| 1. |
- Akhoondi, Shahab, et al.
(författare)
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FBXW7/hCDC4 is a general tumor suppressor in human cancer
- 2007
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 67:19, s. 9006-9012
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Tidskriftsartikel (refereegranskat)abstract
- The ubiquitin-proteasome system is a major regulatory pathway of protein degradation and plays an important role in cellular division. Fbxw7 (or hCdc4), a member of the F-box family of proteins, which are substrate recognition components of the multisubunit ubiquitin ligase SCF (Skpl-Cdc53/ Cullin-F-box-protein), has been shown to mediate the ubiquitin-dependent proteolysis of several oncoproteins including cyclin El, c-Myc, c-Jun, and Notch. The oncogenic potential of Fbxw7 substrates, frequent allelic loss in human cancers, and demonstration that mutation of FBXW7 cooperates with p53 in mouse tumorigenesis have suggested that Fbxw7 could function as a tumor suppressor in human cancer. Here, we carry out an extensive genetic screen of primary tumors to evaluate the role of FBXW7 as a tumor suppressor in human tumorigenesis. Our results indicate that FBXW7 is inactivated by mutation in diverse human cancer types with an overall mutation frequency of ∼ 6%. The highest mutation frequencies were found in tumors of the bile duct (cholangio-carcinomas, 35%), blood (T-cell acute lymphocytic leukemia, 31%), endometrium (9%), colon (9%), and stomach (6%). Approximately 43% of all mutations occur at two mutational "hotspots," which alter Arg residues (Arg465 and Arg479) that are critical for substrate recognition. Furthermore, we show that Fbxw7Arg465 hotspot mutant can abrogate wild-type Fbxw7 function through a dominant negative mechanism. Our study is the first comprehensive screen of FBXW7 mutations in various human malignancies and shows that FBXW7 is a general tumor suppressor in human cancer.
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| 2. |
- Båth, Magnus, 1974, et al.
(författare)
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A conceptual optimisation strategy for radiography in a digital environment.
- 2005
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Ingår i: Radiation protection dosimetry. - : Oxford University Press (OUP). - 0144-8420 .- 1742-3406. ; 114:1-3, s. 230-5
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Tidskriftsartikel (refereegranskat)abstract
- Using a completely digital environment for the entire imaging process leads to new possibilities for optimisation of radiography since many restrictions of screen/film systems, such as the small dynamic range and the lack of possibilities for image processing, do not apply any longer. However, at the same time these new possibilities lead to a more complicated optimisation process, since more freedom is given to alter parameters. This paper focuses on describing an optimisation strategy that concentrates on taking advantage of the conceptual differences between digital systems and screen/film systems. The strategy can be summarised as: (a) always include the anatomical background during the optimisation, (b) perform all comparisons at a constant effective dose and (c) separate the image display stage from the image collection stage. A three-step process is proposed where the optimal setting of the technique parameters is determined at first, followed by an optimisation of the image processing. In the final step the optimal dose level-given the optimal settings of the image collection and image display stages-is determined.
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| 3. |
- Gao, Ying, et al.
(författare)
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Granule targeting of soluble tumor necrosis factor (TNF) receptor expressed during granulopoietic maturation in murine bone marrow cells.
- 2006
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Ingår i: European Cytokine Network. - 1952-4005. ; 17:2, s. 98-108
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Tidskriftsartikel (refereegranskat)abstract
- In this experiment, we explored the potential of secretory lysosomes of hematopoietic cells to act as vehicles for immunomodulatory protein delivery at an inflammation site. We investigated whether exogenous soluble TNF-receptor 1 (sTNFR1) could be expressed in primary hematopoietic progenitor cells and become targeted for storage and secretion during granulopoietic differentiation. An sTNFR1 construct with a transmembrane domain (tm) and a cytosol sorting signal (Y) taken from CD63, was retrovirally transduced to lineage-negative murine hematopoietic bone marrow stem/progenitor cells. This process was followed by cytokine-driven granulopoietic maturation. The sTNFR1-tm-Y was found to be synthesized in precursor cells and to persist in mature granulocytes and monocytes/macrophages. Immunofluorescence-localization studies showed a granule pattern of sTNFR1-tm-Y in both precursor and mature granulocytes and secretion to phagosomes after ingestion of bacteria. Immunoelectron microscopy revealed co-localization between the sTNFR1-tm-Y and the primary (azurophil) granule marker myeloperoxidase. Collectively, our results demonstrated granule targeting, storage, and secretion of exogenous sTNFR1-tm-Y constitutively expressed during normal granulopoietic differentiation. These findings support the concept of using storage organelles of circulating hematopoietic cells as vehicles for targeting sites of inflammation with immunoregulatory agents.
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| 4. |
- Hansson, Jonny, et al.
(författare)
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An optimisation strategy in a digital environment applied to neonatal chest imaging.
- 2005
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Ingår i: Radiation protection dosimetry. - : Oxford University Press (OUP). - 0144-8420 .- 1742-3406. ; 114:1-3, s. 278-85
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to find the optimum tube voltage for neonatal chest imaging in computed radiography. The study was designed to take full advantage of the benefits of digital imaging, for example, by comparing the tube voltages at constant effective dose. A phantom study using a living rabbit was first conducted. Images were collected at tube voltages ranging from 40 to 90 kV(p). The reproduction of four structures (central vessels, peripheral vessels, carina and thoracic vertebrae) was rated by 10 radiologists. The reproduction of both central and peripheral vessels was relatively independent of tube voltage. The carina was better reproduced at higher tube voltages whereas the opposite was true for the thoracic vertebrae. Based on the higher importance of the reproduction of the carina it was decided that 90 kV(p) was the optimal tube voltage. To validate the result from the phantom study, a follow-up study was conducted in which images of neonates collected at the tube voltage regularly used at Sahlgrenska University Hospital (70 kV(p)) were compared with images collected at the tube voltage proposed by the phantom study. The follow-up study confirmed the results from the phantom study that the reproduction of the carina was better at 90 than at 70 kV(p). In conclusion, for neonatal chest imaging-given the same effective dose-90 kVp gives better reproduction of important structures than the regularly used 70 kV(p).
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| 5. |
- Hansson, Markus, et al.
(författare)
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Biosynthesis, processing, and sorting of human myeloperoxidase.
- 2006
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Ingår i: Archives of Biochemistry and Biophysics. - : Elsevier BV. - 0003-9861. ; 445:2, s. 214-224
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Forskningsöversikt (refereegranskat)abstract
- Exclusively synthesized by normal neutrophil and monocyte precursor cells, myeloperoxidase (MPO) functions not only in host defense by mediating efficient microbial killing but also can contribute to progressive tissue damage in chronic inflammatory states Such as atherosclerosis. The biosynthetic precursor, apoproMPO, is processed slowly in the ER, undergoing cotranslational N-glycosylation, transient interactions with the molecular chaperones calreticulin and calnexin, and heme incorporation to generate enzymatically active proMPO that is competent for export into the Golgi. After exiting the Golgi the propeptide is removed prior to final proteolytic processing in azurophil granules, resulting in formation of a symmetric MPO homodimer linked by a disulfide bond. Some proMPO escapes granule targeting and becomes constitutively secreted to the extracellular environment. Although the precise mechanism is Unknown, the pro-segirient is required for normal processing and targeting. as propeptide-deleted MPO precursor is either degraded or constitutively secreted. Characterizing the molecular consequences of naturally Occurring mutations that cause inherited MPO deficiency provides unique insight into the structural determinants of MPO involved in biosynthesis, processing and targeting. (C) 2005 Elsevier Inc. All rights reserved.
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| 6. |
- Hansson, Markus, et al.
(författare)
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Biphenotypic bigenotypic lymphoma with simultaneous expression of PAX5/BSAP and B- and T-cell markers
- 2007
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Ingår i: European Journal of Haematology. - : Wiley. - 1600-0609 .- 0902-4441. ; 79:2, s. 159-165
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Tidskriftsartikel (refereegranskat)abstract
- Lymphomas are currently categorized according to their origin from a B or T lymphocyte. Immature and less commonly mature (peripheral) lymphomas may harbor rearrangements of both the B- and T-cell antigen receptor genes (dual genotype or bigenotype). Rarely, cells in lymphoma with a single genotype simultaneously express both B- and T-cell markers (biphenotypic lymphomas). We discuss the diagnostic and clinical implications in the case of a 42-yr-old female with a peripheral CD30(+) lymphoma that displayed both characteristic B- and T-cell surface antigens and clonal rearrangement of B- and T-cell antigen receptor gene loci. Simultaneous nuclear expression of the transcription factor gene PAX5 suggested that this major driver of B-cell differentiation did not preclude expression of CD3 epsilon, generally assumed to be a T-cell associated antigen.
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| 7. |
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| 8. |
- Hansson, Markus
(författare)
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Sårbarhet och möjligheter - Om papperslösa immigranters situation i majoritetssamhället
- 2008
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- This study aims to increase the knowledge and understanding regarding the situation for undocumented immigrants in the Scandinavian welfare states, mainly from a Swedish perspective, but the situation in Denmark is also included in the discussion. Sweden and Denmark position themselves at the opposite sides of the spectrum regarding immigration policies within the European Union; Swedish immigration policies are regarded as one of the most liberal in the EU, whilst the Danish policies are considered to be among the harshest. The results from this study support the theory that the immigration policies of the host country impose a major influence on the daily lives of undocumented immigrants. Perhaps the most distinguishing characteristic of the undocumented experience, revealed through interviews with undocumented immigrants and voluntary aides in associations formed to help these people, is the high degree of vulnerability in the majority society. This vulnerability is a product of the lack of legal status, resulting in a vast discrepancy between the rights of the citizen and the rights of the undocumented immigrant. Subjectively, this vulnerability is perceived by the undocumented immigrant primarily in two ways, which I have chosen to refer to as legal vulnerability and social vulnerability. Legal vulnerability denotes a permanent disadvantage for the undocumented immigrant in the relationship to the citizen, in any situation that may occur. This means for example that the undocumented immigrant is effectively prevented from reporting any crime or negotiating salary levels that are perceived as unfair, with an employer. Social vulnerability refers to the exclusion from the official institutions of the welfare state, such as healthcare, social services and education. This vulnerability means that the undocumented immigrant has to seek their opportunities through alternative channels, such as informal institutions (i.e. the personal, social network, voluntary organizations etc.) or through an informal use of formal institutions. Different categories of undocumented immigrants handle their vulnerability in different ways. Undocumented immigrants that don’t suffer from a high degree of political vulnerability in their home country tend to have a larger interface with the host society than political refugees, which make them somewhat less vulnerable as undocumented immigrants as well, since they are more likely to have broader social networks. The possession of social capital as a compensation for the lack of human capital is more important for immigrants in general than for natives. Undocumented immigrants are even more dependent on social capital than their documented compatriots. Social capital is generated in the ethnical networks through the mechanisms of bounded solidarity and enforceable trust. Cultural distance and lack of options to the benefits provided by the networks make the networks stronger. The stronger the social networks, the more social capital they generate. Being the ones most dependant on social capital, the undocumented immigrants are also the most subordinate in those networks. They are frequently exploited by their documented compatriots in the ethnic market, and the strong ties of the ethnic networks often hinder the members’ integration in the majority society. The results from this study indicate that the harsher immigration laws of Denmark makes the undocumented immigrants go “further underground” and thus making them more vulnerable than the undocumented immigrants in Sweden.
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| 9. |
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| 10. |
- Johansson, Åsa, et al.
(författare)
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Secretory lysosome targeting and induced secretion of human soluble TNF-alpha receptor in murine hematopoietic cells in vivo as a principle for immunoregulation in inflammation and malignancy
- 2009
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Ingår i: Experimental Hematology. - : Elsevier BV. - 0301-472X .- 1873-2399. ; 37:8, s. 969-978
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Systemic administration of immunotherapeutics often gives rise to severe side effects. A local deposition, using secretory lysosomes of hematopoietic cells as vehicles for delivery, can overcome this problem. In the present study, the validity of this concept was investigated using retroviral transduction of the human soluble tumor necrosis factor-alpha receptor 1 (hsTNFR1) into murine bone marrow cells, followed by transfer of the genetically modified cells into irradiated mice. MATERIALS AND METHODS: Bone marrow cells from donor mice were transduced with retroviral vector containing cDNA for hsTNFR1, together with a transmembrane domain and a tyrosine-sorting signal in order to facilitate the endoplasmic reticulum export and to achieve secretory lysosome loading. Expression of hsTNFR1 in recipient mice was investigated using flow cytometry and Western blot. Enzyme-linked immunosorbent assay was used to measure levels of tumor necrosis factor-alpha, hsTNFR1, and murine TNFR1. RESULTS: Stable long-term expression of hsTNFR1 was achieved in transplanted mice. Hematopoietic cells, such as natural killer, T and B cells, and neutrophils contained hsTNFR1. Exposure of lipopolysaccaride (in vivo) or phorbole-myristrate esterase (in vitro) induced significant secretion of hsTNFR1. Release of endogeneous murine sTNFR1 did not differ between cells transduced with hsTNFR1 or an "empty" vector. CONCLUSION: Long-term expression in vivo and inducible secretion of hsTNFR1 in murine hematopoietic cells support the potential use of storage organelles in hematopoietic cells as vehicles for targeting inflamed/malignant sites with therapeutically active agents.
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