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  • 1. Akyurek, L. M.
    et al.
    Funa, K.
    Wanders, A.
    Larsson, E.
    Fellstrom, B. C.
    Inhibition of transplant arteriosclerosis in rat aortic grafts by low molecular weight heparin derivatives1995In: Transplantation, Vol. 59, no 11, 1517-24 p.Article in journal (Refereed)
    Abstract [en]

    The effects of low molecular weight heparin derivatives with a low anticoagulant activity on transplant arteriosclerosis (TA) in a rat aortic transplant model were investigated. TA was induced by ischemia in the syngeneic transplants and primarily by immunological mechanisms in the allogeneic transplants. Treatment with the heparin derivatives, OAM 71262 or LA-heparin, was administered in a dosage of 250 micrograms/kg/hr by mini-osmotic pumps during 8 weeks. No immunosuppressive regimen was given to the recipient rats in either model. All rats were killed 8 weeks after aortic grafting. The grafts were examined for intimal and medial changes using an image analysis system. Heparin derivatives had a beneficial effect on both the intimal thickening and the medial injury in the syngeneic transplants, but not in the allogeneic grafts. In the syngeneic LA-heparin treated grafts, the thickness of the intima was less than that in the syngeneic control grafts (P < 0.05). In the syngeneic transplants, a significant increase was observed in the media after treatment with OAM 71262 (P < 0.01) as well as those with LA-heparin (P < 0.001). In the syngeneic grafts treated with both heparin derivatives, a significant reduction in the antigen expression of alpha-actin-containing smooth muscle cells in the intima, transforming growth factor-beta 1 both in the media and adventitia, and platelet-derived growth factor-beta receptors in the adventitia was observed immunohistochemically. In summary, low molecular weight heparin derivatives with low anticoagulant activity partially inhibited ischemia-induced syngeneic TA, whereas no such effect could be demonstrated in nonimmunosuppressed recipients with allogeneic grafts.

  • 2. Akyurek, M. L.
    et al.
    Funa, K.
    Wanders, A.
    Larsson, E.
    Fellstrom, B. C.
    Expression of CD11b and ICAM-1 in an in vivo model of transplant arteriosclerosis1995In: Transpl Immunol, Vol. 3, no 2, 107-13 p.Article in journal (Refereed)
    Abstract [en]

    Adhesion molecules play a crucial role in transplant rejection in regulating the interaction of inflammatory cells with cells in the vascular wall. In an aortic transplantation model, we have previously analysed the early adhesion process (7.5 min to 24 h) and the impact of cold ischaemia time (1-24 h) upon transplant arteriosclerosis during the first 2 months after transplantation in the rat. The aim of this investigation was to study adhesion molecules in accelerated transplant arteriosclerosis in a rat model by analysing the immunohistochemical expression of CD11b and ICAM-1 up to 2 months and followed by a semiquantitative evaluation and multivariant analysis. Antigen expression of CD11b and ICAM-1 adhesion molecules was stronger in the aortic allografts than in the ischaemia-induced syngeneic aortic grafts in the whole vessel wall. Neither ICAM-1 nor CD11b antigen expression correlated significantly with time periods of ischaemia/reperfusion injury in allogeneic or syngeneic aortic transplants. CD11b and ICAM-1 are induced by allogeneic stimuli in transplanted aortas suggesting a role in the pathogenesis of transplant arteriosclerosis. Our findings have implications for understanding the role of cell adhesion activation in the vascular wall subject to chronic graft rejection.

  • 3. Akyurek, M. L.
    et al.
    Larsson, E.
    Funa, K.
    Wanders, A.
    Kaijser, M.
    Fellstrom, B. C.
    Experimental transplant arteriosclerosis: inhibition by angiopeptin and low molecular weight heparin derivatives1995In: Transplant Proc, Vol. 27, no 6, 3555-6 p.Article in journal (Refereed)
  • 4. Akyurek, M. L.
    et al.
    Wanders, A.
    Aurivillius, M.
    Larsson, E.
    Funa, K.
    Fellstrom, B. C.
    Effects of angiopeptin on transplant arteriosclerosis in the rat1995In: Transpl Int, Vol. 8, no 2, 103-10 p.Article in journal (Refereed)
    Abstract [en]

    The influence of the somatostatin analogue angiopeptin on transplant arteriosclerosis was investigated using two aortic transplantation rat models. One was characterized by ischemia/reperfusion-induced changes in syngeneic transplants while immunologically induced changes dominated in the other allogeneic model. Angiopeptin, 100 micrograms/kg per day, was administered continuously until the sacrifice of the rats after 8 weeks. No additional immunosuppression was used in either model. An image analysis system was used to quantify the intimal and medial thicknesses of the grafts. In the syngeneic grafts, the intimal thickness was less than 50% of that of control grafts (P < 0.05), but no difference was seen in the allogeneic model. The expression of selected cells, TGF-beta s, and PDGF and PDGF alpha-receptors was detected immunohistochemically and displayed a similar picture in control and angiopeptin-treated grafts in both models. We conclude that angiopeptin has no clear immunosuppressive properties but may counteract ischemia-induced transplant arteriosclerosis.

  • 5. Anders, H. J.
    et al.
    Wanders, A.
    Rihl, M.
    Kruger, K.
    Myocardial fibrosis in polymyositis1999In: J Rheumatol, Vol. 26, no 8, 1840-2 p.Article in journal (Refereed)
    Abstract [en]

    Myocardial involvement in polymyositis is commonly suspected in noninvasive studies, but symptomatic cardiac disease is rare. We describe a 27-year-old woman with a 6 year history of severe polymyositis and persistent elevation of creatine phosphokinase-MB isoenzyme who suddenly developed congestive heart failure and bradycardia-tachycardia syndrome. Autopsy revealed severe myocardial fibrosis without inflammatory cell infiltrates concomitant to active polymyositis of the skeletal muscles despite intensive longterm immunosuppressive therapy.

  • 6. Andreasson, H.
    et al.
    Wanders, A.
    Sun, X. F.
    Willen, R.
    Graf, W.
    Nygren, P.
    Glimelius, B.
    Zhang, Z. Y.
    Mahteme, H.
    Histopathological classification of pseudomyxoma peritonei and the prognostic importance of PINCH protein2012In: Anticancer Res, Vol. 32, no 4, 1443-8 p.Article in journal (Refereed)
    Abstract [en]

    AIM: The aims of this study were i) to assess a new and more detailed histopathological classification and to analyze concordance between pathologists in the histopathological classification of pseudomyxoma peritonei (PMP); ii) to analyze the expression in the stroma of the particularly interesting new cysteine-histidine (PINCH) protein and its prognostic importance in PMP. MATERIALS AND METHODS: Surgical specimens from 81 patients, classified according to the Ronnett et al histopathological classification were compared to a new system with four groups ranging from indolent to aggressive growth patterns. PINCH protein expression was analyzed and was related to clinical variables. RESULTS: The new four-group classification provided better prognostic information than the classification according to Ronnett et al. (p=0.04). Expression of the PINCH protein in the stroma was found in 83% of the cases and was associated with high tumor burden (p=0.002) and a poor prognosis (p=0.04). CONCLUSION: The proposed new PMP classification system may provide additional prognostic information. PINCH protein is expressed in PMP and has prognostic information.

  • 7. Bersztel, A.
    et al.
    Wanders, A.
    Wadstrom, J.
    Ekberg, H.
    Olausson, M.
    Tufveson, G.
    Gannedahl, G.
    Deoxyspergualin is synergistic with cyclosporin A, but not with FK506 in a rat heart allograft transplantation model1995In: Transplant Proc, Vol. 27, no 6, 3547- p.Article in journal (Refereed)
  • 8. Biglarnia, A. R.
    et al.
    Nilsson, B.
    Nilsson, T.
    von Zur-Muhlen, B.
    Wagner, M.
    Berne, C.
    Wanders, A.
    Magnusson, A.
    Tufveson, G.
    Prompt reversal of a severe complement activation by eculizumab in a patient undergoing intentional ABO-incompatible pancreas and kidney transplantation2011In: Transpl Int, Vol. 24, no 8, e61-6 p.Article in journal (Refereed)
    Abstract [en]

    We describe the presumably first intentional ABO-incompatible deceased-donor kidney and pancreas transplantation with a severe antibody-mediated rejection during a rebound of isoagglutinins. Rejection was successfully treated with eculizumab, which inhibits the terminal pathway of complement. Complement analysis (C3, C3d,g, and a modified assay of classical complement-related hemolytic function) documented complement activation and confirmed that eculizumab completely blocked complement function. At 6 months, the patient had normal kidney and pancreas function, and histological evaluations revealed no evidence of sustained graft damage. This successful transplantation suggests that ABO barriers can safely be overcome without extensive preconditioning, when the complement inhibitor eculizumab is included.

  • 9. Ciray, I.
    et al.
    Lindman, H.
    Astrom, G. K.
    Wanders, A.
    Bergh, J.
    Ahlstrom, H. K.
    Effect of granulocyte colony-stimulating factor (G-CSF)-supported chemotherapy on MR imaging of normal red bone marrow in breast cancer patients with focal bone metastases2003In: Acta Radiol, Vol. 44, no 5, 472-84 p.Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To investigate the effect of granulocyte colony-stimulating factor (G-CSF)-supported chemotherapy on normal red bone marrow MR imaging in breast cancer patients with focal bone metastases. MATERIAL AND METHODS: Fifteen breast cancer patients who were examined before and after chemotherapy with T1-weighted-SE and long echo-time inversion-recovery turbo-spin-echo (long TE IR-TSE) sequences in the thoracolumbar spine and pelvis were retrospectively studied. Nine of them received G-CSF therapy after the administration of each chemotherapy course. Of these 9 patients, the MR follow-ups were performed during G-CSF in 4 patients and after G-CSF therapy in 5 patients. Six patients did not receive G-CSF. Signal intensity (SI) changes in normal bone marrow were evaluated visually in all patients and quantitatively in 13 patients. RESULTS: In all 4 patients investigated during G-CSF therapy a diffuse, homogeneous SI increase on long TE IR-TSE was observed visually and quantitatively in initially normal bone marrow. This change obscured some focal lesions in 2 patients. No such SI change was visible after G-CSF therapy (p = 0.008) or in patients not receiving G-CSF. On T1-weighted images an SI decrease was found both during and after G-CSF therapy, but an increase occurred in patients not receiving G-CSF. CONCLUSION: G-CSF-supported chemotherapy can induce diffuse SI changes in normal red bone marrow on MR imaging. On long TE IR-TSE, the changes are visible during G-CSF treatment and can lead to misinterpretations in the response evaluation of bone metastases to therapy.

  • 10. Dallman, M. J.
    et al.
    Montgomery, R. A.
    Larsen, C. P.
    Wanders, A.
    Wells, A. F.
    Cytokine gene expression: analysis using northern blotting, polymerase chain reaction and in situ hybridization1991In: Immunol Rev, Vol. 119, 163-79 p.Article in journal (Refereed)
    Abstract [en]

    We describe here the use of northern blotting, PCR and in situ hybridization for the analysis of cytokine gene expression. These techniques, each with their advantages and disadvantages, have been used to monitor cytokine gene expression in sites of immune reactivity and in the developing thymus. Whilst expression of a gene usually correlates well with protein production from that gene, this may not always be the case. The development of methods to analyze protein production in situ, for instance by immunohistochemistry, together with analysis of mRNA expression will allow us to begin to understand the role of cytokines within the immune system of the intact animal.

  • 11. Dieterich, L. C.
    et al.
    Schiller, P.
    Huang, H.
    Wawrousek, E. F.
    Loskog, A.
    Wanders, A.
    Moons, L.
    Dimberg, A.
    alphaB-Crystallin regulates expansion of CD11b(+)Gr-1(+) immature myeloid cells during tumor progression2013In: FASEB J, Vol. 27, no 1, 151-62 p.Article in journal (Refereed)
    Abstract [en]

    The molecular chaperone alphaB-crystallin has emerged as a target for cancer therapy due to its expression in human tumors and its role in regulating tumor angiogenesis. alphaB-crystallin also reduces neuroinflammation, but its role in other inflammatory conditions has not been investigated. Here, we examined whether alphaB-crystallin regulates inflammation associated with tumors and ischemia. We found that CD45(+) leukocyte infiltration is 3-fold increased in tumors and ischemic myocardium in alphaB-crystallin-deficient mice. Notably, alphaB-crystallin is prominently expressed in CD11b(+) Gr-1(+) immature myeloid cells (IMCs), known as regulators of angiogenesis and immune responses, while lymphocytes and mature granulocytes show low alphaB-crystallin expression. alphaB-Crystallin deficiency results in a 3-fold higher accumulation of CD11b(+) Gr-1(+) IMCs in tumors and a significant rise in CD11b(+) Gr-1(+) IMCs in spleen and bone marrow. Similarly, we noted a 2-fold increase in CD11b(+) Gr-1(+) IMCs in chronically inflamed livers in alphaB-crystallin-deficient mice. The effect of alphaB-crystallin on IMC accumulation is limited to pathological conditions, as CD11b(+) Gr-1(+) IMCs are not elevated in naive mice. Through ex vivo differentiation of CD11b(+) Gr-1(+) cells, we provide evidence that alphaB-crystallin regulates systemic expansion of IMCs through a cell-intrinsic mechanism. Our study suggests a key role of alphaB-crystallin in limiting expansion of CD11b(+) Gr-1(+) IMCs in diverse pathological conditions.

  • 12. Dreilich, M.
    et al.
    Bergqvist, M.
    Moberg, M.
    Brattstrom, D.
    Gustavsson, I.
    Bergstrom, S.
    Wanders, A.
    Hesselius, P.
    Wagenius, G.
    Gyllensten, U.
    High-risk human papilloma virus (HPV) and survival in patients with esophageal carcinoma: a pilot study2006In: BMC Cancer, Vol. 6, 94- p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Human papilloma virus (HPV) in patients with esophageal carcinoma has previously been studied with an average detection rate of 15%, but the role of HPV in relation to survival is less clear. In cervical cancer, lung cancer and tonsil cancer HPV viral load is a predictive factor for survival and outcome of treatment. The primary aim was to study the spectrum of high-risk HPV types in esophageal tumors. Secondary, as a pilot study we investigated the association between HPV status and the survival rates. METHODS: We compared both the presence and the viral load of high-risk HPV types 16, 18, 31, 33, 39, 45, 52, 58, and 67 in relation to clinical data from patients with esophageal carcinoma. Survival data and tumor samples were retrieved from 100 patients receiving treatment at the Department of Oncology, Uppsala Hospital, Uppsala, Sweden. The tumor samples were investigated for HPV viral load using real-time PCR. RESULTS: HPV 16 was detected in 16% of the patients; no other HPV type was detected. HPV 16 infection had no significant effect on survival (p = 0.72). Also, HPV 16 did not improve survival after treatment (radiotherapy or chemotherapy). CONCLUSION: Only HPV 16 was detected among the patients. HPV 16 in esophageal carcinoma patients did not influence survival or improve therapy response. However, given the size of the study there is a need to examine a larger cohort in order to understand in more detail the effect of high risk HPV types in esophageal carcinoma.

  • 13. Dreilich, M.
    et al.
    Wanders, A.
    Brattstrom, D.
    Bergstrom, S.
    Hesselius, P.
    Wagenius, G.
    Bergqvist, M.
    HER-2 overexpression (3+) in patients with squamous cell esophageal carcinoma correlates with poorer survival2006In: Dis Esophagus, Vol. 19, no 4, 224-31 p.Article in journal (Refereed)
    Abstract [en]

    The incidence of esophageal carcinoma is increasing worldwide. In Sweden, approximately 400 patients are diagnosed each year. The present study retrospectively investigates survival in 97 patients with esophageal carcinoma in regard to their HER-2 status as examined by immunohistochemistry (IHC) and chromogen in situ hybridization (CISH). Sixty-eight patients had localised disease and 29 patients had advanced disease. Seventy patients had squamous cell carcinoma, and nine of these patients (13%) had HER-2 overexpression (3+). Eight (30%) of 27 adenocarcinoma patients overexpressed (3+) HER-2. In patients overexpressing (3+) HER-2 a statistical trend towards poorer survival was observed (P = 0.057). In squamous cell carcinoma patients, HER-2 overexpression (3+) correlated with poorer survival (P = 0.035), whereas in adenocarcinoma patients, HER-2 status (3+) did not. HER-2 amplification according to CISH was present in five (two squamous cell carcinomas and three adenocarcinomas) out of 17 HER-2 overexpressing (3+) tumours. In conclusion, HER-2 overexpression (3+) seems to be associated with poorer survival in esophageal carcinomas, especially in patients with squamous cell esophageal carcinoma.

  • 14. Enroth, S.
    et al.
    Rada-Iglesisas, A.
    Andersson, R.
    Wallerman, O.
    Wanders, A.
    Pahlman, L.
    Komorowski, J.
    Wadelius, C.
    Cancer associated epigenetic transitions identified by genome-wide histone methylation binding profiles in human colorectal cancer samples and paired normal mucosa2011In: BMC Cancer, Vol. 11, 450- p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Despite their well-established functional roles, histone modifications have received less attention than DNA methylation in the cancer field. In order to evaluate their importance in colorectal cancer (CRC), we generated the first genome-wide histone modification profiles in paired normal colon mucosa and tumor samples. METHODS: Chromatin immunoprecipitation and microarray hybridization (ChIP-chip) was used to identify promoters enriched for histone H3 trimethylated on lysine 4 (H3K4me3) and lysine 27 (H3K27me3) in paired normal colon mucosa and tumor samples from two CRC patients and for the CRC cell line HT29. RESULTS: By comparing histone modification patterns in normal mucosa and tumors, we found that alterations predicted to have major functional consequences were quite rare. Furthermore, when normal or tumor tissue samples were compared to HT29, high similarities were observed for H3K4me3. However, the differences found for H3K27me3, which is important in determining cellular identity, indicates that cell lines do not represent optimal tissue models. Finally, using public expression data, we uncovered previously unknown changes in CRC expression patterns. Genes positive for H3K4me3 in normal and/or tumor samples, which are typically already active in normal mucosa, became hyperactivated in tumors, while genes with H3K27me3 in normal and/or tumor samples and which are expressed at low levels in normal mucosa, became hypersilenced in tumors. CONCLUSIONS: Genome wide histone modification profiles can be used to find epigenetic aberrations in genes associated with cancer. This strategy gives further insights into the epigenetic contribution to the oncogenic process and may identify new biomarkers.

  • 15. Fellstrom, B.
    et al.
    Akyurek, M. L.
    Larsson, F.
    Waltenberger, J.
    Wanders, A.
    Funa, K.
    Ischemia induced upregulation of growth factor expression in experimental transplant arteriosclerosis1997In: Transplant Proc, Vol. 29, no 6, 2558- p.Article in journal (Refereed)
  • 16. Fellstrom, B. C.
    et al.
    Akyurek, M. L.
    Dimeny, E. M.
    Kaijser, M.
    Larsson, E.
    Wanders, A.
    Wahlberg, J.
    Nonimmunologic factors involved in long-term renal allograft deterioration1996In: Adv Nephrol Necker Hosp, Vol. 25, 51-62 p.Article in journal (Refereed)
  • 17. Fellstrom, B.
    et al.
    Dimeny, E.
    Foegh, M. L.
    Larsson, E.
    Wanders, A.
    Tufvesson, G.
    Accelerated atherosclerosis in heart transplants in the rat simulating chronic vascular rejection: effects of prostacyclin and angiopeptin1991In: Transplant Proc, Vol. 23, no 1 Pt 1, 525-8 p.Article in journal (Refereed)
  • 18. Gannedahl, G.
    et al.
    Wanders, A.
    Carlsson, M.
    Tufveson, G.
    15-deoxyspergualin effects in rat heart allograft transplantation--relation to dose, timing, and cyclosporine1993In: Transplantation, Vol. 55, no 2, 455-6 p.Article in journal (Refereed)
  • 19. Gannedahl, G.
    et al.
    Wanders, A.
    Carlsson, M.
    Tufveson, G.
    15-Deoxyspergualin potentiates the immunosuppressive effect of cyclosporine A in a rat heart allograft model1993In: Transplant Proc, Vol. 25, no 1 Pt 1, 768-9 p.Article in journal (Refereed)
  • 20. Gannedahl, G.
    et al.
    Wanders, A.
    Wadstrom, J.
    Olausson, M.
    Ekberg, H.
    Tufveson, G.
    Azathioprine does not potentiate the immunosuppressive effect of 15-deoxyspergualin in rat heart allografting1994In: Transplant Proc, Vol. 26, no 6, 3108-10 p.Article in journal (Refereed)
  • 21. Gerdin, B.
    et al.
    Wanders, A.
    Tufveson, G.
    Rat cardiac allografts protected with cyclosporin A are rejected in the presence of LS-2616 (Linomide)1989In: Transplant Proc, Vol. 21, no 1 Pt 1, 853-5 p.Article in journal (Refereed)
  • 22. Gremel, Gabriela
    et al.
    Wanders, Alkwin
    Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University.
    Cedernaes, Jonathan
    Fagerberg, Linn
    Hallström, Björn
    Edlund, Karolina
    Sjöstedt, Evelina
    Uhlén, Mathias
    Pontén, Fredrik
    The human gastrointestinal tract-specific transcriptome and proteome as defined by RNA sequencing and antibody-based profiling2015In: Journal of gastroenterology, ISSN 0944-1174, E-ISSN 1435-5922, Vol. 50, no 1, 46-57 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The gastrointestinal tract (GIT) is subdivided into different anatomical organs with many shared functions and characteristics, but also distinct differences. We have combined a genome-wide transcriptomics analysis with immunohistochemistry-based protein profiling to describe the gene and protein expression patterns that define the human GIT. METHODS: RNA sequencing data derived from stomach, duodenum, jejunum/ileum and colon specimens were compared to gene expression levels in 23 other normal human tissues analysed with the same method. Protein profiling based on immunohistochemistry and tissue microarrays was used to sub-localize the corresponding proteins with GIT-specific expression into sub-cellular compartments and cell types. RESULTS: Approximately 75% of all human protein-coding genes were expressed in at least one of the GIT tissues. Only 51 genes showed enriched expression in either one of the GIT tissues and an additional 83 genes were enriched in two or more GIT tissues. The list of GIT-enriched genes with validated protein expression patterns included various well-known but also previously uncharacterised or poorly studied genes. For instance, the colon-enriched expression of NXPE family member 1 (NXPE1) was established, while NLR family, pyrin domain-containing 6 (NLRP6) expression was primarily found in the human small intestine. CONCLUSIONS: We have applied a genome-wide analysis based on transcriptomics and antibody-based protein profiling to identify genes that are expressed in a specific manner within the human GIT. These genes and proteins constitute important starting points for an improved understanding of the normal function and the different states of disease associated with the GIT.

  • 23. Hall, H.
    et al.
    Velikyan, I.
    Blom, E.
    Ulin, J.
    Monazzam, A.
    Pahlman, L.
    Micke, P.
    Wanders, A.
    McBride, W.
    Goldenberg, D. M.
    Langstrom, B.
    In vitro autoradiography of carcinoembryonic antigen in tissue from patients with colorectal cancer using multifunctional antibody TF2 and (67/68Ga)-labeled haptens by pretargeting2012In: Am J Nucl Med Mol Imaging, Vol. 2, no 2, 141-50 p.Article in journal (Refereed)
    Abstract [en]

    The carcinoembryonic antigen (CEA) was visualized in vitro in tissue from patients with colorectal cancer with trivalent bispecific antibody TF2 and two hapten molecules, [(67/68)Ga]Ga-IMP461 and [(67/68)Ga]Ga-IMP485 by means of pretargeting. Colorectal cancer tissue samples obtained from surgery at Uppsala University Hospital, were frozen fresh and cryosectioned. The two hapten molecules comprising 1,4,7-triazacyclononanetriacetic acid chelate moiety (NOTA) were labeled with (67)Ga or (68)Ga. The autoradiography was conducted by incubating the tissue samples with the bispecific antibody TF2, followed by washing and incubation with one of the radiolabeled hapten molecules. After washing, drying and exposure to phosphor imager plates, the autoradiograms were analyzed and compared to standard histochemistry (hematoxylin-eosin). Pronounced binding was found in the tissue from colorectal cancer using the bispecific antibody TF2 and either of the haptens [(67/68)Ga]Ga-IMP461 and [(67/68)Ga]Ga-IMP485. Distinct binding was also detected in the epithelium of most samples of neighboring tissue, taken at a minimum of 10 cm from the site of the tumor. It is concluded that pretargeting CEA with the bispecific antibody TF2 followed by the addition of (67/68)Ga-labeled hapten is extremely sensitive for visualizing this marker for colorectal cancer. This methodology is therefore a very specific complement to other histochemical techniques in the diagnosis of biopsies or in samples taken from surgery. Use of the pretargeting technique in vivo may also be an advance in diagnosing patients with colorectal cancer, either using (67)Ga and SPECT or (68)Ga and PET.

  • 24. Hallén, Karin
    et al.
    Sangfelt, Per
    Nilsson, Thomas
    Nordgren, Hans
    Wanders, Alkwin
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Molin, Daniel
    Vanishing bile duct-like syndrome in a patient with Hodgkin lymphoma: pathological development and restitution2014In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 53, no 9, 1271-5 p.Article in journal (Refereed)
  • 25. Hogberg, N.
    et al.
    Stenback, A.
    Carlsson, P. O.
    Wanders, A.
    Lilja, H. E.
    Genes regulating tight junctions and cell adhesion are altered in early experimental necrotizing enterocolitis2013In: J Pediatr Surg, Vol. 48, no 11, 2308-12 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND/PURPOSE: Necrotizing enterocolitis (NEC) represents one of the gravest complications in preterm infants and carries significant morbidity and mortality. Increased intestinal permeability may play an important role in the pathogenesis of NEC. In this study we investigated the genes regulating structural proteins such as tight junctions (TJ) and cell adhesion in a neonatal rat model of early NEC. METHODS: The studies were performed on Sprague-Dawley rat pups. Experimental NEC was induced using hypoxia/re-oxygenation treatment on day 1 after birth. Intestinal specimens from the ileum were obtained, mRNA was purified, and the transcriptome was analyzed using microarray. RESULTS: We found several TJ genes such as claudins 1, 8, 14, 15, and gap junction protein to be affected. Alterations in genes involved in the inflammatory response was confirmed, along with several genes regulating proteins used as biomarkers for NEC. CONCLUSION: This study indicates that tight junctions and cell adhesion may play a critical role in the pathogenesis of early experimental NEC. Better understanding of the pathogenesis of NEC may lead to novel strategies for the prevention and treatment of NEC.

  • 26. Klar, Joakim
    et al.
    Raykova, Doroteya
    Gustafson, Elisabet
    Tothova, Iveta
    Ameur, Adam
    Wanders, Alkwin
    Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Biomedical Centre, Uppsala University, Uppsala, Sweden.
    Dahl, Niklas
    Phenotypic expansion of visceral myopathy associated with ACTG2 tandem base substitution2015In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 23, no 12, 1679-1683 p.Article in journal (Refereed)
    Abstract [en]

    Familial visceral myopathy (FVM) is a rare heritable and heterogeneous condition due to impaired smooth muscle function. We identified a family segregating 11 individuals with a spectrum of visceral symptoms involving the small intestine, colon, biliary tract, urinary tract and uterus. Whole-exome sequencing revealed a novel heterozygous tandem base substitution c.806_807delinsAA (p.(Gly269Glu)) in ACTG2, encoding smooth muscle actin gamma-2, in affected family members. Variants in ACTG2 were recently identified in FVM with intestinal pseudo-obstruction as well as with the congenital megacystics-microcolon-intestinal hypoperistalsis syndrome. In our family, eight affected members presented with severe complications from the biliary and/or the urinary tracts in addition to gastrointestinal pseudo-obstructions. Furthermore, all affected mothers had a history of assisted deliveries owing to poor progress during labor and weak uterine contractions. The variable involvement of multiple smooth muscle-dependent organs in our family, including the biliary tract and the uterus, add to the phenotypic spectrum associated with ACTG2 missense variants.

  • 27. Konig, G.
    et al.
    Wanders, A.
    Krombach, F.
    Schorer, C.
    Vogelmeier, C.
    Hammer, C.
    [The effect of broncho-alveolar lavage on free lung cells]1988In: Prax Klin Pneumol, Vol. 42, no 3, 83-4 p.Article in journal (Refereed)
  • 28. Kristjansson, G.
    et al.
    Venge, P.
    Wanders, A.
    Loof, L.
    Hallgren, R.
    Clinical and subclinical intestinal inflammation assessed by the mucosal patch technique: studies of mucosal neutrophil and eosinophil activation in inflammatory bowel diseases and irritable bowel syndrome2004In: Gut, Vol. 53, no 12, 1806-12 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIMS: There is a clear need for a rapid, simple, safe, and sensitive method of determining the type and intensity of inflammation in the gut mucosa in clinical practice. In this study, we have evaluated the potential of a new method, the mucosal patch technique, in patients with and without apparent gut inflammation, as assessed by conventional diagnostic procedures. SUBJECTS AND METHODS: The technique tested is based on the idea that inflammatory mediators released from the rectal mucosa can be absorbed by and then extracted from cellulose patches brought into contact with the mucosa by use of an instrument with an inflatable balloon. Measurements were performed in healthy controls (n = 16) and in patients with active (n = 19) and inactive ulcerative colitis (UC, n = 8), collagen colitis (CC, n = 12), coeliac disease (n = 13), and irritable bowel syndrome (IBS, n = 13). RESULTS: Inflammatory mediators from neutrophils (myeloperoxidase (MPO)) and eosinophils (eosinophil cationic protein (ECP)) were increased on average 300- and 10-fold, respectively, in patients with active UC compared with healthy controls and were correlated with the endoscopic score. Patients with inactive UC, CC, coeliac disease, and IBS exhibited no endoscopic signs of inflammation. These patient groups had significantly lower levels of MPO and ECP than the active UC group but showed on average a four- to sevenfold increase in MPO compared with healthy controls. CONCLUSION: The mucosal patch technique was well tolerated by patients and easily applied by the investigator. Pronounced neutrophil and eosinophil involvement in UC was demonstrated. With the high sensitivity of the technique, low degree mucosal neutrophil activation could also be quantified in patients with CC and UC in clinical remission. The finding of increased neutrophil involvement in patients with IBS contributes to the pathophysiological ideas of this disease.

  • 29. Lampinen, M.
    et al.
    Fredricsson, A.
    Vessby, J.
    Wanders, Alkwin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Rorsman, F.
    Carlson, M.
    Expression of the liver homing receptor CXCR3+on colonic CD8+T lymphocytes in patients with primary sclerosing cholangitis provides a possible link between colonic and biliary duct inflammation2016In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 10, S109-S109 p.Article in journal (Other academic)
  • 30. Lampinen, M.
    et al.
    Ronnblom, A.
    Amin, K.
    Kristjansson, G.
    Rorsman, F.
    Sangfelt, P.
    Safsten, B.
    Wagner, M.
    Wanders, A.
    Winqvist, O.
    Carlson, M.
    Eosinophil granulocytes are activated during the remission phase of ulcerative colitis2005In: Gut, Vol. 54, no 12, 1714-20 p.Article in journal (Refereed)
    Abstract [en]

    AIM: The aim of this study was to establish a method of investigating intestinal eosinophil and neutrophil granulocytes by flow cytometry, and to compare the distribution and activity of these cells in different stages of ulcerative colitis (UC). METHODS: Biopsy samples were taken from six locations of the entire colon and from the terminal ileum in 10 patients with active total UC, 10 patients with inactive total UC, eight patients with active distal UC, and 11 control subjects. Cell suspensions from biopsies and from peripheral blood were incubated with fluorophore conjugated monoclonal antibodies. The use of scatter plot-gating and specific antibodies was established in a flow cytometry assay. RESULTS: Eosinophils were more numerous and more active in patients with active UC than in controls. Interestingly, during inactive UC, the number of activated eosinophils was even larger. Eosinophil activity was high in the rectum of patients with distal colitis but was also slightly elevated in the proximal colon. Neutrophils were increased in number and activity during active but not inactive UC. In patients with distal colitis, activated neutrophils were only found in the sigmoid colon and rectum. CONCLUSION: With this method, we confirm that neutrophils participate in the inflammatory process during active UC, and that they express a resting phenotype during remission. The finding of activated eosinophils in inflamed intestine strengthens the view of these cells as proinflammatory and tissue damaging. Nevertheless, our new finding of high eosinophil activation during inactive UC suggests that eosinophils play a role in repair of injured epithelium.

  • 31. Malmstrom, P. U.
    et al.
    Loskog, A. S.
    Lindqvist, C. A.
    Mangsbo, S. M.
    Fransson, M.
    Wanders, A.
    Gardmark, T.
    Totterman, T. H.
    AdCD40L immunogene therapy for bladder carcinoma--the first phase I/IIa trial2010In: Clin Cancer Res, Vol. 16, no 12, 3279-87 p.Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Immunotherapy with Bacillus Calmette-Guerin (BCG) instillation is recommended for high-risk, non-muscle invasive bladder cancer. Bacillus Calmette-Guerin is not effective in advanced tumors, and better alternatives are warranted. Immunostimulating gene therapy with adenoviral vectors expressing CD40 ligand (AdCD40L) has shown efficacy in tumor models. CD40 ligand stimulates systemic immunity and may be effective in local and invasive human disease. EXPERIMENTAL DESIGN: Patients with invasive bladder cancer scheduled for cystectomy or patients with T(a) tumors were enrolled in a phase I/IIa trial. Patients were treated with three cycles of intrabladder Clorpactin WCS-90 prewash, followed by AdCD40L instillation 1 week apart. Safety, gene transfer, immune effects, and antitumor responses were monitored. RESULTS: All eight recruited patients were treated as scheduled, and therapy was well tolerated. The main adverse effect was transient local pain during prewash. Postoperatively, urinary tract infections and one case of late septicemia with elevated potassium were reported. No adverse events were ascribed to vector therapy. Gene transfer was detected in biopsies, and bladders were heavily infiltrated with T cells. The effector marker IFN-gamma increased in biopsies, whereas levels of circulating T regulatory cells were reduced. Histologic evaluation indicated that AdCD40L therapy reduced the load of malignant cells. CONCLUSIONS: To our knowledge, this is the first report on immunogene therapy in bladder cancer and the first using AdCD40L in vivo. Local AdCD40L gene therapy was safe, boosted immune activation, and should be further evaluated as a single or an adjuvant therapy for urothelial malignancies.

  • 32. Marits, P.
    et al.
    Karlsson, M.
    Dahl, K.
    Larsson, P.
    Wanders, A.
    Thorn, M.
    Winqvist, O.
    Sentinel node lymphocytes: tumour reactive lymphocytes identified intraoperatively for the use in immunotherapy of colon cancer2006In: Br J Cancer, Vol. 94, no 10, 1478-84 p.Article in journal (Refereed)
    Abstract [en]

    The sentinel node is the first lymph node to receive lymphatic drainage from a tumour and is usually the first site of metastases. Today, the sentinel node is used for tumour staging. Here, we focus on its immunological role and investigate lymphocytic function in sentinel nodes, identified intraoperatively by peritumoural dye injection, from 15 patients with colon cancer. Tumour infiltrating lymphocytes, sentinel and nonsentinel lymph node cells and peripheral blood leukocytes were studied by flow cytometry, proliferation assays and interferon-gamma secretion after activation with autologous tumour homogenate. Whereas tumour-infiltrating lymphocytes were nonresponsive in the proliferation assays, lymphocytes from sentinel nodes proliferated dose dependently and secreted interferon-gamma upon stimulation with tumour homogenate. The responses were of varying magnitude and tended to be weaker in metastatic sentinel nodes. Sentinel node lymphocytes represents an enriched source of tumour reactive lymphocytes, and may be useful in future trials of adoptive immunotherapy.

  • 33. Marthinsen, L.
    et al.
    Saksena, P.
    Saalman, R.
    Korlen, B.
    Lucas, S.
    Sabzwari, N.
    Carlen, B.
    Engstrand, L.
    Wanders, A.
    Willen, R.
    [Colonic spirochetosis--treatable and worth consideration. Experiences from a pediatric practice]2006In: Lakartidningen, Vol. 103, no 46, 3600-2 p.Article in journal (Refereed)
  • 34. Nystrom, N.
    et al.
    Berg, T.
    Lundin, E.
    Skog, O.
    Hansson, I.
    Frisk, G.
    Juko-Pecirep, I.
    Nilsson, M.
    Gyllensten, U.
    Finkel, Y.
    Fuxe, J.
    Wanders, A.
    Human enterovirus species B in ileocecal Crohn's disease2013In: Clin Transl Gastroenterol, Vol. 4, e38- p.Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Advanced ileocecal Crohn's disease (ICD) is characterized by strictures, inflammation in the enteric nervous system (myenteric plexitis), and a high frequency of NOD2 mutations. Recent findings implicate a role of NOD2 and another CD susceptibility gene, ATG16L1, in the host response against single-stranded RNA (ssRNA) viruses. However, the role of viruses in CD is unknown. We hypothesized that human enterovirus species B (HEV-B), which are ssRNA viruses with dual tropism both for the intestinal epithelium and the nervous system, could play a role in ICD. METHODS: We used immunohistochemistry and in situ hybridization to study the general presence of HEV-B and the presence of the two HEV-B subspecies, Coxsackie B virus (CBV) and Echovirus, in ileocecal resections from 9 children with advanced, stricturing ICD and 6 patients with volvulus, and in intestinal biopsies from 15 CD patients at the time of diagnosis. RESULTS: All patients with ICD had disease-associated polymorphisms in NOD2 or ATG16L1. Positive staining for HEV-B was detected both in the mucosa and in myenteric nerve ganglia in all ICD patients, but in none of the volvulus patients. Expression of the cellular receptor for CBV, CAR, was detected in nerve cell ganglia. CONCLUSIONS: The common presence of HEV-B in the mucosa and enteric nervous system of ICD patients in this small cohort is a novel finding that warrants further investigation to analyze whether HEV-B has a role in disease onset or progress. The presence of CAR in myenteric nerve cell ganglia provides a possible route of entry for CBV into the enteric nervous system.

  • 35. Rada-Iglesias, A.
    et al.
    Enroth, S.
    Andersson, R.
    Wanders, A.
    Pahlman, L.
    Komorowski, J.
    Wadelius, C.
    Histone H3 lysine 27 trimethylation in adult differentiated colon associated to cancer DNA hypermethylation2009In: Epigenetics, Vol. 4, no 2, 107-13 p.Article in journal (Refereed)
    Abstract [en]

    DNA hypermethylation of gene promoters is a common epigenetic alteration occurring in cancer cells. However, little is known about the mechanisms instructing these cancer-specific DNA hypermethylation events. Recent reports have suggested that genes bound by polycomb/Histone H3 lysine 27 trimethylation (H3K27me3) in embryonic stem (ES) cells are frequent targets for cancer-specific DNA hypermethylation. This polycomb-premarking is assumed to be restrained to ES cells, even though almost no polycomb/H3K27me3 binding profiles are available for differentiated tissues. We generated H3K27me3 profiles in human normal colon and they significantly overlapped with those of ES cells and genes hypermethylated in colorectal cancer (CRC). Moreover, colon H3K27me3 was more restricted to genes hypermethylated in CRC, while ES H3K27me3 was also common in genes hypermethylated in other tumors. Therefore, the suggested polycomb pre-marking of genes for cancer DNA hypermethylation is not necessarily limited to ES or early precursor cells but can occur later in differentiated tissues.

  • 36. Ramachandran, M.
    et al.
    Yu, D.
    Wanders, A.
    Essand, M.
    Eriksson, F.
    An infection-enhanced oncolytic adenovirus secreting H. pylori neutrophil-activating protein with therapeutic effects on neuroendocrine tumors2013In: Mol Ther, Vol. 21, no 11, 2008-18 p.Article in journal (Refereed)
    Abstract [en]

    Helicobacter pylori neutrophil-activating protein (HP-NAP) is a major virulence factor involved in H. pylori infection. HP-NAP can mediate antitumor effects by recruiting neutrophils and inducing Th1-type differentiation in the tumor microenvironment. It therefore holds strong potential as a therapeutic gene. Here, we armed a replication-selective, infection-enhanced adenovirus with secretory HP-NAP, Ad5PTDf35-[Delta24-sNAP], and evaluated its therapeutic efficacy against neuroendocrine tumors. We observed that it could specifically infect and eradicate a wide range of tumor cells lines from different origin in vitro. Insertion of secretory HP-NAP did not affect the stability or replicative capacity of the virus and infected tumor cells could efficiently secrete HP-NAP. Intratumoral administration of the virus in nude mice xenografted with neuroendocrine tumors improved median survival. Evidence of biological HP-NAP activity was observed 24 hours after treatment with neutrophil infiltration in tumors and an increase of proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha and MIP2-alpha in the systemic circulation. Furthermore, evidence of Th1-type immune polarization was observed as a result of increase in IL-12/23 p40 cytokine concentrations 72 hours postvirus administration. Our observations suggest that HP-NAP can serve as a potent immunomodulator in promoting antitumor immune response in the tumor microenvironment and enhance the therapeutic effect of oncolytic adenovirus.

  • 37. Rönnblom, Anders
    et al.
    Holmström, Tommy
    Tanghöj, Hans
    Wanders, Alkwin
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Sjöberg, Daniel
    Celiac disease, collagenous sprue and microscopic colitis in IBD: observations from a population-based cohort of IBD (ICURE)2015In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 50, no 10, 1234-1240 p.Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Inflammatory bowel disease (IBD), microscopic colitis and celiac disease are all diseases with worldwide distribution and increased incidence has been reported from many areas. There is a shortage of studies investigating the occurrence of these diseases in the same individual and whether those affected demonstrate any particular phenotype. The aim of the study was to describe the concomitant incidence of microscopic colitis and celiac disease in a population-based IBD cohort. METHODS: All 790 individuals in a prospective population-based cohort included 2005-09 from Uppsala region, Sweden, were reviewed regarding the appearance of microscopic or celiac disease before or after IBD diagnosis. RESULTS: Fifty percent (396/790) of the patients had been examined for the possibility of celiac disease. Seventeen patients with celiac disease were found, representing 2.2% of the cohort. Patients with celiac disease were younger compared to the non-celiac patients and those with colitis had more often an extensive inflammation of the colon. Seventy-one percent (12/17) were women. The majority of the patients were diagnosed with celiac disease before IBD. Five patients with IBD had an earlier diagnosis of microscopic colitis or developed it after the IBD diagnosis. One teenager developed collagenous sprue, misinterpreted as a severe relapse of ulcerative colitis (UC) resulting in colectomy. CONCLUSIONS: The risk for celiac disease seems not to be increased in IBD, but those affected by both diseases seem to be predominantly women with extensive UC. There is a potential association between microscopic colitis and IBD.

  • 38. Sangfelt, P.
    et al.
    Sundin, A.
    Wanders, A.
    Rasmussen, I.
    Karlson, B. M.
    Bergquist, A.
    Rorsman, F.
    Monitoring dominant strictures in primary sclerosing cholangitis with brush cytology and FDG-PET2014In: J Hepatol, Vol. 61, no 6, 1352-7 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND & AIMS: Despite a high risk of cholangiocellular adenocarcinoma (CCA) it is unclear how surveillance of patients with primary sclerosing cholangitis (PSC) should be performed. METHODS: We evaluated a follow-up algorithm of brush cytology and positron emission tomography/computed tomography with [(18)F] fluorodeoxyglucose ([(18)F]FDG-PET/CT), measured as maximum standardized uptake values, normalized to the liver background (SUVmax/liver) at 180 min, in PSC patients with dominant bile duct strictures. RESULTS: Brush cytology with high grade dysplasia (HGD) was detected in 12/70 patients (17%), yielding a diagnostic sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 56%, 89%, 75%, and 88%, respectively. Preemptive liver transplantations due to repeated HGD before manifest CCA were performed in six patients. Receiver operating characteristic (ROC) analysis of [(18)F]FDG uptake showed that a SUVmax/liver quotient of 3.3 was able to discriminate between CCA and non-malignant disease with a sensitivity, specificity, PPV and NPV for CCA of 89%, 92%, 62%, 98%, respectively. A SUVmax/liver >3.3 detected CCA in 8/9 patients whereas a quotient <2.4 excluded CCA. Combining brush cytology and quantitative [(18)F]FDG-PET/CT yielded a sensitivity for HGD and/or CCA of 100% and a specificity of 88%. CONCLUSION: Early detection of HGD before manifest CCA is feasible with repeated brush cytology and may allow for preemptive liver transplantation. [(18)F]FDG-PET/CT has a high sensitivity for manifest CCA and a negative scan indicates a non-malignant state of the disease. Brush cytology and [(18)F]FDG-PET/CT are complementary in monitoring and managing PSC patients with dominant strictures.

  • 39. Sarapa, N.
    et al.
    Britto, M. R.
    Speed, W.
    Jannuzzo, M.
    Breda, M.
    James, C. A.
    Porro, M.
    Rocchetti, M.
    Wanders, A.
    Mahteme, H.
    Nygren, P.
    Assessment of normal and tumor tissue uptake of MAG-CPT, a polymer-bound prodrug of camptothecin, in patients undergoing elective surgery for colorectal carcinoma2003In: Cancer Chemother Pharmacol, Vol. 52, no 5, 424-30 p.Article in journal (Refereed)
    Abstract [en]

    PURPOSE: MAG-camptothecin (MAG-CPT) is the lead compound of a novel drug delivery system in which an active cytotoxic moiety, camptothecin (CPT), is covalently linked to a soluble polymeric carrier (MAG) to form an inactive prodrug. The mechanism of action of CPT remains unaltered, but the delivery system is thought to allow the carrier-bound drug to accumulate in tumor tissues and release the active CPT locally. This proof-of-concept clinical study was designed to determine whether MAG-CPT was preferentially delivered to or retained in tumor tissue compared to adjacent normal tissue or plasma, and to estimate the degree of intratissue release of CPT. METHODS: This was an open, non-randomized study in ten adult patients scheduled for elective surgery for colorectal cancer. Patients received a single dose of 60 mg/m2 (CPT equivalent) of MAG-CPT 24 h, 3 days or 7 days prior to surgery. Plasma, tumor, and adjacent normal tissue samples were collected simultaneously at the time of surgery and analyzed for MAG-bound and released CPT concentrations. RESULTS: MAG-bound and free CPT concentrations in plasma, tumor, and normal tissue achieved equilibrium by 24 h after dosing, declining in parallel up to 7 days after dosing. MAG-bound CPT was delivered to similar levels to tumor and normal tissue. At 24 h after dosing, the mean+/-SD MAG-bound CPT concentrations were 861+/-216 ng/g in tumor and 751+/-215 ng/g in adjacent normal tissue, and free CPT concentrations were lower in tumor than in normal tissue (12.2+/-4.7 ng/g and 21.9+/-6.7 ng/g, respectively). At 24 h after dosing, mean+/-SD ratios of MAG-bound and free CPT in tumor and plasma were 0.13+/-0.03 and 0.22+/-0.09, respectively, and the ratios did not change for up to 7 days after dosing, indicating a lack of preferential retention of MAG-bound CPT or release of free CPT in tumor. These results are in marked contrast to previous data from animal tumor xenograft studies, where MAG-CPT levels were higher in tissue than in plasma at 3 and 7 days after a single i.v. dose. CONCLUSIONS: Delivery of CPT to the target tumor tissue is achievable by means of the MAG-CPT polymer-bound delivery system, with the equilibrium between plasma and tumor tissue concentrations of released CPT being established within 24 h after dosing. However, preferential retention of MAG-bound or released CPT in the tumor relative to normal tissue or plasma was not detected during the 7 days after dosing. The methods employed in our study could be of use in making "go/no-go" decisions on further development of anticancer drugs.

  • 40. Siilin, H.
    et al.
    Wanders, A.
    Gustavsson, S.
    Sundbom, M.
    The proximal gastric pouch invariably contains acid-producing parietal cells in Roux-en-Y gastric bypass2005In: Obes Surg, Vol. 15, no 6, 771-7 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Roux-en-Y gastric bypass (RYGBP) is well tolerated and effective in ameliorating diseases common to morbidly obese patients. A potential drawback, however, is the risk for stomal ulcers, probably due to acid and peptic digestion of the mucosa in the proximal Roux limb. METHODS: In 23 RYGBP patients (mean BMI 45 kg/m(2), age 39 years), the gastro-jejunostomy was performed by circular stapler and the gastric suture ring retrieved for histological examination. 13 consecutive patients received our standard totally transected 4 x 3 cm proximal gastric pouch. The anvil was passed transgastricly and reference biopsies were taken from the gastrotomy in the corpus of the stomach. In the last 10 patients, the pouch size was reduced to 2 x 3 cm by a modified surgical technique. RESULTS: All suture rings from the standard pouches consisted of corpus-fundus mucosa with a large amount of parietal cells, histologically identical to the reference biopsies from the gastrotomy. Also, the 10 suture rings from the modified small pouches contained corpus-fundus mucosa. In 5 of these samples, cardiac mucosa was found, but only in a small segment (6 mm). In addition, 3 patients had esophageal epithelium in the suture ring. CONCLUSION: The proximal pouch invariably contains acid-producing parietal cells. In order to reduce acid production and, hence, the risk of stomal ulcers, the pouch has to be made as small as possible.

  • 41. Thorn, M.
    et al.
    Sjoberg, D.
    Ekbom, A.
    Holmstrom, T.
    Larsson, M.
    Nielsen, A. L.
    Holmquist, L.
    Thelander, U.
    Wanders, A.
    Ronnblom, A.
    Microscopic colitis in Uppsala health region, a population-based prospective study 2005-20092013In: Scand J Gastroenterol, Vol. 48, no 7, 825-30 p.Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The aim of this study is to report on the incidence of microscopic colitis (MC), any possible relation with inflammatory bowel disease (IBD), concomitant drug consumption, related diseases and the clinical course of the diseases. METHODS: Both new cases of IBD and MC were registered at the same time in the same geographical area. The study started in the county of Uppsala 2005-2006, and other parts of the surrounding health region were included 2007-2009. Established morphological criteria were used, i.e. a layer of subepithelial collagen band >/= 10 mum in collagenous colitis (CC) with concomitant inflammation and at least 20 lymphocytes per 100 epithelial cells in lymphocytic colitis (LC). RESULTS: The authors found 272 new cases of MC, 154 with CC and 118 with LC. The mean age-adjusted incidence was 7.0/1,000,000 for CC and 4.8/100,000 for LC. The clinical course was dominated by single episodes with diarrhea or intermittent symptoms, but 14% suffered from chronic diarrhea. In 10% of the cases, diagnosis was made in individuals without chronic watery diarrhea. Although not systematically tested, concomitant celiac disease was found in approximately 5% of the patients. CONCLUSIONS: The incidence of MC in Uppsala health region is similar to other studied areas. The majority of patients had a self-limiting or easily treated condition, but 14% need a more or less continuous medication. Ten percent of the patients demonstrate other symptoms than chronic watery diarrhea. The possibility of concomitant celiac disease should be considered in new cases of MC.

  • 42. Tufveson, G.
    et al.
    Gannedahl, G.
    Johnsson, C.
    Olausson, M.
    Wanders, A.
    Ekberg, H.
    New immunosuppressants: testing and development in animal models and the clinic1993In: Immunol Rev, Vol. 136, 99-109 p.Article in journal (Refereed)
  • 43. Urdzik, J.
    et al.
    Bjerner, T.
    Wanders, A.
    Duraj, F.
    Haglund, U.
    Noren, A.
    Magnetic resonance imaging flowmetry demonstrates portal vein dilatation subsequent to oxaliplatin therapy in patients with colorectal liver metastasis2013In: HPB (Oxford), Vol. 15, no 4, 265-72 p.Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Sinusoidal injury (SI) after oxaliplatin-based therapies for colorectal liver metastasis (CRLM) can increase postoperative morbidity. Preoperative methods to estimate SI are lacking. The aim of this study was to identify SI by evaluating portal vein haemodynamics. METHODS: Magnetic resonance imaging flowmetry (MRIF) was used to estimate portal vein haemodynamics in 29 patients with CRLM before liver surgery. Sinusoidal injury was evaluated from resected non-tumorous liver parenchyma according to the combined vascular injury (CVI) score of >/=3. RESULTS: All patients with SI (six of 29) received oxaliplatin; however, a significant association could not be proven (P= 0.148). Oxaliplatin-treated patients showed portal vein dilatation in both the SI and non-SI groups compared with patients who had not received oxaliplatin (Bonferroni corrected P= 0.003 and P= 0.039, respectively). Mean portal velocity tended to be lower in patients with SI compared with oxaliplatin-treated patients without SI (Bonferroni corrected P= 0.087). A mean portal velocity of </=14.35 cm/s together with a cross-section area of >/=1.55 cm(2) was found to predict SI with sensitivity of 100% and specificity of 78%. CONCLUSIONS: Oxaliplatin treatment was associated with portal vein dilatation. Patients with SI showed a tendency towards decreased mean portal flow velocity. This may indicate that SI is associated with an increased resistance to blood flow in the liver parenchyma. Portal vein haemodynamic variables estimated by MRIF can identify patients without SI non-invasively.

  • 44. Urdzik, J.
    et al.
    Bjerner, T.
    Wanders, A.
    Weis, J.
    Duraj, F.
    Haglund, U.
    Noren, A.
    The value of pre-operative magnetic resonance spectroscopy in the assessment of steatohepatitis in patients with colorectal liver metastasis2012In: J Hepatol, Vol. 56, no 3, 640-6 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND & AIMS: Neoadjuvant chemotherapy prior to liver surgery for colorectal metastases can cause marked steatosis (>/= 33%) and steatohepatitis defined by non-alcoholic fatty liver disease activity score (NAS) as adverse effects on liver parenchyma. The aim of this study was to evaluate the steatosis level prior to liver resection using proton magnetic resonance spectroscopy ((1)H MRS) and to compare it with digital quantification of steatosis (DQS) and "classical" histopathology. METHODS: (1)H MRS at 3T evaluated steatosis in 35 patients with colorectal liver metastasis, planned for liver resection. Non-tumorous liver parenchyma samples were obtained after surgery for classical histopathology and DQS utilising automated software for quantification of histopathological slides using image processing. RESULTS: Classical histopathology defined marked steatosis in nine patients. Histopathology was less reliable than DQS (interclass correlation coefficient - ICC 0.771) or (1)H MRS (ICC 0.722) in steatosis estimation. (1)H MRS showed very similar steatosis levels and high reliability compared to DQS (ICC 0.955). Steatohepatitis was observed in seven patients (NAS >/= 4) and (1)H MRS was able to predict it with 100% sensitivity and 89% specificity at threshold 10.9%, without knowing lobular inflammation or hepatocyte ballooning. BMI was significantly higher in the groups with marked steatosis and steatohepatitis. Standard blood tests or chemotherapy had no predictive value. CONCLUSIONS: (1)H MRS is a reliable non-invasive tool for steatosis assessment, and interestingly, it was able to predict steatohepatitis defined by NAS >/= 4 in patients planned for liver resection of colorectal metastases after neoadjuvant chemotherapy.

  • 45. Vogeser, M.
    et al.
    Wanders, Alkwin
    Haas, A.
    Ruckdeschel, G.
    A four-year review of fatal Aspergillosis1999In: Eur J Clin Microbiol Infect Dis, Vol. 18, no 1, 42-5 p.Article in journal (Refereed)
    Abstract [en]

    To investigate the incidence, underlying diseases, and macropathological and microbiological features of invasive aspergillosis in a university hospital, the protocols of 1187 autopsies performed during the 4-year period 1993-1996 were reviewed. Invasive aspergillosis was diagnosed as the cause of death in 48 (4%) cases, four (8%) of which did not involve severe primary immunosuppression. In seven (15%) cases no pulmonary involvement was found; in six of these cases the portal of infection could not be established, whereas in one case invasive aspergillosis originated from Aspergillus peritonitis. Aspergillus grew in 42% of the samples obtained from the respiratory tracts of 32 patients with pulmonary aspergillosis and submitted within 10 days antemortem; at least one positive culture was obtained from 20 (63%) of these patients. It is concluded that the diagnosis of aspergillosis by means of culture has an appreciable sensitivity. Fatal invasive aspergillosis was rare among patients without severe immunosuppression, whereas invasive aspergillosis without pulmonary involvement was unexpectedly frequent.

  • 46. Waltenberger, J.
    et al.
    Akyurek, M. L.
    Aurivillius, M.
    Wanders, A.
    Larsson, E.
    Fellstrom, B.
    Funa, K.
    Ischemia-induced transplant arteriosclerosis in the rat. Induction of peptide growth factor expression1996In: Arterioscler Thromb Vasc Biol, Vol. 16, no 12, 1516-23 p.Article in journal (Refereed)
    Abstract [en]

    Peptide growth factors have been reported to contribute to the atherogenic process, and they are known to mediate signals for vascular remodeling. Using syngeneic and allogeneic rat aorta transplant models, we analyzed the impact of cold ischemia time up to 24 hours and reperfusion injury on development of transplant arteriosclerosis during the first 2 months after transplantation. The expression of the transforming growth factor-beta (TGF-beta) family as well as the platelet-derived growth factor (PDGF) and its receptors was studied by use of immunohistochemistry, followed by semiquantitative evaluation and multivariate analysis. In the syngeneically transplanted aortas, the expression of TGF-beta 1, PDGF, and the two PDGF receptors in the neointima increased significantly with the extent of cold ischemia time. Furthermore, there was a significant induction of the latent TGF-beta binding protein in the neointima as well as TGF-beta 2 in the media, both correlating with the observation time after transplantation. In the allogeneic grafts, all examined proteins were already induced strongly 2 weeks after transplantation, even at the shortest ischemic period studied (1 hour). However, no positive correlation between growth factor expression and cold ischemia or observation time could be found. Double immunohistochemistry revealed that macrophages express PDGF and its receptors as well as TGF-beta 1. Smooth muscle cells express both types of PDGF receptors, and a few T cells express TGF-beta 1 as well as PDGF receptors. In summary, TGF-beta and PDGF are induced by allogeneic as well as ischemic stimuli in transplanted aortas, suggesting a role in the pathogenesis of transplant arteriosclerosis and representing a potential target for therapeutic intervention.

  • 47. Waltenberger, J.
    et al.
    Miyazono, K.
    Funa, K.
    Wanders, A.
    Fellstrom, B.
    Heldin, C. H.
    Transforming growth factor-beta and organ transplantation1993In: Transplant Proc, Vol. 25, no 2, 2038-40 p.Article in journal (Refereed)
  • 48. Waltenberger, J.
    et al.
    Wanders, A.
    Fellstrom, B.
    Miyazono, K.
    Heldin, C. H.
    Funa, K.
    Induction of transforming growth factor-beta during cardiac allograft rejection1993In: J Immunol, Vol. 151, no 2, 1147-57 p.Article in journal (Refereed)
    Abstract [en]

    The polypeptides of the transforming growth factor-beta (TGF-beta) family are potent endogenous immuno-regulators. Using a rat cardiac allograft transplant model, we investigated the expression of the precursor forms of TGF-beta 1, TGF-beta 2, and TGF-beta 3 and the latent TGF-beta binding protein (LTBP) by immunohistochemistry. The activity of TGF-beta in the extracts from transplanted as well as normal hearts was measured using a bioassay, and Northern blot analysis was performed on RNA extracts. The transplanted hearts were analyzed both during acute rejection up to 6 days and during chronic rejection up to 6 mo after transplantation and compared with normal controls. The animals of the chronic rejection group received cyclosporin A for immunosuppression. The TGF-beta bioactivity dramatically increased in the transplanted allografts during the chronic rejection process compared to the normal hearts, and so did the immunostaining as well as the mRNA levels for TGF-beta 1 and, to a lesser extent, the immunostaining for TGF-beta 2. TGF-beta 3 expression remained unchanged and was only found in the myocardium in trace amounts. During the acute rejection process up to 6 days after transplantation, TGF-beta immunoreactivity increased only slightly, whereas the TGF-beta mRNA was severalfold increased. Control animals treated with cyclosporin A showed a similar pattern at day 6 with regard to TGF-beta expression. LTBP was induced simultaneously with TGF-beta 1 and occurred within interstitial spaces of the myocardium. The TGF-beta was produced by macrophage-like infiltrating lymphocytes. In conclusion, highly elevated levels of TGF-beta and LTBP were found during chronic rejection of cardiac allografts in rats. The induction of TGF-beta may counteract the rejection process and could be useful for new therapeutic approaches in the prevention of allograft rejection.

  • 49. Wanders, A.
    et al.
    Akyurek, M. L.
    Larsson, E.
    Fellstrom, B. C.
    Presence of polymorphonuclear granulocytes during the early stage of transplant arteriosclerosis after prolonged ischemia in the rat1994In: Transpl Int, Vol. 7 Suppl 1, S371-5 p.Article in journal (Refereed)
    Abstract [en]

    The presence and function of polymorphonuclear granulocytes has been investigated, in particular, in the microcirculation in many short-term models of ischaemia/reperfusion injury. The aim of this study was to examine the presence of granulocytes in the aorta in a recently established long-term model of transplant arteriosclerosis, based on prolonged cold graft ischaemia time in the rat. Aortic grafts of PVG donors were subjected to two different cold ischaemia times of 1 and 4 h (n = 5 in each group) before an orthotopic transplantation to syngeneic recipients. The grafts were explanted shortly after various times post-reperfusion (7.5 min 24 h) and examined with conventional staining, immunohistochemistry and transmission electron microscopy for the presence of granulocytes. The results showed the presence of these cells adherent to the endothelial layer or in the subendothelial layer in grafts with both ischaemia times and with a maximum seen 2 h after transplantation. The internal elastic lamina was interrupted at sites of granulocyte adherence. We concluded that the polymorphonuclear granulocyte may be involved in the ischaemia/reperfusion injury in this model, thus, contributing to the development of accelerated transplant arteriosclerosis.

  • 50. Wanders, A.
    et al.
    Akyurek, M. L.
    Waltenberger, J.
    Ren, Z. P.
    Stafberg, C.
    Funa, K.
    Larsson, E.
    Fellstrom, B.
    Ischemia-induced transplant arteriosclerosis in the rat1995In: Arterioscler Thromb Vasc Biol, Vol. 15, no 1, 145-55 p.Article in journal (Refereed)
    Abstract [en]

    The effect of cold graft ischemia time on the development of transplant arteriosclerosis was investigated. Aorta grafts from DA or PVG rats were stored in a cold perfusion solution for 1, 4, or 24 hours before being orthotopically transplanted to PVG recipients. After observation times ranging from 2 to 8 weeks, the grafts were examined for various cell populations. Regional changes in the intima and media layers were measured by using an image analysis system. The arteriosclerosis-like changes seen in syngeneic grafts with the longest ischemia time could be almost as prominent as those seen in the allogeneic transplants. The magnitude of the regional intima changes in the syngeneic group correlated well with the ischemia time and in the allogeneic group with the observation time. The cell composition found in the intima and media of the allogeneic vessels consisted of macrophages, T-lymphocytes, MHC class II-expressing cells, and smooth muscle cells, whereas the syngeneic grafts contained almost exclusively smooth muscle cells and macrophages. We therefore conclude that the damage due to prolonged cold ischemia time is sufficient to cause pronounced graft arteriosclerosis. The pathophysiological mechanism leading to ischemia-induced arteriosclerosis is different from the one seen in the allogeneic situation.

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