hALK in vivo when ectopically co-expressed in the fly. In conclusion, our data suggest that Alk is not activated by MDK/PTN related growth factors Miple1 and Miple 2 in vivo.
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| 8. |
- Maier, Stephan E, 1959, et al.
(författare)
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Prostate Cancer Diffusion-Weighted Magnetic Resonance Imaging: Does the Choice of Diffusion-Weighting Level Matter?
- 2022
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Ingår i: Journal of Magnetic Resonance Imaging. - : Wiley. - 1053-1807 .- 1522-2586. ; 55:3, s. 842-853
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Tidskriftsartikel (refereegranskat)abstract
- Background Diffusion-weighted magnetic resonance imaging plays an important role in multiparametric assessment of prostate lesions. The derived apparent diffusion coefficient (ADC) could be a useful quantitative biomarker for malignant growth, but lacks acceptance because of low reproducibility. Purpose To investigate the impact of the choice of diffusion-weighting levels (b-values) on contrast-to-noise ratio and quantitative measures in prostate diffusion-weighted MRI. Study Type Retrospective and simulation based on published data. Subjects Patient cohort (21 men with Prostate Imaging-Reporting and Data System (PI-RADS) version 2 score >= 3) from a single-center study. Field Strength/Sequence 3 T/diffusion-weighted imaging with single-shot echo-planar imaging. Assessment Both clinical data and simulations based on previously acquired data were used to quantify the influence of b-value choice in normal peripheral zone (PZ) and PZ tumor lesions. For clinical data, ADC was determined for different combinations of b-values. Contrast-to-noise ratio and quantitative diffusion measures were simulated for a wide range of b-values. Statistical Tests Tissue ADC and the lesion-to-normal tissue ADC ratios of different b-value combinations were compared with paired two-tailed Student's t-tests. A P-value Findings about b-value dependence derived from clinical data and from simulations agreed with each other. Provided measurement was limited to two b-values, simulation-derived optimal b-value choices coincided with PI-RADSv2 recommendations. For two-point measurements, ADC decreased by 15% when the maximum b-value increased from 1000 to 1500 seconds/mm(2), but corresponding lesion-to-normal tissue ADC ratio showed no significant change (P = 0.86 for acquired data). Simulations with three or more measurement points produced ADCs that declined by only 8% over this range of maximum b-value. Corresponding ADC ratios declined between 2.6% (three points) and 3.8% (21 points). Simulations also revealed an ADC reduction of about 19% with the shorter echo and diffusion time evaluated. Data Conclusion The comprehensive assessment of b-value dependence permits better formulation of protocol and analysis recommendations for obtaining reproducible results in prostate cancer diffusion-weighted MRI. Level of Evidence 4 Technical Efficacy Stage 2
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| 9. |
- Mendoza-Garcia, Patricia, 1988-, et al.
(författare)
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The Zic family homologue Odd-paired regulates Alk expression in Drosophila.
- 2017
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 13:4
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Tidskriftsartikel (refereegranskat)abstract
- The Anaplastic Lymphoma Kinase (Alk) receptor tyrosine kinase (RTK) plays a critical role in the specification of founder cells (FCs) in the Drosophila visceral mesoderm (VM) during embryogenesis. Reporter gene and CRISPR/Cas9 deletion analysis reveals enhancer regions in and upstream of the Alk locus that influence tissue-specific expression in the amnioserosa (AS), the VM and the epidermis. By performing high throughput yeast one-hybrid screens (Y1H) with a library of Drosophila transcription factors (TFs) we identify Odd-paired (Opa), the Drosophila homologue of the vertebrate Zic family of TFs, as a novel regulator of embryonic Alk expression. Further characterization identifies evolutionarily conserved Opa-binding cis-regulatory motifs in one of the Alk associated enhancer elements. Employing Alk reporter lines as well as CRISPR/Cas9-mediated removal of regulatory elements in the Alk locus, we show modulation of Alk expression by Opa in the embryonic AS, epidermis and VM. In addition, we identify enhancer elements that integrate input from additional TFs, such as Binou (Bin) and Bagpipe (Bap), to regulate VM expression of Alk in a combinatorial manner. Taken together, our data show that the Opa zinc finger TF is a novel regulator of embryonic Alk expression.
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| 10. |
- Möller, Fredrik, et al.
(författare)
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Prostate Cancers in the Prostate-specific Antigen Interval of 1.8-3 ng/ml: Results from the Göteborg-2 Prostate Cancer Screening Trial.
- 2024
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Ingår i: European urology. - 1873-7560.
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Tidskriftsartikel (refereegranskat)abstract
- Magnetic resonance imaging (MRI) and targeted biopsies reduce overdiagnosis of prostate cancer (PC). It is uncertain how this strategy performs for low prostate-specific antigen (PSA) levels.To investigate the Prostate Imaging Reporting and Data System (PI-RADS) distribution, frequency, and characteristics of screen-detected PC with PSA of 1.8-<3 ng/ml and 3-<10 ng/ml.In the population-based Göteborg-2 screening study, 17974 men choose to participate by having a PSA test (2015-2020). One-third of the participants (n=6006) were randomized to arm 3, men with a PSA value of ≥1.8 ng/ml were recommended for MRI. Men with positive MRI (PI-RADS 3-5) had four targeted biopsies from each MRI-visible lesion.Clinically significant PC was defined as Gleason score ≥3+4.A total of 6006 men were included. The median age was 55.9 yr (interquartile range [IQR] 52.6-59.6). Of them, 4929 (82%) had PSA of <1.8 ng/ml, 670 (11%) had PSA of 1.8-<3 ng/ml (low-PSA group, median PSA 2.1 ng/ml [IQR 1.9-2.5]), and 377 (6.3%) had PSA of 3-<10 ng/ml (high-PSA group, median PSA 3.9 ng/ml [IQR 3.3-5.0]). PI-RADS scores of 3, 4, and 5 were observed in 7.8%, 15%, and 1.0% of men in the low-PSA group, and in 6.9%, 17%, and 5.3% of men in the high-PSA group, respectively. PC was found in 64 men (41%, 95% confidence interval [CI] 0.33-0.49) with positive MRI findings in the low-PSA group, of whom 33 (21%) had Gleason 6 (insignificant PC) and 31 (20%) had Gleason ≥7 (significant PC). In the high-PSA group, PC was detected in 61 men (56%, 95% CI 0.46-0.66), of whom 26 (24%) had Gleason 6 (insignificant PC) and 35 (32%) had Gleason ≥7 (significant PC). Limitations include results from only a single screening round.A non-negligible number of men with PSA 1.8-3 ng/ml have clinically significant PC. Whether a delay in the diagnosis of these tumors until they reached PSA ≥3 ng/ml would impair their chance of cure remains to be evaluated.We studied screening using prostate-specific antigen (PSA) and magnetic resonance imaging in men with PSA 1.8-3 ng/ml. We found a non-negligible number of potentially harmful prostate cancers in these men.
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