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  • 1.
    Arce, Maximiliano
    et al.
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile;Adv Ctr Chron Dis ACCDiS, Santiago, Chile.
    Pinto, Mauricio P.
    Pontificia Univ Catolica Chile, Fac Med, Santiago 8331150, Chile.
    Galleguillos, Macarena
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile.
    Munoz, Catalina
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile.
    Lange, Soledad
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile.
    Ramirez, Carolina
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile.
    Erices, Rafaela
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile;Univ Mayor, Vicerrectoria Invest, Santiago 7510041, Chile.
    Gonzalez, Pamela
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile.
    Velasquez, Ethel
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile;Comis Chilena Energia Nucl CCHEN, Santiago, Chile.
    Tempio, Fabian
    Univ Chile, Fac Med, Inst Biomed Sci, Santiago 8380453, Chile.
    Lopez, Mercedes N.
    Univ Chile, Fac Med, Inst Biomed Sci, Santiago 8380453, Chile;Millennium Inst Immunol & Immunotherapy, Santiago 8331150, Chile.
    Salazar-Onfray, Flavio
    Univ Chile, Fac Med, Inst Biomed Sci, Santiago 8380453, Chile;Millennium Inst Immunol & Immunotherapy, Santiago 8331150, Chile.
    Cautivo, Kelly
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile.
    Kalergis, Alexis M.
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile;Millennium Inst Immunol & Immunotherapy, Santiago 8331150, Chile;Biomed Res Consortium Chile, Santiago 8331010, Chile.
    Cruz, Sebastian
    Fdn Ciencia & Vida, Lab Immunoncol, Santiago, Chile.
    Lladser, Alvaro
    Millennium Inst Immunol & Immunotherapy, Santiago 8331150, Chile;Fdn Ciencia & Vida, Lab Immunoncol, Santiago, Chile.
    Lobos-Gonzalez, Lorena
    Adv Ctr Chron Dis ACCDiS, Santiago, Chile;Fdn Ciencia & Vida, Lab Immunoncol, Santiago, Chile;Univ Desarrollo, Fac Med, Regenerat Med Ctr, Clin Alemana, Santiago 7650568, Chile.
    Valenzuela, Guillermo
    Pontificia Univ Catolica Chile, Fac Med, Santiago 8331150, Chile.
    Olivares, Nixa
    Pontificia Univ Catolica Chile, Fac Med, Santiago 8331150, Chile.
    Saez, Claudia
    Pontificia Univ Catolica Chile, Fac Med, Santiago 8331150, Chile.
    Koning, Tania
    Univ Austral Chile, Fac Med, Immunol Inst, Valdivia 5110566, Chile.
    Sanchez, Fabiola A.
    Univ Austral Chile, Fac Med, Immunol Inst, Valdivia 5110566, Chile.
    Fuenzalida, Patricia
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile.
    Godoy, Alejandro
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile;Roswell Pk Comprehens Canc Ctr, Dept Urol, Buffalo, NY 14203 USA.
    Contreras Orellana, Pamela
    Adv Ctr Chron Dis ACCDiS, Santiago, Chile;Univ Chile, Fac Med, Lab Cellular Commun, ICBM, Santiago 8380453, Chile.
    Leyton, Lisette
    Adv Ctr Chron Dis ACCDiS, Santiago, Chile;Univ Chile, Fac Med, Lab Cellular Commun, ICBM, Santiago 8380453, Chile.
    Lugano, Roberta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Dimberg, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Quest, Andrew F. G.
    Adv Ctr Chron Dis ACCDiS, Santiago, Chile;Univ Chile, Fac Med, Lab Cellular Commun, ICBM, Santiago 8380453, Chile.
    Owen, Gareth, I
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile;Adv Ctr Chron Dis ACCDiS, Santiago, Chile;Pontificia Univ Catolica Chile, Fac Med, Santiago 8331150, Chile;Millennium Inst Immunol & Immunotherapy, Santiago 8331150, Chile.
    Coagulation Factor Xa Promotes Solid Tumor Growth, Experimental Metastasis and Endothelial Cell Activation2019Inngår i: Cancers, ISSN 2072-6694, Vol. 11, nr 8, artikkel-id 1103Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Hypercoagulable state is linked to cancer progression; however, the precise role of the coagulation cascade is poorly described. Herein, we examined the contribution of a hypercoagulative state through the administration of intravenous Coagulation Factor Xa (FXa), on the growth of solid human tumors and the experimental metastasis of the B16F10 melanoma in mouse models. FXa increased solid tumor volume and lung, liver, kidney and lymph node metastasis of tail-vein injected B16F10 cells. Concentrating on the metastasis model, upon coadministration of the anticoagulant Dalteparin, lung metastasis was significantly reduced, and no metastasis was observed in other organs. FXa did not directly alter proliferation, migration or invasion of cancer cells in vitro. Alternatively, FXa upon endothelial cells promoted cytoskeleton contraction, disrupted membrane VE-Cadherin pattern, heightened endothelial-hyperpermeability, increased inflammatory adhesion molecules and enhanced B16F10 adhesion under flow conditions. Microarray analysis of endothelial cells treated with FXa demonstrated elevated expression of inflammatory transcripts. Accordingly, FXa treatment increased immune cell infiltration in mouse lungs, an effect reduced by dalteparin. Taken together, our results suggest that FXa increases B16F10 metastasis via endothelial cell activation and enhanced cancer cell-endothelium adhesion advocating that the coagulation system is not merely a bystander in the process of cancer metastasis.

  • 2.
    Crona, Joakim
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Neuroendocrinol, NIH, 10 Ctr Dr,Bldg 10,Room 1E-3140, Bethesda, MD 20892 USA.
    Backman, Samuel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Experimentell kirurgi.
    Welin, Staffan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Taieb, David
    Aix Marseille Univ, Dept Nucl Med, La Timone Univ Hosp, European Ctr Res Med Imaging, F-13385 Marseille, France.
    Hellman, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Experimentell kirurgi.
    Stålberg, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Skogseid, Britt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Pacak, Karel
    Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Neuroendocrinol, NIH, 10 Ctr Dr,Bldg 10,Room 1E-3140, Bethesda, MD 20892 USA.
    RNA-Sequencing Analysis of Adrenocortical Carcinoma, Pheochromocytoma and Paraganglioma from a Pan-Cancer Perspective2018Inngår i: Cancers, ISSN 2072-6694, Vol. 10, nr 12, artikkel-id 518Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Adrenocortical carcinoma (ACC) and pheochromocytoma and paraganglioma (PPGL) are defined by clinicopathological criteria and can be further sub-divided based on different molecular features. Whether differences between these molecular subgroups are significant enough to re-challenge their current clinicopathological classification is currently unknown. It is also not fully understood to which other cancers ACC and PPGL show similarity to. To address these questions, we included recent RNA-Seq data from the Cancer Genome Atlas (TCGA) and Therapeutically Applicable Research to Generate Effective Treatments (TARGET) datasets. Two bioinformatics pipelines were used for unsupervised clustering and principal components analysis. Results were validated using consensus clustering model and interpreted according to previous pan-cancer experiments. Two datasets consisting of 3319 tumors from 35 disease categories were studied. Consistent with the current classification, ACCs clustered as a homogenous group in a pan-cancer context. It also clustered close to neural crest derived tumors, including gliomas, neuroblastomas, pancreatic neuroendocrine tumors, and PPGLs. Contrary, some PPGLs mixed with pancreatic neuroendocrine tumors or neuroblastomas. Thus, our unbiased gene-expression analysis of PPGL did not overlap with their current clinicopathological classification. These results emphasize some importances of the shared embryological origin of these tumors, all either related or close to neural crest tumors, and opens for investigation of a complementary categorization based on gene-expression features.

  • 3.
    Ding, Haozhong
    et al.
    KTH Royal Inst Technol, Dept Prot Sci, Roslagstullsbacken 21, S-11417 Stockholm, Sweden.
    Altai, Mohamed
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Rinne, Sara S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Vorobyeva, Anzhelika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Gräslund, Torbjorn
    KTH Royal Inst Technol, Dept Prot Sci, Roslagstullsbacken 21, S-11417 Stockholm, Sweden.
    Orlova, Anna
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Incorporation of a Hydrophilic Spacer Reduces Hepatic Uptake of HER2-Targeting Affibody-DM1 Drug Conjugates2019Inngår i: Cancers, ISSN 2072-6694, Vol. 11, nr 8, artikkel-id 1168Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Affibody molecules are small affinity-engineered scaffold proteins which can be engineered to bind to desired targets. The therapeutic potential of using an affibody molecule targeting HER2, fused to an albumin-binding domain (ABD) and conjugated with the cytotoxic maytansine derivate MC-DM1 (AffiDC), has been validated. Biodistribution studies in mice revealed an elevated hepatic uptake of the AffiDC, but histopathological examination of livers showed no major signs of toxicity. However, previous clinical experience with antibody drug conjugates have revealed a moderateto high-grade hepatotoxicity in treated patients, which merits efforts to also minimize hepatic uptake of the AffiDCs. In this study, the aim was to reduce the hepatic uptake of AffiDCs and optimize their in vivo targeting properties. We have investigated if incorporation of hydrophilic glutamate-based spacers adjacent to MC-DM1 in the AffiDC, (Z(HER2:2891))(2) -ABD-MC-DM1, would counteract the hydrophobic nature of MC-DM1 and, hence, reduce hepatic uptake. Two new AffiDCs including either a triglutamate-spacer-, (Z(HER2:2891))(2)-ABD-E-3-MC-DM1, or a hexaglutamate-spacer-, (Z(HER2:2891))(2)-ABD-E-6-MC-DM1 next to the site of MC-DM1 conjugation were designed. We radiolabeled the hydrophilized AffiDCs and compared them, both in vitro and in vivo, with the previously investigated (Z(HER2:2891))(2)-ABD-MC-DM1 drug conjugate containing no glutamate spacer. All three AffiDCs demonstrated specific binding to HER2 and comparable in vitro cytotoxicity. A comparative biodistribution study of the three radiolabeled AffiDCs showed that the addition of glutamates reduced drug accumulation in the liver while preserving the tumor uptake. These results confirmed the relation between DM1 hydrophobicity and liver accumulation. We believe that the drug development approach described here may also be useful for other affinity protein-based drug conjugates to further improve their in vivo properties and facilitate their clinical translatability.

  • 4.
    Dubbelboer, Ilse R
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Pavlovic, Natasa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Heindryckx, Femke
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Sjögren, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Lennernäs, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Liver Cancer Cell Lines Treated with Doxorubicin under Normoxia and Hypoxia: Cell Viability and Oncologic Protein Profile2019Inngår i: Cancers, ISSN 2072-6694, Vol. 11, nr 7, artikkel-id 1024Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Hepatocellular carcinoma is often treated with a combination of doxorubicin and embolization, exposing it to high concentrations and hypoxia. Separation of the possible synergistic effect of this combination in vivo is difficult. Here, treatment with doxorubicin, under hypoxia or normoxia in different liver cancer cell lines, was evaluated. Liver cancer cells HepG2, Huh7, and SNU449 were exposed to doxorubicin, hypoxia, or doxorubicin + hypoxia with different duration. Treatment response was evaluated with cell viability, apoptosis, oxidative stress, and summarized with IC50. The protein profile of a 92-biomarker panel was analyzed on cells treated with 0 or 0.1 mu M doxorubicin during 6 or 72 h, under normoxia or hypoxia. Hypoxia decreased viability of HepG2 and SNU499. HepG2 was least and SNU449 most tolerant to doxorubicin treatment. Cytotoxicity of doxorubicin increased over time in HepG2 and Huh7. The combination of doxorubicin + hypoxia affected the cells differently. Normalized protein expression was lower for HepG2 than Huh7 and SNU449. Hierarchical clustering separated HepG2 from Huh7 and SNU449. These three commonly used cell lines have critically different responses to chemotherapy and hypoxia, which was reflected in their different protein expression profile. These different responses suggest that tumors can respond differently to the combination of local chemotherapy and embolization.

  • 5.
    Martikainen, Miika
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Essand, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Virus-Based Immunotherapy of Glioblastoma2019Inngår i: Cancers, ISSN 2072-6694, Vol. 11, nr 2, artikkel-id 186Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Glioblastoma (GBM) is the most common type of primary brain tumor in adults. Despite recent advances in cancer therapy, including the breakthrough of immunotherapy, the prognosis of GBM patients remains dismal. One of the new promising ways to therapeutically tackle the immunosuppressive GBM microenvironment is the use of engineered viruses that kill tumor cells via direct oncolysis and via stimulation of antitumor immune responses. In this review, we focus on recently published results of phase I/II clinical trials with different oncolytic viruses and the new interesting findings in preclinical models. From syngeneic preclinical GBM models, it seems evident that oncolytic virus-mediated destruction of GBM tissue coupled with strong adjuvant effect, provided by the robust stimulation of innate antiviral immune responses and adaptive anti-tumor T cell responses, can be harnessed as potent immunotherapy against GBM. Although clinical testing of oncolytic viruses against GBM is at an early stage, the promising results from these trials give hope for the effective treatment of GBM in the near future.

  • 6.
    Mitran, Bogdan
    et al.
    Uppsala Univ, Dept Med Chem, S-75123 Uppsala, Sweden.
    Varasteh, Zohreh
    Uppsala Univ, Dept Med Chem, S-75123 Uppsala, Sweden;Klinikum Rechts Isar TUM, Dept Nucl Med, D-81675 Munich, Germany.
    Abouzayed, Ayman
    Uppsala Univ, Dept Med Chem, S-75123 Uppsala, Sweden.
    Rinne, Sara S.
    Uppsala Univ, Dept Med Chem, S-75123 Uppsala, Sweden.
    Puuvuori, Emmi
    Uppsala Univ, Dept Med Chem, S-75123 Uppsala, Sweden.
    De Rosa, Maria
    Uppsala Univ, Dept Med Chem, S-75123 Uppsala, Sweden;RiMED Fdn, Drug Discovery Unit, I-90133 Palermo, Italy.
    Larhed, Mats
    Uppsala Univ, Dept Med Chem, S-75123 Uppsala, Sweden;Uppsala Univ, Dept Med Chem, Sci Life Lab, S-75123 Uppsala, Sweden.
    Tolmachev, Vladimir
    Uppsala Univ, Dept Immunol Genet & Pathol, S-75123 Uppsala, Sweden.
    Orlova, Anna
    Uppsala Univ, Dept Med Chem, S-75123 Uppsala, Sweden;Uppsala Univ, Dept Med Chem, Sci Life Lab, S-75123 Uppsala, Sweden.
    Rosenstrom, Ulrika
    Uppsala Univ, Dept Med Chem, S-75123 Uppsala, Sweden.
    Bispecific GRPR-Antagonistic Anti-PSMA/GRPR Heterodimer for PET and SPECT Diagnostic Imaging of Prostate Cancer2019Inngår i: Cancers, ISSN 2072-6694, Vol. 11, nr 9, artikkel-id 1371Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Simultaneous targeting of the prostate-specific membrane antigen (PSMA) and gastrin-releasing peptide receptor (GRPR) could improve the diagnostic accuracy in prostate cancer (PCa). The aim of this study was to develop a PSMA/GRPR-targeting bispecific heterodimer for SPECT and positron emission tomography (PET) diagnostic imaging of PCa. The heterodimer NOTA-DUPA-RM26 was produced by manual solid-phase peptide synthesis. NOTA-DUPA-RM26 was labeled with In-111 and Ga-68, with yields >98%, and demonstrated a high stability and binding specificity to PSMA and GRPR. IC50 values for In-nat-NOTA-DUPA-RM26 were 4 +/- 1 nM towards GRPR and 824 +/- 230 nM towards PSMA. An in vivo binding specificity 1 h pi of In-111-NOTA-DUPA-RM26 in PC3-PIP-xenografted mice demonstrated partially blockable tumor uptake when co-injected with an excess of PSMA- or GRPR-targeting agents. Simultaneous co-injection of both agents induced pronounced blocking. The biodistribution of In-111-NOTA-DUPA-RM26 and Ga-68-NOTA-DUPA-RM26 revealed fast activity clearance from the blood and normal organs via the kidneys. Tumor uptake exceeded normal organ uptake for both analogs 1 h pi. Ga-68-NOTA-DUPA-RM26 had a significantly lower tumor uptake (8 +/- 2%ID/g) compared to In-111-NOTA-DUPA-RM26 (12 +/- 2%ID/g) 1 h pi. Tumor-to-organ ratios increased 3 h pi, but decreased 24 h pi, for In-111-NOTA-DUPA-RM26. MicroPET/CT and microSPECT/CT scans confirmed biodistribution data, suggesting that Ga-68-NOTA-DUPA-RM26 and In-111-NOTA-DUPA-RM26 are suitable candidates for the imaging of GRPR and PSMA expression in PCa shortly after administration.

  • 7.
    Mitran, Bogdan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Varasteh, Zohreh
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Puuvuori, Emmi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Abousayed, Ayman
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Rinne, Sara S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Rosenström, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Preparativ läkemedelskemi.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Bispecific GRPR-antagonistic anti-PSMA/GRPR heterodimer for PET and SPECT diagnostic imaging of prostate cancer2019Inngår i: Cancers, ISSN 2072-6694, Vol. 11, nr 9, artikkel-id 1371Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Prostate specific membrane antigen (PSMA) and gastrin-releasing peptide receptor (GRPR) are wellvalidated molecular targets that are overexpressed in most prostate cancers (PCa). Given thecomplexity and heterogeneity of PCa, targeting both receptors using bispecific radiotracers couldimprove the diagnostic accuracy and therapeutic outcome. The aim of this study was to develop aPSMA/GRPR-targeting bispecific heterodimer for SPECT and PET diagnostic imaging of PCa.Bispecific anti-GRPR/PSMA dimer NOTA-DUPA-RM26 was produced using a combination of solidphase and manual peptide synthesis. The heterodimer was successfully labeled with111In for SPECTand 68Ga for PET with radiochemical yields exceeding 99% for 111In and 98% for 68Ga. Theradiolabeled heterodimers demonstrated high label stability and retained binding specificity to PSMAand GRPR when tested using PC3-PIP cell line expressing both PSMA and GRPR. IC50 values fornatIn-NOTA-DUPA-RM26 were 4±1 nM towards GRPR and 350±240 nM towards PSMA. Cellularprocessing assay revealed a low degree of internalization for 111In-NOTA-DUPA-RM26. In vivobinding specificity tests in PC3-PIP xenografted mice 1 h pi of 111In-NOTA-DUPA-RM26demonstrated partially blockable tumor uptake when co-injected with excess of either PSMA- orGRPR-targeting agents. A pronounced blocking effect was observed for 111In and 68Ga-labeledheterodimer when co-injected simultaneously with excess of PSMA- and GRPR-targeting agents 1 hpi. Biodistribution was studied 1, 3 and 24 h pi for 111In-NOTA-DUPA-RM26, and 1 and 3 h pi for68Ga-NOTA-DUPA-RM26 and revealed a fast clearance of radioprobes from blood and normal organsvia renal excretion. Tumor uptake exceeded the uptake in all normal organs including excretory organsfor both 111In and 68Ga-labeled heterodimers 1 h pi. 68Ga-NOTA-DUPA-RM26 had a significantlylower tumor uptake (8±2%ID/g) compared to 111In-NOTA-DUPA-RM26 (12±2%ID/g), but a two-foldhigher uptake in liver 1h pi. The faster clearance of radioactivity from normal tissues compared totumor lead to an overall increase in tumor-to-organ ratios for both 111In and 68Ga-labeled heterodimers3 h pi. At 24 h pi, tumor-to-organ ratios decreased for 111In-NOTA-DUPA-RM26. MicroPET/CT andmicroSPECT/CT scans confirmed the ex vivo data and suggested that anti-GRPR/PSMA heterodimerNOTA-DUPA-RM26 labeled with galium-68 (for PET) and indium-111 (for SPECT) is a suitablecandidate for imaging of GRPR and PSMA expression in PCa shortly after administration.

  • 8.
    Pavlovic, Natasa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Rani, Bhavna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Gerwins, Pär
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Heindryckx, Femke
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Platelets as Key Factors in Hepatocellular Carcinoma2019Inngår i: Cancers, ISSN 2072-6694, Vol. 11, nr 7, artikkel-id 1022Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Hepatocellular carcinoma (HCC) is a primary liver cancer that usually develops in the setting of chronic inflammation and liver damage. The hepatic microenvironment plays a crucial role in the disease development, as players such as hepatic stellate cells, resident liver macrophages (Kupffer cells), endothelial cells, extracellular matrix, and a variety of immune cells interact in highly complex and intertwined signaling pathways. A key factor in these cross-talks are platelets, whose role in cancer has gained growing evidence in recent years. Platelets have been reported to promote HCC cell proliferation and invasion, but their involvement goes beyond the direct effect on tumor cells, as they are known to play a role in pro-fibrinogenic signaling and the hepatic immune response, as well as in mediating interactions between these factors in the stroma. Anti-platelet therapy has been shown to ameliorate liver injury and improve the disease outcome. However, platelets have also been shown to play a crucial role in liver regeneration after organ damage. Therefore, the timing and microenvironmental setting need to be kept in mind when assessing the potential effect and therapeutic value of platelets in the disease progression, while further studies are needed for understanding the role of platelets in patients with HCC.

  • 9.
    Thoren, Matilda Munksgaard
    et al.
    Xintela AB, SE-22381 Lund, Sweden.
    Masoumi, Katarzyna Chmielarska
    Xintela AB, SE-22381 Lund, Sweden.
    Krona, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Huang, Xiaoli
    Xintela AB, SE-22381 Lund, Sweden.
    Kundu, Soumi
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Schmidt, Linnea
    Xintela AB, SE-22381 Lund, Sweden.
    Forsberg Nilsson, Karin
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Keep, Marcus Floyd
    Sanford Brain & Spine Inst, Dept Neurosurg, Fargo, ND 58102 USA;Univ North Dakota, Sch Med, Dept Surg, Fargo, ND 58102 USA.
    Englund, Elisabet
    Lund Univ, Dept Clin Sci, Div Oncol & Pathol, Neuropathol Lab, SE-22184 Lund, Sweden.
    Nelander, Sven
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Holmqvist, Bo
    ImaGene iT AB, SE-22381 Lund, Sweden.
    Lundgren-Åkerlund, Evy
    Xintela AB, SE-22381 Lund, Sweden.
    Integrin alpha 10, a Novel Therapeutic Target in Glioblastoma, Regulates Cell Migration, Proliferation, and Survival2019Inngår i: Cancers, ISSN 2072-6694, Vol. 11, nr 4, artikkel-id 587Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    New, effective treatment strategies for glioblastomas (GBMs), the most malignant and invasive brain tumors in adults, are highly needed. In this study, we investigated the potential of integrin alpha 10 beta 1 as a therapeutic target in GBMs. Expression levels and the role of integrin alpha 10 beta 1 were studied in patient-derived GBM tissues and cell lines. The effect of an antibody-drug conjugate (ADC), an integrin alpha 10 antibody conjugated to saporin, on GBM cells and in a xenograft mouse model was studied. We found that integrin alpha 10 beta 1 was strongly expressed in both GBM tissues and cells, whereas morphologically unaffected brain tissues showed only minor expression. Partial or no overlap was seen with integrins alpha 3, alpha 6, and alpha 7, known to be expressed in GBM. Further analysis of a subpopulation of GBM cells selected for high integrin alpha 10 expression demonstrated increased proliferation and sphere formation. Additionally, siRNA-mediated knockdown of integrin alpha 10 in GBM cells led to decreased migration and increased cell death. Furthermore, the ADC reduced viability and sphere formation of GBM cells and induced cell death both in vitro and in vivo. Our results demonstrate that integrin alpha 10 beta 1 has a functional role in GBM cells and is a novel, potential therapeutic target for the treatment of GBM.

  • 10.
    Toxopeus, Eelke L. A.
    et al.
    Erasmus Univ, Med Ctr, Dept Surg, Doctor Molewaterpl 40, NL-3015 GD Rotterdam, Netherlands.
    de Man, Femke M.
    Erasmus Univ, Erasmus Med Ctr, Med Ctr, Canc Inst,Dept Med Oncol, Doctor Molewaterpl 40, NL-3015 GD Rotterdam, Netherlands.
    Krak, Nanda
    Erasmus Univ, Med Ctr, Dept Radiol, Doctor Molewaterpl 40, NL-3015 GD Rotterdam, Netherlands.
    Biermann, Katharina
    Erasmus Univ, Med Ctr, Dept Pathol, Doctor Molewaterpl 40, NL-3015 GD Rotterdam, Netherlands.
    Nieuweboer, Annemieke J. M.
    Erasmus Univ, Erasmus Med Ctr, Med Ctr, Canc Inst,Dept Med Oncol, Doctor Molewaterpl 40, NL-3015 GD Rotterdam, Netherlands.
    Friberg, Lena E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Oomen-de Hoop, Esther
    Erasmus Univ, Erasmus Med Ctr, Med Ctr, Canc Inst,Dept Med Oncol, Doctor Molewaterpl 40, NL-3015 GD Rotterdam, Netherlands.
    van Lanschot, Jan J. B.
    Erasmus Univ, Med Ctr, Dept Surg, Doctor Molewaterpl 40, NL-3015 GD Rotterdam, Netherlands.
    Shapiro, Joel
    Erasmus Univ, Med Ctr, Dept Surg, Doctor Molewaterpl 40, NL-3015 GD Rotterdam, Netherlands.
    Wijnhoven, Bas P. L.
    Erasmus Univ, Med Ctr, Dept Surg, Doctor Molewaterpl 40, NL-3015 GD Rotterdam, Netherlands.
    Mathijssen, Ron H. J.
    Erasmus Univ, Erasmus Med Ctr, Med Ctr, Canc Inst,Dept Med Oncol, Doctor Molewaterpl 40, NL-3015 GD Rotterdam, Netherlands.
    Association between Paclitaxel Clearance and Tumor Response in Patients with Esophageal Cancer2019Inngår i: Cancers, ISSN 2072-6694, Vol. 11, nr 2, artikkel-id 173Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Inter-individual variability in paclitaxel pharmacokinetics may play a role in the response to chemotherapy. Therefore, we studied the association between paclitaxel clearance and treatment response in patients with esophageal cancer. All patients who received paclitaxel (plus carboplatin) treatment for esophageal cancer between 2007 and 2013 were included. The treatment was given as neoadjuvant chemoradiotherapy (nCRT), induction chemotherapy (iCT), or palliative chemotherapy (pCT). The treatment response was assessed by the tumor regression grade (TRG) or by the RECIST1.1 criteria, respectively. The unbound paclitaxel clearance (CL) was estimated with NONMEM. The log-transformed clearance was related to response with ANOVA and independent sample t-tests. A total of 166 patients were included, of whom 113 received nCRT, 23 iCT and 30 pCT. In patients receiving nCRT, paclitaxel clearance was not associated with tumor regression grade (p-value = 0.25), nor with pathologically complete response (geometric mean 561.6 L/h) and residual disease (geometric mean 566.1 L/h, p-value = 0.90). In patients who underwent iCT or pCT, also no association between paclitaxel clearance and RECIST outcome was identified (iCT: p-value = 0.08 and pCT: p-value = 0.81, respectively). In conclusion, systemic paclitaxel exposure was not associated with response to common paclitaxel-based treatment regimens for esophageal cancer. Future studies should focus on tumor exposure in relation to systemic exposure and treatment outcome.

  • 11.
    Vieler, Maximilian
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Sanyal, Suparna
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    p53 Isoforms and Their Implications in Cancer2018Inngår i: Cancers, ISSN 2072-6694, Vol. 10, nr 9, artikkel-id 288Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    In this review we focus on the major isoforms of the tumor-suppressor protein p53, dysfunction of which often leads to cancer. Mutations of the TP53 gene, particularly in the DNA binding domain, have been regarded as the main cause for p53 inactivation. However, recent reports demonstrating abundance of p53 isoforms, especially the N-terminally truncated ones, in the cancerous tissues suggest their involvement in carcinogenesis. These isoforms are Delta 40p53, Delta 133p53, and Delta 160p53 (the names indicate their respective N-terminal truncation). Due to the lack of structural and functional characterizations the modes of action of the p53 isoforms are still unclear. Owing to the deletions in the functional domains, these isoforms can either be defective in DNA binding or more susceptive to altered 'responsive elements' than p53. Furthermore, they may exert a 'dominant negative effect' or induce more aggressive cancer by the 'gain of function'. One possible mechanism of p53 inactivation can be through tetramerization with the Delta 133p53 and Delta 160p53 isoforms-both lacking part of the DNA binding domain. A recent report and unpublished data from our laboratory also suggest that these isoforms may inactivate p53 by fast aggregation-possibly due to ectopic overexpression. We further discuss the evolutionary significance of the p53 isoforms.

  • 12.
    Vyakaranam, Achyut Ram
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Crona, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Norlén, Olov
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Granberg, Dan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Garske-Román, Ulrike
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Sahlgrens Univ Hosp, Dept Nucl Med, Gothenburg, Sweden.
    Sandström, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Fröss-Baron, Katarzyna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Thiis-Evensen, Espen
    Oslo Univ Hosp, Rikshosp, Dept Gastroenterol, Oslo, Norway.
    Hellman, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Sundin, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Favorable Outcome in Patients with Pheochromocytoma and Paraganglioma Treated with 177Lu-DOTATATE.2019Inngår i: Cancers, ISSN 2072-6694, Vol. 11, nr 7, artikkel-id 909Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Peptide receptor radiotherapy (PRRT) with 177Lu-DOTATATE has emerged as a promising therapy for neuroendocrine tumors (NETs). This retrospective cohort study aimed to assess the outcome of PRRT for 22 patients with histopathologically confirmed pheochromocytoma (PCC) and paraganglioma (PGL), of which two were localized and 20 metastatic. Radiological response utilized response evaluation criteria in solid tumors 1.1 and toxicity was graded according to common terminology criteria for adverse events version 4. Median 4 (range 3-11) 7.4 GBq cycles of 177Lu-DOTATATE were administered as first-line therapy (n = 13) or because of progressive disease (n = 9). Partial response (PR) was achieved in two and stable disease (SD) in 20 patients. The median overall survival (OS) was 49.6 (range 8.2-139) months and median progression-free survival (PFS) was 21.6 (range 6.7-138) months. Scintigraphic response >50% was achieved in 9/19 (47%) patients. Biochemical response (>50% decrease) of chromogranin A was found in 6/15 (40%) patients and of catecholamines in 3/12 (25%) patients. Subgroup analysis showed Ki-67 <15% associated with longer OS (p = 0.013) and PFS (p = 0.005). PRRT as first-line therapy was associated with increased OS (p = 0.041). No hematological or kidney toxicity grade 3-4 was registered. 177Lu-DOTATATE therapy was associated with favorable outcome and low toxicity. High Ki-67 (≥15%) and PRRT received because of progression on previous therapy could constitute negative predictive factors for OS.

  • 13.
    Vyakaranam, Achyut Ram
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Crona, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Norlén, Olov
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Hellman, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Sundin, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    C-11-hydroxy-ephedrine-PET/CT in the Diagnosis of Pheochromocytoma and Paraganglioma2019Inngår i: Cancers, ISSN 2072-6694, Vol. 11, nr 6, artikkel-id 847Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Pheochromocytomas (PCC) and paragangliomas (PGL) may be difficult to diagnose because of vague and uncharacteristic symptoms and equivocal biochemical and radiological findings. This was a retrospective cohort study in 102 patients undergoing C-11-hydroxy-ephedrine (C-11-HED)-PET/CT because of symptoms and/or biochemistry suspicious for PCC/PGL and/or with radiologically equivocal adrenal incidentalomas. Correlations utilized CT/MRI, clinical, biochemical, surgical, histopathological and follow-up data. C-11-HED-PET/CT correctly identified 19 patients with PCC and six with PGL, missed one PCC, attained one false positive result (nodular hyperplasia) and correctly excluded PCC/PGL in 75 patients. Sensitivity, specificity, positive and negative predictive values of C-11-HED-PET/CT for PCC/PGL diagnosis was 96%, 99%, 96% and 99%, respectively. In 41 patients who underwent surgical resection and for whom correlation to histopathology was available, the corresponding figures were 96%, 93%, 96% and 93%, respectively. Tumor C-11-HED-uptake measurements (standardized uptake value, tumor-to-normal-adrenal ratio) were unrelated to symptoms of catecholamine excess (p > 0.05) and to systolic blood pressure (p > 0.05). In PCC/PGL patients, norepinephrine and systolic blood pressure increased in parallel (R-2 = 0.22, p = 0.016). C-11-HED-PET/CT was found to be an accurate tool to diagnose and rule out PCC/PGL in complex clinical scenarios and for the characterization of equivocal adrenal incidentalomas. PET measurements of tumor C-11-HED uptake were not helpful for tumor characterization.

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