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  • 51.
    Ohlson, Nina
    et al.
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi.
    Bergh, Anders
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi.
    Persson, Malin Lindhagen
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi.
    Wikström, Pernilla
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi.
    Castration rapidly decreases local insulin-like growth factor-1 levels and inhibits its effects in the ventral prostate in mice.2006Ingår i: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 66, nr 16, s. 1687-1697Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: The mechanisms by which castration induces prostate involution are largely unknown. METHODS: Early responses to castration in mouse ventral prostate (VP) were explored by quantitative microscopy, cDNA array expression, quantitative RT-PCR, and Western blot analysis. As several changes occurred in the insulin-like growth factor (IGF) system this was studied in more detail. Laser micro-dissection was used to localize sites of IGF-1 and IGF-1 receptor (IGF-R1) production. IGF-1 protein levels and IGF-R1 mediated signaling via insulin regulated substrate 1 and 2 (IRS-1 and 2) were examined. IGF-1 was injected into the VP in intact, and castrated mice and effects studied 1 day later. RESULTS: IGF-1 and IGF binding protein 2 (IGFBP-2) mRNA were rapidly reduced whereas IGFBP-3 and IGF-R1 mRNA were increased after castration. IGF-1 was principally produced in the stromal compartment, while IGF-R1 was produced in both epithelial and stromal cells. IGF-1 and IRS-1 protein levels were decreased 1 and 3 days after castration, respectively, while IRS-2 was unchanged. Inactivating phosphorylation of IRS-1 at serine 307 was increased 1 day after castration, and activating phosphorylation at tyrosine 612 was decreased 2 days later. These changes were accompanied by decreased cell proliferation and increased cell death in the glandular and vascular compartment. Local injection of IGF-1 increased vascular density and epithelial cell proliferation in intact mice, but had no effect in castrated animals. CONCLUSION: Decreased IGF-1 levels and action may mediate some of the key features of castration-induced prostate involution.

  • 52.
    Ohlson, Nina
    et al.
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi.
    Bergh, Anders
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi.
    Stattin, Pär
    Umeå universitet, Medicinsk fakultet, Kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Wikström, Pernilla
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi.
    Castration-induced epithelial cell death in human prostate tissue is related to locally reduced IGF-1 levels.2007Ingår i: Prostate, ISSN 1097-0045, Vol. 67, nr 1, s. 32-40Artikel i tidskrift (Refereegranskat)
  • 53.
    Ohlson, Nina
    et al.
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi.
    Wikström, Pernilla
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi.
    Stattin, Pär
    Umeå universitet, Medicinsk fakultet, Kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Bergh, Anders
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi.
    Cell proliferation and apoptosis in prostate tumors and adjacent non-malignant prostate tissue in patients at different time-points after castration treatment.2005Ingår i: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 62, nr 4, s. 307-315Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Androgen ablation is the standard treatment for advanced prostate cancer but the short-term cellular effects are largely unknown. METHODS: Sextant prostate biopsies were taken from 77 prostate cancer patients before and 1-10 days after castration treatment. Apoptosis, cell proliferation, and morphology were studied in malignant and non-malignant tissue, using stereological and immunohistochemical methods. RESULTS: Epithelial cell proliferation was significantly decreased both in non-malignant and malignant epithelium already 1 day after therapy. It remained low until day 7, but increased thereafter in the remaining non-malignant epithelial cells and in some tumors. Epithelial cell apoptosis was significantly increased during the first week and then returned to basal levels. The maximal apoptotic indexes, seven- and two-times the intact levels in the non-malignant and malignant glands, respectively, were found at days 3-4 or even earlier in the tumors. Signs of tumor shrinkage such as glandular collapse and decreased tumor cell size were observed from day 3 in most tumors. DISCUSSION: The present study shows that the magnitude and kinetics of the response to castration in the normal human prostate is very similar to the response previously described in rodents. We also demonstrate that most human prostate tumors rapidly respond to castration indicating the need for further evaluation of when and how to best monitor the effects of hormone ablation therapy in prostate cancer patients. (c) 2004 Wiley-Liss, Inc.

  • 54. Pernemalm, Maria
    et al.
    Orre, Lukas M
    Lengqvist, Johan
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Lewensohn, Rolf
    Lehtiö, Janne
    Evaluation of three principally different intact protein prefractionation methods for plasma biomarker discovery.2008Ingår i: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 7, nr 7, s. 2712-2722Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The aim of this study was to evaluate three principally different top-down protein prefractionation methods for plasma: high-abundance protein depletion, size fractionation and peptide ligand affinity beads, focusing in particular on compatibility with downstream analysis, reproducibility and analytical depth. Our data clearly demonstrates the benefit of high-abundance protein depletion. However, MS/MS analysis of the proteins eluted from the high-abundance protein depletion column show that more proteins than aimed for are removed and, in addition, that the depletion efficacy varies between the different high-abundance proteins. Although a smaller number of proteins were identified per fraction using the peptide ligand affinity beads, this technique showed to be both robust and versatile. Size fractionation, as performed in this study, focusing on the low molecular weight proteome using a combination of gel filtration chromatography and molecular weight cutoff filters, showed limitations in the molecular weight cutoff precision leading detection of high molecular weight proteins and, in the case of the cutoff filters, high variability. GeLC-MS/MS analysis of the fractionation methods in combination with pathway analysis demonstrates that increased fractionation primarily leads to high proteome coverage of pathways related to biological functions of plasma, such as acute phase reaction, complement cascade and coagulation. Further, the prefractionation methods in this study induces limited effect on the proportion of tissue proteins detected, thereby highlighting the importance of extensive or targeted downstream fractionation.

  • 55.
    Rudolfsson, Stina Häggström
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Jonsson, Andreas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Collin, Ola
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Hormonal regulation and functional role of vascular endothelial growth factor a in the rat testis.2004Ingår i: Biol Reprod, ISSN 0006-3363, Vol. 70, nr 2, s. 340-7Artikel i tidskrift (Refereegranskat)
  • 56.
    Sandlund, Johanna
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Ljungberg, Börje
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Lindh, Gudrun
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Rasmuson, Torgny
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hypoxia-inducible factor-2alpha mRNA expression in human renal cell carcinoma2009Ingår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 48, nr 6, s. 909-914Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background. Hypoxia-inducible factor (HIF)-2alpha is upregulated in hypoxia or by inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene. In a number of malignancies, increased HIF-2alpha expression may indicate worse prognosis. The aim of this study was to evaluate the prognostic information of HIF-2alpha mRNA expression in renal cell carcinoma (RCC). Material and methods. HIF-2alpha mRNA was quantified by real time polymerase chain reaction (rt-PCR) in tumour tissue samples from 202 patients. Samples from 50 corresponding kidney cortex tissue were analysed as controls. mRNA levels were evaluated in relation to tumour cell type, TNM stage, nuclear grade and disease specific survival. Results. The levels of HIF-2alpha mRNA were significantly higher in 168 clear cell (c)RCC than in 23 papillary (p)RCC (p<0.001) or 11 chromophobe (ch)RCC (p<0.006). Among cRCC there was an inverse correlation between HIF-2alpha mRNA levels and TNM stage I and II-IV tumours (p=0.01), and nuclear grade (p=0.006). After a median follow-up time of 99 months (range 34-247), 106 patients had died of RCC. No correlation of HIF-2alpha mRNA to survival was observed. A multivariate analysis of prognostic factors in cRCC showed that TNM stage alone was an independent predictor of prognosis; HIF-2alpha mRNA levels did not add further prognostic information. Discussion. The results demonstrated that HIF-2alpha mRNA levels were higher in cRCC compared to pRCC and chRCC. Furthermore, HIF-2alpha mRNA levels were inversely related to TNM stage and nuclear grade in cRCC.

  • 57.
    Shiryaeva, Liudmila
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Antti, Henrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Kieselbach, Thomas
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Schröder, Wolfgang P.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Two-dimensional difference gel electrophoresis to reveal proteins in plasma associated with high risk prostate cancerManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Prostate cancer is a common but highly variable disease. Conventional methods for prognostication are limited and needed to be complemented by novel biomarkers which could identify clinically significant tumors at a curable timepoint. With the aim to find biomarkers in plasma for high risk prostate cancer, we combined the ProteoMiner technology for protein fractionation with 2-dimentional difference gel electrophoresis (2D-DIGE). Plasma samples from patients with high risk tumors, defined to have bone metastases (M1, N=7) or locally advanced or poorly differentiated prostate cancer (M0, N=14), or benign disease (N=15) were analyzed. As a result of combined univariate and multivariate analyses (orthogonal partial least-squares discriminant analysis, OPLS-DA), 338 protein spots were found to be significantly associated with high risk prostate cancer. Ninety-eight (98) of the spots were successfully identified by LC-MS/MS, and OPLS-DA of those resulted in a reliable method for class separation; M1 vs. M0 vs. B (R2Xcum: 31.1%, R2Y cum: 59.9%, Q2cum: 41.4%, P < 0.0001). The panel of identified potential protein markers for high risk prostate cancer included highly to intermediately abundant plasma proteins involved in key processes such as lipid transport, coagulation, inflammation, and immune responses. Their putative roles for prostate cancer progression are discussed.

  • 58.
    Skytt, Åsa
    et al.
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi.
    Thysell, Elin
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Stattin, Pär
    Umeå universitet, Medicinsk fakultet, Kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Stenman, Ulf-Håkan
    Antti, Henrik
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Wikström, Pernilla
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi.
    SELDI-TOF MS versus prostate specific antigen analysis of prospective plasma samples in a nested case-control study of prostate cancer2007Ingår i: International Journal of Cancer, ISSN 0020-7136, Vol. 121, nr 3, s. 615-20Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    There is an urgent need for better biomarkers for detection of clinically significant prostate cancer (PCa). Recent studies suggest that surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) analysis of serum may provide diagnostic information. The aim of this study was to investigate if PCa cases could be identified by applying predefined SELDI-TOF analysis conditions on prospectively, uniformly collected plasma samples from PCa cases and matched controls. Prospective samples from 387 incident PCa cases and an equal number of controls, matched for age and time for recruitment, were analyzed by SELDI-TOF MS (IMAC30/Cu chip) and multivariate classification analysis. Prospective prostate specific antigen levels were subjected to ROC curve analysis giving an AUC of 0.87 for the total cohort with a median lag time between blood sampling and diagnosis of 6.1 years. No markers were found by SELDI-TOF MS that significantly discriminated between cases and controls in the total cohort or in subanalysis of cases with less than 2 years between blood donation and diagnosis (n = 42). Cases with aggressive disease at the time of diagnosis who gave blood less than 4 years prior to diagnosis (n = 23) could however be separated from their controls (sensitivity 70%, specificity 83%) by a model based on SELDI-TOF MS and OPLS-DA data analysis. We were thus not able to confirm previous results with SELDI-TOF MS identifying men with PCa from healthy individuals, but we report an optimal experimental set-up for verification of markers for early detection of cancer in prospectively collected samples.

  • 59.
    Surowiec, Izabella
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Koc, Mariusz
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Antti, Henrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Moritz, Thomas
    LC-MS/MS profiling for detection of endogenous steroids and prostaglandins in tissue samples2011Ingår i: Journal of Separation Science, ISSN 1615-9306, E-ISSN 1615-9314, Vol. 34, nr 19, s. 2650-2658Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Roles of steroid hormones, and compounds that can influence their levels in cells, are of increasing interest in e.g. cancer research, partly because resistance to hormone therapies often complicates treatment. To elucidate the processes involved, the hormones and related compounds need to be accurately measured. Reversed-phase liquid chromatography with dynamic multiple reaction monitoring mass spectrometric detection in electrospray mode is capable of providing such measurements. Therefore, LC-MS/MS was developed for sensitive, selective analysis of 11 steroid hormones, cholesterol and two prostaglandins. The effects of the tissue matrix, and solid-phase extraction (SPE) sample clean-up, on the LC-MS/MS signals of the hormones were also investigated. The results show that the developed LC-MS/MS method, following SPE clean-up to reduce matrix interference, can detect selected steroids in extracts of mouse tissues. The method provides linear measurements of the steroids at concentrations up to few ng/μL, and limits of detection in the range 0.03–0.2 pg/μL (for some compounds lower than those of previously reported methods).

  • 60.
    Svenson, Ulrika
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Roos, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Long leukocyte telomere length in prostate cancer patients at diagnosis is associated with poor metastasis-free and cancer-specific survival2017Ingår i: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 39, nr 2Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Previous studies have suggested that leukocyte telomere length is associated with risk of developing prostate cancer. Investigations of leukocyte telomere length as a prognostic factor in prostate cancer are, however, lacking. In this study, leukocyte telomere length was investigated both as a risk marker, comparing control subjects and patient risk groups (based on serum levels of prostate-specific antigen, tumor differentiation, and tumor stage), and as a prognostic marker for metastasis-free and cancer-specific survival. Relative telomere length was measured by a well-established quantitative polymerase chain reaction method in 415 consecutively sampled individuals. Statistical evaluation included 162 control subjects without cancer development during follow-up and 110 untreated patients with newly diagnosed localized prostate cancer at the time of blood draw. Leukocyte telomere length did not differ significantly between control subjects and patients, or between patient risk groups. Interestingly, however, and in line with our previous results in breast and kidney cancer patients, relative telomere length at diagnosis was an independent prognostic factor. Patients with long leukocyte telomeres (>= median) had a significantly worse prostate cancer-specific and metastasisfree survival compared to patients with short telomere length. In contrast, for patients who died of other causes than prostate cancer, long relative telomere length was not coupled to shorter survival time. To our knowledge, these results are novel and give further strength to our hypothesis that leukocyte telomere length might be used as a prognostic marker in malignancy.

  • 61.
    Thysell, Elin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Bovinder Ylitalo, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Jernberg, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    A Systems Approach to Prostate Cancer Classification: Letter2017Ingår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 77, nr 24, s. 7131-7132Artikel i tidskrift (Refereegranskat)
  • 62.
    Thysell, Elin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Bovinder Ylitalo, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Jernberg, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Clinically relevant molecular subgroups of prostate cancer bone metastases2018Ingår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 78, nr 16, s. 123-123Artikel i tidskrift (Övrigt vetenskapligt)
  • 63.
    Thysell, Elin
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Moritz, Thomas
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Antti, Henrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Evaluation of metabolic alterations in patient plasma associated with disease aggressiveness in prostate cancerManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    GC-MS was used for the study of plasma metabolite profiles in prostate cancer patients. Multivariate analysis of the acquired data revealed metabolites and metabolite patterns associated with prostate cancer disease progression from benign disease to distant metastases. Moreover, by evaluation of plasma metabolite patterns before and after radical prostatectomy differences associated with biochemical relapse was detected. Specifically we found two unidentified plasma metabolites which showed decreased plasma levels with increased disease progression and, furthermore, increased plasma levels post compared to pre surgery in patients who later experienced biochemical relapse. We hypothesize that those metabolites are consumed by aggressive tumors more than by indolent tumors. Identification of those metabolites are hence crucial, and under-way, in order to enable biological interpretation of the results. We further hypothesized that any tumor-derived metabolite secreted into plasma would show increased concentrations with increased PCa risk. Notably we did not detect any such metabolite, but only a few metabolites which showed increased plasma concentrations in patients with metastases compared to patients with benign disease and low risk PCa. In addition, verification of metabolite markers for metastatic disease detected previously by us and others was made, and included decreased plasma levels of stearic acid and increased levels of pseudouridine with metastatic disease.

  • 64.
    Thysell, Elin
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Surowiec, Izabella
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Hörnberg, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap.
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Johansson, Annika I
    Swedish University of Agricultural Sciences, Umeå.
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Moritz, Thomas
    Swedish University of Agricultural Sciences, Umeå.
    Antti, Henrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Metabolomic characterization of human prostate cancer bone metastases reveals increased levels of cholesterol2010Ingår i: PLoS One, ISSN eISSN-1932-6203, Vol. 5, nr 12, s. e14175-Artikel i tidskrift (Refereegranskat)
    Abstract [sv]

    Dottertumörer vid prostatacancer kan spåras via kolesterolDottertumörer i skelettet hos patienter med prostatacancer innehåller höga nivåer av kolesterol och olika aminosyror. Att mäta nivåerna är därför en möjlig väg för att spåra misstänkta dottertumörer. Det visar forskare vid Umeå universitet i en ny studie.Ofta är det förekomsten av dottertumörer, metastaser, som avgör allvaret vid en cancersjukdom. För att behandla patienter med avancerad prostatacancer är det därför viktigt att hitta och identifiera metastaser på ett tidigt stadium. Metastaser från prostatacancer finns ofta i skelettets ben.I studien har forskarna analyserat normal prostatavävnad och vävnad från benmetastaser från patienter med prostatacancer och andra cancersjukdomar. Forskarna har på detta sätt försökt hitta entydiga mönster som utmärker benmetastaser hos patienter med prostatacancer.Något oväntat fann forskarna höga halter av kolesterol i metastasvävnad från patienter med prostatacancer, jämfört med de andra undersökta vävnaderna.– Tumörcellerna verkar både kunna bilda kolesterol och ta upp kolesterol från omgivningen, till exempel från blodet. Vi tror att kolesterol används till olika processer som är viktiga för en tumörcell, till exempel för att den ska kunna växa och invadera omkringliggande vävnad, förklarar Pernilla Wikström, forskare vid institutionen för medicinsk biovetenskap.Spridd prostatacancer brukar behandlas genom att man blockerar produktionen eller effekten av det manliga könshormonet testosteron, så kallad kastrationsbehandling.– Kolesterol används möjligen också till att göra könshormon och det motverkar i sådana fall kastrationsbehandling. Vi håller nu på att utreda detta vidare, tillägger hon.Forskarna fann även höga nivåer av andra metaboliter, substanser som förekommer vid ämnesomsättning i kroppens celler och vävnader. Bland annat upptäckte de vissa aminosyror, och intressant nog gick några av dessa även att spåra i blod hos patienter med metastaser.För att analysera metaboliterna har forskarna använt sig av Sverigeledande teknik på SLU:s laboratorium för metabolomik vid kemiskt biologiskt centrum (KBC) som förestås av professor Thomas Moritz. Genom att haltbestämma metaboliter i olika vävnader eller kroppsvätskor hoppas forskarna kunna hitta specifika mönster av metaboliter för flera olika sjukdomar. Dessa metaboliter skulle sedan kunna mätas i blod hos patienter som till exempel har misstänkta metastaser.– Min forskargrupp har länge arbetat med att utveckla metoder för att använda metabolomik inom medicinska frågeställningar. Målet är att öka möjligheterna att diagnostisera, förstå och i förlängningen behandla allvarliga sjukdomar, säger Henrik Antti, forskare vid kemiska institutionen och handledare till doktoranden Elin Thysell, som genomfört analyserna.Pernilla Wikström och Henrik Antti, som ansvarat för studien, är överens om att de lyckats väl tack vare ett bra samarbete mellan forskare vid prekliniska och kliniska institutioner. Studien har involverat forskare vid kemiska institutionen och Computational Life Science Cluster (CliC), institutionen för medicinisk biovetenskap, Umeå Plant Science Centre (UPSC), samt kliniska forskare inom patologi, onkologi, ortopedi och urologi vid Umeå universitet. Det faktum att man i Umeå har tillgång till en av få biobanker i världen innehållande benmetastaser från patienter var också avgörande för studiens genomförande.

  • 65.
    Thysell, Elin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Vidman, Linda
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Bovinder Ylitalo, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Jernberg, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Iglesias-Gato, Diego
    Flores-Morales, Amilcar
    Stattin, Pär
    Egevad, Lars
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Gene expression profiles define molecular subtypes of prostate cancer bone metastases with different outcomes and morphology traceable back to the primary tumor2019Ingår i: Molecular Oncology, ISSN 1574-7891, E-ISSN 1878-0261, Vol. 13, nr 8, s. 1763-1777Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Bone metastasis is the lethal end-stage of prostate cancer (PC), but the biology of bone metastases is poorly understood. The overall aim of this study was therefore to explore molecular variability in PC bone metastases of potential importance for therapy. Specifically, genome-wide expression profiles of bone metastases from untreated patients (n = 12) and patients treated with androgen-deprivation therapy (ADT, n = 60) were analyzed in relation to patient outcome and to morphological characteristics in metastases and paired primary tumors. Principal component analysis and unsupervised classification were used to identify sample clusters based on mRNA profiles. Clusters were characterized by gene set enrichment analysis and related to histological and clinical parameters using univariate and multivariate statistics. Selected proteins were analyzed by immunohistochemistry in metastases and matched primary tumors (n = 52) and in transurethral resected prostate (TUR-P) tissue of a separate cohort (n = 59). Three molecular subtypes of bone metastases (MetA-C) characterized by differences in gene expression pattern, morphology, and clinical behavior were identified. MetA (71% of the cases) showed increased expression of androgen receptor-regulated genes, including prostate-specific antigen (PSA), and glandular structures indicating a luminal cell phenotype. MetB (17%) showed expression profiles related to cell cycle activity and DNA damage, and a pronounced cellular atypia. MetC (12%) exhibited enriched stroma-epithelial cell interactions. MetB patients had the lowest serum PSA levels and the poorest prognosis after ADT. Combined analysis of PSA and Ki67 immunoreactivity (proliferation) in bone metastases, paired primary tumors, and TUR-P samples was able to differentiate MetA-like (high PSA, low Ki67) from MetB-like (low PSA, high Ki67) tumors and demonstrate their different prognosis. In conclusion, bone metastases from PC patients are separated based on gene expression profiles into molecular subtypes with different morphology, biology, and clinical outcome. These findings deserve further exploration with the purpose of improving treatment of metastatic PC.

  • 66.
    Thysell, Elin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Ylitalo, Erik B.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Jernberg, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Reply to Isabel Heidegger, Renate Pichler, and Andreas Pircher's Letter to the Editor re: Erik Bovinder Ylitalo, Elin Thysell, Emma Jernberg, et al. Subgroups of Castration-resistant Prostate Cancer Bone Metastases Defined Through an Inverse Relationship Between Androgen Receptor Activity and Immune Response. Eur Urol 2017;71:776-872017Ingår i: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 72, nr 4, s. e104-e105Artikel i tidskrift (Refereegranskat)
  • 67.
    Thysell, Elin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Ylitalo, Erik B.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Jernberg, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Reply to Isabel Heidegger, Renate Pichler, and Andreas Pircher's Letter to the Editor re: Erik Bovinder Ylitalo, Elin Thysell, Emma Jernberg, et al. Subgroups of Castration-resistant Prostate Cancer Bone Metastases Defined Through an Inverse Relationship Between Androgen Receptor Activity and Immune Response. Eur Urol 2017;71:776-872017Ingår i: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 72, nr 4, s. E104-E105Artikel i tidskrift (Refereegranskat)
  • 68.
    Tidehag, Viktor
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Hammarsten, Peter
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Egevad, Lars
    Grantors, Torvald
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Leanderson, Tomas
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Josefsson, Andreas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Hägglöf, Christina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    High density of S100A9 positive inflammatory cells in prostate cancer stroma is associated with poor outcome2014Ingår i: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 50, nr 10, s. 1829-1835Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose: To elucidate if the density of inflammatory cells expressing S100A9 in malignant and surrounding non-malignant prostate tissues is a prognostic marker for outcome in prostate cancer patients. Experimental design: Tissue was obtained from 358 men diagnosed with prostate cancer at transurethral resection of the prostate due to obstructive voiding problems, of which 260 were then followed with watchful waiting. Tissue microarrays of both malignant and non-malignant tissues were stained with an antibody against S100A9. The number of stained inflammatory cells was scored and related to clinical outcome and histopathological parameters of known prognostic value. Results: A high number of inflammatory cells expressing S100A9 in both malignant and surrounding non-malignant tissues were associated with significantly shorter cancer-specific survival. This association remained significant when Gleason score and local tumour stage were analysed together with S100A9 in a Cox regression model. Low number of S100A9 positive cells in non-malignant stroma was correlated to significantly longer cancer-specific survival also in patients with Gleason score 8-10 tumours. S100A9 positive cells in tumour stroma were correlated with Gleason score, hyaluronan, platelet-derived growth factor receptor beta (PDGFR-beta), and androgen receptor (inverse correlation) in tumour stroma. S100A9 positive cells in non-malignant stroma correlated with androgen receptor in this tissue compartment (inverse correlation). Conclusions: A high number of S100A9 positive inflammatory cells in tumour stroma and in non-malignant stroma were associated with shorter cancer-specific survival in prostate cancer patients.

  • 69.
    Tjon-Kon-Fat, Lee-Ann
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Lundholm, Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Schröder, Mona
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wurdinger, Thomas
    Thellenberg-Karlsson, Camilla
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Nilsson, Rolf Jonas Andreas
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Platelets harbor prostate cancer biomarkers and the ability to predict therapeutic response to abiraterone in castration resistant patients2018Ingår i: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 78, nr 1, s. 48-53Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Novel therapies for castration resistant prostate cancer (CRPC) have been introduced in the clinic with possibilities for individualized treatment plans. Best practice of those expensive drugs requires predictive biomarker monitoring. This study used circulating biomarker analysis to follow cancer-derived transcripts implicated in therapy resistance.

    METHOD: The isolated platelet population of blood samples and digital-PCR were used to identify selected biomarker transcripts in patients with CRPC prior chemo- or androgen synthesis inhibiting therapy.

    RESULTS: Fifty patients received either docetaxel (n = 24) or abiraterone (n = 26) therapy, with therapy response rates of 54% and 48%, respectively. Transcripts for the PC-associated biomarkers kallikrein-related peptidase-2 and -3 (KLK2, KLK3), folate hydrolase 1 (FOLH1), and neuropeptide-Y (NPY) were uniquely present within the platelet fraction of cancer patients and not detected in healthy controls (n = 15). In the abiraterone treated cohort, the biomarkers provided information on therapy outcome, demonstrating an association between detectable biomarkers and short progression free survival (PFS) (FOLH1, P < 0.01; KLK3, P < 0.05; and NPY, P < 0.05). Patients with biomarker-negative platelets had the best outcome, while FOLH1 (P < 0.05) and NPY (P = 0.05) biomarkers provided independent predictive information in a multivariate analysis regarding PFS. KLK2 (P < 0.01), KLK3 (P < 0.001), and FOLH1 (P < 0.05) biomarkers were associated with short overall survival (OS). Combining three biomarkers in a panel (KLK3, FOLH1, and NPY) made it possible to separate long-term responders from short-term responders with 87% sensitivity and 82% specificity.

    CONCLUSION: Analyzing tumor-derived biomarkers in platelets of CRPC patients enabled prediction of the outcome after abiraterone therapy with higher accuracy than baseline serum PSA or PSA response.

  • 70.
    Wikström, Pernilla
    et al.
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi. Patologi.
    Bylund, Annika
    Umeå universitet, Medicinsk fakultet, Samhällsmedicin och rehabilitering, Geriatrik. Geriatrik.
    Zhang, Jie-Xian
    Umeå universitet, Medicinsk fakultet, Folkhälsa och klinisk medicin, Näringsforskning.
    Hallmans, Goran
    Umeå universitet, Medicinsk fakultet, Folkhälsa och klinisk medicin, Näringsforskning.
    Stattin, Pär
    Umeå universitet, Medicinsk fakultet, Kirurgisk och perioperativ vetenskap, Urologi och andrologi. Urologi och andrologi.
    Bergh, Anders
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi. Patologi.
    Rye bran diet increases epithelial cell apoptosis and decreases epithelial cell volume in TRAMP (transgenic adenocarcinoma of the mouse prostate) tumors.2005Ingår i: Nutrition Cancer, ISSN 0163-5581, Vol. 53, nr 1, s. 111-6Artikel i tidskrift (Refereegranskat)
  • 71.
    Wikström, Pernilla
    et al.
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi.
    Lindahl, Charlotta
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi.
    Bergh, Anders
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi.
    Characterization of the autochthonous transgenic adenocarcinoma of the mouse prostate (TRAMP) as a model to study effects of castration therapy.2005Ingår i: Prostate, ISSN 0270-4137, Vol. 62, nr 2, s. 148-64Artikel i tidskrift (Refereegranskat)
  • 72.
    Wikström, Pernilla
    et al.
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi.
    Marusic, Josip
    Stattin, Pär
    Umeå universitet, Medicinsk fakultet, Kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Bergh, Anders
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi.
    Low stroma androgen receptor level in normal and tumor prostate tissue is related to poor outcome in prostate cancer patients.2009Ingår i: The Prostate, ISSN 1097-0045, Vol. 69, nr 8, s. 799-809Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: The role of androgen receptors (ARs) in the prostate tumor cell environment is largely unknown. METHODS: AR immunostaining was evaluated in relation to stroma morphology, expression of AR co-activator ARA55, tumor characteristics and clinical outcome in normal and prostate cancer (PCa) tissue obtained at transurethral resection in men treated with expectancy, and in diagnostic transrectal core biopsies in men treated with surgical castration. Stroma composition was studied by Masson-trichrome and desmin staining. Levels of AR and ARA55 mRNA were quantified by laser micro-dissection and RT-PCR. RESULTS: The percentage of cells with positive nuclear AR immunostaining in the tumor and normal stroma was inversely related to Gleason score, tumor size, tumor stage, metastasis, response to castration therapy, and cancer-specific survival. The AR staining in the normal stroma provided independent prognostic information in Cox multiple linear regression analysis. Loss of stroma AR staining was linked to low expression of ARA55 in stroma smooth muscle cells, and in tumors also to gradual disappearance of this cell type. CONCLUSIONS: PCa aggressiveness and efficacy of castration therapy are related to AR levels in the tumor stroma and importantly to AR levels in the surrounding normal prostate tissue stroma. .

  • 73.
    Wikström, Pernilla
    et al.
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi.
    Ohlson, Nina
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi.
    Stattin, Pär
    Umeå universitet, Medicinsk fakultet, Kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Bergh, Anders
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi.
    Nuclear androgen receptors recur in the epithelial and stromal compartments of malignant and non-malignant human prostate tissue several months after castration therapy.2007Ingår i: Prostate, ISSN 0270-4137, Vol. 67, nr 12, s. 1277-84Artikel i tidskrift (Refereegranskat)
12 51 - 73 av 73
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