Skotland T.,University of Oslo |
Skotland T.,Norwegian Radium Hospital
Contrast Media and Molecular Imaging | Year: 2012
Molecular imaging (MI) takes advantage of several new techniques to detect biomarkers or biochemical and cellular processes, with the goal of obtaining high sensitivity, specificity and signal-to-noise ratio imaging of disease. The imaging modalities bearing the most promise for MI are positron emission tomography (PET), single photon emission computer tomography (SPECT) and different optical imaging techniques with high sensitivity. Also magnetic resonance imaging (MRI) with contrast agents like ultra-small superparamagnetic iron oxide particles (USPIO), magnetic resonance spectroscopy and ultrasound imaging with contrast agents may be useful approaches. MI techniques have been used in the clinic for many years, i.e. PET imaging using 18F-labeled fluorodeoxyglucose. Animal studies have during the last years revealed great potential for MI also with several other agents. The focus of the present article is the challenges of clinical imaging of intracellular targets following intravenous injection of the agents. Thus, the great challenge of getting enough contrast agent into the cytosol and at the same time obtaining a low signal from tissue just outside the diseased area is discussed. © 2012 John Wiley & Sons, Ltd.
Wesche J.,University of Oslo |
Wesche J.,Norwegian Radium Hospital |
Haglund K.,University of Oslo |
Haglund K.,Norwegian Radium Hospital |
And 2 more authors.
Biochemical Journal | Year: 2011
FGFs (fibroblast growth factors) and their receptors (FGFRs) play essential roles in tightly regulating cell proliferation, survival, migration and differentiation during development and adult life. Deregulation of FGFR signalling, on the other hand, has been associated with many developmental syndromes, and with human cancer. In cancer, FGFRs have been found to become overactivated by several mechanisms, including gene amplification, chromosomal translocation and mutations. FGFR alterations are detected in a variety of human cancers, such as breast, bladder, prostate, endometrial and lung cancers, as well as haematological malignancies. Accumulating evidence indicates that FGFs and FGFRs may act in an oncogenic fashion to promote multiple steps of cancer progression by inducing mitogenic and survival signals, as well as promoting epithelial - mesenchymal transition, invasion and tumour angiogenesis. Therapeutic strategies targeting FGFs and FGFRs in human cancer are therefore currently being explored. In the present review we will give an overview of FGF signalling, the main FGFR alterations found in human cancer to date, how they may contribute to specific cancer types and strategies for therapeutic intervention. ©The Authors Journal compilation ©2011 Biochemical Society.
Juzeniene A.,Norwegian Radium Hospital |
Nizauskaite Z.,Norwegian Radium Hospital
Journal of Photochemistry and Photobiology B: Biology | Year: 2013
Vitamin B12 (cobalamin) is required for proper red blood cell formation, neurologic function, and DNA synthesis. Cobalamins in solutions are light sensitive, but no comprehensive study has been performed to compare the photostability of different cobalamins under UVA exposure. Their indirect photodegradation due to their antioxidant properties and their photostability in vivo have also not been studied so far. The photodegradation of four cobalamins (methylcobalamin (MeCbl), adenosylcobalamin (AdCbl), hydroxocobalamin (OHCbl) and cyanocobalamin (CNCbl)) under UVA exposure in aqueous solutions (pH = 7.4) have been investigated by absorption spectroscopy. The photodegradation of OHCbl in the absence and presence of the endogenous photosensitizer riboflavin was studied. Serum vitamin B12 concentrations before and after summer were measured in four patients with psoriasis. All studied cobalamins are photolabile. The biologically active forms of cobalamin, AdCbl and MeCbl, are converted to OHCbl within seconds during UVA exposure. OHCbl is the most stable cobalamin. However, reactive oxygen species increases the degradation rate of OHCbl. Our pilot study on humans demonstrates that serum vitamin B12 concentrations are not significantly affected during summertime in Norway. Further work is needed to determine vitamin B12 photostability in humans living at lower latitudes or using sunbeds. © 2013 Elsevier B.V. All rights reserved.
Reiners Jr. J.J.,Wayne State University |
Agostinis P.,Catholic University of Leuven |
Berg K.,Norwegian Radium Hospital |
Oleinick N.L.,Case Western Reserve University |
Kessel D.,Wayne State University
Autophagy | Year: 2010
Photodynamic therapy (PDT) is a procedure that has applications in the selective eradication of neoplasia where sites of malignant lesions are clearly delineated. It is a twostep process whereby cells are first sensitized to light and then photoirradiated. This results in the formation of singlet molecular oxygen and other reactive oxygen species that can cause photodamage at sites where the photosensitizing agent has localized. Photosensitizers found to be clinically useful show affinity for the endoplasmic reticulum (ER), mitochondria, lysosomes, or combinations of these sites. The induction of apoptosis and/or autophagy in photosensitized cells is a common outcome of PDT. This report explores the following issues: (1) Does the induction of autophagy in PDT protocols occur independent of, or in association with, apoptosis? (2) Does the resulting autophagy play a prosurvival or prodeath role? (3) Do photosensitizers damage/inactivate specific proteins that are components of, or that modulate the autophagic process? (4) Can an autophagic response be mounted in cells in which lysosomes are specifically photodamaged? In brief, autophagy can occur independently of apoptosis in PDT protocols, and appears to play a prosurvival role in apoptosis competent cells, and a prodeath role in apoptosis incompetent cells. Mitochondrial and ER-localized sensitizers cause selective photodamage to some (i.e., Bcl-2, Bcl-xL' mTOR) proteins involved in the apoptotic/autophagic process. Finally, an aborted autophagic response occurs in cells with photodamaged lysosomes. Whereas autophagosomes form, digestion of their cargo is compromised because of the absence of functional lysosomes. © 2010 Landes Bioscience.
Moller P.,Norwegian Radium Hospital |
Clark N.,Norwegian Radium Hospital
Human Mutation | Year: 2011
CGEN (Clinical GENetics) is a software application built to manage the IT requirements of genetic clinics with the specific focus to collect well-organized and verified data for genetic research. This article describes the functionality of CGEN, the IT requirements for CGEN, and the unique position that CGEN has for clinics who may wish to collaborate data exchange with other clinics or central repositories of genetic data. CGEN was also represented at The Human Variome Project in Paris, 2010, and is a candidate for data collection for this project. © 2011 Wiley-Liss, Inc.
Pankiv S.,University of Tromsø |
Alemu E.A.,University of Tromsø |
Brech A.,Norwegian Radium Hospital |
Bruun J.-A.,University of Tromsø |
And 5 more authors.
Journal of Cell Biology | Year: 2010
Autophagy is the main eukaryotic degradation pathway for long-lived proteins, protein aggregates, and cytosolic organelles. Although the protein machinery involved in the biogenesis of autophagic vesicles is well described, very little is known about the mechanism of cytosolic transport of autophagosomes. In this study, we have identified an adaptor protein complex, formed by the two autophagic membrane-associated proteins LC3 and Rab7 and the novel FYVE and coiled-coil (CC) domain - containing protein FYCO1, that promotes microtubule (MT) plus end - directed transport of autophagic vesicles. We have characterized the LC3-, Rab7-, and phosphatidylinositol-3-phosphate - binding domains in FYCO1 and mapped part of the CC region essential for MT plus end - directed transport. We also propose a mechanism for selective autophagosomal membrane recruitment of FYCO1. © 2010 Pankiv et al.
Sioud M.,Norwegian Radium Hospital |
Mobergslien A.,Norwegian Radium Hospital
Biochemical Pharmacology | Year: 2012
Antimicrobial peptides selectively kill bacteria while maintaining low mammalian cell cytotoxicity. However, they become cytotoxic subsequent to internalization. Here we have conjugated the lytic peptide (KLAKLAK)2 to either a cancer-cell binding peptide (LTVSPWY) selected from peptide libraries or to a gastrin-releasing peptide (GNHWAVGHLM) in order to direct the lytic peptide to cancer cells. Peptide cytotoxicity was tested in breast MCF-7 and MDA-MB-231 cancer cells. The fusion peptides were internalized by cancer cells, disintegrated the cell membrane and induced rapid killing of the cells with IC50 values as low as 4-7 μM. Peptide cytotoxicity was dependent on the targeting receptor. Indeed, addition of free targeting peptide reduced cell killing. Blood lymphocytes and normal human mammary epithelial cells were less sensitive to the fusion peptides. Although most of the cells were killed by necrosis, fusion peptides branched with DNA oligonucleotides induced apoptosis as assayed by annexin V staining and activation of caspase 3. Therefore, the new designed drug peptides might provide a potent and selective anticancer therapy. © 2012 Elsevier Inc. All rights reserved.
Gulliksrud K.,Norwegian Radium Hospital |
Ovrebo K.M.,Norwegian Radium Hospital |
Mathiesen B.,Norwegian Radium Hospital |
Rofstad E.K.,Norwegian Radium Hospital
Radiotherapy and Oncology | Year: 2011
Background and purpose: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has been suggested to be a useful method for detecting tumor hypoxia. In this study, we investigated whether DCE-MRI can differentiate between hypoxic and non-hypoxic experimental tumors. Materials and methods: Three tumor models with hypoxic tissue and three tumor models without hypoxic tissue were subjected to DCE-MRI. Parametric images of Ktrans (the volume transfer constant of Gd-DTPA) and ve (the fractional distribution volume of Gd-DTPA) were produced by pharmacokinetic analysis of the DCE-MRI series. Tumor oxygenation status was assessed by using a radiobiological assay and a pimonidazole-based immunohistochemical assay. Tumor response to fractionated irradiation (six fractions of 2 Gy in 60 h) was measured in vitro by using a clonogenic assay. Results: Tumors with hypoxic regions were more resistant to radiation treatment than were tumors without hypoxia. Ktrans was significantly higher for radiation sensitive tumors without hypoxia than for radiation resistant tumors with hypoxic regions, whereas ve did not differ significantly between non-hypoxic and hypoxic tumors. Conclusion: This study supports the clinical attempts to establish DCE-MRI as a noninvasive method for providing useful biomarkers for personalized radiation therapy. © 2011 Elsevier Ireland Ltd. All rights reserved.
Wesche J.,Norwegian Radium Hospital
Molecular Cancer Research | Year: 2010
The fibroblast growth factor receptors (FGFR) play essential roles both during development and in the adult. Upon ligand binding, FGFRs induce intracellular signaling networks that tightly regulate key biological processes, such as cell proliferation, survival, migration, and differentiation. Deregulation of FGFR signaling can thus alter tissue homeostasis and has been associated with several developmental syndromes as well as with many types of cancer. In human cancer, FGFRs have been found to be deregulated by multiple mechanisms, including aberrant expression, mutations, chromosomal rearrangements, and amplifications. In this review, we will give an overview of the main FGFR alterations described in human cancer to date and discuss their contribution to cancer progression. ©2010 AACR.
Fung C.,University of Rochester |
Fossa S.D.,Norwegian Radium Hospital |
Beard C.J.,Dana-Farber Cancer Institute |
Travis L.B.,University of Rochester
JNCCN Journal of the National Comprehensive Cancer Network | Year: 2012
Second malignant neoplasms (SMNs) are a potentially life-threatening late effect of testicular cancer (TC) and its therapy. Although the increased risk for developing solid tumors among TC survivors is largely attributed to radiotherapy, chemotherapy may also be associated with excess risks. However, the baseline risks of developing site-specific SMNs in TC survivors have not yet been quantified, nor have interactions between treatments and other risk factors been elucidated. Studies to date report overall relative risks ranging from 1.4- to 2.8-fold for SMN in TC survivors, with significantly elevated risks apparent for more than 35 years. Analytic investigations show relationships between increasing radiation dose and/or field size and solid tumor risk. Small excess risks of leukemia follow treatment with either chemotherapy or radiotherapy. Recently, concern has been expressed about the increased risk of SMN from radiation exposure during imaging surveillance for recurrence. A small number of studies have examined this issue, generating inconclusive results. Given the current changes in TC treatment that result in lower radiation doses, in the future solid tumors will likely have a considerably lower impact on the lives of TC survivors, although diligent follow-up will be required to accurately quantify long-term risks and to ascertain risks associated with chemotherapy. (JNCCN 2012;10:545-556) © JNCCN-Journal of the National Comprehensive Cancer Network.