uu.seUppsala universitets publikasjoner
1 - 5 of 5
rss atomLink til resultatlisten
Permanent link
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Annet format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annet språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
  • Disputas: 2018-08-21 13:00 B42, Uppsala
    Pilia, Giulia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Ludwig Institute for Cancer Research, Uppsala.
    Novel Roles of the Ack1 Kinase in Epithelial Biology2018Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Epithelial homeostasis is maintained through integration of diverse signals that regulate cell fate. A strict control of such signals is required to prevent overproliferation and, ultimately, oncogenesis. In this thesis we identify novel roles of Activated Cdc42-associated kinase 1 (Ack1) in maintenance of epithelial homeostasis. Ack1 has been previously linked to cytoskeletal remodeling, signal transduction and gene expression regulation. Interestingly, our work reveals that Ack1 is also important for I) promoting extrinsic apoptosis, II) mediating mechanically-induced inhibition of proliferation and III) attenuating mitogenic signals, fundamental functions to prevent aberrant tissue growth.

    Apoptosis is a program of regulated cell death that can be triggered by several pathways. Among them, the TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis cascade has raised interest for cancer treatment, as many cancer cell lines are susceptible to it. We found that Ack1 increases sensitivity to TRAIL by promoting translocation of ligand-bound TRAIL-Receptor to lipid rafts. Localisation at the lipid rafts, in turn, favors recruitment of downstream signalling effectors, enhancing the apoptotic response.

    Yap and Taz are transcriptional co-factors that integrate mechanical and soluble cues to regulate cell proliferation and differentiation. Yap/Taz regulation is mediated by cytoplasmic sequestration and, particularly for Taz, proteasomal degradation via ubiquitination by the E3 ligase β-TrCP. We discovered that Ack1 is activated by mechanical signals and promotes nuclear exclusion of Yap/Taz. Ack1 promotes Yap/Taz interaction with β-TRCP and it is required for efficient degradation of Taz. Consequently, Ack1 limits Yap/Taz-dependent gene expression and cell proliferation.

    The ErbB family of receptor tyrosine kinases mediates pro-survival and proliferative signals of crucial importance in development and cancer. Among the ErbB family members, ErbB3 has significant oncogenic properties as it potently activates the PI3K/Akt signaling pathway. We observe that Ack1 depletion increases ErbB3 total levels, but not EGFR and ErbB2, and is required for both basal turnover of ErbB3 and its ligand-induced degradation. Consequently, Ack1 attenuates ErbB3-dependent signalling upon Neuregulin-1β treatment. Additionally, Ack1 reduces ErbB3 gene expression both at steady state and upon stimulation, revealing its importance as multi-level regulator of ErbB3.

    Taken together, our data depict new roles for Ack1 in epithelial cells, highlighting its multifaceted role in maintenance of epithelial homeostasis.

    Delarbeid
    1. Activated Cdc42-associated Kinase 1 (Ack1) Is Required for Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) Receptor Recruitment to Lipid Rafts and Induction of Cell Death
    Åpne denne publikasjonen i ny fane eller vindu >>Activated Cdc42-associated Kinase 1 (Ack1) Is Required for Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) Receptor Recruitment to Lipid Rafts and Induction of Cell Death
    2013 (engelsk)Inngår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 288, nr 46, s. 32922-32931Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    TNF-related apoptosis-inducing ligand (TRAIL) holds promise for treatment of cancer due to its ability to selectively kill cancer cells while sparing normal cells. Ligand-induced translocation of TRAIL receptors (TRAIL-R) 1 and 2 (also called DR4 and DR5, respectively) into lipid raft membrane microdomains is required for TRAIL-induced cell death by facilitating receptor clustering and formation of the death-inducing signaling complex, yet the underlying regulatory mechanisms remain largely unknown. We show here that the non-receptor tyrosine kinase Ack1, previously implicated in the spatiotemporal regulation of the EGF receptor, is required for TRAIL-induced cell death in multiple epithelial cell lines. TRAIL triggered a transient up-regulation of Ack1 and its recruitment to lipid rafts along with TRAIL-R1/2. siRNA-mediated depletion of Ack1 disrupted TRAIL-induced accumulation of TRAIL-R1/2 in lipid rafts and efficient recruitment of caspase-8 to the death-inducing signaling complex. Pharmacological inhibition of Ack1 did not affect TRAIL-induced cell death, indicating that Ack1 acts in a kinase-independent manner to promote TRAIL-R1/2 accumulation in lipid rafts. These findings identify Ack1 as an essential player in the spatial regulation of TRAIL-R1/2.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-212597 (URN)10.1074/jbc.M113.481507 (DOI)000328841700010 ()24085293 (PubMedID)
    Forskningsfinansiär
    Swedish Cancer Society, CAN 2012/581NIH (National Institute of Health), 1R01CA135328
    Tilgjengelig fra: 2013-12-12 Laget: 2013-12-12 Sist oppdatert: 2018-04-26bibliografisk kontrollert
    2. ACK1 is a mechanoresponsive kinase required for SCF (β-TrCP)-mediated degradation of YAP/TAZ
    Åpne denne publikasjonen i ny fane eller vindu >>ACK1 is a mechanoresponsive kinase required for SCF (β-TrCP)-mediated degradation of YAP/TAZ
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-349179 (URN)
    Tilgjengelig fra: 2018-04-23 Laget: 2018-04-23 Sist oppdatert: 2018-04-26
    3. Ack1 is a negative regulator of ErbB3 that acts both by promoting its degradation and suppressing its expression
    Åpne denne publikasjonen i ny fane eller vindu >>Ack1 is a negative regulator of ErbB3 that acts both by promoting its degradation and suppressing its expression
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-349182 (URN)
    Tilgjengelig fra: 2018-04-23 Laget: 2018-04-23 Sist oppdatert: 2018-04-26
  • Disputas: 2018-08-24 13:00 Rudbecksalen, Uppsala
    Lundberg, Marcus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Characterization of the Pancreas in Type 1 and Type 2 Diabetes2018Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Diabetes is recognized by hyperglycaemia and polyuria. Complications, reduced quality of life and staggering health-care costs are all derived from the disease. Two subclasses of diabetes are Type 1 diabetes (T1D) and Type 2 diabetes (T2D). The beta cell mass is reduced in T1D, which is generally considered to be caused by an immune-mediated beta-cell destruction, but definitive evidence for this hypothesis remains absent. Development of insulin resistance and dysfunctional beta cells are commonly recognized as important factors that contribute to fulminant T2D. The literature that describes human T1D and T2D pancreata is sparse due to the limited number of specimens available for study. If more features of the respective pancreata are described, we might be able to elucidate the mechanisms involved in the pathoaetiology of the diseases.

    Accordingly, in this thesis pancreatic biopsies obtained from subjects with T1D or T2D have been examined with the aim to provide a more comprehensive picture of the respective pancreata. Paper I reports that aggregates of leucocytes substantiated mostly by macrophages are present in several T2D pancreata. Furthermore, as 28% of the T2D pancreata met the consensus definition of insulitis developed for T1D, a redefinition of insulitis is proposed. In Paper II, the density of parasympathetic axons was found to be reduced in the exocrine compartment in recent-onset T1D subjects compared to non-diabetic and long-standing T1D subjects. However, no alteration was discovered in islet-associated parasympathetic axons. In Paper III, interferon-stimulated genes were found to be over-expressed in recent-onset T1D islets, but no inducer explaining this expression has been discovered. Paper IV shows that T2D islets exhibit a stress response on a transcriptional level, and expression of these genes were investigated in islets from subjects with elevated HbA1c levels but without a clinical T2D diagnosis.

    In conclusion, this thesis explores several new areas of the pancreas in both T1D and T2D, and demonstrate several important findings that increase our knowledge on how diabetes develops.

    Delarbeid
    1. Insulitis in human diabetes: a histological evaluation of donor pancreases
    Åpne denne publikasjonen i ny fane eller vindu >>Insulitis in human diabetes: a histological evaluation of donor pancreases
    Vise andre…
    2017 (engelsk)Inngår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, nr 2, s. 346-353Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Aims/hypothesis According to the consensus criteria developed for type 1 diabetes, an individual can be diagnosed with insulitis when >= 15 CD45(+) cells are found within the parenchyma or in the islet-exocrine interface in >= 3 islets. The aim of this study was to determine the frequency of individuals with type 2 diabetes fulfilling these criteria with reference to non-diabetic and type 1 diabetic individuals. Methods Insulitis was determined by examining CD45(+) cells in the pancreases of 50, 13 and 44 organ donors with type 2 diabetes, type 1 diabetes and no diabetes, respectively. CD3(+) cells (T cells) infiltrating the islets were evaluated in insulitic donors. In insulitic donors with type 2 diabetes, the pancreases were characterised according to the presence of CD68 (macrophages), myeloperoxidase (MPO; neutrophils), CD3, CD20 (B cells) and HLA class I hyperstained islets. In all type 2 diabetic donors, potential correlations of insulitis with dynamic glucose-stimulated insulin secretion in vitro or age, BMI, HbA(1c) or autoantibody positivity were examined. Results Overall, 28% of the type 2 diabetic donors fulfilled the consensus criteria for insulitis developed for type 1 diabetes. Of the type 1 diabetic donors, 31% fulfilled the criteria. None of the non-diabetic donors met the criteria. Only type 1 diabetic donors had >= 15 CD3(+) cells in >= 3 islets. Type 2 diabetic donors with insulitis also had a substantial number of CD45(+) cells in the exocrine parenchyma. Macrophages constituted the largest fraction of CD45(+) cells, followed by neutrophils and T cells. Of type 2 diabetic pancreases with insulitis, 36% contained islets that hyperstained for HLA class I. Isolated islets from type 2 diabetic donors secreted less insulin than controls, although with preserved dynamics. Insulitis in the type 2 diabetic donors did not correlate with glucose-stimulated insulin secretion, the presence of autoantibodies, BMI or HbA(1c). Conclusions/interpretation The current definition of insulitis cannot be used to distinguish pancreases retrieved from individuals with type 1 diabetes from those with type 2 diabetes. On the basis of our findings, we propose a revised definition of insulitis, with a positive diagnosis when >= 15 CD3(+) cells, not CD45(+) cells, are found in >= 3 islets.

    Emneord
    HLA, Inflammation, Insulin secretion, Insulitis, Islets, Macrophages, Tcells, Type 1 diabetes, Type 2 diabetes
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-315054 (URN)10.1007/s00125-016-4140-z (DOI)000391359800016 ()27796420 (PubMedID)
    Forskningsfinansiär
    EU, FP7, Seventh Framework Programme, 261441 PEVNETNovo NordiskÅke Wiberg FoundationSwedish Diabetes Association
    Tilgjengelig fra: 2017-03-08 Laget: 2017-03-08 Sist oppdatert: 2018-05-02bibliografisk kontrollert
    2. The density of parasympathetic axons is reduced in the exocrine pancreas of individuals recently diagnosed with type 1 diabetes
    Åpne denne publikasjonen i ny fane eller vindu >>The density of parasympathetic axons is reduced in the exocrine pancreas of individuals recently diagnosed with type 1 diabetes
    Vise andre…
    2017 (engelsk)Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 6, artikkel-id e0179911Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    To elucidate the etiology of type 1 diabetes, the affected pancreas needs to be thoroughly characterized. Pancreatic innervation has been suggested to be involved in the pathology of the disease and a reduction of sympathetic innervation of the islets was recently reported. In the present study, we hypothesized that parasympathetic innervation would be altered in the type 1 diabetes pancreas. Human pancreatic specimens were obtained from a unique cohort of individuals with recent onset or long standing type 1 diabetes. Density of parasympathetic axons was assessed by immunofluorescence and morphometry. Our main finding was a reduced density of parasympathetic axons in the exocrine, but not endocrine compartment of the pancreas in individuals with recent onset type 1 diabetes. The reduced density of parasympathetic axons in the exocrine compartment could have functional implications, e.g. be related to the exocrine insufficiency reported in type 1 diabetes patients. Further studies are needed to understand whether reduced parasympathetic innervation is a cause or consequence of type 1 diabetes.

    sted, utgiver, år, opplag, sider
    PUBLIC LIBRARY SCIENCE, 2017
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-330731 (URN)10.1371/journal.pone.0179911 (DOI)000404043100049 ()28628651 (PubMedID)
    Forskningsfinansiär
    Novo NordiskEU, FP7, Seventh Framework Programme, 261441 PEVNETSwedish Child Diabetes FoundationSwedish Research Council, 65X-12219-15-6, K2015-54X-12219-19-4, 2008-4216, 521-2012-2119Swedish Diabetes AssociationMagnus Bergvall Foundation
    Tilgjengelig fra: 2017-10-10 Laget: 2017-10-10 Sist oppdatert: 2018-05-02bibliografisk kontrollert
    3. Expression of Interferon-Stimulated Genes in Insulitic Pancreatic Islets of Patients Recently Diagnosed With Type 1 Diabetes
    Åpne denne publikasjonen i ny fane eller vindu >>Expression of Interferon-Stimulated Genes in Insulitic Pancreatic Islets of Patients Recently Diagnosed With Type 1 Diabetes
    Vise andre…
    2016 (engelsk)Inngår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 65, nr 10, s. 3104-3110Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    A primary insult to the pancreatic islets of Langerhans, leading to the activation of innate immunity, has been suggested as an important step in the inflammatory process in type 1 diabetes (T1D). The aim of this study was to examine whether interferon (IFN)-stimulated genes (ISGs) are overexpressed in human T1D islets affected with insulitis. By using laser capture microdissection and a quantitative PCR array, 23 of 84 examined ISGs were found to be overexpressed by at least fivefold in insulitic islets from living patients with recent-onset T1D, participating in the Diabetes Virus Detection (DiViD) study, compared with islets from organ donors without diabetes. Most of the overexpressed ISGs, including GBP1, TLR3, OAS1, EIF2AK2, HLA-E, IFI6, and STAT1, showed higher expression in the islet core compared with the peri-islet area containing the surrounding immune cells. In contrast, the T-cell attractant chemokine CXCL10 showed an almost 10-fold higher expression in the peri-islet area than in the islet, possibly partly explaining the localization of T cells mainly to this region. In conclusion, insulitic islets from recent-onset T1D subjects show overexpression of ISGs, with an expression pattern similar to that seen in islets infected with virus or exposed to IFN-gamma/interleukin-1 beta or IFN-alpha.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-311223 (URN)10.2337/db16-0616 (DOI)000388372900029 ()27422384 (PubMedID)
    Forskningsfinansiär
    Novo NordiskSwedish Research Council, K2011-65X-12219-15-6, K2015-54X-12219-19-4Åke Wiberg FoundationSwedish Diabetes AssociationSwedish Child Diabetes FoundationEXODIAB - Excellence of Diabetes Research in Sweden
    Tilgjengelig fra: 2016-12-22 Laget: 2016-12-22 Sist oppdatert: 2018-05-02bibliografisk kontrollert
    4. Expression profiles of stress-related genes in islets from donors with progressively impaired glucose metabolism.
    Åpne denne publikasjonen i ny fane eller vindu >>Expression profiles of stress-related genes in islets from donors with progressively impaired glucose metabolism.
    Vise andre…
    2018 (engelsk)Inngår i: Islets, ISSN 1938-2014, E-ISSN 1938-2022, Vol. 10, nr 2, s. 69-79Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    It is currently unknown how the islet transcriptional pattern changes as glucose metabolism deteriorates and progresses to fulminant type 2 diabetes (T2D). In this study, we hypothesized that islets from donors with elevated HbA1c levels, but not yet diagnosed with T2D, would show signs of cell stress on a transcriptional level. Laser capture microdissection and qPCR arrays including 330 genes related to mitochondria, oxidative stress, or the unfolded protein response were used to extract and analyze islets from organ donors with HbA1c <5.5% (37 mmol/mol), elevated HbA1c (6.0-6.5% (42-48 mmol/mol)), high HbA1c (>6.5% (48 mmol/mol)) or established T2D. Principal component analysis and hierarchical clustering based on the expression of all 330 genes displayed no obvious separation of the four different donor groups, indicating that the inter-donor variations were larger than the differences between groups. However, 44 genes were differentially expressed (P < 0.05, false discovery rate <30%) between islets from donors with HbA1c <5.5% (37 mmol/mol) compared with islets from T2D subjects. Twelve genes were differentially expressed compared to control islets in both donors with established T2D and donors with elevated HbA1c (6.0-6.5% (42-48 mmol/mol)). Overexpressed genes were related mainly to the unfolded protein response, whereas underexpressed genes were related to mitochondria. Our data on transcriptional changes in human islets retrieved by LCM from high-quality biopsies, as pre-diabetes progresses to established T2D, increase our understanding on how islet stress contributes to the disease development.

    Emneord
    HbA1c, laser capture, transcriptome, type 2 diabetes
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-342882 (URN)10.1080/19382014.2018.1433980 (DOI)000428814700003 ()29446696 (PubMedID)
    Forskningsfinansiär
    Swedish Research Council, 65X-12219-15-6, K2015-54X-12219-19-4Novo NordiskÅke Wiberg FoundationTore Nilsons Stiftelse för medicinsk forskningMagnus Bergvall FoundationErnfors FoundationSwedish Child Diabetes FoundationSwedish Diabetes Association
    Tilgjengelig fra: 2018-02-23 Laget: 2018-02-23 Sist oppdatert: 2018-06-04bibliografisk kontrollert
  • Disputas: 2018-08-31 09:00 Rudbecksalen, Uppsala
    Åström, Lennart
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Dose Escalation with High Dose Rate Brachytherapy or Protons in Curative Radiotherapy of Prostate Cancer2018Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The aim of the thesis was to study the outcome and side effects after dose-escalated radiotherapy with high dose rate brachytherapy (HDR-BT) or proton beam therapy (PBT) boost in prostate cancer.

    The first cohorts of men in Sweden treated with either HDR-BT or PBT in combination with conventional photon beam therapy (2 Gray (Gy) fractions to 50 Gy) were analysed. The HDR-BT was given with two 10 Gy fractions, and the PBT with four fractions of 5 Gy. The analyses included 823 men in two HDR-BT cohorts, and 265 men in the PBT cohort. A large proportion of the cohorts, from 38% to 53%, were classified as high risk. After a follow-up between four and eleven years, both combinations showed low risks for relapse. The overall 5-year risk for PSA relapse was 0% for men with low risk. After PBT, the 5-year PSA relapse risk for intermediate and high risk were 5% and 26% respectively. After HDR-BT the 10-year risks for PSA relapse were 0%, 21% and 33% for low, intermediate, and high risk, respectively.

    The risk for early and late toxicity was low. Genitourinary (GU) toxicity was more frequent than gastrointestinal (GI) toxicity. GU toxicity may have a late onset and progress slowly with time after HDR-BT. The 5- and 10-year actuarial incidences of urethral stricture were 6% and 10% respectively after HDR-BT. With applied dose constraints to the urethra the 10-year risk was 5%. The actuarial prevalence of GI toxicity declined slowly with time after HDR-BT as well as after PBT.

    A PSA bounce after HDR-BT was seen in 26% of the patients, more frequent with younger age and lower Gleason score, and followed by a low risk for relapse.

    For dose-escalated radiotherapy with HDR-BT or PBT:

    • long-term tumour control was achieved, not only for low- and intermediate risk, but also for the majority of high risk patients,
    • a PSA bounce after HDR-BT was folled by a good prognosis,
    • levels of late toxicity were low,
    • genitourinary toxicity was more frequent than gastrointestinal toxicity,
    • dose constraints to risk organs must be applied to minimise risks for late toxicity.
    Delarbeid
    1. Long-term outcome of high dose rate brachytherapy in radiotherapy of localised prostate cancer
    Åpne denne publikasjonen i ny fane eller vindu >>Long-term outcome of high dose rate brachytherapy in radiotherapy of localised prostate cancer
    Vise andre…
    2005 (engelsk)Inngår i: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 74, nr 2, s. 157-61Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Background and purpose: High dose rate brachytherapy (HDR-BT) in prostate cancer (PC) is receiving increasing interest. The steep dose gradient gives a possibility to escalate the dose to the prostate. If the a/b ratio is low for PC, hypofractionation will be of advantage. A retrospective analysis of outcome in patients (pts) consecutively treated with combined HDR-BT and conformal external beam radiotherapy (ERT) was performed. Material and methods: Data from 214 pts treated consecutively from 1988 to 2000 were analysed. The median age was 64 years (50–77). Median follow up was 4 years (12–165 months). Pre-irradiatory endocrine therapy was given to 150 pts (70%). The pts were divided into low-, intermediate- and high (80/87/47 pts) risk groups according to the occurrence of none, one, or more risk factors defined by T-classification, PSA and histopathology. ERT was given with 2 Gy fractions to 50 Gy. HDR-BT consisted of two 10 Gy fractions. Results: Overall 5-year biochemical no evidence of disease (bNED) was 82%, and for the low-, intermediate-, and high-risk group bNED was 92, 88 and 61%, respectively. PSA-relapse was found in 17, local recurrence in 3 and distant metastases in 13 pts. Five pts died of PC. No recurrences were observed after 5 years. Severe late complications were few. Urethral stricture (13 pts) was the most frequent. No severe rectal complications were seen. Conclusion: Dose escalation with HDR-BT is safe and effective in radiotherapy of localised PC.

    Emneord
    Prostate cancer, Radiotherapy, Brachytherapy, High dose rate
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-72860 (URN)10.1016/j.radonc.2004.10.014 (DOI)15734203 (PubMedID)
    Tilgjengelig fra: 2006-06-29 Laget: 2006-06-29 Sist oppdatert: 2018-05-08bibliografisk kontrollert
    2. Hypofractionated proton boost combined with external beam radiotherapy for treatment of localized prostate cancer
    Åpne denne publikasjonen i ny fane eller vindu >>Hypofractionated proton boost combined with external beam radiotherapy for treatment of localized prostate cancer
    Vise andre…
    2012 (engelsk)Inngår i: Prostate Cancer, ISSN 2090-3111, E-ISSN 2090-312X, Vol. 2012, artikkel-id 654861Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Proton boost of 20 Gy in daily 5 Gy fractions followed by external beam radiotherapy (EBRT) of 50 Gy in daily 2 Gy fractions were given to 278 patients with prostate cancer with T1b to T4N0M0 disease. Fifty-three percent of the patients received neoadjuvant androgen deprivation therapy (N-ADT). The medium followup was 57 months. The 5-year PSA progression-free survival was 100%, 95%, and 74% for low-, intermediate-, and high-risk patients, respectively. The toxicity evaluation was supported by a patient-reported questionnaire before every consultant visit. Cumulative probability and actuarial prevalence of genitourinary (GU) and gastrointestinal (GI) toxicities are presented according to the RTOG classification. N-ADT did not influence curability. Mild pretreatment GU-symptoms were found to be a strong predictive factor for GU-toxicity attributable to treatment. The actuarial prevalence declined over 3 to 5 years for both GU and GI toxicities, indicating slow resolution of epithelial damage to the genitourinary and gastrointestinal tract. Bladder toxicities rather than gastrointestinal toxicities seem to be dose limiting. More than 5-year followup is necessary to reveal any sign of true progressive late side effects of the given treatment. Hypofractionated proton-boost combined with EBRT is associated with excellent curability of localized PC and acceptable frequencies of treatment toxicity.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-347410 (URN)10.1155/2012/654861 (DOI)22848840 (PubMedID)
    Tilgjengelig fra: 2018-03-31 Laget: 2018-03-31 Sist oppdatert: 2018-05-08bibliografisk kontrollert
    3. Two decades of high dose rate brachytherapy with external beam radiotherapy for prostate cancer
    Åpne denne publikasjonen i ny fane eller vindu >>Two decades of high dose rate brachytherapy with external beam radiotherapy for prostate cancer
    Vise andre…
    2018 (engelsk)Inngår i: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, artikkel-id S0167-8140(17)32780-9Artikkel i tidsskrift (Fagfellevurdert) Epub ahead of print
    Abstract [en]

    BACKGROUND: High-dose-rate brachytherapy (HDR-BT) has optimal prerequisites in radiotherapy of prostate cancer (PC) with a conformal dose distribution and high doses per fraction giving a biological dose escalation. We report the outcome after HDR-BT and external beam radiotherapy (EBRT) after 20 years of experience.

    MATERIAL AND METHODS: The study includes 623 patients, median age of 66 years, treated from 1995 to 2008 and a median follow up of 11 years (range 2-266 months). Androgen deprivation therapy was given to 429 patients (69%). The HDR-BT was given with two 10 Gy fractions and the EBRT with 2 Gy fractions to 50 Gy.

    RESULTS: The 10-year PC-specific survival was 100%, 92%, 91%, and 75% for low-, intermediate-, high- and very high-risk patients respectively, and the 10-year probability of PSA relapse was 0%, 21%, 33%, and 65% respectively. The 10-year actuarial prevalence for ≥grade 2 GU- and GI-toxicities were 28% and 12% respectively and for ≥grade 3, 4% and 1% respectively. Urethral stricture was the most frequent GU complication with a 10-year actuarial incidence of 10%. Treatment without dose constraints for the urethra conferred a higher incidence 18%, compared to 5% after 2003 (p < 0.001). Sixteen patients experienced grade 4 GU toxicity, of which 13 were treated before 2003. No grade 4 rectal toxicity was seen.

    CONCLUSION: The combination of EBRT and HDR-BT with adequate dose constraints to risk organs provides satisfactory long-term tumour control even in high-risk patients. GI toxicity stabilised but GU toxicity progressed during the 10-year follow up.

    Emneord
    Brachytherapy, High dose rate, Prostate cancer, Radiotherapy
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-347411 (URN)10.1016/j.radonc.2017.12.025 (DOI)29496280 (PubMedID)
    Tilgjengelig fra: 2018-03-31 Laget: 2018-03-31 Sist oppdatert: 2018-05-08bibliografisk kontrollert
    4. Good Prognosis following a PSA Bounce after High Dose Rate Brachytherapy with External Radiotherapy in Prostate Cancer.
    Åpne denne publikasjonen i ny fane eller vindu >>Good Prognosis following a PSA Bounce after High Dose Rate Brachytherapy with External Radiotherapy in Prostate Cancer.
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Background

    PSA kinetics after curative radiotherapy for prostate cancer is an important part of the posttreatment evaluation. We analysed PSA bounce occurrence after combined high dose rate brachytherapy (HDR-BT) and external radiotherapy (ERT).

    Material & methods

    We analysed 623 patients treated from 1995 to 2008. The median age was 66 years (47-79). The median initial PSA was 12 ng/ml (0.1-224). Neoadjuvant endocrine therapy was given to 429 patients. ERT was given with 2 Gy fractions to 50 Gy and HDR-BT in two 10 Gy fractions. The median follow-up was 11 years (range 2-266 months). PSA bounce was defined as a temporary rise in PSA >0.2 ng/ml. PSA failure was defined according to the Phoenix definition.

    Results

    PSA bounce occurred in 159 patients (26%), where 56 patients had a bounce amplitude >2 ng/ml and 31 patients had multiple bounces. Median time to bounce peak was 15 (3-103) months with a median bounce value of 1.5 (0.3-12) ng/ml. Younger age and lower Gleason scores were associated with PSA bounce. In a Cox regression analysis with PSA bounce as a time-dependent covariate and adjusted for other prognostic factors, PSA bounce was associated with a lower risk for PSA failure (HR=0.42; 95% confidence interval 0.26-0.70).

    Conclusion

    PSA bounce after HDR-BT combined with ERT is common and associated with a good prognosis. As the relapse risk after an early bounce is very low, the findings should alert clinicians not to initiate salvage treatment too early. Research in prospective identification of PSA bounce is clinically relevant.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-347416 (URN)
    Tilgjengelig fra: 2018-03-31 Laget: 2018-03-31 Sist oppdatert: 2018-05-08
  • Disputas: 2018-09-03 14:00 Ihresalen, Engelska parken, Uppsala
    Linderborg, Otto H.
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Språkvetenskapliga fakulteten, Institutionen för lingvistik och filologi.
    Herodotus and the Origins of Political Philosophy: The Beginnings of Western Thought from the Viewpoint of its Impending End2018Doktoravhandling, monografi (Annet vitenskapelig)
    Abstract [en]

    This investigation proposes a historical theory of the origins of political philosophy. It is assumed that political philosophy was made possible by a new form of political thinking commencing with the inauguration of the first direct democracies in Ancient Greece. The pristine turn from elite rule to rule of the people – or to δημοκρατία, a term coined after the event – brought with it the first ever political theory, wherein fundamentally different societal orders, or different principles of societal rule, could be argumentatively compared. The inauguration of this alternative-envisioning “secular” political theory is equaled with the beginnings of classical political theory and explained as the outcome of the conjoining of a new form of constitutionalized political thought (cratistic thinking) and a new emphasis brought to the inner consistency of normative reasoning (‘internal critique’). The original form of political philosophy, Classical Political Philosophy, originated when a political thought launched, wherein non-divinely sanctioned visions of transcendence of the prevailing rule, as well as of the full range of alternatives disclosed by Classical Political Theory, first began to be envisioned. Each of the hypotheses forming the theory – the hypotheses concerning the Ancient Greek beginnings of a “secular”-autonomous political rationale, political theory and political philosophy – is weighed against central evidence provided by the Histories of Herodotus. The passages thus given new interpretations are the Deioces episode in Book I, the Constitutional Debate in Book III and Xerxes’ War Councils in Book VII. Aside from the Herodotean evidence, a range of other relevant Greek literary sources from the archaic and classical ages – e.g. passages from Homer, Hesiod, several pre-Socratic thinkers, Plato and Aristotle – are duly taken into consideration. Included is also a reading of the Mytilenean Debate of Thucydides’ Book III, which shows how the political thought of the classical democracies worked in practice. Finally, the placing of the historical theory against a background of contemporary relevance provides an alternative to all text-oriented approaches not reckoning with the possibility of reaching historically plausible knowledge of real-world events and processes.

  • Disputas: 2018-09-12 10:15 E22, Visby
    Simisiroglou, Nikolaos
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Geovetenskapliga sektionen, Institutionen för geovetenskaper, Luft-, vatten och landskapslära.
    Wind power wake modelling: Development and application of an actuator disc method for industrial utilization.2018Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    As a wind turbine extracts energy from the wind it creates a region downstream where the wind velocity is decreased and the urbulence intensity is increased, this region is commonly called the wake region. Today’s wind farms include a large number of wind turbines position in tight layouts. These tight layouts result in increased power losses due to wakes, rendering accurate wind turbine wake modelling crucial in developing cost effective projects.

    The primary aim of this study is to create a method capable of conducting full-scale wind farm wake computations accurately in a time efficient manner by taking into account the computational resources and data availability of a typical industrial user. As a first step of this study, an actuator disc (ACD) method (old ACD) used within WindSim, is evaluated against power production data from the Lillgrund offshore wind. This study is followed by the development of a new ACD method. The new ACD method differs from the previous ACD method in terms of how the thrust distribution and the power production is calculated. A series of validation studies are performed on this newly introduced ACD method. These consist of validating the method against two cases with known analytical solutions, the research code EllipSys3D which uses Large Eddy Simulation (LES) based computations with an ACD approach and three differentwind tunnel set–ups. Lastly, a comparative analysis of the two ACD methods (old and new) and two analytical wake models is done using wind turbine power production data from Lillgrund.

    Results from the validation studies show that this new ACD method is able to predict the overall behaviour of the flow with low computational effort while also taking into account the availability of data for a typical industrial user. One may say that the new ACD method in RANS, which has much lower computational requirements than the ACD method in LES at the cost of lower accuracy, represents a good compromise. Lastly, the results from the new ACD method show a clear improvement in the estimated power production for the Lillgrund wind farm in comparison to the old ACD method.

    Delarbeid
    1. Numerical CFD comparison of Lillgrund employing RANS EERA
    Åpne denne publikasjonen i ny fane eller vindu >>Numerical CFD comparison of Lillgrund employing RANS EERA
    Vise andre…
    2014 (engelsk)Konferansepaper, Oral presentation only (Fagfellevurdert)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-238295 (URN)
    Konferanse
    DeepWind 2014, 11th Deep Sea Offshore Wind R&D Conference
    Forskningsfinansiär
    StandUp for Wind
    Tilgjengelig fra: 2014-12-11 Laget: 2014-12-11 Sist oppdatert: 2018-05-03
    2. Description and validation of the actuator disc approach in PHOENICS.
    Åpne denne publikasjonen i ny fane eller vindu >>Description and validation of the actuator disc approach in PHOENICS.
    2016 (engelsk)Rapport (Annet (populærvitenskap, debatt, mm))
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-350027 (URN)
    Tilgjengelig fra: 2018-05-03 Laget: 2018-05-03 Sist oppdatert: 2018-05-03
    3. Validation of the actuator disc approach using small-scale model wind turbines
    Åpne denne publikasjonen i ny fane eller vindu >>Validation of the actuator disc approach using small-scale model wind turbines
    2017 (engelsk)Inngår i: Wind Energy Science, ISSN 2213-3968, E-ISSN 2366-7443, Vol. 2, s. 587-601Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The aim of the present study is the validation of the implementation of an actuator disc (ACD) model in the computational fluid dynamics (CFD) code PHOENICS. The flow behaviour for three wind turbine cases is investigated numerically and compared to wind tunnel measurements: (A) the flow around a single model wind turbine, (B) the wake interaction between two in-line model wind turbines for a uniform inflow of low turbulence intensity and (C) the wake interaction between two in-line model wind turbines at different separation distances in a uniform or sheared inflow of high turbulence intensity. This is carried out using Reynolds-averaged Navier–Stokes (RANS) simulations and an ACD technique in the CFD code PHOENICS. The computations are conducted for the design condition of the rotors using four different turbulence closure models and five different thrust distributions. The computed axial velocity field as well as the turbulence kinetic energy are compared with hot-wire anemometry (HWA) measurements. For the cases with two in-line wind turbines, the thrust coefficient is also computed and compared with measurements. The results show that for different inflow conditions and wind turbine spacings the proposed method is able to predict the overall behaviour of the flow with low computational effort. When using the k-ε and Kato–Launder k-ε turbulence models the results are generally in closer agreement with the measurements.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-338124 (URN)10.5194/wes-2-587-2017 (DOI)000416160500001 ()
    Tilgjengelig fra: 2018-01-08 Laget: 2018-01-08 Sist oppdatert: 2018-05-03bibliografisk kontrollert
    4. The actuator disc concept in PHOENICS
    Åpne denne publikasjonen i ny fane eller vindu >>The actuator disc concept in PHOENICS
    Vise andre…
    2016 (engelsk)Inngår i: Energy Procedia / [ed] Tande, JOG; Kvamsdal, T; Muskulus, M, 2016, Vol. 94, s. 269-277Konferansepaper, Publicerat paper (Fagfellevurdert)
    Abstract [en]

    This study presents two models to simulate a wind turbine. This is done by employing the 1D momentum actuator disc theory in PHOENICS, a general purpose computational fluid dynamics software. To test the general applicability of these models, single wind turbine simulations are conducted using eight different wind turbine models from two manufacturers. The simulations are performed by imposing sheared inflow with hub height wind speeds ranging from 3 m/s up to 25 m/s. A range of computational parameters are investigated, including the resolution of the domain, the thickness of the actuator disc and the iterative convergence criteria. To investigate the wake development produced by these methods, a comparison study is performed with the more complex large-eddy simulation software EllipSys3D using an actuator disc approach for validation purposes. The resulting wind turbine thrust and power outputs from PHOENICS are compared with the experimental power curves and thrust values provided by the manufacturers for each wind turbine. The results show that actuator disc methods are able to provide a reasonable estimation of the conventional wind turbine power and thrust output with low computational effort. Moreover, the results from the preliminary comparison of the wake produced from these two rotor models compare well with the wake produced by the actuator disc in EllipSys3D.

    Serie
    Energy Procedia, ISSN 1876-6102 ; 94
    Emneord
    Wind energy, Computational Fluid Dynamics (CFD), Reynolds averaged Navier-Stokes (RANS), Actuator Disc (ACD), Large-eddy simulation (LES)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-306640 (URN)10.1016/j.egypro.2016.09.182 (DOI)000387586600028 ()
    Konferanse
    13th Deep Sea Offshore Wind R&D Conference, EERA DeepWind’ JAN 20-22, 2016, Trondheim, Norway
    Forskningsfinansiär
    StandUp for Wind
    Tilgjengelig fra: 2016-10-31 Laget: 2016-10-31 Sist oppdatert: 2018-05-03bibliografisk kontrollert
    5. Wind farm power production assessment: a comparative analysis of two actuator disc methods and two analytical wake models
    Åpne denne publikasjonen i ny fane eller vindu >>Wind farm power production assessment: a comparative analysis of two actuator disc methods and two analytical wake models
    2018 (engelsk)Inngår i: Wind Energy Science, ISSN 2213-3968, E-ISSN 2366-7443, Vol. 2018, s. 1-13Artikkel i tidsskrift (Fagfellevurdert) Epub ahead of print
    Abstract [en]

    The aim of the present study is to perform a comparative analysis of two actuator disc methods (ACD) and two analytical wake models for wind farm power production assessment. To do so wind turbine power production data from the Lillgrund offshore wind farm in Sweden is used. The measured power production for individual wind turbines is compared with results from simulations, done in the WindSim software, using two ACD methods (old and new) and two analytical wake models widely used within the wind industry (Jensen and Larsen wake models). It was found that the new ACD method and the Larsen model outperform the other method and model in most cases. Furthermore, results from the new ACD method show a clear improvement in the estimated power production in comparison to the old ACD method. The Jensen method seems to overestimate the power deficit for all cases. The new ACD method, despite it's simplicity, is capable of capturing the power production within the given error margin although it tends to underestimate the power deficit.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-350026 (URN)10.5194/wes-2018-8 (DOI)
    Tilgjengelig fra: 2018-05-03 Laget: 2018-05-03 Sist oppdatert: 2018-05-07bibliografisk kontrollert
    6. Validation of the actuator disc approach inPHOENICS using small scale model wind turbines
    Åpne denne publikasjonen i ny fane eller vindu >>Validation of the actuator disc approach inPHOENICS using small scale model wind turbines
    2016 (engelsk)Inngår i: Journal of Physics: Conference Series, 2016, Vol. 753, s. 032-028Konferansepaper, Publicerat paper (Fagfellevurdert)
    Abstract [en]

    In this study two wind turbine setups are investigated numerically: (a) the flow around a single model wind turbine and (b) the wake interaction between two in-line model wind turbines. This is done by using Reynolds averaged Navier-Stokes (RANS) and an actuator disc (ACD) technique in the computational fluid dynamics code PHOENICS. The computations are conducted for the design condition of the rotors using four different turbulence closure models. The computed axial velocity field as well as the turbulent kinetic energy are compared with PIV measurements. For the two model wind turbine setup, the thrust and power coefficient are also computed and compared with measurements. The results show that this RANS ACD method is able to predict the overall behaviour of the flow with low computational effort and that the turbulence closure model has a direct effect on the predicted wake development.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-306642 (URN)10.1088/1742-6596/753/3/032028 (DOI)
    Konferanse
    Science of Making Torque from Wind
    Forskningsfinansiär
    StandUp for Wind
    Tilgjengelig fra: 2016-10-31 Laget: 2016-10-31 Sist oppdatert: 2018-05-03