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  • 1. Alkharusi, Amira
    et al.
    Yu, Shengze
    KTH, Skolan för bioteknologi (BIO).
    Landazuri, Natalia
    Zadjali, Fahad
    Davodi, Belghis
    Nystrom, Thomas
    Gräslund, Torbjörn
    KTH, Skolan för bioteknologi (BIO), Proteinteknologi.
    Rahbar, Afsar
    Norstedt, Gunnar
    Stimulation of prolactin receptor induces STAT-5 phosphorylation and cellular invasion in glioblastoma multiforme2016Inngår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, nr 48, s. 79558-79569Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in humans and is characterized with poor outcome. In this study, we investigated components of prolactin (Prl) system in cell models of GBM and in histological tissue sections obtained from GBM patients. Expression of Prolactin receptor (PrlR) was detected at high levels in U251-MG, at low levels in U87-MG and barely detectable in U373 cell lines and in 66% of brain tumor tissues from 32 GBM patients by immunohistochemical technique. In addition, stimulation of U251-MG and U87-MG cells but not U373 with Prl resulted in increased STAT5 phosphorylation and only in U251-MG cells with increased cellular invasion. Furthermore, STAT5 phosphorylation and cellular invasion induced in Prl stimulated cells were significantly reduced by using a Prl receptor antagonist that consists of Prl with four amino acid replacements. We conclude that Prl receptor is expressed at different levels in the majority of GBM tumors and that blocking of PrlR in U251-MG cells significantly reduce cellular invasion.

  • 2.
    Andersson, Ken G.
    et al.
    KTH, Skolan för bioteknologi (BIO), Proteinteknologi.
    Oroujeni, Maryam
    Garousi, Javad
    Mitran, Bogdan
    Ståhl, Stefan
    KTH, Skolan för bioteknologi (BIO), Proteinteknologi.
    Orlova, Anna
    Löfblom, John
    KTH, Skolan för bioteknologi (BIO), Proteinteknologi.
    Tolmachev, Vladimir
    Feasibility of imaging of epidermal growth factor receptor expression with ZEGFR:2377 affibody molecule labeled with Tc-99m using a peptide-based cysteine-containing chelator2016Inngår i: International Journal of Oncology, ISSN 1019-6439, Vol. 49, nr 6, s. 2285-2293Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The epidermal growth factor receptor (EGFR) is overexpressed in a number of malignant tumors and is a molecular target for several specific anticancer antibodies and tyrosine kinase inhibitors. The overexpression of EGFR is a predictive biomarker for response to several therapy regimens. Radionuclide molecular imaging might enable detection of EGFR overexpression by a non-invasive procedure and could be used repeatedly. Affibody molecules are engineered scaffold proteins, which could be selected to have a high affinity and selectivity to predetermined targets. The anti-EGFR ZEGFR:2377 affibody molecule is a potential imaging probe for EGFR detection. The use of the generator-produced radionuclide Tc-99m should facilitate clinical translation of an imaging probe due to its low price, availability and favorable dosimetry of the radionuclide. In the present study, we evaluated feasibility of ZEGFR:2377 labeling with Tc-99m using a peptide-based cysteine-containing chelator expressed at the C-terminus of ZEGFR:2377. The label was stable in vitro under cysteine challenge. In addition, Tc-99m-ZEGFR:2377 was capable of specific binding to EGFR-expressing cells with high affinity (274 pM). Studies in BALB/C nu/nu mice bearing A431 xenografts demonstrated that Tc-99m-ZEGFR:2377 accumulates in tumors in an EGFR-specific manner. The tumor uptake values were 3.6 1 and 2.5 0.4% ID/g at 3 and 24 h after injection, respectively. The corresponding tumor-to-blood ratios were 1.8 0.4 and 8 3. The xenografts were clearly visualized at both time-points. This study demonstrated the potential of Tc-99m-labeled ZEGFR:2377 for imaging of EGFR in vivo.

  • 3.
    Asem, Heba
    et al.
    KTH, Skolan för informations- och kommunikationsteknik (ICT), Material- och nanofysik, Funktionella material, FNM. Karolinska Inst, Sweden.
    Abd El-Fattah, Ahmed
    Nafee, Noha
    Zhao, Ying
    Khalil, Labiba
    Muhammed, Mamoun
    KTH, Skolan för informations- och kommunikationsteknik (ICT), Material- och nanofysik, Funktionella material, FNM.
    Hassan, Moustapha
    Kandil, Sherif
    Development and biodistribution of a theranostic aluminum phthalocyanine nanophotosensitizer2016Inngår i: Photodiagnosis and Photodynamic Therapy, ISSN 1572-1000, E-ISSN 1873-1597, Vol. 13, s. 48-57Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Aluminum phthalocyanine (AlPc) is an efficient second generation photosensitizer (PS) with high fluorescence ability. Its use in photodynamic therapy (PDT) is hampered by hydrophobicity and poor biodistribution. Methods: AlPc was converted to a biocompatible nanostructure by incorporation into amphiphilic polyethylene glycol-polycaprolactone (PECL) copolymer nanoparticles, allowing efficient entrapment of the PS in the hydrophobic core, water dispersibility and biodistribution enhancement by PEG-induced surface characteristics. A series of synthesized PECL copolymers were used to prepare nanophotosensitizers with an average diameter of 66.5-99.1 nm and encapsulation efficiency (EE%) of 66.4-78.0%. One formulation with favorable colloidal properties and relatively slow release over 7 days was selected for in vitro photophysical assessment and in vivo biodistribution studies in mice. Results: The photophysical properties of AlPc were improved by encapsulating AlPc into PECL-NPs, which showed intense fluorescence emission at 687 nm and no AlPc aggregation has been induced after entrapment into the nanoparticles. Biodistribution of AlPc loaded NPs (AlPc-NPs) and free AlPc drug in mice was monitored by in vivo whole body fluorescence imaging and ex vivo organ imaging, with in vivo imaging system (IVIS). Compared to a AlPc solution in aqueous TWEEN 80 (2 w/v%), the developed nanophotosensitizer showed targeted drug delivery to lungs, liver and spleen as monitored by the intrinsic fluorescence of AlPc at different time points (1 h, 24 h and 48 h) post iv. administration. Conclusions: The AlPc-based copolymer nanoparticles developed offer potential as a single agent multifunctional theranostic nanophotosensitizer for PDT coupled with imaging-guided drug delivery and biodistribution, and possibly also fluorescence diagnostics.

  • 4.
    Benfeitas, Rui
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Uhlén, Mathias
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Nielsen, Jens
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Mardinoglu, A.
    New challenges to study heterogeneity in cancer redox metabolism2017Inngår i: Frontiers in Cell and Developmental Biology, ISSN 2296-634X, Vol. 5, nr JUL, artikkel-id 65Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Reactive oxygen species (ROS) are important pathophysiological molecules involved in vital cellular processes. They are extremely harmful at high concentrations because they promote the generation of radicals and the oxidation of lipids, proteins, and nucleic acids, which can result in apoptosis. An imbalance of ROS and a disturbance of redox homeostasis are now recognized as a hallmark of complex diseases. Considering that ROS levels are significantly increased in cancer cells due to mitochondrial dysfunction, ROS metabolism has been targeted for the development of efficient treatment strategies, and antioxidants are used as potential chemotherapeutic drugs. However, initial ROS-focused clinical trials in which antioxidants were supplemented to patients provided inconsistent results, i.e., improved treatment or increased malignancy. These different outcomes may result from the highly heterogeneous redox responses of tumors in different patients. Hence, population-based treatment strategies are unsuitable and patient-tailored therapeutic approaches are required for the effective treatment of patients. Moreover, due to the crosstalk between ROS, reducing equivalents [e.g., NAD(P)H] and central metabolism, which is heterogeneous in cancer, finding the best therapeutic target requires the consideration of system-wide approaches that are capable of capturing the complex alterations observed in all of the associated pathways. Systems biology and engineering approaches may be employed to overcome these challenges, together with tools developed in personalized medicine. However, ROS- and redox-based therapies have yet to be addressed by these methodologies in the context of disease treatment. Here, we review the role of ROS and their coupled redox partners in tumorigenesis. Specifically, we highlight some of the challenges in understanding the role of hydrogen peroxide (H2O2), one of the most important ROS in pathophysiology in the progression of cancer. We also discuss its interplay with antioxidant defenses, such as the coupled peroxiredoxin/thioredoxin and glutathione/glutathione peroxidase systems, and its reducing equivalent metabolism. Finally, we highlight the need for system-level and patient-tailored approaches to clarify the roles of these systems and identify therapeutic targets through the use of the tools developed in personalized medicine. © 2017 Benfeitas, Uhlen, Nielsen and Mardinoglu.

  • 5.
    Berglund, Emelie
    et al.
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Genteknologi.
    Maaskola, Jonas
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Genteknologi.
    Schultz, Niklas
    Friedrich, Stefanie
    Marklund, Maja
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Genteknologi.
    Bergenstrahle, Joseph
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Genteknologi.
    Tarish, Firas
    Tanoglidi, Anna
    Vickovic, Sanja
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Larsson, Ludvig
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Genteknologi.
    Salmén, Fredrik
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Ogris, Christoph
    Wallenborg, Karolina
    Lagergren, Jens
    KTH, Skolan för elektroteknik och datavetenskap (EECS), Beräkningsvetenskap och beräkningsteknik (CST).
    Ståhl, Patrik
    Sonnhammer, Erik
    Helleday, Thomas
    Lundeberg, Joakim
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Spatial maps of prostate cancer transcriptomes reveal an unexplored landscape of heterogeneity2018Inngår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, artikkel-id 2419Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 6. Bersani, Cinzia
    et al.
    Huss, Mikael
    KTH, Skolan för bioteknologi (BIO). KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Giacomello, Stefania
    KTH, Skolan för bioteknologi (BIO). KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Xu, Li-Di
    Bianchi, Julie
    Eriksson, Sofi
    Jerhammar, Fredrik
    Alexeyenko, Andrey
    Vilborg, Anna
    Lundeberg, Joakim
    KTH, Skolan för bioteknologi (BIO). KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Lui, Weng-Onn
    Wiman, Klas G.
    Genome-wide identification of Wig-1 mRNA targets by RIP-Seq analysis2016Inngår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, nr 2, s. 1895-1911Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    RNA-binding proteins (RBPs) play important roles in the regulation of gene expression through a variety of post-transcriptional mechanisms. The p53-induced RBP Wig-1 (Zmat3) binds RNA through its zinc finger domains and enhances stability of p53 and N-Myc mRNAs and decreases stability of FAS mRNA. To identify novel Wig-1-bound RNAs, we performed RNA-immunoprecipitation followed by high-throughput sequencing (RIP-Seq) in HCT116 and Saos-2 cells. We identified 286 Wig-1-bound mRNAs common between the two cell lines. Sequence analysis revealed that AU-rich elements (AREs) are highly enriched in the 3'UTR of these Wig-1-bound mRNAs. Network enrichment analysis showed that Wig-1 preferentially binds mRNAs involved in cell cycle regulation. Moreover, we identified a 2D Wig-1 binding motif in HIF1A mRNA. Our findings confirm that Wig-1 is an ARE-BP that regulates cell cycle-related processes and provide a novel view of how Wig-1 may bind mRNA through a putative structural motif. We also significantly extend the repertoire of Wig-1 target mRNAs. Since Wig-1 is a transcriptional target of the tumor suppressor p53, these results have implications for our understanding of p53-dependent stress responses and tumor suppression.

  • 7. Boman, K.
    et al.
    Larsson, A. H.
    Segersten, U.
    Kuteeva, E.
    Johannesson, H.
    Nodin, B.
    Eberhard, J.
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Malmström, P-U
    Jirström, K.
    Membranous expression of podocalyxin-like protein is an independent factor of poor prognosis in urothelial bladder cancer2013Inngår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 108, nr 11, s. 2321-2328Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Membranous expression of the anti-adhesive glycoprotein podocalyxin-like (PODXL) has previously been found to correlate with poor prognosis in several major cancer forms. Here we examined the prognostic impact of PODXL expression in urothelial bladder cancer. Methods: Immunohistochemical PODXL expression was examined in tissue microarrays with tumours from two independent cohorts of patients with urothelial bladder cancer: n = 100 (Cohort I) and n = 343 (Cohort II). The impact of PODXL expression on disease-specific survival (DSS; Cohort II), 5-year overall survival (OS; both cohorts) and 2-year progression-free survival (PFS; Cohort II) was assessed. Results: Membranous PODXL expression was significantly associated with more advanced tumour (T) stage and high-grade tumours in both cohorts, and a significantly reduced 5-year OS (unadjusted HR = 2.25 in Cohort I and 3.10 in Cohort II, adjusted HR = 2.05 in Cohort I and 2.18 in Cohort II) and DSS (unadjusted HR = 4.36, adjusted HR = 2.70). In patients with Ta and T1 tumours, membranous PODXL expression was an independent predictor of a reduced 2-year PFS (unadjusted HR = 6.19, adjusted HR = 4.60) and DSS (unadjusted HR = 8.34, adjusted HR = 7.16). Conclusion: Membranous PODXL expression is an independent risk factor for progressive disease and death in patients with urothelial bladder cancer.

  • 8. Borsics, Tamas
    et al.
    Lundberg, Emma
    KTH, Skolan för bioteknologi (BIO), Centra, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Geerts, Dirk
    Koomoa, Dana-Lynn T.
    Koster, Jan
    Wester, Kenneth
    Bachmann, Andres S.
    Subcellular distribution and expression of prenylated Rab acceptor 1 domain family, member 2 (PRAF2) in malignant glioma: Influence on cell survival and migration2010Inngår i: Cancer Science, ISSN 1347-9032, E-ISSN 1349-7006, Vol. 101, nr 7, s. 1624-1631Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Our previous studies revealed that the expression of the 19-kDa protein prenylated Rab acceptor 1 domain family, member 2 (PRAF2) is elevated in cancer tissues of the breast, colon, lung, and ovary, when compared to noncancerous tissues of paired samples. PRAF2 mRNA expression also correlated with several genetic and clinical features and is a candidate prognostic marker in the pediatric cancer neuroblastoma. The PRAF2-related proteins, PRAF1 and PRAF3, play multiple roles in cellular processes, including endo/exocytic vesicle trafficking and glutamate uptake. PRAF2 shares a high sequence homology with these family members, but its function remains unknown. In this study, we examined PRAF2 mRNA and protein expression in 20 different human cancer types using Affymetrix microarray and human tissue microarray (TMA) analyses, respectively. In addition, we investigated the subcellular distribution of PRAF2 by immunofluorescence microscopy and cell fractionation studies. PRAF2 mRNA and protein expression was elevated in several cancer tissues with highest levels in malignant glioma. At the molecular level, we detected native PRAF2 in small, vesicle-like structures throughout the cytoplasm as well as in and around cell nuclei of U-87 malignant glioma cells. We further found that monomeric and dimeric forms of PRAF2 are associated with different cell compartments, suggesting possible functional differences. Importantly, PRAF2 down-regulation by RNA interference significantly reduced the cell viability, migration, and invasiveness of U-87 cells. This study shows that PRAF2 expression is elevated in various tumors with exceptionally high expression in malignant gliomas, and PRAF2 therefore presents a candidate molecular target for therapeutic intervention. (Cancer Sci 2010).

  • 9. Brennan, Donal J.
    et al.
    Laursen, Henriette
    O'Connor, Darran P.
    Borgquist, Signe
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik.
    Gallagher, William M.
    Ponten, Fredrik
    Millikan, Robert C.
    Ryden, Lisa
    Jirström, Karin
    Tumor-specific HMG-CoA reductase expression in primary premenopausal breast cancer predicts response to tamoxifen2011Inngår i: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 13, nr 1, s. R12-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction: We previously reported an association between tumor-specific 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMG-CoAR) expression and a good prognosis in breast cancer. Here, the predictive value of HMG-CoAR expression in relation to tamoxifen response was examined. Methods: HMG-CoAR protein and RNA expression was analyzed in a cell line model of tamoxifen resistance using western blotting and PCR. HMG-CoAR mRNA expression was examined in 155 tamoxifen-treated breast tumors obtained from a previously published gene expression study (Cohort I). HMG-CoAR protein expression was examined in 422 stage II premenopausal breast cancer patients, who had previously participated in a randomized control trial comparing 2 years of tamoxifen with no systemic adjuvant treatment (Cohort II). Kaplan-Meier analysis and Cox proportional hazards modeling were used to estimate the risk of recurrence-free survival (RFS) and the effect of HMG-CoAR expression on tamoxifen response. Results: HMG-CoAR protein and RNA expression were decreased in tamoxifen-resistant MCF7-LCC9 cells compared with their tamoxifen-sensitive parental cell line. HMG-CoAR mRNA expression was decreased in tumors that recurred following tamoxifen treatment (P < 0.001) and was an independent predictor of RFS in Cohort I (hazard ratio = 0.63, P = 0.009). In Cohort II, adjuvant tamoxifen increased RFS in HMG-CoAR-positive tumors (P = 0.008). Multivariate Cox regression analysis demonstrated that HMG-CoAR was an independent predictor of improved RFS in Cohort II (hazard ratio = 0.67, P = 0.010), and subset analysis revealed that this was maintained in estrogen receptor (ER)-positive patients (hazard ratio = 0.65, P = 0.029). Multivariate interaction analysis demonstrated a difference in tamoxifen efficacy relative to HMG-CoAR expression (P = 0.05). Analysis of tamoxifen response revealed that patients with ER-positive/HMG-CoAR tumors had a significant response to tamoxifen (P = 0.010) as well as patients with ER-positive or HMG-CoAR-positive tumors (P = 0.035). Stratification according to ER and HMG-CoAR status demonstrated that ER-positive/HMG-CoAR-positive tumors had an improved RFS compared with ER-positive/HMG-CoAR-negative tumors in the treatment arm (P = 0.033); this effect was lost in the control arm (P = 0.138), however, suggesting that HMG-CoAR predicts tamoxifen response. Conclusions: HMG CoAR expression is a predictor of response to tamoxifen in both ER-positive and ER-negative disease. Premenopausal patients with tumors that express ER or HMG-CoAR respond to adjuvant tamoxifen.

  • 10.
    Byström, Sanna
    et al.
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi.
    Eklund, Martin
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi.
    Hong, Mun-Gwan
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi.
    Fredolini, Claudia
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi.
    Eriksson, Mikael
    Czene, Kamila
    Hall, Per
    Schwenk, Jochen. M.
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi.
    Gabrielson, Marike
    Affinity proteomic profiling of plasma for proteins associated to mammographic breast densityManuskript (preprint) (Annet vitenskapelig)
  • 11.
    Byström, Sanna
    et al.
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi.
    Fredolini, Claudia
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi.
    Edqvist, Per-Henrik
    Nyaiesh, Etienne-Nicholas
    Drobin, Kimi
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi.
    Uhlén, Matthias
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi.
    Bergqvist, Michael
    Pontén, Fredrik
    Schwenk, Jochen M.
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi.
    Affinity proteomics exploration of melanoma identifies proteins in serum with associations to T-stage and recurrenceManuskript (preprint) (Annet vitenskapelig)
  • 12.
    Dewyngaert, J. Keith
    et al.
    New York University.
    Noz, Marilyn E.
    New York University, Department of Radiology.
    Ellerin, B.
    New York University.
    Kramer, Elissa L.
    New York University, Department of Radiology.
    Maguire Jr., Gerald Q.
    KTH, Tidigare Institutioner, Mikroelektronik och informationsteknik, IMIT.
    Zeleznik, Michael P.
    RAHD Oncology Products, St. Louis, MO, USA.
    Procedure for unmasking localization information from ProstaScint scans for prostate radiation therapy treatment planning2004Inngår i: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 60, nr 2, s. 654-662Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: To demonstrate a method to extract the meaningful biologic information from In-111-radiolabeled capromab pendetide (ProstaScint) SPECT scans for use in radiation therapy treatment planning by removing that component of the In-111 SPECT images associated with normal structures. Methods and Materials: We examined 20 of more than 80 patients who underwent simultaneous Tc-99m/In-111 SPECT scans, which were subsequently registered to the corresponding CT/MRI scans. A thresholding algorithm was used to identify Tc-99m uptake associated with blood vessels and CT electron density associated with bone marrow. Corresponding voxels were removed from the In-111 image set. Results: No single threshold value was found to be associated with the Tc-99m uptake that corresponded to the blood vessels. Intensity values were normalized to a global maximum and, as such, were dependent upon the quantity of Tc-99m pooled in the bladder. The reduced ProstaScint volume sets were segmented by use of a thresholding feature of the planning system and superimposed on the CT/MRI scans. Conclusions: ProstaScint images are now closer to becoming a biologically and therapeutically useful and accurate image set. After known sources of normal intensity are stripped away, the remaining areas that demonstrate uptake may be segmented and superimposed on the treatment-planning CT/MRI volume.

  • 13. Dijksterhuis, Jacomijn P.
    et al.
    Arthofer, Elisa
    Marinescu, Voichita D.
    Nelander, Sven
    Uhlen, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi.
    Ponten, Frederik
    Mulder, Jan
    Schulte, Gunnar
    High levels of WNT-5A in human glioma correlate with increased presence of tumor-associated microglia/monocytes2015Inngår i: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 339, nr 2, s. 280-288Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Malignant gliomas are among the most severe types of cancer, and the most common primary brain tumors. Treatment options are limited and the prognosis is poor. WNT-5A, a member of the WNT family of lipoglycoproteins, plays a role in oncogenesis and tumor progression in various cancers, whereas the role of WNT-5A in glioma remains obscure. Based on the role of WNT-5A as an oncogene, its potential to regulate microglia cells and the glioma-promoting capacities of microglia cells, we hypothesize that WNT-5A has a role in regulation of immune functions in glioma. We investigated WNT-5A expression by in silico analysis of the cancer genome atlas (TCGA) transcript profiling of human glioblastoma samples and immunohistochemistry experiments of human glioma tissue microarrays (TMA). Our results reveal higher WNT-5A protein levels and mRNA expression in a subgroup of gliomas (WNT-5A(high)) compared to non-malignant control brain tissue. Furthermore, we show a significant correlation between WNT-5A in the tumor and presence of major histocompatibility complex Class II-positive microglia/monocytes. Our data pinpoint a positive correlation between WNT-5A and a proinflammatory signature in glioma. We identify increased presence of microglia/monocytes as an important aspect in the inflammatory transformation suggesting a novel role for WNT-5A in human glioma.

  • 14. Djureinovic, Dijana
    et al.
    Hallström, Björn
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Mattsson, Johanna Sofia Margareta
    La Fleur, Linnea
    Botling, Johan
    Fagerberg, Linn
    Brunnstrom, Hans
    Ekman, Simon
    Stahle, Elisabeth
    Koyi, Hirsh
    Lambe, Mats
    Branden, Eva
    Lindskog, Cecilia
    Ponten, Fredrik
    Uhlen, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Micke, Patrick
    The Identification of Therapeutic Targets in Lung Cancer Based on Transcriptomic and Proteomic Characterization of Cancer-Testis Antigens2015Inngår i: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 10, nr 9, s. S256-S256Artikkel i tidsskrift (Annet vitenskapelig)
  • 15.
    Dyczynski, Matheus
    et al.
    Karolinska Inst, Dept Oncol Pathol, Canc Ctr Karolinska, Stockholm, Sweden..
    Yu, Yasmin
    Karolinska Inst, Dept Oncol Pathol, Canc Ctr Karolinska, Stockholm, Sweden.;Sprint Biosci, Huddinge, Sweden..
    Otrocka, Magdalena
    Karolinska Inst, Dept Med Biochem & Biophys, Sci Life Lab Stockholm, Chem Biol Consortium Sweden, Solna, Sweden..
    Parpal, Santiago
    Sprint Biosci, Huddinge, Sweden..
    Braga, Tiago
    Sprint Biosci, Huddinge, Sweden..
    Henley, Aine Brigette
    Sprint Biosci, Huddinge, Sweden..
    Zazzi, Henric
    KTH, Skolan för elektroteknik och datavetenskap (EECS), Centra, Parallelldatorcentrum, PDC.
    Lerner, Mikael
    Karolinska Inst, Dept Oncol Pathol, Canc Ctr Karolinska, Stockholm, Sweden..
    Wennerberg, Krister
    Univ Helsinki, Inst Mol Med Finland, FIMM, Helsinki, Finland..
    Viklund, Jenny
    Sprint Biosci, Huddinge, Sweden..
    Martinsson, Jessica
    Sprint Biosci, Huddinge, Sweden..
    Grander, Dan
    Karolinska Inst, Dept Oncol Pathol, Canc Ctr Karolinska, Stockholm, Sweden..
    De Milito, Angelo
    Karolinska Inst, Dept Oncol Pathol, Canc Ctr Karolinska, Stockholm, Sweden.;Sprint Biosci, Huddinge, Sweden..
    Tamm, Katja Pokrovskaja
    Karolinska Inst, Dept Oncol Pathol, Canc Ctr Karolinska, Stockholm, Sweden..
    Targeting autophagy by small molecule inhibitors of vacuolar protein sorting 34 (Vps34) improves the sensitivity of breast cancer cells to Sunitinib2018Inngår i: Cancer Letters, ISSN 0304-3835, E-ISSN 1872-7980, Vol. 435, s. 32-43Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Resistance to chemotherapy is a challenging problem for treatment of cancer patients and autophagy has been shown to mediate development of resistance. In this study we systematically screened a library of 306 known anti-cancer drugs for their ability to induce autophagy using a cell-based assay. 114 of the drugs were classified as autophagy inducers; for 16 drugs, the cytotoxicity was potentiated by siRNA-mediated knock-down of Atg7 and Vps34. These drugs were further evaluated in breast cancer cell lines for autophagy induction, and two tyrosine kinase inhibitors, Sunitinib and Erlotinib, were selected for further studies. For the pharmacological inhibition of autophagy, we have characterized here a novel highly potent selective inhibitor of Vps34, SB02024. SB02024 blocked autophagy in vitro and reduced xenograft growth of two breast cancer cell lines, MDA-MB-231 and MCF-7, in vivo. Vps34 inhibitor significantly potentiated cytotoxicity of Sunitinib and Erlotinib in MCF-7 and MDA-MB-231 in vitro in monolayer cultures and when grown as multicellular spheroids. Our data suggests that inhibition of autophagy significantly improves sensitivity to Sunitinib and Erlotinib and that Vps34 is a promising therapeutic target for combination strategies in breast cancer.

  • 16. Ehlén, Å.
    et al.
    Nodin, B.
    Rexhepaj, E.
    Brändstedt, J.
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik (stängd 20130101). KTH, Skolan för bioteknologi (BIO), Centra, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Alvarado-Kristensson, M.
    Pontén, F.
    Brennan, D. J.
    Jirström, K.
    RBM3-regulated genes promote DNA integrity and affect clinical outcome in epithelial ovarian cancer2011Inngår i: Translational Oncology, ISSN 1936-5233, Vol. 4, nr 4, s. 202-211Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The RNA-binding motif protein 3 (RBM3) was initially discovered as a putative cancer biomarker based on its differential expression in various cancer forms in the Human Protein Atlas (HPA). We previously reported an association between high expression of RBM3 and prolonged survival in breast and epithelial ovarian cancer (EOC). Because the function of RBM3 has not been fully elucidated, the aim of this study was to use gene set enrichment analysis to identify the underlying biologic processes associated with RBM3 expression in a previously analyzed EOC cohort (cohort 1, n = 267). This revealed an association between RBM3 expression and several cellular processes involved in the maintenance of DNA integrity. RBM3-regulated genes were subsequently screened in the HPA to select for putative prognostic markers, and candidate proteins were analyzed in the ovarian cancer cell line A2780, whereby an up-regulation of Chk1, Chk2, and MCM3 was demonstrated in siRBM3-treated cells compared to controls. The prognostic value of these markers was assessed at the messenger RNA level in cohort 1 and the protein level in an independent EOC cohort (cohort 2, n = 154). High expression levels of Chk1, Chk2, and MCM3 were associated with a significantly shorter survival in both cohorts, and phosphorylated Chk2 was an adverse prognostic marker in cohort 2. These results uncover a putative role for RBM3 in DNA damage response, which might, in part, explain its cisplatin-sensitizing properties and good prognostic value in EOC. Furthermore, it is demonstrated that Chk1, Chk2, and MCM3 are poor prognostic markers in EOC.

  • 17. Eissler, N.
    et al.
    Mao, Y.
    Brodin, D.
    Reuterswärd, Philippa
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi.
    Svahn Andersson, Helene
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi.
    Johnsen, J. I.
    Kiessling, R.
    Kogner, P.
    Combination Therapy of Anti-PD-1 Antibody and CSF-1R Inhibitor Reverses Induction of Suppressive Myeloid Cells and Controls Spontaneous Neuroblastoma Progression2016Inngår i: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 63, s. S28-S28Artikkel i tidsskrift (Fagfellevurdert)
  • 18.
    Engberg, L.
    et al.
    Raysearch Labs AB, Res Dept, Stockholm, Sweden..
    Eriksson, K.
    Raysearch Labs AB, Res Dept, Stockholm, Sweden..
    Forsgren, Anders
    KTH, Skolan för teknikvetenskap (SCI), Matematik (Inst.).
    Automated planning through explicit optimization of plan quality2018Inngår i: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 127, s. S1025-S1026Artikkel i tidsskrift (Annet vitenskapelig)
  • 19. Falkenius, J
    et al.
    Lindberg, J
    Johansson, H.
    Frostvik-Stolt, M.
    Lundeberg, Joakim
    KTH, Skolan för bioteknologi (BIO), Genteknologi.
    Hansson, J.
    Egyhazi, S.
    A gene expression profile associated with clinical outcome in stage III melanoma2011Inngår i: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 29, nr 15Artikkel i tidsskrift (Annet vitenskapelig)
  • 20. Fridberg, Marie
    et al.
    Nodin, Björn
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik (stängd 20130101). KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Jirström, Karin
    Dachshund homologue 2 is a marker of good prognosis in breast cancer2012Inngår i: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 33, s. 87-87Artikkel i tidsskrift (Annet vitenskapelig)
  • 21. Fristedt, Richard
    et al.
    Elebro, Jacob
    Gaber, Alexander
    Jonsson, Liv
    Heby, Margareta
    Yudina, Yulyana
    Nodin, Bjorn
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab. AlbaNova University, Sweden.
    Eberhard, Jakob
    Jirstrom, Karin
    Reduced Expression of the Polymeric Immunoglobulin Receptor in Pancreatic and Periampullary Adenocarcinoma Signifies Tumour Progression and Poor Prognosis2014Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 11, s. e112728-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The polymeric immunoglobulin receptor (pIgR) is a key component of the mucosal immune system that mediates epithelial transcytosis of immunoglobulins. High pIgR expression has been reported to correlate with a less aggressive tumour phenotype and an improved prognosis in several human cancer types. Here, we examined the expression and prognostic significance of pIgR in pancreatic and periampullary adenocarcinoma. The study cohort encompasses a consecutive series of 175 patients surgically treated with pancreaticoduodenectomy for pancreatic and periampullary adenocarcinoma in Malmo and Lund University Hospitals, Sweden, between 2001-2011. Tissue microarrays were constructed from primary tumours (n = 175) and paired lymph node metastases (n = 105). A multiplied score was calculated from the fraction and intensity of pIgR staining. Classification and regression tree analysis was used to select the prognostic cut-off. Unadjusted and adjusted hazard ratios (HR) for death and recurrence within 5 years were calculated. pIgR expression could be evaluated in 172/175 (98.3%) primary tumours and in 96/105 (91.4%) lymph node metastases. pIgR expression was significantly down-regulated in lymph node metastases as compared with primary tumours (p = 0.018). Low pIgR expression was significantly associated with poor differentiation grade (p<0.001), perineural growth (p = 0.027), lymphatic invasion (p = 0.016), vascular invasion (p = 0.033) and infiltration of the peripancreatic fat (p = 0.039). In the entire cohort, low pIgR expression was significantly associated with an impaired 5-year survival (HR = 2.99, 95% confidence interval (CI) 1.71-5.25) and early recurrence (HR = 2.89, 95% CI 1.67-4.98). This association remained significant for survival after adjustment for conventional clinicopathological factors, tumour origin and adjuvant treatment (HR = 1.98, 95% CI 1.10-3.57). These results demonstrate, for the first time, that high tumour-specific pIgR expression signifies a more favourable tumour phenotype and that low expression independently predicts a shorter survival in patients with pancreatic and periampullary cancer. The mechanistic basis for the putative tumour suppressing properties of pIgR in these cancers merits further study.

  • 22. Gaballa, A.
    et al.
    Norberg, A.
    Stikvoort, A.
    Mattsson, J.
    Sundberg, B.
    Uzunel, M.
    Remberger, M.
    Uhlin, Michael
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik. Karolinska Institutet, Sverige.
    Assessment of TREC, KREC and telomere length in long-term survivors after allogeneic HSCT: the role of GvHD and graft source and evidence for telomere homeostasis in young recipients2018Inngår i: Bone Marrow Transplantation, ISSN 0268-3369, E-ISSN 1476-5365, Vol. 53, nr 1, s. 69-77Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Reconstitution of the adaptive immune system following allogeneic hematopoietic stem cell transplantation is crucial for beneficial outcome and is affected by several factors, such as GvHD and graft source. The impact of these factors on immune reconstitution has been thoroughly investigated during the early phase after transplantation. However, little is known about their long-term effect. Similarly, leukocyte telomere length (TL) shortening has been reported shortly after transplantation. Nevertheless, whether TL shortening continues in long-term aspect is still unsettled. Here, we assessed T-cell receptor excision circle (TREC), kappa deleting recombination excision circle (KREC) and leukocyte TL in recipients and donors several years post transplantation (median 17 years). Our analysis showed that, recipients who received bone marrow (BM) as the graft source have higher levels of both TREC and KREC. Also, chronic GvHD affected TREC levels and TL but not KREC levels. Finally, we show that recipient's TL was longer than respective donors in a group of young age recipients with high KREC levels. Our results suggest that BM can be beneficial for long-term adaptive immune recovery. We also present supporting evidence for recipient telomere homeostasis, especially in young age recipients, rather than telomere shortening.

  • 23. Garousi, Javad
    et al.
    Anderson, Ken G.
    KTH, Skolan för bioteknologi (BIO), Proteinteknologi.
    Mitran, Bogdan
    Pichl, Marie-Louise
    Ståhl, Stefan
    KTH, Skolan för bioteknologi (BIO), Proteinteknologi.
    Orlova, Anna
    Löfblom, John
    KTH, Skolan för bioteknologi (BIO), Proteinteknologi.
    Tolmachev, Vladimir
    PET imaging of epidermal growth factor receptor expression in tumours using Zr-89-labelled ZEGFR:2377 affibody molecules2016Inngår i: International Journal of Oncology, ISSN 1019-6439, Vol. 48, nr 4, s. 1325-1332Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Epidermal growth factor receptor (EGFR) is a transmembrane tyrosine kinase receptor, which is overexpressed in many types of cancer. The use of EGFR-targeting monoclonal antibodies and tyrosine-kinase inhibitors improves significantly survival of patients with colorectal, non-small cell lung cancer and head and neck squamous cell carcinoma. Detection of EGFR overexpression provides important prognostic and predictive information influencing management of the patients. The use of radionuclide molecular imaging would enable non-invasive repeatable determination of EGFR expression in disseminated cancer. Moreover, positron emission tomography (PET) would provide superior sensitivity and quantitation accuracy in EGFR expression imaging. Affibody molecules are a new type of imaging probes, providing high contrast in molecular imaging. In the present study, an EGFR-binding affibody molecule (ZEGFR:2377) was site-specifically conjugated with a deferoxamine (DFO) chelator and labelled under mild conditions (room temperature and neutral pH) with a radionuclide Zr-89. The Zr-89-DFO-ZEGFR:2377 tracer demonstrated specific high affinity (160 +/- 60 pM) binding to EGFR-expressing A431 epidermoid carcinoma cell line. In mice bearing A431 xenografts, Zr-89-DFO-ZEGFR: 2377 demonstrated specific uptake in tumours and EGFR-expressing tissues. The tracer provided tumour uptake of 2.6 +/- 0.5% ID/g and tumour-to-blood ratio of 3.7 +/- 0.6 at 24 h after injection. Zr-89-DFO-ZEGFR: 2377 provides higher tumour-to-organ ratios than anti-EGFR antibody Zr-89-DFO-cetuximab at 48 h after injection. EGFR-expressing tumours were clearly visualized by microPET using Zr-89-DFO-ZEGFR: 2377 at both 3 and 24 h after injection. In conclusion, Zr-89-DFO-ZEGFR: 2377 is a potential probe for PET imaging of EGFR-expression in vivo.

  • 24. Garousi, Javad
    et al.
    Lindbo, Sarah
    KTH, Skolan för bioteknologi (BIO), Proteinteknologi.
    Nilvebrant, Johan
    KTH, Skolan för bioteknologi (BIO), Proteinteknologi.
    Åstrand, Mikael
    KTH, Skolan för bioteknologi (BIO), Proteinteknologi.
    Buijs, Jos
    Sandstrom, Mattias
    Honarvar, Hadis
    Orlova, Anna
    Tolmachev, Vladimir
    Hober, Sophia
    KTH, Skolan för bioteknologi (BIO), Proteinteknologi.
    ADAPT, a Novel Scaffold Protein-Based Probe for Radionuclide Imaging of Molecular Targets That Are Expressed in Disseminated Cancers2015Inngår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, nr 20, s. 4364-4371Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Small engineered scaffold proteins have attracted attention as probes for radionuclide-based molecular imaging. One class of these imaging probes, termed ABD-Derived Affinity Proteins (ADAPT), has been created using the albumin-binding domain (ABD) of streptococcal protein G as a stable protein scaffold. In this study, we report the development of a clinical lead probe termed ADAPT6 that binds HER2, an oncoprotein overexpressed in many breast cancers that serves as a theranostic biomarker for several approved targeting therapies. Surface-exposed amino acids of ABD were randomized to create a combinatorial library enabling selection of high-affinity binders to various proteins. Furthermore, ABD was engineered to enable rapid purification, to eradicate its binding to albumin, and to enable rapid blood clearance. Incorporation of a unique cysteine allowed site-specific conjugation to a maleimido derivative of a DOTA chelator, enabling radionuclide labeling, In-111 for SPECT imaging and Ga-68 for PET imaging. Pharmacologic studies in mice demonstrated that the fully engineered molecule In-111/Ga-68-DOTA(HE) 3-ADAPT6 was specifically bound and taken up by HER2-expressing tumors, with a high tumor-to-normal tissue ratio in xenograft models of human cancer. Unbound tracer underwent rapid renal clearance followed by high renal reabsorption. HER2-expressing xenografts were visualized by gamma-camera or PET at 1 hour after infusion. PET experiments demonstrated feasibility for discrimination of xenografts with high or low HER2 expression. Our results offer a preclinical proof of concept for the use of ADAPT probes for noninvasive in vivo imaging.

  • 25. Glimelius, Bengt
    et al.
    Melin, Beatrice
    Enblad, Gunilla
    Alafuzoff, Irina
    Beskow, Anna
    Ahlström, Håkan
    Bill-Axelson, Anna
    Birgisson, Helgi
    Björ, Ove
    Edqvist, Per-Henrik
    Hansson, Tony
    Helleday, Thomas
    Hellman, Per
    Henriksson, Kerstin
    Hesselager, Göran
    Hultdin, Magnus
    Häggman, Michael
    Höglund, Martin
    Jonsson, Håkan
    Larsson, Chatarina
    Lindman, Henrik
    Ljuslinder, Ingrid
    Mindus, Stephanie
    Nygren, Peter
    Pontén, Fredrik
    Riklund, Katrine
    Rosenquist, Richard
    Sandin, Fredrik
    Schwenk, Jochen M.
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap.
    Stenling, Roger
    Stålberg, Karin
    Stålberg, Peter
    Sundström, Christer
    Karlsson, Camilla Thellenberg
    Westermark, Bengt
    Bergh, Anders
    Claesson-Welsh, Lena
    Palmqvist, Richard
    Sjöblom, Tobias
    U-CAN: a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden2018Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 57, nr 2, s. 187-194Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Progress in cancer biomarker discovery is dependent on access to high-quality biological materials and high-resolution clinical data from the same cases. To overcome current limitations, a systematic prospective longitudinal sampling of multidisciplinary clinical data, blood and tissue from cancer patients was therefore initiated in 2010 by Uppsala and Umea Universities and involving their corresponding University Hospitals, which are referral centers for one third of the Swedish population. Material and Methods: Patients with cancer of selected types who are treated at one of the participating hospitals are eligible for inclusion. The healthcare-integrated sampling scheme encompasses clinical data, questionnaires, blood, fresh frozen and formalin-fixed paraffin-embedded tissue specimens, diagnostic slides and radiology bioimaging data. Results: In this ongoing effort, 12,265 patients with brain tumors, breast cancers, colorectal cancers, gynecological cancers, hematological malignancies, lung cancers, neuroendocrine tumors or prostate cancers have been included until the end of 2016. From the 6914 patients included during the first five years, 98% were sampled for blood at diagnosis, 83% had paraffin-embedded and 58% had fresh frozen tissues collected. For Uppsala County, 55% of all cancer patients were included in the cohort. Conclusions: Close collaboration between participating hospitals and universities enabled prospective, longitudinal biobanking of blood and tissues and collection of multidisciplinary clinical data from cancer patients in the U-CAN cohort. Here, we summarize the first five years of operations, present U-CAN as a highly valuable cohort that will contribute to enhanced cancer research and describe the procedures to access samples and data.

  • 26.
    Green, Henrik
    et al.
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab. Linköping University, Sweden; National Board of Forensic Medicine, Sweden.
    Hasmats, Johanna
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Kupershmidt, Ilya
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab. NextBio, USA.
    Edsgärd, Daniel
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    de Petris, Luigi
    Lewensohn, Rolf
    Blackhall, Fiona
    Vikingsson, Svante
    Besse, Benjamin
    Lindgren, Andrea
    Branden, Eva
    Koyi, Hirsh
    Peterson, Curt
    Lundeberg, Joakim
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Using Whole-Exome Sequencing to Identify Genetic Markers for Carboplatin and Gemcitabine-Induced Toxicities2016Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 22, nr 2, s. 366-373Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: Chemotherapies are associated with significant interindividual variability in therapeutic effect and adverse drug reactions. In lung cancer, the use of gemcitabine and carboplatin induces grade 3 or 4 myelosuppression in about a quarter of the patients, while an equal fraction of patients is basically unaffected in terms of myelosuppressive side effects. We therefore set out to identify genetic markers for gemcitabine/carboplatin-induced myelosuppression. Experimental Design: We exome sequenced 32 patients that suffered extremely high neutropenia and thrombocytopenia (grade 3 or 4 after first chemotherapy cycle) or were virtually unaffected (grade 0 or 1). The genetic differences/polymorphism between the groups were compared using six different bioinformatics strategies: (i) whole-exome nonsynonymous single-nucleotide variants association analysis, (ii) deviation from Hardy-Weinberg equilibrium, (iii) analysis of genes selected by a priori biologic knowledge, (iv) analysis of genes selected from gene expression meta-analysis of toxicity datasets, (v) Ingenuity Pathway Analysis, and (vi) FunCoup network enrichment analysis. Results: A total of 53 genetic variants that differed among these groups were validated in an additional 291 patients and were correlated to the patients' myelosuppression. In the validation, we identified rs1453542 in OR4D6 (P = 0.0008; OR, 5.2; 95% CI, 1.8-18) as a marker for gemcitabine/carboplatin-induced neutropenia and rs5925720 in DDX53 (P = 0.0015; OR, 0.36; 95% CI, 0.17-0.71) as a marker for thrombocytopenia. Patients homozygous for the minor allele of rs1453542 had a higher risk of neutropenia, and for rs5925720 the minor allele was associated with a lower risk for thrombocytopenia. Conclusions: We have identified two new genetic markers with the potential to predict myelosuppression induced by gemcitabine/ carboplatin chemotherapy.

  • 27. Gremel, Gabriela
    et al.
    Djureinovic, Dijana
    Niinivirta, Marjut
    Laird, Alexander
    Ljungqvist, Oscar
    Johannesson, Henrik
    Bergman, Julia
    Edqvist, Per-Henrik
    Navani, Sanjay
    Khan, Naila
    Patil, Tushar
    Sivertsson, Åsa
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Harrison, David J.
    Ullenhag, Gustav J.
    Stewart, Grant D.
    Ponten, Fredrik
    A systematic search strategy identifies cubilin as independent prognostic marker for renal cell carcinoma2017Inngår i: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 17, artikkel-id 9Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: There is an unmet clinical need for better prognostic and diagnostic tools for renal cell carcinoma (RCC). Methods: Human Protein Atlas data resources, including the transcriptomes and proteomes of normal and malignant human tissues, were searched for RCC-specific proteins and cubilin (CUBN) identified as a candidate. Patient tissue representing various cancer types was constructed into a tissue microarray (n = 940) and immunohistochemistry used to investigate the specificity of CUBN expression in RCC as compared to other cancers. Two independent RCC cohorts (n = 181; n = 114) were analyzed to further establish the sensitivity of CUBN as RCC-specific marker and to explore if the fraction of RCCs lacking CUBN expression could predict differences in patient survival. Results: CUBN was identified as highly RCC-specific protein with 58% of all primary RCCs staining positive for CUBN using immunohistochemistry. In venous tumor thrombi and metastatic lesions, the frequency of CUBN expression was increasingly lost. Clear cell RCC (ccRCC) patients with CUBN positive tumors had a significantly better prognosis compared to patients with CUBN negative tumors, independent of T-stage, Fuhrman grade and nodal status (HR 0.382, CI 0.203-0.719, P = 0.003). Conclusions: CUBN expression is highly specific to RCC and loss of the protein is significantly and independently associated with poor prognosis. CUBN expression in ccRCC provides a promising positive prognostic indicator for patients with ccRCC. The high specificity of CUBN expression in RCC also suggests a role as a new diagnostic marker in clinical cancer differential diagnostics to confirm or rule out RCC.

  • 28. Haylock, Anna-Karin
    et al.
    Nilvebrant, Johan
    KTH, Skolan för bioteknologi (BIO), Proteinteknologi.
    Mortensen, Anja
    Velikyan, Irina
    Nestor, Marika
    Falk, Ronny
    Generation and evaluation of antibody agents for molecular imaging of CD44v6-expressing cancers2017Inngår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, nr 39, s. 65152-65170Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aim: The aim of this study was to generate and characterize scFv antibodies directed to human CD44v6, as well as to radiolabel and evaluate top candidates in vitro and in vivo for their potential use in CD44v6-targeted molecular imaging in cancer patients. Materials and methods: Phage display selections were used to isolate CD44v6-specific scFvs. A chain shuffling strategy was employed for affinity maturation based on a set of CD44v6-specific first-generation clones. Two second-generation scFv clones were then chosen for labeling with 111In or 125I and assessed for CD44v6-specific binding on cultured tumor cells. In vivo uptake and distribution was evaluated in tumor-bearing mice using a dual tumor model. Finally, a proof-of-concept small animal PET-CT study was performed on one of the candidates labeled with 124I. Results: Two affinity-matured clones, CD44v6-scFv-A11 and CD44v6-scFv-H12, displayed promising binding kinetics. Seven out of eight radiolabeled conjugates demonstrated CD44v6-specific binding. In vivo studies on selected candidates demonstrated very advantageous tumor-to-organ ratios, in particular for iodinated conjugates, where 125I-labeled scFvs exhibited favorable kinetics and tumor-to-blood ratios above five already at 24 hours p. i.. The small animal PET-CT study using 124I-labeled CD44v6-scFv-H12 was in line with the biodistribution data, clearly visualizing the high CD44v6-expressing tumor. Conclusion: The single chain fragments, CD44v6-scFv-A11 and CD44v6-scFv-H12 specifically bind to CD44v6, and the radiolabeled counterparts provide high tumor-to-blood ratios and fast clearance from organs and blood. We conclude that radioiodinated CD44v6-scFv-A11 and CD44v6-scFv-H12 possess features highly suitable for stringent molecular imaging.

  • 29. Hedner, Charlotta
    et al.
    Gaber, Alexander
    Korkocic, Dejan
    Nodin, Bjorn
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Kuteeva, Eugenia
    Johannesson, Henrik
    Jirstrom, Karin
    Eberhard, Jakob
    SATB1 is an independent prognostic factor in radically resected upper gastrointestinal tract adenocarcinoma2014Inngår i: Virchows Archiv, ISSN 0945-6317, E-ISSN 1432-2307, Vol. 465, nr 6, s. 649-659Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Gastric cancer is the second most common cause of cancer-related death worldwide, and the incidence of esophageal adenocarcinoma is rising. While some progress has been made in treatment strategies, overall survival remains very poor for patients with adenocarcinoma in the upper gastrointestinal tract. Special AT-rich sequence binding protein 1 (SATB1) is a global genome organizer that has been demonstrated to promote aggressive tumor behavior in several different types of cancer, including gastric cancer. The prognostic value of SATB1 expression in esophageal cancer has, however, not yet been described. In this study, expression of SATB1 was examined by immunohistochemistry on tissue microarrays prepared from tissue samples from 175 patients with adenocarcinoma of the esophagus, cardia, or stomach and containing normal tissue, intestinal metaplasia, primary tumors, and metastases. A well-validated antibody was used. We found SATB1 to be an independent prognostic factor in patients with a radically resected tumor, correlating with shorter overall survival as well as with shorter recurrence-free survival. SATB1 expression was also found to be significantly lower in primary tumors associated with intestinal metaplasia than those without intestinal metaplasia. This observation is of potential biological interest as it has been proposed that intestinal metaplasia-associated tumors constitute a less aggressive phenotype.

  • 30. Horyath, Gyorgy
    et al.
    Chilo, Jose
    Lindblad, Thomas
    KTH, Skolan för teknikvetenskap (SCI), Fysik.
    Different volatile signals emitted by human ovarian carcinoma and healthy tissue2010Inngår i: FUTURE ONCOL, ISSN 1479-6694, Vol. 6, nr 6, s. 1043-1049Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Many cancers are detected at a late stage resulting in high mortality rates. Thus, it is essential to develop inexpensive and simple methods for early diagnosis. Detection of different malignancies using canine scent, as well as other technical methods, has been reported in peer-reviewed journals, indicating that this may represent a new diagnostic tool for malignancies. Aim: This study aims to test the detection of different volatile organic compound signals emitted by ovarian carcinoma and normal tissues. Materials & methods: A previously tested electronic nose is used in the pilot study to analyze human grade 3 seropapillary ovarian carcinoma samples. The recorded signals were compared with healthy human Fallopian tube specimens. A variety of algorithms were tested and confusion matrices compared. In parallel, an external validation study was performed using the same type and grade of human ovarian carcinomas with healthy myometrium (first part) and postmenopausal ovarium (second part) specimens as controls. Both sample types were obtained from individuals who did not participate in the pilot study. Results: Method sensitivity was 100% (15 of 15) in the pilot study. The first part of the validation study demonstrated that 84.8% of cancer tissues (sensitivity: 84.8%) and 88.6% of the control samples (specificity: 88.6%) were correctly classified. In the second part the JRip algorithm correctly classified 75% of cancer tissues (sensitivity: 75%) and 80% of the control ovarian tissues (specificity: 80%). Collating results gives a sensitivity of 84,4%, whereas overall specificity was 86.8%. Conclusion: Although based on a limited number of samples, our results strongly suggest that specific volatile organic compound signals emitted by ovarian carcinomas may be used for early diagnosis of the disease.

  • 31.
    Janek Strååt, Sara
    et al.
    Karolinska Institutet and Stockholm University.
    Andreassen, Björn
    Karolinska Institutet and Stockholm University.
    Johansson, Cathrine
    Karolinska University Hospital Solna, Sweden.
    Noz, Marilyn E.
    New York University, Department of Radiology.
    Maguire Jr., Gerald Q.
    KTH, Skolan för informations- och kommunikationsteknik (ICT), Kommunikationssystem, CoS, Radio Systems Laboratory (RS Lab).
    Näfstadius, Peder
    Karolinska University Hospital.
    Näslund, Ingemar
    Karolinska Institutet.
    Schoenahl, Frederic
    University Hospital of Geneva, Geneva, Switzerland .
    Brahme, Anders
    Karolinska Institute.
    Clinical application of in vivo treatment delivery verification based on PET/CT imaging of positron activity induced at high energy photon therapy2013Inngår i: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 58, nr 16, s. 5541-5553Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The purpose of this study was to investigate in vivo verification of radiation treatment with high energy photon beams using PET/CT to image the induced positron activity. The measurements of the positron activation induced in a preoperative rectal cancer patient and a prostate cancer patient following 50 MV photon treatments are presented. A total dose of 5 and 8 Gy, respectively, were delivered to the tumors. Imaging was performed with a 64-slice PET/CT scanner for 30 min, starting 7 min after the end of the treatment. The CT volume from the PET/CT and the treatment planning CT were coregistered by matching anatomical reference points in the patient. The treatment delivery was imaged in vivo based on the distribution of the induced positron emitters produced by photonuclear reactions in tissue mapped on to the associated dose distribution of the treatment plan. The results showed that spatial distribution of induced activity in both patients agreed well with the delivered beam portals of the treatment plans in the entrance subcutaneous fat regions but less so in blood and oxygen rich soft tissues. For the preoperative rectal cancer patient however, a 2 +/- (0.5) cm misalignment was observed in the cranial-caudal direction of the patient between the induced activity distribution and treatment plan, indicating a beam patient setup error. No misalignment of this kind was seen in the prostate cancer patient. However, due to a fast patient setup error in the PET/CT scanner a slight mis-position of the patient in the PET/CT was observed in all three planes, resulting in a deformed activity distribution compared to the treatment plan. The present study indicates that the induced positron emitters by high energy photon beams can be measured quite accurately using PET imaging of subcutaneous fat to allow portal verification of the delivered treatment beams. Measurement of the induced activity in the patient 7 min after receiving 5 Gy involved count rates which were about 20 times lower than that of a patient undergoing standard F-18-FDG treatment. When using a combination of short lived nuclides such as O-15 (half-life: 2 min) and C-11 (half-life: 20 min) with low activity it is not optimal to use clinical reconstruction protocols. Thus, it might be desirable to further optimize reconstruction parameters as well as to address hardware improvements in realizing in vivo treatment verification with PET/CT in the future. A significant improvement with regard to O-15 imaging could also be expected by having the PET/CT unit located close to the radiation treatment room.

  • 32. Johansson, C. Hertzman
    et al.
    Azimi, A.
    Pernemalm, M.
    Pawitan, Y.
    Stolt, M. Frostvik
    Lazar, V.
    Lundeberg, Joakim
    KTH, Skolan för bioteknologi (BIO), Genteknologi.
    Lehtio, J.
    Egyhazi, S.
    Hansson, J.
    Proteomics And Gene Expression Profiling Of Melanoma Chemotherapy Response In Tumors2012Inngår i: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 23, s. 27-27Artikkel i tidsskrift (Annet vitenskapelig)
  • 33.
    Kumar, Arvind
    et al.
    University of Freiburg, Germany .
    Singh, Harinder Pal
    Information homeostasis as a fundamental principle governing the cell division and death2011Inngår i: Medical Hypotheses, ISSN 0306-9877, E-ISSN 1532-2777, Vol. 77, nr 3, s. 318-322Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To express the genetic information with minimal error is one of the key functions of a cell. Here we propose an information theory based, phenomenological model for the expression of genetic information. Based on the model we propose the concept of 'information homeostasis' which ensures that genetic information is expressed with minimal error. We suggest that together with energy homeostasis, information homeostasis is a fundamental working principle of a biological cell. This model proposes a novel explanation of why a cell divides and why it stops to divide and, thus, provides novel insights into oncogenesis and various neuro-degenerative diseases. Moreover, the model suggests a theoretical framework to understand cell division and death, beyond specific biochemical pathways.

  • 34. Kvedaraite, Egle
    et al.
    Jess, David Unnersjö
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Cellulär biofysik.
    Gavhed, Desiree
    Idestrom, Maja
    Svensson, Mattias
    Lourda, Magda
    Henter, Jan-Inge
    When Langerhans Met Crohn: A Clinical Case Report and a First Three-Dimentional Reconstruction of Human Gut2017Inngår i: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 64, s. S20-S20Artikkel i tidsskrift (Fagfellevurdert)
  • 35. Lagae, L.
    et al.
    Liu, C. X.
    Latta, D.
    Henry, O.
    O'Sullivan, C.
    Roeser, T.
    Lundeberg, Joakim
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Kvastad, Linda
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Riley, I.
    Borgen, E.
    Lab-on-chip tracing circulating tumour cells2013Inngår i: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 49, s. S74-S74Artikkel i tidsskrift (Annet vitenskapelig)
  • 36. Larsson, Anna
    et al.
    Fridberg, Marie
    Gaber, Alexander
    Nodin, Björn
    Levéen, Per
    Jonsson, Göran
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik.
    Birgisson, Helgi
    Jirström, Karin
    Validation of podocalyxin-like protein as a biomarker of poor prognosis in colorectal cancer2012Inngår i: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 12, s. 282-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Podocalyxin-like 1 (PODXL) is a cell-adhesion glycoprotein and stem cell marker that has been associated with an aggressive tumour phenotype and adverse outcome in several cancer types. We recently demonstrated that overexpression of PODXL is an independent factor of poor prognosis in colorectal cancer (CRC). The aim of this study was to validate these results in two additional independent patient cohorts and to examine the correlation between PODXL mRNA and protein levels in a subset of tumours. Method: PODXL protein expression was analyzed by immunohistochemistry in tissue microarrays with tumour samples from a consecutive, retrospective cohort of 270 CRC patients (cohort 1) and a prospective cohort of 337 CRC patients (cohort 2). The expression of PODXL mRNA was measured by real-time quantitative PCR in a subgroup of 62 patients from cohort 2. Spearman's Rho and Chi-Square tests were used for analysis of correlations between PODXL expression and clinicopathological parameters. Kaplan Meier analysis and Cox proportional hazards modelling were applied to assess the relationship between PODXL expression and time to recurrence (TTR), disease free survival (DFS) and overall survival (OS). Results: High PODXL protein expression was significantly associated with unfavourable clinicopathological characteristics in both cohorts. In cohort 1, high PODXL expression was associated with a significantly shorter 5-year OS in both univariable (HR = 2.28; 95% CI 1.43-3.63, p = 0.001) and multivariable analysis (HR = 2.07; 95% CI 1.25-3.43, p = 0.005). In cohort 2, high PODXL expression was associated with a shorter TTR (HR = 2.93; 95% CI 1.26-6.82, p = 0.013) and DFS (HR = 2.44; 95% CI 1.32-4.54, p = 0.005), remaining significant in multivariable analysis, HR = 2.50; 95% CI 1.05-5.96, p = 0.038 for TTR and HR = 2.11; 95% CI 1.13-3.94, p = 0.019 for DFS. No significant correlation could be found between mRNA levels and protein expression of PODXL and there was no association between mRNA levels and clinicopathological parameters or survival. Conclusions: Here, we have validated the previously demonstrated association between immunohistochemical expression of PODXL and poor prognosis in CRC in two additional independent patient cohorts. The results further underline the potential utility of PODXL as a biomarker for more precise prognostication and treatment stratification of CRC patients.

  • 37. Lazzeroni, M.
    et al.
    Khazraei Manesh, Zohreh
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH).
    Sandstrom, H.
    Barsoum, P.
    Toma-Dasu, I.
    Influence of tumor infiltration on treatment outcome in Gamma Knife Radiosurgery: a modeling study2018Inngår i: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 127, s. S107-S108Artikkel i tidsskrift (Fagfellevurdert)
  • 38. Le Joncour, Vadim
    et al.
    Filppu, Pauliina
    Hyvönen, Maija
    Holopainen, Minna
    Turunen, S Pauliina
    Sihto, Harri
    Burghardt, Isabel
    Joensuu, Heikki
    Tynninen, Olli
    Jääskeläinen, Juha
    Weller, Michael
    Lehti, Kaisa
    Käkelä, Reijo
    Laakkonen, Pirjo
    Vulnerability of invasive glioblastoma cells to lysosomal membrane destabilization.2019Inngår i: EMBO Molecular Medicine, ISSN 1757-4676, E-ISSN 1757-4684, Vol. 11, nr 6, artikkel-id e9034Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The current clinical care of glioblastomas leaves behind invasive, radio- and chemo-resistant cells. We recently identified mammary-derived growth inhibitor (MDGI/FABP3) as a biomarker for invasive gliomas. Here, we demonstrate a novel function for MDGI in the maintenance of lysosomal membrane integrity, thus rendering invasive glioma cells unexpectedly vulnerable to lysosomal membrane destabilization. MDGI silencing impaired trafficking of polyunsaturated fatty acids into cells resulting in significant alterations in the lipid composition of lysosomal membranes, and subsequent death of the patient-derived glioma cells via lysosomal membrane permeabilization (LMP). In a preclinical model, treatment of glioma-bearing mice with an antihistaminergic LMP-inducing drug efficiently eradicated invasive glioma cells and secondary tumours within the brain. This unexpected fragility of the aggressive infiltrating cells to LMP provides new opportunities for clinical interventions, such as re-positioning of an established antihistamine drug, to eradicate the inoperable, invasive, and chemo-resistant glioma cells from sustaining disease progression and recurrence.

  • 39. Lehtio, J.
    et al.
    Branca, M.
    Johansson, H.
    Orre, M.
    Granholm, Viktor
    KTH.
    Forshed, J.
    Perez-Bercoff, M.
    Käll, Lukas
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, SeRC - Swedish e-Science Research Centre. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Genome Wide Proteomics Using Peptide High Resolution Isoelectric Focusing Hirief-Ms Allows Detection New Human Gene Models2012Inngår i: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 23, s. 33-34Artikkel i tidsskrift (Annet vitenskapelig)
  • 40. Li, Qin
    et al.
    Wennborg, Anders
    Aurell, Erik
    KTH.
    Dekel, Erez
    Zou, Jie-Zhi
    Xu, Yuting
    Huang, Sui
    Ernberg, Ingemar
    Dynamics inside the cancer cell attractor reveal cell heterogeneity, limits of stability, and escape2016Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, nr 10, s. 2672-2677Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The observed intercellular heterogeneity within a clonal cell population can be mapped as dynamical states clustered around an attractor point in gene expression space, owing to a balance between homeostatic forces and stochastic fluctuations. These dynamics have led to the cancer cell attractor conceptual model, with implications for both carcinogenesis and new therapeutic concepts. Immortalized and malignant EBV-carrying B-cell lines were used to explore this model and characterize the detailed structure of cell attractors. Any subpopulation selected from a population of cells repopulated the whole original basin of attraction within days to weeks. Cells at the basin edges were unstable and prone to apoptosis. Cells continuously changed states within their own attractor, thus driving the repopulation, as shown by fluorescent dye tracing. Perturbations of key regulatory genes induced a jump to a nearby attractor. Using the Fokker-Planck equation, this cell population behavior could be described as two virtual, opposing influences on the cells: one attracting toward the center and the other promoting diffusion in state space (noise). Transcriptome analysis suggests that these forces result from high-dimensional dynamics of the gene regulatory network. We propose that they can be generalized to all cancer cell populations and represent intrinsic behaviors of tumors, offering a previously unidentified characteristic for studying cancer.

  • 41.
    Liao, Xiwen
    et al.
    Guangxi Med Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Shuang Yong Rd 6, Nanning 530021, Guangxi Zhuang, Peoples R China..
    Wang, Xiangkun
    Guangxi Med Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Shuang Yong Rd 6, Nanning 530021, Guangxi Zhuang, Peoples R China..
    Huang, Ketuan
    Guangxi Med Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Shuang Yong Rd 6, Nanning 530021, Guangxi Zhuang, Peoples R China..
    Han, Chuangye
    Guangxi Med Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Shuang Yong Rd 6, Nanning 530021, Guangxi Zhuang, Peoples R China..
    Deng, Jianlong
    Guangxi Med Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Shuang Yong Rd 6, Nanning 530021, Guangxi Zhuang, Peoples R China.;Guangxi Med Univ, Affiliated Hosp 6, Dept Hepatobiliary Surg, Yulin 537000, Guangxi Zhuang, Peoples R China..
    Yu, Tingdong
    Guangxi Med Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Shuang Yong Rd 6, Nanning 530021, Guangxi Zhuang, Peoples R China..
    Yang, Chengkun
    Guangxi Med Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Shuang Yong Rd 6, Nanning 530021, Guangxi Zhuang, Peoples R China..
    Huang, Rui
    Guangxi Med Univ, Affiliated Hosp 1, Dept Hematol, Nanning 530021, Guangxi Zhuang, Peoples R China..
    Liu, Xiaoguang
    Guangxi Med Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Shuang Yong Rd 6, Nanning 530021, Guangxi Zhuang, Peoples R China.;Guangdong Med Univ, Dept Hepatobiliary Surg, Affiliated Hosp, Zhanjiang 524001, Guangdong, Peoples R China..
    Yu, Long
    Guangxi Med Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Shuang Yong Rd 6, Nanning 530021, Guangxi Zhuang, Peoples R China.;Zhengzhou Univ, Affiliated Hosp 1, Dept Hepatobiliary & Pancreat Surg, Zhengzhou 450000, Henan, Peoples R China..
    Zhu, Guangzhi
    Guangxi Med Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Shuang Yong Rd 6, Nanning 530021, Guangxi Zhuang, Peoples R China..
    Su, Hao
    Guangxi Med Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Shuang Yong Rd 6, Nanning 530021, Guangxi Zhuang, Peoples R China..
    Qin, Wei
    Guangxi Med Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Shuang Yong Rd 6, Nanning 530021, Guangxi Zhuang, Peoples R China..
    Zeng, Xianmin
    Guangxi Med Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Shuang Yong Rd 6, Nanning 530021, Guangxi Zhuang, Peoples R China..
    Han, Bowen
    Guangxi Med Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Shuang Yong Rd 6, Nanning 530021, Guangxi Zhuang, Peoples R China..
    Han, Quanfa
    Guangxi Med Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Shuang Yong Rd 6, Nanning 530021, Guangxi Zhuang, Peoples R China..
    Liu, Zhengqian
    Guangxi Med Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Shuang Yong Rd 6, Nanning 530021, Guangxi Zhuang, Peoples R China..
    Zhou, Xin
    Guangxi Med Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Shuang Yong Rd 6, Nanning 530021, Guangxi Zhuang, Peoples R China..
    Gong, Yizhen
    Guangxi Med Univ, Affiliated Hosp 1, Dept Colorectal & Anal Surg, Nanning 530021, Guangxi Zhuang, Peoples R China.;Guangxi Med Univ, Affiliated Hosp 1, Dept Evidence Based Med, Nanning 530021, Guangxi Zhuang, Peoples R China..
    Liu, Zhengtao
    KTH, Centra, Science for Life Laboratory, SciLifeLab. Guangxi Med Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Shuang Yong Rd 6, Nanning 530021, Guangxi Zhuang, Peoples R China.;Minist Publ Hlth, Key Lab Combined Multiorgan Transplantat, Hangzhou 310003, Zhejiang, Peoples R China.;Key Lab Organ Transplantat Zhejiang Prov, Hangzhou 310003, Zhejiang, Peoples R China.
    Huang, Jianly
    Guangxi Med Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Shuang Yong Rd 6, Nanning 530021, Guangxi Zhuang, Peoples R China.;Guangxi Med Univ, Affiliated Hosp 3, Dept Hepatobiliary Surg, Nanning 530031, Guangxi Zhuang, Peoples R China..
    Winkler, Cheryl A.
    NCI, Basic Res Lab, CCR, Frederick Natl Lab, Frederick, MD 21702 USA.;Frederick Natl Lab, Leidos Biomed Res, Frederick, MD 21702 USA..
    O'Brien, Stephen J.
    St Petersburg State Univ, Theodosius Dobzhansky Ctr Genome Bioinformat, St Petersburg 199004, Russia.;Nova Southeastern Univ, Oceanog Ctr, Ft Lauderdale, FL 33004 USA..
    Ye, Xinping
    Guangxi Med Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Shuang Yong Rd 6, Nanning 530021, Guangxi Zhuang, Peoples R China..
    Peng, Tao
    Guangxi Med Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Shuang Yong Rd 6, Nanning 530021, Guangxi Zhuang, Peoples R China..
    Integrated analysis of competing endogenous RNA network revealing potential prognostic biomarkers of hepatocellular carcinoma2019Inngår i: Journal of Cancer, ISSN 1837-9664, E-ISSN 1837-9664, Vol. 10, nr 14, s. 3267-3283Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: The goal of our study is to identify a competing endogenous RNA (ceRNA) network using dysregulated RNAs between HCC tumors and the adjacent normal liver tissues from The Cancer Genome Atlas (TCGA) datasets, and to investigate underlying prognostic indicators in hepatocellular carcinoma (HCC) patients. Methods: All of the RNA- and miRNA-sequencing datasets of HCC were obtained from TCGA, and dysregulated RNAs between HCC tumors and the adjacent normal liver tissues were investigated by DESeq and edgeR algorithm. Survival analysis was used to confirm underlying prognostic indicators. Results: In the present study, we constructed a ceRNA network based on 16 differentially expressed genes (DEGs), 7 differentially expressed microRNAs and 34 differentially expressed long non-coding RNAs (DELs). Among these dysregulated RNAs, three DELs (AP002478.1, HTR2A-AS1, and ERVMER61-1) and six DEGs (enhancer of zeste homolog 2 [EZH2], kinesin family member 23 [KIF23], chromobox 2 [CBX2], centrosomal protein 55 [CEP55], cell division cycle 25A [CDC25A], and claspin [CLSPN]) were used for construct a prognostic signature for HCC overall survival (OS), and performed well in HCC OS (adjusted P<0.0001, adjusted hazard ratio = 2.761, 95% confidence interval = 1.838-4.147). Comprehensive survival analysis demonstrated that this prognostic signature may be act as an independent prognostic indicator of HCC OS. Functional assessment of these dysregulated DEGs in the ceRNA network and gene set enrichment of this prognostic signature suggest that both were enriched in the biological processes and pathways of the cell cycle, cell division and cell proliferation. Conclusions: Our current study constructed a ceRNA network for HCC, and developed a prognostic signature that may act as an independent indicator for HCC OS.

  • 42.
    Lindberg, Hanna
    et al.
    KTH, Skolan för bioteknologi (BIO), Molekylär Bioteknologi (stängd 20130101).
    Hofström, Camilla
    KTH, Skolan för bioteknologi (BIO), Molekylär Bioteknologi (stängd 20130101).
    Altai, Mohamed
    Honorvar, Hadis
    Wållberg, Helena
    KTH, Skolan för bioteknologi (BIO), Molekylär Bioteknologi (stängd 20130101).
    Orlova, Anna
    Ståhl, Stefan
    KTH, Skolan för bioteknologi (BIO), Molekylär Bioteknologi (stängd 20130101).
    Gräslund, Torbjörn
    KTH, Skolan för bioteknologi (BIO), Molekylär Bioteknologi (stängd 20130101).
    Tolmachev, Vladimir
    Evaluation of a HER2-targeting affibody molecule combining an N-terminal HEHEHE-tag with a GGGC chelator for Tc-99m-labelling at the C terminus2012Inngår i: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 33, nr 3, s. 641-651Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Affibody molecules are a class of small (ca.7 kDa) robust scaffold proteins with high potential as tracers for radionuclide molecular imaging in vivo. Incorporation of a cysteine-containing peptide-based chelator at the C terminus provides an opportunity for stable labelling with the radionuclide Tc-99m. The use of a GGGC chelator at the C terminus has provided the lowest renal radioactivity retention of the previously investigated peptide-based chelators. Previously, it has also been demonstrated that replacement of the His(6)-tag with the negatively charged histidine-glutamate-histidine-glutamate-histidine-glutamate (HEHEHE)-tag permits purification of affibody molecules by immobilized metal ion affinity chromatography (IMAC) and provides low hepatic accumulation of radioactivity of conjugates site-specifically labelled at the C terminus using several different nuclides. We hypothesized that the combination of a HEHEHE-tag at the N terminus and a GGGC chelator at the C terminus of an affibody molecule would be a favourable format permitting IMAC purification and providing low uptake in excretory organs. To investigate this hypothesis, a (HE)(3)-Z(HER2:342)-GGGC affibody molecule was generated. It could be efficiently purified by IMAC and stably labelled with Tc-99m. Tc-99m-(HE)(3)-Z(HER2:342)-GGGC preserved specific binding to HER2-expressing cells. In NMRI mice, hepatic uptake of Tc-99m-(HE)(3)-Z(HER2:342)-GGGC was lower than the uptake of the control affibody molecules, Tc-99m-Z(HER2:2395)-VDC and Tc-99m-Z(HER2:342)-GGGC. At 1 and 4 h after injection, the renal uptake of Tc-99m-(HE)(3)-Z(HER2:342)-GGGC was 2-3-fold lower than uptake of Tc-99m-Z(HER2:2395)-VDC, but it was substantially higher than uptake of Tc-99m-Z(HER2:342)-GGGC. Further investigation indicated that a fraction of Tc-99m was chelated by the HEHEHE-tag which caused a higher accumulation of radioactivity in the kidneys. Thus, a combination of a HEHEHE-tag and the GGGC chelator in targeting scaffold proteins was found to be undesirable in the case of Tc-99m labelling due to a partial loss of site-specificity of nuclide chelation.

  • 43.
    Liu, Hao
    et al.
    KTH, Skolan för bioteknologi (BIO), Proteinteknologi.
    Seijsing, Johan
    KTH, Skolan för bioteknologi (BIO), Proteinteknologi.
    Frejd, Fredrik Y.
    Tolmachev, Vladimir
    Gräslund, Torbjörn
    KTH, Skolan för bioteknologi (BIO), Proteinteknologi.
    Target-specific cytotoxic effects on HER2-expressing cells by the tripartite fusion toxin Z(HER2:2891)-ABD-PE38X8, including a targeting affibody molecule and a half-life extension domain2015Inngår i: International Journal of Oncology, ISSN 1019-6439, Vol. 47, nr 2, s. 601-609Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Development of cancer treatment regimens including immunotoxins is partly hampered by their immunogenicity. Recently, deimmunized versions of toxins have been described, potentially being better suited for translation to the clinic. In this study, a recombinant tripartite fusion toxin consisting of a deimmunized version of exotoxin A from Pseudomonas aeruginosa (PE38) genetically fused to an affibody molecule specifically interacting with the human epidermal growth factor receptor 2 (HER2), and also an albumin binding domain (ABD) for half-life extension, has been produced and characterized in terms of functionality of the three moieties. Biosensor based assays showed that the fusion toxin was able to interact with human and mouse serum albumin, but not with bovine serum albumin and that it interacted with HER2 (K-D=5 nM). Interestingly, a complex of the fusion toxin and human serum albumin also interacted with HER2 but with a somewhat weaker affinity (K-D=12 nM). The IC50-values of the fusion toxin ranged from 6 to 300 pM on SKOV-3, SKBR-3 and A549 cells and was lower for cells with higher surface densities of HER2. The fusion toxin was found specific for HER2 as shown by blocking available HER2 receptors with free affibody molecule before subjecting the cells to the toxin. Analysis of contact time showed that 10 min was sufficient to kill 50% of the cells. In conclusion, all three regions of the fusion toxin were found to be functional.

  • 44. Lund, Mikael
    et al.
    von Dobeln, Gabriella Alexandersson
    Nilsson, Magnus
    Winter, Reidar
    KTH, Skolan för teknik och hälsa (STH), Medicinsk teknik, Medicinsk bildteknik. Karolinska Institutet, Sweden.
    Lundell, Lars
    Tsai, Jon A.
    Kalman, Sigridur
    Effects on heart function of neoadjuvant chemotherapy and chemoradiotherapy in patients with cancer in the esophagus or gastroesophageal junction: a prospective cohort pilot study within a randomized clinical trial2015Inngår i: Radiation Oncology, ISSN 1748-717X, E-ISSN 1748-717X, Vol. 10, artikkel-id 16Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Neoadjuvant therapy for cancer of the esophagus or gastroesophageal (GE)-junction is well established. The pros and cons of chemoradiotherapy and chemotherapy are debated. Chemoradiotherapy might impair cardiac function eliciting postoperative morbidity. The aim of this pilot study was to describe acute changes in left ventricular function following chemoradiotherapy or chemotherapy. Methods: Patients with esophageal and (GE)-junction cancer enrolled at our center into a multicenter trial comparing neoadjuvant chemoradiotherapy and chemotherapy were eligible. Patients were randomized to receive cisplatin and 5-fluorouracil with or without the addition of 40 Gy radiotherapy prior to surgery. Left ventricular function was evaluated using echocardiography and plasma N-Terminal Pro-B-Type Natriuretic Peptide (NT-proBNP) before and after neoadjuvant treatment. The primary outcome measure was left ventricular global strain (GS). Clinical effects were assessed using repeated exercise tests. Linear mixed models were used to analyze the effects of treatment group, and the interaction between groups. Results: 40 patients participated (chemoradiotherapy, n = 17; chemotherapy, n = 23). In the chemoradiotherapy group there was no change in left ventricular global strain but mitral annular plane systolic excursion (MAPSE) of the ventricular septum, early diastolic filling velocity (E-velocity), and the ratio of early to late ventricular filling velocities (E/A ratio) decreased significantly (p = 0.02, p = 0.01, and p = 0.03, respectively). No changes were observed in the chemotherapy group. There was a trend towards an interaction effect for MAPSE sept and E (p = 0.09 and p = 0.09). NT-proBNP increased following chemoradiotherapy (p = 0.05) but not after chemotherapy (p > 0.99), and there was a trend towards an interaction effect (p = 0.07). Working capacity decreased following neoadjuvant treatment (chemoradiotherapy p = 0.001, chemotherapy p = 0.03) and was more pronounced after chemoradiotherapy with a trend towards an interaction effect (p = 0.10). Conclusions: Neoadjuvant chemoradiotherapy but not chemotherapy before surgery for cancer of the esophagus or GE-junction seems to induce an acute negative effect on both systolic and diastolic left ventricular function. Future studies on neoadjuvant treatment for esophageal cancer are suggested to add measurements of cardiac function.

  • 45. Mattsson, Johanna S. M.
    et al.
    Svensson, Maria A.
    Hallström, Björn
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Koyi, Hirsh
    Branden, Eva
    Brunnstrom, Hans
    Edlund, Karolina
    Ekman, Simon
    La Fleur, Linnea
    Grinberg, Marianna
    Rahnenfuehrer, Joerg
    Jirstrom, Karin
    Ponten, Fredrik
    Karlsson, Mats G.
    Karlsson, Christina
    Helenius, Gisela
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Botling, Johan
    Micke, Patrick
    ALK Rearrangements in Non-Small Cell Lung Cancer: Comprehensive Integration of Genomic, Gene Expression and Protein Analysis2015Inngår i: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 10, nr 9, s. S298-S298Artikkel i tidsskrift (Annet vitenskapelig)
  • 46.
    Narangifard, A.
    et al.
    KI, Dept Med, Solna MedS, Stockholm, Sweden.;ERCO Pharma AB, Sci Life Lab, Stockholm, Sweden..
    den Hollander, L.
    Karolinska Inst, Dept Cell & Mol Biol CMB, SE-17177 Stockholm, Sweden..
    Wennberg, Christian L.
    KTH, Skolan för teknikvetenskap (SCI), Fysik. KTH, Centra, SeRC - Swedish e-Science Research Centre. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Lundborg, M.
    ERCO Pharma AB, Sci Life Lab, Stockholm, Sweden..
    Lindahl, Erik
    KTH, Skolan för teknikvetenskap (SCI), Fysik. KTH, Centra, SeRC - Swedish e-Science Research Centre. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Iwai, I.
    Karolinska Inst, Dept Cell & Mol Biol CMB, SE-17177 Stockholm, Sweden..
    Han, H.
    Max Planck Inst Mol Physiol, Syst Cell Biol, Dortmund, Germany..
    Masich, S.
    Karolinska Inst, Dept Cell & Mol Biol CMB, SE-17177 Stockholm, Sweden..
    Daneholt, B.
    Karolinska Inst, Dept Cell & Mol Biol CMB, SE-17177 Stockholm, Sweden..
    Norlen, L.
    Karolinska Inst, Dept Cell & Mol Biol CMB, SE-17177 Stockholm, Sweden.;Karolinska Univ Hosp, Dermatol Clin, Stockholm, Sweden..
    Human skin barrier formation takes place via a cubic to lamellar lipid phase transition as analyzed by cryo-electron microscopy and EM-simulation2018Inngår i: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 366, nr 2, s. 139-151Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The skin's permeability barrier consists of stacked lipid sheets of splayed ceramides, cholesterol and free fatty acids, positioned intercellularly in the stratum corneum. We report here on the early stage of skin barrier formation taking place inside the tubuloreticular system in the secretory cells of the topmost viable epidermis and in the intercellular space between viable epidermis and stratum corneum. The barrier formation process was analysed in situ in its near-native state, using cryo-EM combined with molecular dynamics modeling and EM simulation. Stacks of lamellae appear towards the periphery of the tubuloreticular system and they are closely associated with granular regions. Only models based on a bicontinuous cubic phase organization proved compatible with the granular cryo-EM patterns. Only models based on a dehydrated lamellar phase organization agreed with the lamellar cryo-EM patterns. The data support that human skin barrier formation takes place via a cubic to lamellar lipid phase transition.

  • 47. Nguyen-Vu, Trang
    et al.
    Wang, Jun
    Mesmar, Fahmi
    Mukhopadhyay, Srijita
    Saxena, Ashish
    McCollum, Catherine W.
    Gustafsson, Jan-Ake
    Bondesson, Maria
    Williams, Cecilia
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Estrogen receptor beta reduces colon cancer metastasis through a novel miR-205-PROX1 mechanism2016Inngår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, nr 27, s. 42159-42171Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Colon cancer is a common cause of cancer death in the Western world. Accumulating evidence supports a protective role of estrogen via estrogen receptor beta (ER beta) but the mechanism of action is not known. Here, we elucidate a molecular mechanism whereby ER beta represses the oncogenic prospero homebox 1 (PROX1) through the upregulation of miR-205. We show that PROX1 is a potential target of miR-205 and that in clinical specimens from The Cancer Genome Atlas data, ER beta and miR-205 are decreased in colorectal cancer tissue compared to non-tumorous colon, while PROX1 levels are increased. Through mechanistic studies in multiple colorectal cancer cell lines, we show that ER beta upregulates miR-205, and that miR-205 targets and represses PROX1 through direct interaction with its 3' UTR. Through the generation of intestine-specific ER beta knockout mice, we establish that this pathway is correspondingly regulated in normal intestinal epithelial cells in vivo. Functionally, we demonstrate that miR-205 decreases cell proliferation and decreases migratory and invasive potential of colon cancer cells, leading to a reduction of micrometastasis in vivo. In conclusion, ER beta in both normal and cancerous colon epithelial cells upregulates miRNA-205, which subsequently reduces PROX1 through direct interaction with its 3' UTR. This results in reduced proliferative and metastatic potential of the cells. Our study proposes a novel pathway that may be exploited using ER beta-selective agonists and/or miR-205-replacement therapy in order to improve preventive and therapeutic approaches against colon cancer.

  • 48. Nodin, Björn
    et al.
    Hedner, Charlotta
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik (stängd 20130101). KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Fridberg, Marie
    Jirström, Karin
    Expression of the global regulator SATB1 is an independent factor of poor prognosis in high grade epithelial ovarian cancer2012Inngår i: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 33, s. 89-89Artikkel i tidsskrift (Annet vitenskapelig)
  • 49. O'Leary, Patrick C.
    et al.
    Terrile, Marta
    Bajor, Malgorzata
    Gaj, Pawel
    Hennessy, Bryan T.
    Mills, Gordon B.
    Zagozdzon, Agnieszka
    O'Connor, Darran P.
    Brennan, Donal J.
    Connor, Kate
    Li, Jane
    Gonzalez-Angulo, Ana Maria
    Sun, Han-Dong
    Pu, Jian-Xin
    Pontén, Fredrik
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi.
    Jirstrom, Karin
    Nowis, Dominika A.
    Crown, John P.
    Zagozdzon, Radoslaw
    Gallagher, William M.
    Peroxiredoxin-1 protects estrogen receptor alpha from oxidative stress-induced suppression and is a protein biomarker of favorable prognosis in breast cancer2014Inngår i: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 16, nr 4, s. R79-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction: Peroxiredoxin-1 (PRDX1) is a multifunctional protein, acting as a hydrogen peroxide (H2O2) scavenger, molecular chaperone and immune modulator. Although differential PRDX1 expression has been described in many tumors, the potential role of PRDX1 in breast cancer remains highly ambiguous. Using a comprehensive antibody-based proteomics approach, we interrogated PRDX1 protein as a putative biomarker in estrogen receptor (ER)-positive breast cancer. Methods: An anti-PRDX1 antibody was validated in breast cancer cell lines using immunoblotting, immunohistochemistry and reverse phase protein array (RPPA) technology. PRDX1 protein expression was evaluated in two independent breast cancer cohorts, represented on a screening RPPA (n = 712) and a validation tissue microarray (n = 498). In vitro assays were performed exploring the functional contribution of PRDX1, with oxidative stress conditions mimicked via treatment with H2O2, peroxynitrite, or adenanthin, a PRDX1/2 inhibitor. Results: In ER-positive cases, high PRDX1 protein expression is a biomarker of improved prognosis across both cohorts. In the validation cohort, high PRDX1 expression was an independent predictor of improved relapse-free survival (hazard ratio (HR) = 0.62, 95% confidence interval (CI) = 0.40 to 0.96, P = 0.032), breast cancer-specific survival (HR = 0.44, 95% CI = 0.24 to 0.79, P = 0.006) and overall survival (HR = 0.61, 95% CI = 0.44 to 0.85, P = 0.004). RPPA screening of cancer signaling proteins showed that ER alpha protein was upregulated in PRDX1 high tumors. Exogenous H2O2 treatment decreased ER alpha protein levels in ER-positive cells. PRDX1 knockdown further sensitized cells to H2O2- and peroxynitrite-mediated effects, whilst PRDX1 overexpression protected against this response. Inhibition of PRDX1/2 antioxidant activity with adenanthin dramatically reduced ER alpha levels in breast cancer cells. Conclusions: PRDX1 is shown to be an independent predictor of improved outcomes in ER-positive breast cancer. Through its antioxidant function, PRDX1 may prevent oxidative stress-mediated ER alpha loss, thereby potentially contributing to maintenance of an ER-positive phenotype in mammary tumors. These results for the first time imply a close connection between biological activity of PRDX1 and regulation of estrogen-mediated signaling in breast cancer.

  • 50. Omazic, B.
    et al.
    Ayoglu, Burcu
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Löhr, M.
    Segersvärd, R.
    Verbeke, C.
    Magalhaes, I.
    Potacova, Z.
    Mattsson, J.
    Terman, A.
    Ghazi, S.
    Albiin, N.
    Kartalis, N.
    Nilsson, Peter
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Poiret, T.
    Zhenjiang, L.
    Heuchel, R.
    Schwenk, Jochen M.
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Permert, J.
    Maeurer, M. J.
    Ringden, O.
    A Preliminary Report: Radical Surgery and Stem Cell Transplantation for the Treatment of Patients with Pancreatic Cancer2017Inngår i: Journal of immunotherapy (1997), ISSN 1524-9557, E-ISSN 1537-4513, Vol. 40, nr 4, s. 132-139Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We examined the immunologic effects of allogeneic hematopoietic stem cell transplantation (HSCT) in the treatment of pancreatic ductal adenocarcinoma, a deadly disease with a median survival of 24 months for resected tumors and a 5-year survival rate of 6%. After adjuvant chemotherapy, 2 patients with resected pancreatic ductal adenocarcinoma underwent HSCT with HLA-identical sibling donors. Comparable patients who underwent radical surgery, but did not have a donor, served as controls (n=6). Both patients developed humoral and cellular (ie, HLA-A∗01:01-restricted) immune responses directed against 2 novel tumor-associated antigens (TAAs), INO80E and UCLH3 after HSCT. Both TAAs were highly expressed in the original tumor tissue suggesting that HSCT promoted a clinically relevant, long-lasting cellular immune response. In contrast to untreated controls, who succumbed to progressive disease, both patients are tumor-free 9 years after diagnosis. Radical surgery combined with HSCT may cure pancreatic adenocarcinoma and change the cellular immune repertoire capable of responding to clinically and biologically relevant TAAs.

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