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  • 1.
    Aasa, Jenny
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Granath, Fredrik
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Cancer risk estimation of glycidol based on rodent carcinogenicity studies, a multiplicative risk model and in vivo dosimetry2019In: Food and Chemical Toxicology, ISSN 0278-6915, E-ISSN 1873-6351, Vol. 128, p. 54-60Article in journal (Refereed)
    Abstract [en]

    Here we evaluate a multiplicative (relative) risk model for improved cancer risk estimation of genotoxic compounds. According to this model, cancer risk is proportional to the background tumor incidence and to the internal dose of the genotoxic compound. Furthermore, the relative risk coefficient per internal dose is considered to be approximately the same across tumor sites, sex, and species. In the present study, we demonstrate that the relative risk model is valid for cancer risk estimation of glycidol, a common food contaminant. Published tumor data from glycidol carcinogenicity studies in mice and rats were evaluated in combination with internal dose estimates from hemoglobin adduct measurements in blood from mice and rats treated with glycidol in short-term studies. A good agreement between predicted and observed tumor incidence in responding sites was demonstrated in the animals, supporting a relative risk coefficient that is independent of tumor site, sex, and species. There was no significant difference between the risk coefficients for mice (5.1% per mMh) and rats (5.4% per mMh) when considering internal doses of glycidol. Altogether, this mechanism-based risk model gives a reliable risk coefficient, which then was extrapolated to humans considering internal dose, and background cancer incidence.

  • 2.
    Ahnesjö, Anders
    Stockholm University.
    Dose calculation methods in photon beam therapy using energy deposition kernels1991Doctoral thesis, comprehensive summary (Other academic)
  • 3. Ai, Jiaoyu
    et al.
    Wörmann, Sonja M.
    Görgülü, Kıvanç
    Vallespinos, Mireia
    Zagorac, Sladjana
    Alcala, Sonia
    Wu, Nan
    Kabacaoglu, Derya
    Berninger, Alexandra
    Navarro, Diego
    Kaya-Aksoy, Ezgi
    Ruess, Dietrich A.
    Ciecielski, Katrin J.
    Kowalska, Marlena
    Demir, Ihsan Ekin
    Ceyhan, Güralp O.
    Heid, Irina
    Braren, Rickmer
    Riemann, Marc
    Schreiner, Sabrina
    Hofmann, Samuel
    Kutschke, Maria
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Jastroch, Martin
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Slotta-Huspenina, Julia
    Muckenhuber, Alexander
    Schlitter, Anna Melissa
    Schmid, Roland M.
    Steiger, Katja
    Diakopoulos, Kalliope N.
    Lesina, Marina
    Sainz Jr, Bruno
    Algül, Hana
    Bcl3 Couples Cancer Stem Cell Enrichment With Pancreatic Cancer Molecular Subtypes2021In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 161, no 1, p. 318-332Article in journal (Refereed)
    Abstract [en]

    Background & Aims: The existence of different subtypes of pancreatic ductal adenocarcinoma (PDAC) and their correlation with patient outcome have shifted the emphasis on patient classification for better decision-making algorithms and personalized therapy. The contribution of mechanisms regulating the cancer stem cell (CSC) population in different subtypes remains unknown.

    Methods: Using RNA-seq, we identified B-cell CLL/lymphoma 3 (BCL3), an atypical nf-κb signaling member, as differing in pancreatic CSCs. To determine the biological consequences of BCL3 silencing in vivo and in vitro, we generated bcl3-deficient preclinical mouse models as well as murine cell lines and correlated our findings with human cell lines, PDX models, and 2 independent patient cohorts. We assessed the correlation of bcl3 expression pattern with clinical parameters and subtypes.

    Results: Bcl3 was significantly down-regulated in human CSCs. Recapitulating this phenotype in preclinical mouse models of PDAC via BCL3 genetic knockout enhanced tumor burden, metastasis, epithelial to mesenchymal transition, and reduced overall survival. Fluorescence-activated cell sorting analyses, together with oxygen consumption, sphere formation, and tumorigenicity assays, all indicated that BCL3 loss resulted in CSC compartment expansion promoting cellular dedifferentiation. Overexpression of BCL3 in human PDXs diminished tumor growth by significantly reducing the CSC population and promoting differentiation. Human PDACs with low BCL3 expression correlated with increased metastasis, and BCL3-negative tumors correlated with lower survival and nonclassical subtypes.

    Conclusions: We demonstrate that bcl3 impacts pancreatic carcinogenesis by restraining CSC expansion and by curtailing an aggressive and metastatic tumor burden in PDAC across species. Levels of BCL3 expression are a useful stratification marker for predicting subtype characterization in PDAC, thereby allowing for personalized therapeutic approaches.

  • 4.
    Akuwudike, Pamela
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Lopez Riego, Milagrosa
    Marczyk, Michal
    Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut, USA.
    Brückner, Fabian
    Biberach University of Applied Sciences.
    Polanska, Joanna
    Department of Data Science and Engineering, Silesian University of Technology, .
    Wojcik, Andrzej
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Institute of Biology, Jan Kochanowski University, Kielce, Poland.
    Lundholm, Lovisa
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Short- and long-term effects of radiation exposure  at low dose and low dose rate on normal human  VH10 fibroblastsManuscript (preprint) (Other academic)
    Abstract [en]

    Experimental studies complement epidemiological data on the biological effects of low doses and dose rates of ionizing radiation and help in determining the dose and dose rate effectiveness factor.  Here, human VH10 skin fibroblasts exposed to 25, 50 and 100 mGy of 137Cs gamma radiation at 1.6, 8, 12 mGy/h, and at a high dose rate of 23.4 Gy/h, were analyzed for radiation-induced short- and long-term effects. Two sample cohorts, i.e. discovery (n=30) and validation (n=12), were subjected to RNA sequencing. Results from the pool of those samples with shared conditions among six experiments constituted a third cohort (n=12). The 100 mGy-exposed cells at all the abovementioned dose rates, harvested at early and late time points after exposure, showed no strong gene expression changes. DMXL2, involved in the regulation of the NOTCH signalling pathway, presented a consistent upregulation among both the discovery and validation cohorts. Gene set enrichment analysis revealed that the NOTCH pathway was upregulated in the pooled cohort (p=0.76, NES=0.86). Apart from upregulated apical junction and downregulated DNA repair, few pathways were consistently changed across exposed cohorts. In agreement, cell viability assays, performed 1-, 3-, and 6-days post-irradiation, and colony forming assay, seeded just after exposure, did not reveal any statistically significant early effects in cell growth or survival patterns. Tendencies of increased growth and reduced colony size were observed at 12 mGy/h and 23.4 Gy/min. Furthermore, no long-term changes were observed in cell growth curves generated up to 70 days after exposure. In conclusion, low doses of gamma radiation given at low dose rates had no strong cytotoxic effects on VH10 cells.

  • 5.
    Akuwudike, Pamela
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    López Riego, Milagrosa
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Ginter, Józef
    Cheng, Lei
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Wieczorek, Anna
    Życieńska, Katarzyna
    Łysek-Gładysińska, Małgorzata
    Wojcik, Andrzej
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Brzozowska, Beata
    Lundholm, Lovisa
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Mechanistic insights from high resolution DNA damage analysis to understand mixed radiation exposure2023In: DNA Repair, ISSN 1568-7864, E-ISSN 1568-7856, Vol. 130, article id 103554Article in journal (Refereed)
    Abstract [en]

    Cells exposed to densely ionising high and scattered low linear energy transfer (LET) radiation (50 % dose of each) react more strongly than to the same dose of each separately. The relationship between DNA double strand break location inside the nucleus and chromatin structure was evaluated, using high-resolution transmission electron microscopy (TEM) in breast cancer MDA-MB-231 cells at 30 min post 5 Gy. Additionally, response to high and/or low LET radiation was assessed using single (1 ×1.5 Gy) versus fractionated dose delivery (5 ×0.3 Gy). By TEM analysis, the highest total number of γH2AX nanobeads were found in cells irradiated with alpha radiation just prior to gamma radiation (called mixed beam), followed by alpha, then gamma radiation. γH2AX foci induced by mixed beam radiation tended to be surrounded by open chromatin (lighter TEM regions), yet foci containing the highest number of beads, i.e. larger foci representing complex damage, remained in the heterochromatic areas. The γH2AX large focus area was also greater in mixed beam-treated cells when analysed by immunofluorescence. Fractionated mixed beams given daily induced the strongest reduction in cell viability and colony formation in MDA-MB-231 and osteosarcoma U2OS cells compared to the other radiation qualities, as well as versus acute exposure. This may partially be explained by recurring low LET oxidative DNA damage by every fraction together with a delay in recompaction of chromatin after high LET, demonstrated by low levels of heterochromatin marker H3K9me3 at 2 h after the last mixed beam fraction in MDA-MB-231. In conclusion, early differences in response to complex DNA damage may lead to a stronger cell kill induced by fractionated exposure, which suggest a therapeutic potential of combined high and low LET irradiation.

  • 6.
    Akuwudike, Pamela
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    López Riego, Milagrosa
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Marczyk, Michal
    Kocibalova, Zuzana
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Brückner, Fabian
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Polańska, Joanna
    Wojcik, Andrzej
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Jan Kochanowski University, Poland.
    Lundholm, Lovisa
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Short- and long-term effects of radiation exposure at low dose and low dose rate in normal human VH10 fibroblasts2023In: Frontiers In Public Health, ISSN 2296-2565, Vol. 11, article id 1297942Article in journal (Refereed)
    Abstract [en]

    Introduction: Experimental studies complement epidemiological data on the biological effects of low doses and dose rates of ionizing radiation and help in determining the dose and dose rate effectiveness factor.

    Methods: Human VH10 skin fibroblasts exposed to 25, 50, and 100 mGy of 137Cs gamma radiation at 1.6, 8, 12 mGy/h, and at a high dose rate of 23.4 Gy/h, were analyzed for radiation-induced short- and long-term effects. Two sample cohorts, i.e., discovery (n = 30) and validation (n = 12), were subjected to RNA sequencing. The pool of the results from those six experiments with shared conditions (1.6 mGy/h; 24 h), together with an earlier time point (0 h), constituted a third cohort (n = 12).

    Results: The 100 mGy-exposed cells at all abovementioned dose rates, harvested at 0/24 h and 21 days after exposure, showed no strong gene expression changes. DMXL2, involved in the regulation of the NOTCH signaling pathway, presented a consistent upregulation among both the discovery and validation cohorts, and was validated by qPCR. Gene set enrichment analysis revealed that the NOTCH pathway was upregulated in the pooled cohort (p = 0.76, normalized enrichment score (NES) = 0.86). Apart from upregulated apical junction and downregulated DNA repair, few pathways were consistently changed across exposed cohorts. Concurringly, cell viability assays, performed 1, 3, and 6 days post irradiation, and colony forming assay, seeded just after exposure, did not reveal any statistically significant early effects on cell growth or survival patterns. Tendencies of increased viability (day 6) and reduced colony size (day 21) were observed at 12 mGy/h and 23.4 Gy/min. Furthermore, no long-term changes were observed in cell growth curves generated up to 70 days after exposure.

    Discussion: In conclusion, low doses of gamma radiation given at low dose rates had no strong cytotoxic effects on radioresistant VH10 cells.

  • 7.
    Akuwudike, Pamela
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    López-Riego, Milagrosa
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Dehours, Cloé
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Polytech Angers l École d’Ingénieurs, France.
    Lundholm, Lovisa
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Wojcik, Andrzej
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Jan Kochanowski University, Poland.
    Impact of fractionated cisplatin and radiation treatment on cell growth and accumulation of DNA damage in two normal cell types differing in origin2023In: Scientific Reports, E-ISSN 2045-2322, Vol. 13, article id 14891Article in journal (Refereed)
    Abstract [en]

    Evidence on the impact of chemotherapy on radiotherapy-induced second malignant neoplasms is controversial. We estimated how cisplatin modulates the in vitro response of two normal cell types to fractionated radiation. AHH-1 lymphoblasts and VH10 fibroblasts were irradiated at 1 Gy/fraction 5 and 3 times per week during 12 and 19 days, respectively, and simultaneously treated with 0.1, 0.2, 0.4, 0.8, 1.7 and 3.3 µM of cisplatin twice a week. Cell growth during treatment was monitored. Cell growth/cell death and endpoints related to accumulation of DNA damage and, thus, carcinogenesis, were studied up to 21 days post treatment in cells exposed to radiation and the lowest cisplatin doses. Radiation alone significantly reduced cell growth. The impact of cisplatin alone below 3.3 µM was minimal. Except the lowest dose of cisplatin in VH10 cells, cisplatin reduced the inhibitory effect of radiation on cell growth. Delayed cell death was highest in the combination groups while the accumulation of DNA damage did not reveal a clear pattern. In conclusion, fractionated, concomitant exposure to radiation and cisplatin reduces the inhibitory effect of radiation on cell proliferation of normal cells and does not potentiate delayed effects resulting from accumulation of DNA damage.

  • 8.
    Akuwudike, Pamela
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Tartas, Adrianna
    López-Riego, Milagrosa
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Toma-Daşu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    Wojcik, Andrzej
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Jan Kochanowski University, Poland.
    Lundholm, Lovisa
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Cell Type-Specific Patterns in the Accumulation of DNA Damage Following Multifractional Radiation Exposure2022In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 23, no 21, article id 12861Article in journal (Refereed)
    Abstract [en]

    Predicting the risk of second malignant neoplasms is complicated by uncertainties regarding the shape of the dose–response relationship at high doses. Limited understanding of the competitive relationship between cell killing and the accumulation of DNA lesions at high doses, as well as the effects of other modulatory factors unique to radiation exposure during radiotherapy, such as dose heterogeneity across normal tissue and dose fractionation, contribute to these uncertainties. The aim of this study was to analyze the impact of fractionated irradiations on two cell systems, focusing on the endpoints relevant for cancer induction. To simulate the heterogeneous dose distribution across normal tissue during radiotherapy, exponentially growing VH10 fibroblasts and AHH-1 lymphoblasts were irradiated with 9 and 12 fractions (VH10) and 10 fractions (AHH-1) at 0.25, 0.5, 1, or 2 Gy per fraction. The effects on cell growth, cell survival, radiosensitivity and the accumulation of residual DNA damage lesions were analyzed as functions of dose per fraction and the total absorbed dose. Residual γH2AX foci and other DNA damage markers (micronuclei, nuclear buds, and giant nuclei) were accumulated at high doses in both cell types, but in a cell type-dependent manner. The competitive relationship between cell killing and the accumulation of carcinogenic DNA damage following multifractional radiation exposure is cell type-specific.

  • 9. Andisheh, B.
    et al.
    Edgren, M.
    Belkic, Dzevad
    Stockholm University, Faculty of Science, Department of Physics.
    Mavroidis, P.
    Brahme, A.
    Lind, B. K.
    A Comparative Analysis of Radiobiological Models for Cell Surviving Fractions at High Doses2013In: Technology in Cancer Research & Treatment, ISSN 1533-0346, E-ISSN 1533-0338, Vol. 12, no 2, p. 183-192Article in journal (Refereed)
    Abstract [en]

    For many years the linear-quadratic (LQ) model has been widely used to describe the effects of total dose and dose per fraction at low-to-intermediate doses in conventional fractionated radiotherapy. Recent advances in stereotactic radiosurgery (SRS) and stereotactic radiotherapy (SRT) have increased the interest in finding a reliable cell survival model, which will be accurate at high doses, as well. Different models have been proposed for improving descriptions of high dose survival responses, such as the Universal Survival Curve (USC), the Kavanagh-Newman (KN) and several generalizations of the LQ model, e.g. the Linear-Quadratic-Linear (LQL) model and the Pade Linear Quadratic (PLQ) model. The purpose of the present study is to compare a number of models in order to find the best option(s) which could successfully be used as a fractionation correction method in SRT. In this work, six independent experimental data sets were used: CHOAA8 (Chinese hamster fibroblast), H460 (non-small cell lung cancer, NSLC), NCI-H841 (small cell lung cancer, SCLC), CP3 and DU145 (human prostate carcinoma cell lines) and U1690 (SCLC). By detailed comparisons with these measurements, the performance of nine different radiobiological models was examined for the entire dose range, including high doses beyond the shoulder of the survival curves. Using the computed and measured cell surviving fractions, comparison of the goodness-of-fit for all the models was performed by means of the reduced e-test with a 95% confidence interval. The obtained results indicate that models with dose-independent final slopes and extrapolation numbers generally represent better choices for SRT. This is especially important at high doses where the final slope and extrapolation numbers are presently found to play a major role. The PLQ, USC and LQL models have the least number of shortcomings at all doses. The extrapolation numbers and final slopes of these models do not depend on dose. Their asymptotes for the cell surviving fractions are exponentials at low as well as high doses, and this is in agreement with the behaviour of the corresponding experimental data. This is an important improvement over the LQ model which predicts a Gaussian at high doses. Overall and for the highlighted reasons, it was concluded that the PLQ, USC and LQL models are theoretically well-founded. They could prove useful compared to the other proposed radiobiological models in clinical applications for obtaining uniformly accurate cell surviving fractions encountered in stereotactic high-dose radiotherapy as well as at medium and low doses.

  • 10.
    Andisheh, Bahram
    Stockholm University, Faculty of Science, Department of Physics.
    A comparative analysis of radio-biological models for cell-surviving fractions at high dosesManuscript (preprint) (Other academic)
    Abstract [en]

    For many years the linear-quadratic (LQ) model has been widely used to describe the effects of total dose and dose per fraction at low-to-intermediate doses in conventional fractionated radiotherapy. Recent advances in stereotactic radiosurgery (SRS) and stereotactic radiotherapy (SRT) have increased the interest in finding a reliable cell survival model, which will be accurate at high doses, as well. Different models have been proposed improving descriptions of high dose survival responses, such as the Universal Survival Curve (USC), the     Kavanagh-Newman (KN) and several generalizations of the LQ model, e.g. the Linear-Quadratic-Linear (LQL) model, the Padé Linear Quadratic (PLQ) model, etc. The purpose of the present study is to compare a number of models in order to find the best option(s) which could successfully be used as fractionation correction method in SRT.

    In this work, six independent experimental data sets were used: CHOAA8 (Chinese hamster fibroblast), H460 (non-small cell lung cancer, NSLC), NCI-H841 (small cell lung cancer, SCLC), CP3 and DU145 (human     prostate carcinoma cell lines) and U1690 (SCLC). By detailed comparisons with these measurements, the validity of nine different radiobiological models was examined for the entire dose range, including high doses   beyond the shoulder of the survival curves.

    Using the computed and measured cell surviving fractions, comparison of the goodness-of-fit for all the models was performed by means of the reduced χ2 test for a 95% confidence interval. The obtained results indicate that models with dose-independent final slopes and extrapolation numbers generally represent better choices for SRT. This is especially important at high doses where the final slope and extrapolation numbers are     presently found to play a major role.

    The PLQ, USC and LQL models have the least number of shortcomings at all doses. The extrapolation      numbers and final slopes of these models do not depend on dose. Their asymptotes for the cell surviving      fractions are exponentials at low as well as high doses, and this is in agreement with the behaviour of the    corresponding experimental data. This is an important improvement over the LQ model which predicts a Gaussian at high doses. Overall and for the highlighted reasons, it was concluded that the PLQ, USC and LQL models are theoretically well-founded and, as such, could prove useful and practical choices compare to other proposed radiobiological models in clinical applications for obtaining uniformly accurate cell surviving fractions encountered in stereotactic high-dose radiotherapy as well as at medium and low doses.

  • 11.
    Andisheh, Bahram
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Belkic, D.
    Mavroidis, Panayiotis
    Stockholm University, Faculty of Science, Department of Physics.
    Alahverdi, M.
    Lind, B. K.
    Improving the therapeutic ratio in stereotactic radiosurgery: optimizing treatment protocols based on kinetics of repair of sublethal radiation damage2013In: Technology in Cancer Research & Treatment, ISSN 1533-0346, E-ISSN 1533-0338, Vol. 12, no 4, p. 349-361Article in journal (Refereed)
    Abstract [en]

    Sublethal damage after radiation exposure may become lethal or be repaired according to repair kinetics. This is a well-established concept in conventional radiotherapy. It also plays an important role in single-dose stereotactic radiotherapy treatments, often called stereotactic radiosurgery, when duration of treatment is extended due to source decay or treatment planning protocol. The purpose of this study is to look into the radiobiological characteristics of normal brain tissue and treatment protocols and find a way to optimize the time course of these protocols. The general problem is nonlinear and can be solved numerically. For numerical optimization of the time course of radiation protocol, a biexponential repair model with slow and fast components was considered. With the clinically imposed constraints of a fixed total dose and total treatment time, three parameters for each fraction (dose-rate, fraction duration, time of each fraction) were simultaneously optimized. A biological optimization can be performed by maximizing the therapeutic difference between tumor control probability and normal tissue complication probability. Specifically, for gamma knife radiosurgery, this approach can be implemented for normal brain tissue or tumor voxels separately in a treatment plan. Differences in repair kinetics of normal tissue and tumors can be used to find clinically optimized protocols. Thus, in addition to considering the physical dose in tumor and normal tissue, we also account for repair of sublethal damage in both these tissues.

  • 12. Andreassen, Björn
    et al.
    Holmberg, Rickard
    Brahme, Anders
    Janek Strååt, Sara
    Stockholm University, Faculty of Science, Medical Radiation Physics (together with KI). Stockholm University, Faculty of Science, Department of Physics.
    PET/CT measurements and GEANT4 simulations of the inducedpositron activity from high energy scanned photon beamsManuscript (preprint) (Other academic)
  • 13.
    Andreasson, Anna
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden; Macquarie University, Australia.
    Hagström, Hannes
    Sköldberg, Filip
    Önnerhag, Kristina
    Carlsson, Axel C.
    Schmidt, Peter T.
    Forsberg, Anna M.
    The prediction of colorectal cancer using anthropometric measures: A Swedish population-based cohort study with 22 years of follow-up2019In: United European Gastroenterology journal, ISSN 2050-6406, E-ISSN 2050-6414, Vol. 7, no 9, p. 1250-1260Article in journal (Refereed)
    Abstract [en]

    Background: Obesity is a risk factor for colorectal cancer (CRC).

    Objective: The objective of this article is to investigate whether anthropometric measures reflecting visceral obesity are better predictors of CRC than body mass index (BMI).

    Methods: Data were analysed from the Malmo Diet and Cancer study in Sweden, comprising 16,669 women and 10,805 men (median age 56.6 and 59.1 years) followed for a median 21.5 years. Diagnoses of CRC were identified using Swedish national registers. Cox regression was used to test the associations of BMI, waist circumference (WC), waist-hip ratio, waist-to-height ratio, waist-to-hip-to-height ratio, A Body Shape Index (ABSI) and percentage body fat with the development of CRC adjusted for age, alcohol consumption, smoking, education and physical activity in men and women.

    Results: None of the measures were significantly associated with an increased risk for CRC in women. WC was the strongest predictor of colon cancer (CC) in men and the only measure that was independent of BMI. ABSI was the only measure significantly associated with the risk of rectal cancer in men.

    Conclusions: Visceral obesity, best expressed as WC, is a risk factor for CC in men but a poor predictive marker for CRC in women.

  • 14.
    Antonovic, Laura
    et al.
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    Brahme, Anders
    Furusawa, Yoshiya
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    Radiobiological description of the LET dependence of the cell survival of oxic and anoxic cells irradiated by carbon ions2013In: Journal of radiation research, ISSN 0449-3060, E-ISSN 1349-9157, Vol. 54, no 1, p. 18-26Article in journal (Refereed)
    Abstract [en]

    Light-ion radiation therapy against hypoxic tumors is highly curative due to reduced dependence on the presence of oxygen in the tumor at elevated linear energy transfer (LET) towards the Bragg peak. Clinical ion beams using spread-out Bragg peak (SOBP) are characterized by a wide spectrum of LET values. Accurate treatment optimization requires a method that can account for influence of the variation in response for a broad range of tumor hypoxia, absorbed doses and LETs. This paper presents a parameterization of the Repairable Conditionally-Repairable (RCR) cell survival model that can describe the survival of oxic and hypoxic cells over a wide range of LET values, and investigates the relationship between hypoxic radiation resistance and LET. The biological response model was tested by fitting cell survival data under oxic and anoxic conditions for V79 cells irradiated with LETs within the range of 30 – 500 keV/μm. The model provides good agreement with experimental cell survival data for the range of LET investigated, confirming the robustness of the parameterization method. This new version of the RCR model is suitable for describing the biological response of mixed populations of oxic and hypoxic cells and at the same time taking into account the distribution of doses and LETs in the incident beam and its variation with depth in tissue. The model offers a versatile tool for the selection of LET and dose required in the optimization of the therapeutic effect, without severely affecting normal tissue in realistic tumors presenting highly heterogeneous oxic and hypoxic regions.

  • 15.
    Antonovic, Laura
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Lindblom, Emely
    Stockholm University, Faculty of Science, Department of Physics.
    Dasu, Alexandru
    Bassler, Niels
    Furusawa, Yoshiya
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    Clinical oxygen enhancement ratio of tumors in carbon ion radiotherapy: the influence of local oxygenation changes2014In: Journal of radiation research, ISSN 0449-3060, E-ISSN 1349-9157, Vol. 55, no 5, p. 902-911Article in journal (Refereed)
    Abstract [en]

    The effect of carbon ion radiotherapy on hypoxic tumors has recently been questioned because of low linear energy transfer (LET) values in the spread-out Bragg peak (SOBP). The aim of this study was to investigate the role of hypoxia and local oxygenation changes (LOCs) in fractionated carbon ion radiotherapy. Three-dimensional tumors with hypoxic subvolumes were simulated assuming interfraction LOCs. Different fractionations were applied using a clinically relevant treatment plan with a known LET distribution. The surviving fraction was calculated, taking oxygen tension, dose and LET into account, using the repairable–conditionally repairable (RCR) damage model with parameters for human salivary gland tumor cells. The clinical oxygen enhancement ratio (OER) was defined as the ratio of doses required for a tumor control probability of 50% for hypoxic and well-oxygenated tumors. The resulting OER was well above unity for all fractionations. For the hypoxic tumor, the tumor control probability was considerably higher if LOCs were assumed, rather than static oxygenation. The beneficial effect of LOCs increased with the number of fractions. However, for very low fraction doses, the improvement related to LOCs did not compensate for the increase in total dose required  for tumor control. In conclusion, our results suggest that hypoxia can influence the outcome of carbon ion radiotherapy because of the non-negligible oxygen effect at the low LETs in the SOBP. However, if LOCs occur, a relatively high level of tumor control probability is achievable with a large range of fractionation schedules for tumors with hypoxic subvolumes, but both hyperfractionation and hypofractionation should be pursued with caution.

  • 16. Applegate, K. E.
    et al.
    Rühm, W.
    Wojcik, Andrzej
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Bourguignon, M.
    Brenner, A.
    Hamasaki, K.
    Imai, T.
    Imaizumi, M.
    Imaoka, T.
    Kakinuma, S.
    Kamada, T.
    Nishimura, N.
    Okonogi, N.
    Ozasa, K.
    Rübe, C. E.
    Sadakane, A.
    Sakata, R.
    Shimada, Y.
    Yoshida, K.
    Bouffler, S.
    Individual response of humans to ionising radiation: governing factors and importance for radiological protection2020In: Radiation and Environmental Biophysics, ISSN 0301-634X, E-ISSN 1432-2099, Vol. 59, no 2, p. 185-209Article, review/survey (Refereed)
    Abstract [en]

    Tissue reactions and stochastic effects after exposure to ionising radiation are variable between individuals but the factors and mechanisms governing individual responses are not well understood. Individual responses can be measured at different levels of biological organization and using different endpoints following varying doses of radiation, including: cancers, non-cancer diseases and mortality in the whole organism; normal tissue reactions after exposures; and, cellular endpoints such as chromosomal damage and molecular alterations. There is no doubt that many factors influence the responses of people to radiation to different degrees. In addition to the obvious general factors of radiation quality, dose, dose rate and the tissue (sub)volume irradiated, recognized and potential determining factors include age, sex, life style (e.g., smoking, diet, possibly body mass index), environmental factors, genetics and epigenetics, stochastic distribution of cellular events, and systemic comorbidities such as diabetes or viral infections. Genetic factors are commonly thought to be a substantial contributor to individual response to radiation. Apart from a small number of rare monogenic diseases such as ataxia telangiectasia, the inheritance of an abnormally responsive phenotype among a population of healthy individuals does not follow a classical Mendelian inheritance pattern. Rather it is considered to be a multi-factorial, complex trait.

  • 17.
    Ardenfors, Oscar
    et al.
    Stockholm University, Faculty of Science, Department of Physics. Linköping University, Sweden; Karolinska Institutet, Sweden.
    Josefsson, Dan
    Dasu, Alexandru
    Are IMRT treatments in the head and neck region increasing the risk of secondary cancers?2014In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 53, no 8, p. 1041-1047Article in journal (Refereed)
    Abstract [en]

    Background. Intensity-modulated radiation therapy (IMRT) has been increasingly employed for treating head and neck (H&N) tumours due to its ability to produce isodoses suitable for the complex anatomy of the region. The aim of this study was to assess possible differences between IMRT and conformal radiation therapy (CRT) with regard to risk of radiation-induced secondary malignancies for H&N tumours. Material and methods. IMRT and CRT plans were made for 10 H&N adult patients and the resulting treatment planning data were used to calculate the risk of radiation-induced malignancies in four different tissues. Three risk models with biologically relevant parameters were used for calculations. The influence of scatter radiation and repeated imaging sessions has also been investigated. Results. The results showed that the total lifetime risks of developing radiation-induced secondary malignancies from the two treatment techniques, CRT and IMRT, were comparable and in the interval 0.9-2.5%. The risk contributions from the primary beam and scatter radiation were comparable, whereas the contribution from repeated diagnostic imaging was considerably smaller. Conclusion. The results indicated that the redistribution of the dose characteristic to IMRT leads to a redistribution of the risks in individual tissues. However, the total levels of risk were similar between the two irradiation techniques considered.

  • 18. Astaraki, Mehdi
    et al.
    Wang, Chunliang
    Buizza, Giulia
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    Lazzeroni, Marta
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    Smedby, Örjan
    Early survival prediction in non-small cell lung cancer from PET/CT images using an intra-tumor partitioning method2019In: Physica medica (Testo stampato), ISSN 1120-1797, E-ISSN 1724-191X, Vol. 60, p. 58-65Article in journal (Refereed)
    Abstract [en]

    Purpose

    To explore prognostic and predictive values of a novel quantitative feature set describing intra-tumor heterogeneity in patients with lung cancer treated with concurrent and sequential chemoradiotherapy.

    Methods

    Longitudinal PET-CT images of 30 patients with non-small cell lung cancer were analysed. To describe tumor cell heterogeneity, the tumors were partitioned into one to ten concentric regions depending on their sizes, and, for each region, the change in average intensity between the two scans was calculated for PET and CT images separately to form the proposed feature set. To validate the prognostic value of the proposed method, radiomics analysis was performed and a combination of the proposed novel feature set and the classic radiomic features was evaluated. A feature selection algorithm was utilized to identify the optimal features, and a linear support vector machine was trained for the task of overall survival prediction in terms of area under the receiver operating characteristic curve (AUROC).

    Results

    The proposed novel feature set was found to be prognostic and even outperformed the radiomics approach with a significant difference (AUROCSALoP = 0.90 vs. AUROCradiomic = 0.71) when feature selection was not employed, whereas with feature selection, a combination of the novel feature set and radiomics led to the highest prognostic values.

    Conclusion

    A novel feature set designed for capturing intra-tumor heterogeneity was introduced. Judging by their prognostic power, the proposed features have a promising potential for early survival prediction.

  • 19. Astaraki, Mehdi
    et al.
    Yang, Guang
    Zakko, Yousuf
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    Smedby, Örjan
    Wang, Chunliang
    A Comparative Study of Radiomics and Deep-Learning Based Methods for Pulmonary Nodule Malignancy Prediction in Low Dose CT Images2021In: Frontiers in Oncology, E-ISSN 2234-943X, Vol. 11, article id 737368Article in journal (Refereed)
    Abstract [en]

    Objectives: Both radiomics and deep learning methods have shown great promise in predicting lesion malignancy in various image-based oncology studies. However, it is still unclear which method to choose for a specific clinical problem given the access to the same amount of training data. In this study, we try to compare the performance of a series of carefully selected conventional radiomics methods, end-to-end deep learning models, and deep-feature based radiomics pipelines for pulmonary nodule malignancy prediction on an open database that consists of 1297 manually delineated lung nodules.

    Methods: Conventional radiomics analysis was conducted by extracting standard handcrafted features from target nodule images. Several end-to-end deep classifier networks, including VGG, ResNet, DenseNet, and EfficientNet were employed to identify lung nodule malignancy as well. In addition to the baseline implementations, we also investigated the importance of feature selection and class balancing, as well as separating the features learned in the nodule target region and the background/context region. By pooling the radiomics and deep features together in a hybrid feature set, we investigated the compatibility of these two sets with respect to malignancy prediction.

    Results: The best baseline conventional radiomics model, deep learning model, and deep-feature based radiomics model achieved AUROC values (mean ± standard deviations) of 0.792 ± 0.025, 0.801 ± 0.018, and 0.817 ± 0.032, respectively through 5-fold cross-validation analyses. However, after trying out several optimization techniques, such as feature selection and data balancing, as well as adding context features, the corresponding best radiomics, end-to-end deep learning, and deep-feature based models achieved AUROC values of 0.921 ± 0.010, 0.824 ± 0.021, and 0.936 ± 0.011, respectively. We achieved the best prediction accuracy from the hybrid feature set (AUROC: 0.938 ± 0.010).

    Conclusion: The end-to-end deep-learning model outperforms conventional radiomics out of the box without much fine-tuning. On the other hand, fine-tuning the models lead to significant improvements in the prediction performance where the conventional and deep-feature based radiomics models achieved comparable results. The hybrid radiomics method seems to be the most promising model for lung nodule malignancy prediction in this comparative study.

  • 20. Astaraki, Mehdi
    et al.
    Zakko, Yousuf
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden .
    Smedby, Örjan
    Wang, Chunliang
    Benign-malignant pulmonary nodule classification in low-dose CT with convolutional features2021In: Physica medica (Testo stampato), ISSN 1120-1797, E-ISSN 1724-191X, Vol. 83, p. 146-153Article in journal (Refereed)
    Abstract [en]

    Purpose: Low-Dose Computed Tomography (LDCT) is the most common imaging modality for lung cancer diagnosis. The presence of nodules in the scans does not necessarily portend lung cancer, as there is an intricate relationship between nodule characteristics and lung cancer. Therefore, benign-malignant pulmonary nodule classification at early detection is a crucial step to improve diagnosis and prolong patient survival. The aim of this study is to propose a method for predicting nodule malignancy based on deep abstract features.

    Methods: To efficiently capture both intra-nodule heterogeneities and contextual information of the pulmonary nodules, a dual pathway model was developed to integrate the intra-nodule characteristics with contextual attributes. The proposed approach was implemented with both supervised and unsupervised learning schemes. A random forest model was added as a second component on top of the networks to generate the classification results. The discrimination power of the model was evaluated by calculating the Area Under the Receiver Operating Characteristic Curve (AUROC) metric.

    Results: Experiments on 1297 manually segmented nodules show that the integration of context and target supervised deep features have a great potential for accurate prediction, resulting in a discrimination power of 0.936 in terms of AUROC, which outperformed the classification performance of the Kaggle 2017 challenge winner.

    Conclusion: Empirical results demonstrate that integrating nodule target and context images into a unified network improves the discrimination power, outperforming the conventional single pathway convolutional neural networks.

  • 21. Averbeck, Dietrich
    et al.
    Candéias, Serge
    Chandna, Sudhir
    Foray, Nicolas
    Friedl, Anna A.
    Haghdoost, Siamak
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Caen Normandy, France.
    Jeggo, Penelope A.
    Lumniczky, Katalin
    Paris, Francois
    Quintens, Roel
    Sabatier, Laure
    Establishing mechanisms affecting the individual response to ionizing radiation2020In: International Journal of Radiation Biology, ISSN 0955-3002, E-ISSN 1362-3095, Vol. 96, no 3, p. 297-323Article, review/survey (Refereed)
    Abstract [en]

    Purpose: Humans are increasingly exposed to ionizing radiation (IR). Both low (<100 mGy) and high doses can cause stochastic effects, including cancer; whereas doses above 100 mGy are needed to promote tissue or cell damage. 10-15% of radiotherapy (RT) patients suffer adverse reactions, described as displaying radiosensitivity (RS). Sensitivity to IR's stochastic effects is termed radiosusceptibility (RSu). To optimize radiation protection we need to understand the range of individual variability and underlying mechanisms. We review the potential mechanisms contributing to RS/RSu focusing on RS following RT, the most tractable RS group.

    Conclusions: The IR-induced DNA damage response (DDR) has been well characterized. Patients with mutations in the DDR have been identified and display marked RS but they represent only a small percentage of the RT patients with adverse reactions. We review the impacting mechanisms and additional factors influencing RS/RSu. We discuss whether RS/RSu might be genetically determined. As a recommendation, we propose that a prospective study be established to assess RS following RT. The study should detail tumor site and encompass a well-defined grading system. Predictive assays should be independently validated. Detailed analysis of the inflammatory, stress and immune responses, mitochondrial function and life style factors should be included. Existing cohorts should also be optimally exploited.

  • 22. Bao, Cuiping
    et al.
    Yang, Rongrong
    Pedersen, Nancy
    Xu, Weige
    Xu, Hui
    Song, Ruixue
    Qi, Xiuying
    Xu, Weili
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Tianjin Medical University, China.
    Overweight in midlife and risk of cancer in late life: A nationwide Swedish twin study2019In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 144, no 9, p. 2128-2134Article in journal (Refereed)
    Abstract [en]

    Our study examined whether midlife overweight (body mass index [BMI] >= 25) is associated with late-life cancer risk and explored the role of genetic and early-life environmental factors in this association. The study included 14,766 individuals from the Swedish Twin Registry, whose midlife (30-50 years) height and weight were recorded. Information on cancer diagnoses in late life (>65 years) was derived from the National Patient Registry and Cancer Registry. Generalized estimating equation (GEE) models were used to analyze unmatched case-control data (controlled for the clustering of twins within a pair). A co-twin matched case-control analysis used conditional logistic regression to compare cancer-discordant twins. Of all participants, 3968 (26.9%) were overweight and 4253 (28.8%) had cancer. In multi-adjusted GEE models using normal-weight (BMI 18.5-24.9) participants as the reference group, overweight was related to higher risk of colon cancer (OR 1.36, 95% CI: 1.00-1.84, p = 0.049), liver cancer (OR 2.00, 95% CI: 1.11-3.62), cervix uteri cancer (OR 2.86, 95% CI: 1.19-6.91) and corpus uteri cancer (OR 1.78, 95% CI: 1.14-2.78) but lower risk of nonmelanoma skin cancer (OR 0.77, 95% CI: 0.66-0.90). In conditional logistic regression analysis, these associations were attenuated becoming nonsignificance. The difference in ORs from the unmatched and matched analyses was not significant. In conclusion, midlife overweight is associated with increased risk of late-life colon, liver and uterine cancer but reduced risk of late-life nonmelanoma skin cancer. Further investigations are warranted to explore the role of genetic and early-life environmental factors in these associations.

  • 23. Barnekow, Elin
    et al.
    Hasslow, Johan
    Liu, Wen
    Bryant, Patrick
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). Karolinska Institutet, Sweden.
    Thutkawkorapin, Jessada
    Wendt, Camilla
    Czene, Kamila
    Hall, Per
    Margolin, Sara
    Lindblom, Annika
    A Swedish Familial Genome-Wide Haplotype Analysis Identified Five Novel Breast Cancer Susceptibility Loci on 9p24.3, 11q22.3, 15q11.2, 16q24.1 and Xq21.312023In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 24, no 5, article id 4468Article in journal (Refereed)
    Abstract [en]

    Most breast cancer heritability is unexplained. We hypothesized that analysis of unrelated familial cases in a GWAS context could enable the identification of novel susceptibility loci. In order to examine the association of a haplotype with breast cancer risk, we performed a genome-wide haplotype association study using a sliding window analysis of window sizes 1–25 SNPs in 650 familial invasive breast cancer cases and 5021 controls. We identified five novel risk loci on 9p24.3 (OR 3.4; p 4.9 × 10−11), 11q22.3 (OR 2.4; p 5.2 × 10−9), 15q11.2 (OR 3.6; p 2.3 × 10−8), 16q24.1 (OR 3; p 3 × 10−8) and Xq21.31 (OR 3.3; p 1.7 × 10−8) and confirmed three well-known loci on 10q25.13, 11q13.3, and 16q12.1. In total, 1593 significant risk haplotypes and 39 risk SNPs were distributed on the eight loci. In comparison with unselected breast cancer cases from a previous study, the OR was increased in the familial analysis in all eight loci. Analyzing familial cancer cases and controls enabled the identification of novel breast cancer susceptibility loci.

  • 24. Barnekow, Elin
    et al.
    Liu, Wen
    Helgadottir, Hafdis T.
    Michailidou, Kyriaki
    Dennis, Joe
    Bryant, Patrick
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). Karolinska Institutet, Sweden.
    Thutkawkorapin, Jessada
    Wendt, Camilla
    Czene, Kamila
    Hall, Per
    Margolin, Sara
    Lindblom, Annika
    A Swedish Genome-Wide Haplotype Association Analysis Identifies a Novel Breast Cancer Susceptibility Locus in 8p21.2 and Characterizes Three Loci on Chromosomes 10, 11 and 162022In: Cancers, ISSN 2072-6694, Vol. 14, no 5, article id 1206Article in journal (Refereed)
    Abstract [en]

    Simple Summary: Heritable rare high- and moderate-risk mutations in breast cancer susceptibility genes are known of, alongside 170 common genetic low risk variants with a minor increase in risk. However, based on genetic studies, we know that over half of the breast cancer heritability is still unexplained. By analyzing combinations of chromosomal nearby variants, so-called haplotypes, and their association to breast cancer we could identify a novel genetic breast cancer risk locus on chromosome 8 and confirm three well known low risk loci on Chr 10, 11 and 16. (1)

    Background: The heritability of breast cancer is partly explained but much of the genetic contribution remains to be identified. Haplotypes are often used as markers of ethnicity as they are preserved through generations. We have previously demonstrated that haplotype analysis, in addition to standard SNP association studies, could give novel and more detailed information on genetic cancer susceptibility. (2)

    Methods: In order to examine the association of a SNP or a haplotype to breast cancer risk, we performed a genome wide haplotype association study, using sliding window analysis of window sizes 1-25 and 50 SNPs, in 3200 Swedish breast cancer cases and 5021 controls. (3) Results: We identified a novel breast cancer susceptibility locus in 8p21.1 (OR 2.08; p 3.92 x 10(-8)), confirmed three known loci in 10q26.13, 11q13.3, 16q12.1-2 and further identified novel subloci within these three loci. Altogether 76 risk SNPs, 3302 risk haplotypes of window size 2-25 and 113 risk haplotypes of window size 50 at p < 5 x 10(-8) on chromosomes 8, 10, 11 and 16 were identified. In the known loci haplotype analysis reached an OR of 1.48 in overall breast cancer and in familial cases OR 1.68. (4)

    Conclusions: Analyzing haplotypes, rather than single variants, could detect novel susceptibility loci even in small study populations but the method requires a fairly homogenous study population.

  • 25. Bauerschmidt, Christina
    et al.
    Woodcock, Michael
    Stevens, David L.
    Hill, Mark A.
    Rothkamm, Kai
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Cohesin phosphorylation and mobility of SMC1 at ionizing radiation-induced DNA double-strand breaks in human cells2011In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 317, no 3, p. 330-337Article in journal (Refereed)
    Abstract [en]

    Cohesin, a hetero-tetrameric complex of SMC1, SMC3, Rad21 and Scc3, associates with chromatin after mitosis and holds sister chromatids together following DNA replication. Following DNA damage, cohesin accumulates at and promotes the repair of DNA double-strand breaks. In addition, phosphorylation of the SMC1/3 subunits contributes to DNA damage-induced cell cycle checkpoint regulation. The aim of this study was to determine the regulation and consequences of SMC1/3 phosphorylation as part of the cohesin complex. We show here that the ATM-dependent phosphorylation of SMC1 and SMC3 is mediated by H2AX, 53BP1 and MDC1. Depletion of RAD21 abolishes these phosphorylations, indicating that only the fully assembled complex is phosphorylated. Comparison of wild type SMC1 and SMC1S966A in fluorescence recovery after photo-bleaching experiments shows that phosphorylation of SMC1 is required for an increased mobility after DNA damage in G2-phase cells, suggesting that ATM-dependent phosphorylation facilitates mobilization of the cohesin complex after DNA damage.

  • 26. Beghini, Alessandro
    et al.
    Corlazzoli, Francesca
    Del Giacco, Luca
    Re, Matteo
    Lazzaroni, Francesca
    Brioschi, Matteo
    Valentini, Giorgio
    Ferrazzi, Fulvia
    Ghilardi, Anna
    Righi, Marco
    Turrini, Mauro
    Mignardi, Marco
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Cesana, Clara
    Bronte, Vincenzo
    Nilsson, Mats
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Morra, Enrica
    Cairoli, Roberto
    Regeneration-associated WNT Signaling Is Activated in Long-term Reconstituting AC133(bright) Acute Myeloid Leukemia Cells2012In: Neoplasia, ISSN 1522-8002, E-ISSN 1476-5586, Vol. 14, no 12, p. 1236-+Article in journal (Refereed)
    Abstract [en]

    Acute myeloid leukemia (AML) is a genetically heterogeneous clonal disorder characterized by two molecularly distinct self-renewing leukemic stem cell (LSC) populations most closely related to normal progenitors and organized as a hierarchy. A requirement for WNT/beta-catenin signaling in the pathogenesis of AML has recently been suggested by a mouse model. However, its relationship to a specific molecular function promoting retention of self-renewing leukemia-initiating cells (LICs) in human remains elusive. To identify transcriptional programs involved in the maintenance of a self-renewing state in LICs, we performed the expression profiling in normal (n = 10) and leukemic (n = 33) human long-term reconstituting AC133(+) cells, which represent an expanded cell population in most AML patients. This study reveals the ligand-dependent WNT pathway activation in AC133(bright) AML cells and shows a diffuse expression and release of WNT 10B, a hematopoietic stem cell regenerative-associated molecule. The establishment of a primary AC133(+) AML cell culture (A46) demonstrated that leukemia cells synthesize and secrete WNT ligands, increasing the levels of dephosphorylated beta-catenin in vivo. We tested the LSC functional activity in AC133(+) cells and found significant levels of engraftment upon transplantation of A46 cells into irradiated Rag2(-/-)gamma c(-/-) mice. Owing to the link between hematopoietic regeneration and developmental signaling, we transplanted A46 cells into developing zebrafish. This system revealed the formation of ectopic structures by activating dorsal organizer markers that act downstream of the WNT pathway. In conclusion, our findings suggest that AC133(bright) LSCs are promoted by misappropriating homeostatic WNT programs that control hematopoietic regeneration. Neoplasia (2012) 14, 1236-1248

  • 27.
    Beltran-Pardo, Eliana
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Jonsson, K. Ingemar
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Kristianstad University, Sweden.
    Harms-Ringdahl, Mats
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Haghdoost, Siamak
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Wojcik, Andrzej
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Tolerance to Gamma Radiation in the Tardigrade Hypsibius dujardini from Embryo to Adult Correlate Inversely with Cellular Proliferation2015In: PLOS ONE, E-ISSN 1932-6203, Vol. 10, no 7, article id e0133658Article in journal (Refereed)
    Abstract [en]

    Tardigrades are highly tolerant to desiccation and ionizing radiation but the mechanisms of this tolerance are not well understood. In this paper, we report studies on dose responses of adults and eggs of the tardigrade Hypsibius dujardini exposed to gamma radiation. In adults the LD50/48h for survival was estimated at similar to 4200 Gy, and doses higher than 100 Gy reduced both fertility and hatchability of laid eggs drastically. We also evaluated the effect of radiation (doses 50 Gy, 200 Gy, 500 Gy) on eggs in the early and late embryonic stage of development, and observed a reduced hatchability in the early stage, while no effect was found in the late stage of development. Survival of juveniles from irradiated eggs was highly affected by a 500 Gy dose, both in the early and the late stage. Juveniles hatched from eggs irradiated at 50 Gy and 200 Gy developed into adults and produced offspring, but their fertility was reduced compared to the controls. Finally we measured the effect of low temperature during irradiation at 4000 Gy and 4500 Gy on survival in adult tardigrades, and observed a slight delay in the expressed mortality when tardigrades were irradiated on ice. Since H. dujardini is a freshwater tardigrade with lower tolerance to desiccation compared to limno-terrestrial tardigrades, the high radiation tolerance in adults, similar to limno-terrestrial tardigrades, is unexpected and seems to challenge the idea that desiccation and radiation tolerance rely on the same molecular mechanisms. We suggest that the higher radiation tolerance in adults and late stage embryos of H. dujardini (and in other studied tardigrades) compared to early stage embryos may partly be due to limited mitotic activity, since tardigrades have a low degree of somatic cell division (eutely), and dividing cells are known to be more sensitive to radiation.

  • 28.
    Ben-Aissa, Hedi
    Stockholm University.
    Transitional cell carcinoma of the human urinary bladder: a study of tumor associated antigens and their histochemical distribution1988Doctoral thesis, comprehensive summary (Other academic)
  • 29. Benyi, Emelie
    et al.
    Linder, Marie
    Adami, Johanna
    Kieler, Helle
    Palme, Mårten
    Stockholm University, Faculty of Social Sciences, Department of Economics.
    Sävendahl, Lars
    Adult height is associated with risk of cancer and mortality in 5.5 million Swedish women and men2019In: Journal of Epidemiology and Community Health, ISSN 0143-005X, E-ISSN 1470-2738, Vol. 73, no 8, p. 730-736Article in journal (Refereed)
    Abstract [en]

    Background Previous studies have indicated that taller individuals are at greater risk of developing cancer. Death from cancer and other specific causes have also been linked to height, but the results have been inconclusive. We aimed to shed further light on the associations between height, cancer incidence and mortality.

    Methods We conducted a nationwide, population-based prospective cohort study, including 5.5 million Swedish women and men (aged 20-74). They were followed over a period of up to 54 years. Heights were retrieved from national registers (mainly the Passport Register where heights are most often self-reported). The risks of overall and specific cancers, as well as overall and cause-specific mortality, were presented as HR with 95% CIs per 10 cm increase in height.

    Results A total of 278 299 cases of cancer and 139 393 cases of death were identified. For overall cancer, HR was 1.19 (1.18-1.20) in women and 1.11 (1.10-1.12) in men for every 10 cm increase in height. All 15 specific cancer types were positively associated with height-most strongly for malignant melanoma in both genders, with HRs of 1.39 (1.35-1.43) in women and 1.34 (1.30-1.38) in men. For overall mortality, HR was 0.98 (0.97-0.99) in women and 0.91 (0.90-0.92) in men for every 10 cm increase in height. Cancer mortality was increased in taller individuals, with HR 1.15 (1.13-1.17) in women and 1.05 (1.03-1.07) in men for every 10 cm increase in height, whereas shorter individuals had increased overall mortality due to a number of other causes, such as cardiovascular disease.

    Conclusion Overall and specific cancer risks, particularly malignant melanoma, were positively associated with height. Cancer mortality also increased with height. In contrast, overall mortality was decreased with height, particularly in men due to inverse associations with height for other causes of death.

  • 30. Bergandi, Loredana
    et al.
    Skorokhod, Oleksii A.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Torino, Italy.
    Franzone, Federica
    La Grotta, Rosalba
    Schwarzer, Evelin
    Nuzzi, Raffaele
    Induction of oxidative stress in human aqueous and vitreous humors by Nd: YAG laser posterior capsulotomy2018In: International journal of ophthalmology, ISSN 2222-3959, Vol. 11, no 7, p. 1145-1151Article in journal (Refereed)
    Abstract [en]

    AIM: To evaluate whether the Q-switched Nd:YAG laser treatment applied in routine capsulotomy elicits oxidative stress in aqueous and vitreous humors. METHODS: Thirty-six patients who had to undergo a 25 gauge pars plana vitrectomy due to vitreoretinal disorders were enrolled, 15 of them underwent a Q-switched Nd:YAG laser capsulotomy 7d before vitrectomy due to posterior capsule opacification (PCO) (Nd:YAG laser group) while the remaining 21 patients were not laser treated before vitrectomy (no Nd:YAG laser group). Samples of the aqueous and vitreous humors were collected during vitrectomy from all patients for the assessment of oxidative parameters which were compared between the Nd:YAG laser group and no Nd:YAG laser group. Thiobarbituric acid reactive substances (TBARS), a product of membrane lipid peroxidation, nitrite levels, the antioxidative activities of SOD and catalase, the 4-HNE-protein conjugate formation, indicating structural modifications in proteins due to lipoperoxidation, were assessed in aqueous and vitreous samples. RESULTS: In the human vitreous humor TBARS levels are significantly higher in the Nd:YAG laser group compared to the no Nd:YAG laser group and importantly, there is a significant correlation between the TBARS levels and the total energy of Nd:YAG laser used during capsulotomy. Moreover the anti-oxidative activities of SOD and catalase were significantly decreased by Nd:YAG laser treatment, both in aqueous and vitreous humors. In accordance with the TBARS data and anti-oxidative enzyme activities, significantly higher levels of proteins were conjugated with the lipoperoxidation product 4-HNE in the aqueous and vitreous humors in the Nd:YAG laser-treated group in comparison to no Nd:YAG laser group. CONCLUSION: These data, clearly suggest that any change that Q-switched Nd:YAG photo disruption may cause in the aqueous and vitreous compartments, resulting in a higher level of oxidative damage might be of considerable clinical significance particularly by accelerating the aging of the anterior and posterior segments of the eye and by worsening the intraocular pressure, the uveal, the retinal (especially macular) pathologies.

  • 31. Berglund, Emelie
    et al.
    Maaskola, Jonas
    Schultz, Niklas
    Friedrich, Stefanie
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Marklund, Maja
    Bergenstråhle, Joseph
    Tarish, Firas
    Tanoglidi, Anna
    Vickovic, Sanja
    Larsson, Ludvig
    Salmén, Fredrik
    Ogris, Christoph
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Wallenborg, Karolina
    Lagergren, Jens
    Ståhl, Patrik
    Sonnhammer, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Helleday, Thomas
    Lundeberg, Joakim
    Spatial maps of prostate cancer transcriptomes reveal an unexplored landscape of heterogeneity2018In: Nature Communications, E-ISSN 2041-1723, Vol. 9, article id 2419Article in journal (Refereed)
    Abstract [en]

    Intra-tumor heterogeneity is one of the biggest challenges in cancer treatment today. Here we investigate tissue-wide gene expression heterogeneity throughout a multifocal prostate cancer using the spatial transcriptomics (ST) technology. Utilizing a novel approach for deconvolution, we analyze the transcriptomes of nearly 6750 tissue regions and extract distinct expression profiles for the different tissue components, such as stroma, normal and PIN glands, immune cells and cancer. We distinguish healthy and diseased areas and thereby provide insight into gene expression changes during the progression of prostate cancer. Compared to pathologist annotations, we delineate the extent of cancer foci more accurately, interestingly without link to histological changes. We identify gene expression gradients in stroma adjacent to tumor regions that allow for re-stratification of the tumor microenvironment. The establishment of these profiles is the first step towards an unbiased view of prostate cancer and can serve as a dictionary for future studies.

  • 32. Beskow, Catharina
    et al.
    Ågren-Cronqvist, Anna-Karin
    Lewensohn, Rolf
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics.
    Biological effective dose evaluation and assessment of rectal and bladder complications for cervical cancer treated with radiotherapy and surgery2012In: Journal of Contemporary Brachytherapy, ISSN 1689-832X, E-ISSN 2081-2841, Vol. 4, no 4, p. 205-212Article in journal (Refereed)
    Abstract [en]

    Purpose: This study aims to retrospectively evaluate dosimetric parameters calculated as biological effective dose in relation to outcome in patients with cervical cancer treated with various treatment approaches including radiotherapy, with and without surgery.

    Methods and Materials: Calculations of biological effective dose (BED) were performed on data from a retrospective analysis of 171 patients with cervical carcinoma stages IB-IIB treated with curative intent between January 1989 and December 1991. 43 patients were treated only with radiotherapy and 128 patients were treated with a combination of radiotherapy and surgery. External beam radiotherapy was delivered with 6-21 MV photons from linear accelerators. Brachytherapy was delivered either with a manual radium technique or with a remote afterloading technique. The treatment outcome was evaluated at 5 years.

    Results: The disease-specific survival rate was 87% for stage IB, 75% for stage IIA and 54% for stage IIB, while the overall survival rates were 84% for stage IB, 68% for stage IIA and 43% for stage IIB. Patients treated only with radiotherapy had a local control rate of 77% which was comparable to that for radiotherapy and surgery patients (78%). Late complications were recorded in 25 patients (15%). Among patients treated with radiotherapy and surgery, differences in radiation dose calculated as BED10 did not seem to influence survival. For patients treated with radiotherapy only, a higher BED10 was correlated to a higher overall survival (p=0.0075). The dose response parameters found based on biological effective dose calculations were D50=85.2 Gy10 and γ=1.62 for survival and D50=61.6 Gy10 and γ=0.92 for local control.

    Conclusions: The outcome correlates with biological effective dose for patients treated with radiation therapy alone, but not for patients treated with radiotherapy and surgery. No correlations were found between BED and late toxicity from bladder and rectum.

  • 33. Binder, Zev A.
    et al.
    Haseley Thorne, Amy
    Bakas, Spyridon
    Wileyto, E. Paul
    Bilello, Michel
    Akbari, Hamed
    Rathore, Saima
    Ha, Sung Min
    Zhang, Logan
    Ferguson, Cole J.
    Dahiya, Sonika
    Bi, Wenya Linda
    Reardon, David A.
    Idbaih, Ahmed
    Felsberg, Joerg
    Hentschel, Bettina
    Weller, Michael
    Bagley, Stephen J.
    Morrissette, Jennifer J. D.
    Nasrallah, MacLean P.
    Ma, Jianhui
    Zanca, Ciro
    Scott, Andrew M.
    Orellana, Laura
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Davatzikos, Christos
    Furnari, Frank B.
    O'Rourke, Donald M.
    Epidermal Growth Factor Receptor Extracellular Domain Mutations in Glioblastoma Present Opportunities for Clinical Imaging and Therapeutic Development2018In: Cancer Cell, ISSN 1535-6108, E-ISSN 1878-3686, Vol. 34, no 1, p. 163-177Article in journal (Refereed)
    Abstract [en]

    We explored the clinical and pathological impact of epidermal growth factor receptor (EGFR) extracellular domain missense mutations. Retrospective assessment of 260 de novo glioblastoma patients revealed a significant reduction in overall survival of patients having tumors with EGFR mutations at alanine 289 (EGFR(A289D/T/V)). Quantitative multi-parametric magnetic resonance imaging analyses indicated increased tumor invasion for EGFR(A289D/T/V) mutants, corroborated in mice bearing intracranial tumors expressing EGFR(A289V) and dependent on ERK-mediated expression of matrix metalloproteinase-1. EGFR(A289V) tumor growth was attenuated with an antibody against a cryptic epitope, based on in silico simulation. The findings of this study indicate a highly invasive phenotype associated with the EGFR(A289V) mutation in glioblastoma, postulating EGFR(A289V) as a molecular marker for responsiveness to therapy with EGFR-targeting antibodies.

  • 34.
    Bolsi, Alessandra
    et al.
    Paul Scherrer Institute, Switzerland.
    Peroni, Marta
    Paul Scherrer Institute, Switzerland.
    Amelio, Dante
    Proton Therapy Centre Azienda Provinciale per I Servizi Sanitari (APSS), Italy.
    Dasu, Alexandru
    The Skandion Clinic, Sweden.
    Stock, Markus
    MedAustron Ion Therapy Center, Austria.
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    Witt Nyström, Petra
    The Skandion Clinic, Sweden; Danish Centre for Particle Therapy, Denmark.
    Hoffmann, Aswin
    Technische Universität Dresden, Germany; OncoRay, Germany.
    Practice patterns of image guided particle therapy in Europe: A 2016 survey of the European Particle Therapy Network (EPTN)2018In: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 128, no 1, p. 4-8Article in journal (Refereed)
    Abstract [en]

    Background and purpose: Image guidance is critical in achieving accurate and precise radiation delivery in particle therapy, even more than in photon therapy. However, equipment, quality assurance procedures and clinical workflows for image-guided particle therapy (IGPT) may vary substantially between centres due to a lack of standardization. A survey was conducted to evaluate the current practice of IGPT in European particle therapy centres.

    Material and methods: In 2016, a questionnaire was distributed among 19 particle therapy centres in 12 European countries. The questionnaire consisted of 30 open and 37 closed questions related to image guidance in the general clinical workflow, for moving targets, current research activities and future perspectives of IGPT.

    Results: All centres completed the questionnaire. The IGPT methods used by the 10 treating centres varied substantially. The 9 non-treating centres were in the process to introduce IGPT. Most centres have developed their own IGPT strategies, being tightly connected to their specific technical implementation and dose delivery methods.

    Conclusions: Insight into the current clinical practice of IGPT in European particle therapy centres was obtained. A variety in IGPT practices and procedures was confirmed, which underlines the need for harmonisation of practice parameters and consensus guidelines.

  • 35. Bonagas, Nadilly
    et al.
    Gustafsson, Nina M. S.
    Henriksson, Martin
    Marttila, Petra
    Gustafsson, Robert
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Wiita, Elisée
    Borhade, Sanjay
    Green, Alanna C.
    Vallin, Karl S. A.
    Sarno, Antonio
    Svensson, Richard
    Göktürk, Camilla
    Pham, Therese
    Jemth, Ann-Sofie
    Loseva, Olga
    Cookson, Victoria
    Kiweler, Nicole
    Sandberg, Lars
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Rasti, Azita
    Unterlass, Judith E.
    Haraldsson, Martin
    Andersson, Yasmin
    Scaletti, Emma R.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Lund University, Sweden.
    Bengtsson, Christoffer
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Paulin, Cynthia B. J.
    Sanjiv, Kumar
    Abdurakhmanov, Eldar
    Pudelko, Linda
    Kunz, Ben
    Desroses, Matthieu
    Iliev, Petar
    Färnegårdh, Katarina
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Krämer, Andreas
    Garg, Neeraj
    Michel, Maurice
    Häggblad, Sara
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Jarvius, Malin
    Kalderén, Christina
    Bögedahl Jensen, Amanda
    Almlöf, Ingrid
    Karsten, Stella
    Zhang, Si Min
    Häggblad, Maria
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Eriksson, Anders
    Liu, Jianping
    Glinghammar, Björn
    Nekhotiaeva, Natalia
    Klingegård, Fredrik
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Koolmeister, Tobias
    Martens, Ulf
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Llona-Minguez, Sabin
    Moulson, Ruth
    Nordström, Helena
    Parrow, Vendela
    Dahllund, Leif
    Sjöberg, Birger
    Vargas, Irene L.
    Vo, Duy Duc
    Wannberg, Johan
    Knapp, Stefan
    Krokan, Hans E.
    Arvidsson, Per
    Scobie, Martin
    Meiser, Johannes
    Stenmark, Pål
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Lund University, Sweden.
    Warpman Berglund, Ulrika
    Homan, Evert J.
    Helleday, Thomas
    Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress2022In: Nature cancer, ISSN 2662-1347, Vol. 3, no 2, p. 156-172Article in journal (Refereed)
    Abstract [en]

    The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors. Helleday and colleagues describe a nanomolar MTHFD2 inhibitor that causes replication stress and DNA damage accumulation in cancer cells via thymidine depletion, demonstrating a potential therapeutic strategy in AML tumors in vivo.

  • 36. Bouchet, Audrey
    et al.
    Boumendjel, Ahcene
    Khalil, Enam
    Serduc, Raphael
    Braeuer, Elke
    Siegbahn, Erik Albert
    Stockholm University, Faculty of Science, Department of Physics.
    Laissue, Jean A.
    Boutonnat, Jean
    Chalcone JAI-51 improves efficacy of synchrotron microbeam radiation therapy of brain tumors2012In: Journal of Synchrotron Radiation, ISSN 0909-0495, E-ISSN 1600-5775, Vol. 19, p. 478-482Article in journal (Refereed)
    Abstract [en]

    Microbeam radiation therapy (MRT), a preclinical form of radiosurgery, uses spatially fractionated micrometre-wide synchrotron-generated X-ray beams. As MRT alone is predominantly palliative for animal tumors, the effects of the combination of MRT and a newly synthesized chemotherapeutic agent JAI-51 on 9L gliosarcomas have been evaluated. Fourteen days (D14) after implantation (D0), intracerebral 9LGS-bearing rats received either MRT, JAI-51 or both treatments. JAI-51, alone or immediately after MRT, was administered three times per week. Animals were kept up to similar to 20 weeks after irradiation or sacrificed at D16 or D28 after treatment for cell cycle analysis. MRT plus JAI-51 increased significantly the lifespan compared with MRT alone (p = 0.0367). JAI-51 treatment alone had no effect on rat survival. MRT alone or associated with JAI-51 induced a cell cycle blockade in G2/M (p < 0.01) while the combined treatment also reduced the proportion of G0/G1 cells. At D28 after irradiation, MRT and MRT/JAI-51 had a smaller cell blockade effect in the G2/M phase owing to a significant increase in tumor cell death rate (<2c) and a proportional increase of endoreplicative cells (>8c). The combination of MRT and JAI-51 increases the survival of 9LGS-bearing rats by inducing endoreduplication of DNA and tumor cell death; further, it slowed the onset of tumor growth resumption two weeks after treatment.

  • 37.
    Bryant, Patrick
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). Karolinska Institutet, Sweden.
    Walton Bernstedt, Sophie
    Thutkawkorapin, Jessada
    Backman, Ann-Sofie
    Lindblom, Annika
    Lagerstedt-Robinson, Kristina
    Exome sequencing in a Swedish family with PMS2 mutation with varying penetrance of colorectal cancer: investigating the presence of genetic risk modifiers in colorectal cancer risk2023In: European Journal of Cancer Prevention, ISSN 0959-8278, E-ISSN 1473-5709, Vol. 32, no 2, p. 113-118Article in journal (Refereed)
    Abstract [en]

    Objective  Lynch syndrome is caused by germline mutations in the mismatch repair (MMR) genes, such as the PMS2 gene, and is characterised by a familial accumulation of colorectal cancer. The penetrance of cancer in PMS2 carriers is still not fully elucidated as a colorectal cancer risk has been shown to vary between PMS2 carriers, suggesting the presence of risk modifiers.

    Methods  Whole exome sequencing was performed in a Swedish family carrying a PMS2 missense mutation [c.2113G>A, p.(Glu705Lys)]. Thirteen genetic sequence variants were further selected and analysed in a case-control study (724 cases and 711 controls).

    Results  The most interesting variant was an 18 bp deletion in gene BAG1. BAG1 has been linked to colorectal tumour progression with poor prognosis and is thought to promote colorectal tumour cell survival through increased NF-κB activity.

    Conclusions  We conclude the genetic architecture behind the incomplete penetrance of PMS2 is complicated and must be assessed in a genome wide manner using large families and multifactorial analysis.

  • 38. Bustamante, M.
    et al.
    Hernandez-Ferrer, C.
    Tewari, A.
    Sarria, Y.
    Harrison, G. I.
    Puigdecanet, E.
    Nonell, L.
    Kang, Wenjing
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Friedländer, Marc R.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Estivill, X.
    González, J. R.
    Nieuwenhuijsen, M.
    Young, A. R.
    Dose and time effects of solar-simulated ultraviolet radiation on the in vivo human skin transcriptome2020In: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 182, no 6, p. 1458-1468Article in journal (Refereed)
    Abstract [en]

    Background Terrestrial ultraviolet (UV) radiation causes erythema, oxidative stress, DNA mutations and skin cancer. Skin can adapt to these adverse effects by DNA repair, apoptosis, keratinization and tanning.

    Objectives To investigate the transcriptional response to fluorescent solar-simulated radiation (FSSR) in sun-sensitive human skin in vivo.

    Methods Seven healthy male volunteers were exposed to 0, 3 and 6 standard erythemal doses (SED). Skin biopsies were taken at 6 h and 24 h after exposure. Gene and microRNA expression were quantified with next generation sequencing. A set of candidate genes was validated by quantitative polymerase chain reaction (qPCR); and wavelength dependence was examined in other volunteers through microarrays.

    Results The number of differentially expressed genes increased with FSSR dose and decreased between 6 and 24 h. Six hours after 6 SED, 4071 genes were differentially expressed, but only 16 genes were affected at 24 h after 3 SED. Genes for apoptosis and keratinization were prominent at 6 h, whereas inflammation and immunoregulation genes were predominant at 24 h. Validation by qPCR confirmed the altered expression of nine genes detected under all conditions; genes related to DNA repair and apoptosis; immunity and inflammation; pigmentation; and vitamin D synthesis. In general, candidate genes also responded to UVA1 (340-400 nm) and/or UVB (300 nm), but with variations in wavelength dependence and peak expression time. Only four microRNAs were differentially expressed by FSSR.

    Conclusions The UV radiation doses of this acute study are readily achieved daily during holidays in the sun, suggesting that the skin transcriptional profile of 'typical' holiday makers is markedly deregulated.

  • 39.
    Carlsson Tedgren, Åsa K.
    Stockholm University.
    Development of dose calculation methods for brachytherapy treatment planning2003Doctoral thesis, comprehensive summary (Other academic)
  • 40. Cernvall, Martin
    et al.
    Carlbring, Per
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Ljungman, Lisa
    Ljungman, Gustaf
    von Essen, Louise
    Internet‐based guided self‐help for parents of children on cancer treatment: a randomized controlled trial2015In: Psycho-Oncology, ISSN 1057-9249, E-ISSN 1099-1611, Vol. 24, no 9, p. 1152-1158Article in journal (Refereed)
    Abstract [en]

    Objective

    The aim of the study was to investigate the feasibility and preliminary efficacy of an Internet‐based guided self‐help intervention for posttraumatic stress symptoms (PTSS) and related symptoms in parents of children on cancer treatment.

    Methods

    Parents of children on cancer treatment, who fulfilled the modified symptom criteria on the PTSD Checklist, were randomly allocated to the intervention or to a wait‐list control condition. The intervention group accessed a 10‐week guided self‐help program via the Internet based on principles from cognitve behavior therapy. The primary outcome PTSS and the secondary outcomes depression and anxiety were assessed by self‐report preintervention and postintervention.

    Results

    Seven hundred forty‐seven parents were approached and informed about the study, 92 were assessed for eligibility, and 58 were included and randomized to the intervention ( = 31) or wait list ( = 27). Eightteen participants completed the intervention. Intention‐to‐treat analyses indicated a significant effect of the intervention on PTSS with a large between‐group effect size at postassessment (Cohen's  = 0.88). The intervention group reported reductions in PTSS with a large within‐group effect size ( = 1.62) compared with a minimal reduction in the wait‐list group ( = 0.09). There was a significant intervention effect on depression and anxiety and reductions in the intervention group with large within‐group effect sizes ( = 0.85–1.09).

    Conclusions

    Findings indicate a low enrollment rate and considerable attrition but also that Internet‐based guided self‐help shows promise for parents of children on cancer treatment who report a high level of PTSS and would like to take part in an Internet‐based intervention. 

  • 41. Chen, Baoqing
    et al.
    Dragomir, Mihnea P.
    Fabris, Linda
    Bayraktar, Recep
    Knutsen, Erik
    Liu, Xu
    Tang, Changyan
    Li, Yongfeng
    Shimura, Tadanobu
    Ivkovic, Tina Catela
    De los Santos, Mireia Cruz
    Anfossi, Simone
    Shimizu, Masayoshi
    Shah, Maitri Y.
    Ling, Hui
    Shen, Peng
    Multani, Asha S.
    Pardini, Barbara
    Burks, Jared K.
    Katayama, Hiroyuki
    Reineke, Lucas C.
    Huo, Longfei
    Syed, Muddassir
    Song, Shumei
    Ferracin, Manuela
    Oki, Eiji
    Fromm, Bastian
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab). Oslo University Hospital, Norway.
    Ivan, Cristina
    Bhuvaneshwar, Krithika
    Gusev, Yuriy
    Mimori, Koshi
    Menter, David
    Sen, Subrata
    Matsuyama, Takatoshi
    Uetake, Hiroyuki
    Vasilescu, Catalin
    Kopetz, Scott
    Parker-Thornburg, Jan
    Taguchi, Ayumu
    Hanash, Samir M.
    Girnita, Leonard
    Slaby, Ondrej
    Goel, Ajay
    Varani, Gabriele
    Gagea, Mihai
    Li, Chunlai
    Ajani, Jaffer A.
    Calin, George A.
    The Long Noncoding RNA CCAT2 Induces Chromosomal Instability Through BOP1-AURKB Signaling2020In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 159, no 6, p. 2146-2162Article in journal (Refereed)
    Abstract [en]

    Background & Aims

    Chromosomal instability (CIN) is a carcinogenesis event that promotes metastasis and resistance to therapy by unclear mechanisms. Expression of the colon cancer–associated transcript 2 gene (CCAT2), which encodes a long noncoding RNA (lncRNA), associates with CIN, but little is known about how CCAT2 lncRNA regulates this cancer enabling characteristic.

    Methods

    We performed cytogenetic analysis of colorectal cancer (CRC) cell lines (HCT116, KM12C/SM, and HT29) overexpressing CCAT2 and colon organoids from C57BL/6N mice with the CCAT2 transgene and without (controls). CRC cells were also analyzed by immunofluorescence microscopy, γ-H2AX, and senescence assays. CCAT2 transgene and control mice were given azoxymethane and dextran sulfate sodium to induce colon tumors. We performed gene expression array and mass spectrometry to detect downstream targets of CCAT2 lncRNA. We characterized interactions between CCAT2 with downstream proteins using MS2 pull-down, RNA immunoprecipitation, and selective 2′-hydroxyl acylation analyzed by primer extension analyses. Downstream proteins were overexpressed in CRC cells and analyzed for CIN. Gene expression levels were measured in CRC and non-tumor tissues from 5 cohorts, comprising more than 900 patients.

    Results

    High expression of CCAT2 induced CIN in CRC cell lines and increased resistance to 5-fluorouracil and oxaliplatin. Mice that expressed the CCAT2 transgene developed chromosome abnormalities, and colon organoids derived from crypt cells of these mice had a higher percentage of chromosome abnormalities compared with organoids from control mice. The transgenic mice given azoxymethane and dextran sulfate sodium developed more and larger colon polyps than control mice given these agents. Microarray analysis and mass spectrometry indicated that expression of CCAT2 increased expression of genes involved in ribosome biogenesis and protein synthesis. CCAT2 lncRNA interacted directly with and stabilized BOP1 ribosomal biogenesis factor (BOP1). CCAT2 also increased expression of MYC, which activated expression of BOP1. Overexpression of BOP1 in CRC cell lines resulted in chromosomal missegregation errors, and increased colony formation, and invasiveness, whereas BOP1 knockdown reduced viability. BOP1 promoted CIN by increasing the active form of aurora kinase B, which regulates chromosomal segregation. BOP1 was overexpressed in polyp tissues from CCAT2 transgenic mice compared with healthy tissue. CCAT2 lncRNA and BOP1 mRNA or protein were all increased in microsatellite stable tumors (characterized by CIN), but not in tumors with microsatellite instability compared with nontumor tissues. Increased levels of CCAT2 lncRNA and BOP1 mRNA correlated with each other and with shorter survival times of patients.

    Conclusions

    We found that overexpression of CCAT2 in colon cells promotes CIN and carcinogenesis by stabilizing and inducing expression of BOP1 an activator of aurora kinase B. Strategies to target this pathway might be developed for treatment of patients with microsatellite stable colorectal tumors.

  • 42.
    Chen, Jie
    et al.
    Stockholm University, Faculty of Science, Department of Physical Geography.
    Rodopoulou, Sophia
    Strak, Maciej
    de Hoogh, Kees
    Taj, Tahir
    Poulsen, Aslak Harbo
    Andersen, Zorana J.
    Bellander, Tom
    Brandt, Jørgen
    Zitt, Emanuel
    Fecht, Daniela
    Forastiere, Francesco
    Gulliver, John
    Hertel, Ole
    Hoffmann, Barbara
    Hvidtfeldt, Ulla Arthur
    Verschuren, W. M. Monique
    Jørgensen, Jeanette T.
    Katsouyanni, Klea
    Ketzel, Matthias
    Lager, Anton C. J.
    Stockholm University, Faculty of Social Sciences, The Swedish Institute for Social Research (SOFI). Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Leander, Karin
    Liu, Shuo
    Ljungman, Petter
    Severi, Gianluca
    Boutron-Ruault, Marie-Christine
    Magnusson, Patrik K. E.
    Nagel, Gabriele
    Pershagen, Göran
    Peters, Annette
    Rizzuto, Debora
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Karolinska Institutet, Sweden; Stockholm Gerontology Research Center, Sweden.
    van der Schouw, Yvonne T.
    Samoli, Evangelia
    Sørensen, Mette
    Stafoggia, Massimo
    Tjønneland, Anne
    Weinmayr, Gudrun
    Wolf, Kathrin
    Brunekreef, Bert
    Raaschou-Nielsen, Ole
    Hoek, Gerard
    Long-term exposure to ambient air pollution and bladder cancer incidence in a pooled European cohort: the ELAPSE project2022In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 126, no 10, p. 1499-1507Article in journal (Refereed)
    Abstract [en]

    Background: The evidence linking ambient air pollution to bladder cancer is limited and mixed.

    Methods: We assessed the associations of bladder cancer incidence with residential exposure to fine particles (PM2.5), nitrogen dioxide (NO2), black carbon (BC), warm season ozone (O3) and eight PM2.5 elemental components (copper, iron, potassium, nickel, sulfur, silicon, vanadium, and zinc) in a pooled cohort (N = 302,493). Exposures were primarily assessed based on 2010 measurements and back-extrapolated to the baseline years. We applied Cox proportional hazard models adjusting for individual- and area-level potential confounders.

    Results: During an average of 18.2 years follow-up, 967 bladder cancer cases occurred. We observed a positive though statistically non-significant association between PM2.5 and bladder cancer incidence. Hazard Ratios (HR) were 1.09 (95% confidence interval (CI): 0.93–1.27) per 5 µg/m3 for 2010 exposure and 1.06 (95% CI: 0.99–1.14) for baseline exposure. Effect estimates for NO2, BC and O3 were close to unity. A positive association was observed with PM2.5 zinc (HR 1.08; 95% CI: 1.00–1.16 per 10 ng/m3).

    Conclusions: We found suggestive evidence of an association between long-term PM2.5 mass exposure and bladder cancer, strengthening the evidence from the few previous studies. The association with zinc in PM2.5 suggests the importance of industrial emissions.

  • 43.
    Chiaka Akuwudike, Pamela
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Cellular effects of ionizing radiation: Relevant for understanding cancer risk after medical and environmental radiation exposures2023Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Radiation-induced cancers are stochastic and delayed effects of exposure to ionizing radiation. The dose-response relationship for radiation-induced cancers at both low dose/low dose rates and high doses (doses encountered during radiotherapy) remains unclear. Uncertainties observed in epidemiological studies at low doses and dose rates hamper cancer risk estimation at this dose level. Assessing dose-response relationships for radiotherapy-induced cancers is also complicated due to the inherent difficulty in assessing the doses absorbed by tissues at the site of tumours. In addition, the modulatory effect of chemotherapy on the incidence of radiotherapy-induced cancer risk has been debated. Although included as a modifying factor of the incidence of radiotherapy-induced cancers, results from epidemiological studies do not provide sufficient evidence to support this claim. This thesis summarizes studies conducted to improve the understanding of the association of cancer incidence and radiation dose at clinically relevant (high) doses, low doses and low dose rates, as well as the modulatory role of platinum-based chemotherapy on radiation-induced carcinogenesis. 

    In Paper I, we investigated the competitive relationship between cell killing and the accumulation of DNA damage and genomic instability using two normal cell types (VH10 fibroblasts and AHH-1 lymphoblasts). Dose fractionation schemes were designed based on the cell growth characteristics of each cell type. Cells were irradiated at 0.25, 0.5, 1.0, or 2 Gy per fraction, representing the various dose levels within a radiation field, to simulate the heterogeneous dose distribution across normal tissue during radiotherapy. Following fractionated radiation exposure, the effects on cell growth, cell survival, radiosensitivity, and the accumulation of residual DNA damage and genomic instability were analyzed as a function of dose per fraction and the total absorbed dose. The accumulation of DNA damage and markers of genomic instability associated with DNA damage depended on cell type-specific factors.

    In Paper II, we investigated the modulatory effects of combining cisplatin and radiation on the accumulation of micronuclei (a biomarker of DNA damage and carcinogenesis) in peripheral blood lymphocytes of patients receiving treatment for gynaecological cancers. We also determined the modulatory effects of the combination of both agents on cell death and cell proliferation, by scoring the frequency of apoptotic and binucleated cells. We compared the frequency of these markers between patients receiving treatment with radiotherapy alone and a combination of cisplatin and radiotherapy. There was a decline in the frequency of micronuclei in patients receiving a combination of cisplatin and radiotherapy.

    We conducted in vitro experiments in Paper III using AHH-1 and VH10 cells. We investigated the effects of the concurrent combination of cisplatin treatment and multifractionated radiation exposure at 1 Gy per fraction on cell growth, cell survival, cell death, changes in radiosensitivity, accumulation of DNA damage, and other markers of genomic instability as well as the expression of cancer stem cell markers. We also investigated the interaction between cisplatin and radiation exposure in our schedule. The concurrent combination of cisplatin and radiation did not increase the accumulation of markers of genomic instability.

    In Paper IV, we investigated the short and long-term effects of radiation exposure at low doses and low dose rates on global gene expression, cell growth and cell survival of VH10 fibroblasts to identify unique dose rate signatures that could be useful biomarkers in determining if the application of DDREF is accurate. Except for the differential expression of DMXL2, the long-term effects of LDLDR exposure on global gene expression, cell growth and cell survival of VH10 fibroblasts were negligible. These results suggest that the accumulation of DNA damage and other markers of genomic instability is regulated by cell type-specific factors at these dose levels.

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  • 44.
    Costa Ferreira, Brigida
    et al.
    Stockholm University, Faculty of Science, Medical Radiation Physics (together with KI). University of Aveiro, Portugal; Portuguese Institute of Oncology of Coimbra, Portugal.
    Mavroidis, Panayiotis
    Stockholm University, Faculty of Science, Medical Radiation Physics (together with KI). Larissa University Hospital, Greece.
    Adamus-Górka, Magdalena
    Stockholm University, Faculty of Science, Medical Radiation Physics (together with KI).
    Svensson, Roger
    Stockholm University, Faculty of Science, Medical Radiation Physics (together with KI).
    Lind, Bengt K.
    Stockholm University, Faculty of Science, Medical Radiation Physics (together with KI).
    The impact of different dose-response parameters on biologically optimized IMRT in breast cancer.2008In: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 53, no 10, p. 2733-52Article in journal (Refereed)
    Abstract [en]

    The full potential of biologically optimized radiation therapy can only be maximized with the prediction of individual patient radiosensitivity prior to treatment. Unfortunately, the available biological parameters, derived from clinical trials, reflect an average radiosensitivity of the examined populations. In the present study, a breast cancer patient of stage I-II with positive lymph nodes was chosen in order to analyse the effect of the variation of individual radiosensitivity on the optimal dose distribution. Thus, deviations from the average biological parameters, describing tumour, heart and lung response, were introduced covering the range of patient radiosensitivity reported in the literature. Two treatment configurations of three and seven biologically optimized intensity-modulated beams were employed. The different dose distributions were analysed using biological and physical parameters such as the complication-free tumour control probability (P(+)), the biologically effective uniform dose (D), dose volume histograms, mean doses, standard deviations, maximum and minimum doses. In the three-beam plan, the difference in P(+) between the optimal dose distribution (when the individual patient radiosensitivity is known) and the reference dose distribution, which is optimal for the average patient biology, ranges up to 13.9% when varying the radiosensitivity of the target volume, up to 0.9% when varying the radiosensitivity of the heart and up to 1.3% when varying the radiosensitivity of the lung. Similarly, in the seven-beam plan, the differences in P(+) are up to 13.1% for the target, up to 1.6% for the heart and up to 0.9% for the left lung. When the radiosensitivity of the most important tissues in breast cancer radiation therapy was simultaneously changed, the maximum gain in outcome was as high as 7.7%. The impact of the dose-response uncertainties on the treatment outcome was clinically insignificant for the majority of the simulated patients. However, the jump from generalized to individualized radiation therapy may significantly increase the therapeutic window for patients with extreme radio sensitivity or radioresistance, provided that these are identified. Even for radiosensitive patients a simple treatment technique is sufficient to maximize the outcome, since no significant benefits were obtained with a more complex technique using seven intensity-modulated beams portals.

  • 45. Czub, Joanna
    et al.
    Braziewicz, Janusz
    Kubala-Kukuś, Aldona
    Wójcik, Andrzej
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Jan Kochanowski University, Poland.
    Analysis of elements secreted by CHO-K1 cells exposed to gamma radiation under different treatments2020In: International Journal of Radiation Biology, ISSN 0955-3002, E-ISSN 1362-3095, Vol. 96, no 4, p. 469-481Article in journal (Refereed)
    Abstract [en]

    Purpose: The aim of the study was to determine the concentration of elements using the two methods: total reflection X-ray fluorescence (TXRF) and wavelength dispersive X-ray fluorescence (WD-XRF) in two media, DMEM + and PBS+.

    Materials and methods: Tests were carried out at 37 and 0 degrees C, irradiated by gamma radiation doses of 0, 0.25, 0.5, 5 Gy, both with and without contact with CHO-K1 cells. The survival of non-irradiated CHO-K1 cells was determined after transmission of media from irradiated CHO-K1.

    Results: Normalized concentrations of elements as a percentage of control data (i.e. 0 Gy dose) for Al, P, S, Cl, K, Ca, Zn, Br, were determined using the TXRF method and for Na, P, S, Cl, K, Ca determined using the WD-XRF method in DMEM + and PBS + without and with contact with cells at two temperatures, 37 and 0 degrees C, and three absorbed doses of 0.25, 0.5 and 5 Gy. Concentration of elements, presented on the coordinates of the two principal components (PC) for media without contact with cells, determined by the TXRF method and in contact with cells, determined by the TXRF and WD-XRF methods were presented. Treatments to which the media were subjected, presented as co-ordinates determined by the first two PC when media were without and in contact with cells (TXRF method) and for media in contact with cells (WD-XRF method) were shown.

    Conclusions: The results showed that a statistically significant difference occurred in elemental concentrations for media in contact with the cells at the temperatures used. From principal component analysis (PCA), it was observed that the concentrations of elements such as Al, K, Ca, Zn, Br were similar to each other, in contrast to the concentrations of P, Cl, S, both with contact and without contact with cells. A high correlation between the treatment of media within the group at doses of 0.25 Gy and for the group with 0.5 and 5 Gy doses was confirmed. Numerous correlations were observed between the concentrations of elements for media that were in contact with cells, which were not observed in media without contact with cells. The survival of non-irradiated CHO-K1 cells, was determined after transmission of media from irradiated CHO-K1 cells showing no statistically significant differences.

  • 46. Dabral, Swati
    et al.
    Muecke, Christian
    Valasarajan, Chanil
    Schmoranzer, Mario
    Wietelmann, Astrid
    Semenza, Gregg L.
    Meister, Michael
    Muley, Thomas
    Seeger-Nukpezah, Tamina
    Samakovlis, Christos
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Max-Planck-Institute for Heart and Lung Research, Germany.
    Weissmann, Norbert
    Grimminger, Frich
    Seeger, Werner
    Savai, Rajkumar
    Pullamsetti, Soni S.
    A RASSF1A-HIF1 alpha loop drives Warburg effect in cancer and pulmonary hypertension2019In: Nature Communications, E-ISSN 2041-1723, Vol. 10, article id 2130Article in journal (Refereed)
    Abstract [en]

    Hypoxia signaling plays a major role in non-malignant and malignant hyperproliferative diseases. Pulmonary hypertension (PH), a hypoxia-driven vascular disease, is characterized by a glycolytic switch similar to the Warburg effect in cancer. Ras association domain family 1A (RASSF1A) is a scaffold protein that acts as a tumour suppressor. Here we show that hypoxia promotes stabilization of RASSF1A through NOX-1- and protein kinase C- dependent phosphorylation. In parallel, hypoxia inducible factor-1 alpha (HIF-1 alpha) activates RASSF1A transcription via HIF-binding sites in the RASSF1A promoter region. Vice versa, RASSF1A binds to HIF-1 alpha, blocks its prolyl-hydroxylation and proteasomal degradation, and thus enhances the activation of the glycolytic switch. We find that this mechanism operates in experimental hypoxia-induced PH, which is blocked in RASSF1A knockout mice, in human primary PH vascular cells, and in a subset of human lung cancer cells. We conclude that RASSF1A-HIF-1 alpha forms a feedforward loop driving hypoxia signaling in PH and cancer.

  • 47. Darai-Ramqvist, Eva
    et al.
    Nilsonne, Gustav
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Flores-Staino, Carmen
    Hjerpe, Anders
    Dobra, Katalin
    Microenvironment-dependent phenotypic changes in a SCID mouse model for malignant mesothelioma2013In: Frontiers in Oncology, E-ISSN 2234-943X, Vol. 3, article id 203Article in journal (Refereed)
    Abstract [en]

    Background and Aims: Malignant mesothelioma is an aggressive, therapy-resistant tumor. Mesothelioma cells may assume an epithelioid or a sarcomatoid phenotype, and presence of sarcomatoid cells predicts poor prognosis. In this study, we investigated differentiation of mesothelioma cells in a xenograft model, where mesothelioma cells of both phenotypes were induced to form tumors in severe combined immunodeficiency mice.

    Methods: Xenografts were established and thoroughly characterized using a comprehensive immunohistochemical panel, array comparative genomic hybridization (aCGH) of chromosome 3, fluorescent in situ hybridization, and electron microscopy.

    Results: Epithelioid and sarcomatoid cells gave rise to xenografts of similar epithelioid morphology. While sarcomatoid-derived xenografts had higher growth rates, the morphology and expression of differentiation-related markers was similar between xenografts derived from both phenotypes. aCGH showed a convergent genotype for both xenografts, resembling the original aggressive sarcomatoid cell sub-line.

    Conclusion: Human mesothelioma xenografts from sarcomatoid and epithelioid phenotypes converged to a similar differentiation state, and genetic analyses suggested that clonal selection in the mouse microenvironment was a major contributing factor. This thoroughly characterized animal model can be used for further studies of molecular events underlying tumor cell differentiation.

  • 48.
    Dasu, Alexandru
    et al.
    Linköping University, Sweden.
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    Dose painting by numbers - do the practical limitations of the technique decrease or increase the probability of controlling tumours?2013In: IFMBE Proceedings, ISSN 1680-0737, Vol. 39, p. 1731-1734Article in journal (Refereed)
    Abstract [en]

    One of the important questions regarding the feasibility of dose-painting-by-numbers approaches for treatment planning concerns the influence of the averaging of the imaging techniques used and the resolution of the planned and achieved dose distributions. This study investigates the impact of these aspects on the probability of controlling dynamic tumours. The effectiveness of dose painting approaches to target tumour hypoxia has been investigated in terms of the predicted tumour control probabilities (TCP) for tumours with dynamic oxygenations. Several levels of resolution for the resistance of the tumour or the planned dose distributions have been investigated. A very fine heterogeneous dose distribution ideally calculated at voxel level for a high target TCP would fail to control a tumour with dynamic oxygenation during the course of fractionated radiotherapy as mismatches between hotspots in the dose distribution and resistant hypoxic foci would lead to a significant loss in TCP. Only adaptive treatment would lead to reasonably high TCP. A coarse resolution for imaging or for dose distributions might compensate microscale mismatches in dynamic tumours, but the resulting tumour control could still be below the target levels. These results indicate that there is a complex relationship between the resolution of the dose-painting-by-numbers approaches and the dynamics of tumour oxygenation. Furthermore, the clinical success of hypoxia targeting strategies in the absence of adaptive approaches might be explained by changes in tumour radiation resistance through reoxygenation.

  • 49.
    Dasu, Alexandru
    et al.
    Umeå University.
    Toma-Dasu, Iuliana
    Umeå University.
    Dose-effect models for risk - relationship to cell survival parameters2005In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 44, no 8, p. 829-835Article in journal (Refereed)
    Abstract [en]

    There is an increased interest in estimating the induction of cancers following radiotherapy as the patients have nowadays a much longer life expectancy following the treatment. Clinical investigations have shown that the dose response relationship for cancer induction following radiotherapy has either of two main characteristics: an increase of the risk with dose to a maximum effect followed by a decrease or an increase followed by a levelling-off of the risk. While these behaviours have been described qualitatively, there is no mathematical model that can explain both of them on mechanistic terms. This paper investigates the relationship between the shape of the dose-effect curve and the cell survival parameters of a single risk model. Dose response relationships were described with a competition model which takes into account the probability to induce DNA mutations and the probability of cell survival after irradiation. The shape of the curves was analysed in relation to the parameters that have been used to obtain them. It was found that the two main appearances of clinical data for the induction of secondary cancer following radiotherapy could be the manifestations of the particular sets of parameters that describe the induction of mutations and cell kill for fractionated irradiations. Thus, the levelling off appearance of the dose response curve could be either a sign of moderate to high inducible repair effect in cell survival (but weak for DNA mutations) or the effect of heterogeneity, or both. The bell-shaped appearance encompasses all the other cases. The results also stress the importance of taking into account the details of the clinical delivery of dose in radiotherapy, mainly the fractionated character, as the findings of our study did not appear for single dose models. The results thus indicate that the shapes of clinically observed dose response curves for the induction of secondary cancers can be described by using one single competition model. It was also found that data for cancer induction may be linked to in vivo cell survival parameters that may be used for other modelling applications.

  • 50.
    Dasu, Alexandru
    et al.
    Linköping University, Sweden.
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    Impact of increasing irradiation time on the treatment of prostate cancers2015In: World Congress on Medical Physics and Biomedical Engineering, June 7-12, 2015, Toronto, Canada / [ed] David A. Jaffray, Springer, 2015, p. 490-493Conference paper (Refereed)
    Abstract [en]

    This study aimed to investigate the expected impact of intrafraction repair during increasing irradiation times for the treatment of prostate cancers. Lengthy sessions are indeed expected for some advanced irradiation techniques capable to deliver the large fractional doses required by the increased fractionation sensitivity of the prostates. For this purpose, clinically-derived parameters characterizing repair rates and dose response curves for prostate tumors have been used to calculate the expected loss of effectiveness when increasing the irradiation time. The results have shown that treatment sessions lasting more than about 20 to 40 minutes could reduce the probability of biochemical control of prostate tumors by more than 20 to 30 percentage points. These results are in agreement with some observed clinical results and therefore they suggest that treatment durations in prostate radiation therapy should be carefully recorded in order to explicitly account for intrafraction repair, especially when irradiation techniques make use of multiple beams and imaging sessions. Failure to do so might overestimate the expected effectiveness of the treatment and could lead to disappointing clinical results precisely from the demanding treatment modalities expected to increase the therapeutic gain in prostate radiotherapy.

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