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- Escudero Esparza, Astrid, et al.
(author)
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The novel complement inhibitor human CUB and Sushi multiple domains 1 (CSMD1) protein promotes factor I-mediated degradation of C4b and C3b and inhibits the membrane attack complex assembly.
- 2013
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In: FASEB Journal. - : Wiley. - 1530-6860 .- 0892-6638. ; 27:12, s. 5083-5093
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Journal article (peer-reviewed)abstract
- CUB and Sushi multiple domains 1 (CSMD1) is a transmembrane protein containing 15 consecutive complement control protein (CCP) domains, which are characteristic for complement inhibitors. We expressed a membrane-bound fragment of human CSMD1 composed of the 15 C-terminal CCP domains and demonstrated that it inhibits deposition of C3b by the classical pathway on the surface of Chinese hamster ovary cells by 70% at 6% serum and of C9 (component of membrane attack complex) by 90% at 1.25% serum. Furthermore, this fragment of CSMD1 served as a cofactor to factor I-mediated degradation of C3b. In all functional assays performed, well-characterized complement inhibitors were used as positive controls, whereas Coxsackie adenovirus receptor, a protein with no effect on complement, was a negative control. Moreover, attenuation of expression in human T47 breast cancer cells that express endogenous CSMD1 significantly increased C3b deposition on these cells by 45% at 8% serum compared with that for the controls. Furthermore, by expressing a soluble 17-21 CCP fragment of CSMD1, we found that CSMD1 inhibits complement by promoting factor I-mediated C4b/C3b degradation and inhibition of MAC assembly at the level of C7. Our results revealed a novel complement inhibitor for the classical and lectin pathways.-Escudero-Esparza, A., Kalchishkova, N., Kurbasic, E., Jiang, W. G., Blom, A. M. The novel complement inhibitor human CUB and Sushi multiple domains 1 (CSMD1) protein promotes factor I-mediated degradation of C4b and C3b and inhibits the membrane attack complex assembly.
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| 2. |
- Kurbasic, Emila, et al.
(author)
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Changes in glycoprotein expression between primary breast tumour and synchronous lymph node metastases or asynchronous distant metastases.
- 2015
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In: Clinical Proteomics. - : Springer Science and Business Media LLC. - 1559-0275 .- 1542-6416. ; 12:1
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Journal article (peer-reviewed)abstract
- Breast cancer is a very heterogeneous disease and some patients are cured by the surgical removal of the primary tumour whilst other patients suffer from metastasis and spreading of the disease, despite adjuvant therapy. A number of prognostic and treatment predictive factors have been identified such as tumour size, oestrogen (ER) and progesterone (PgR) receptor status, human epidermal growth factor receptor type 2 (HER2) status, histological grade, Ki67 and age. Lymph node involvement is also assessed during surgery to determine if the tumour has spread which requires dissection of the axilla and adjuvant treatment. The prognostic and treatment predictive factors assessing the nature of the tumour are all routinely based on the status of the primary tumour.
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| 3. |
- Kurbasic, Emila
(author)
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Landscaping the cell surface proteome of breast cancer : Following pathways through organelles to the plasma membrane
- 2017
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Doctoral thesis (other academic/artistic)abstract
- Breast cancer is one of the most common cancers in women. It is most commonly treated by the surgical removal of the tumour in combination with (neo)-adjuvant therapy (hormone, chemo- or radio- therapy before or after surgery). However, a large number of patients are over treated, with approximately 60% being given adjuvant therapy when already cured by surgery alone. This causes many undesirable side effects and cost hence, there is great need for new diagnostic and prognostic methods to decide if patients are in need of adjuvant therapy. A number of prognostic and treatment predictive factors have been established such as tumour size, hormone receptor status, histological grade and age. Hereditary predisposition to developing cancer can be a factor, with several high penetrance genes identified such as BRCA1 and BRCA2 genes as well as many as a dozen lower risk genes that are however additive in effect. Molecular subtyping has significant prognostic value allowing the differentiation of several subtypes having unique survival outcomes, particularly for tumours highly responsive or nonresponsive to hormonal or targeted drug therapies. Currently the prognostic and treatment predictive factors are mainly based on the primary tumour status, even though the distant metastases are the main reason for breast cancer related deaths. Thus, there is need for novel approaches with higher specificity and sensitivity in newly developed targeted therapies. The aim of this thesis was to understand the changes in breast cancer tumour cells and tissues, by comparing protein expression levels in different conditions, using mass spectrometry. Attention was specifically on the analysis of patient samples, with pairs of primary tumours and metastases, in order to try to understand what happens to allow tumour cells to be able to metastasise and to identify novel molecular markers. Hence we also investigated the biological functions of proteins by integrating information about the processes and pathways in which these proteins take part in order to be able to better understand the contribution of different proteins to breast cancer development. Further we have explored molecular classification markers for breast cancer tumours into major intrinsic subtypes. Our results demonstrated a great overlap of subtypes, using gene expression and protein expression profiling. In conclusion, all our findings together show the great need for improved and early cancer detection and treatment as well as need for development and promises of personalized medicine.
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| 4. |
- Waldemarson, Sofia, et al.
(author)
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Proteomic analysis of breast tumors confirms the mRNA intrinsic molecular subtypes using different classifiers : A large-scale analysis of fresh frozen tissue samples
- 2016
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In: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 18:1
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Journal article (peer-reviewed)abstract
- Background: Breast cancer is a complex and heterogeneous disease that is usually characterized by histological parameters such as tumor size, cellular arrangements/rearrangments, necrosis, nuclear grade and the mitotic index, leading to a set of around twenty subtypes. Together with clinical markers such as hormone receptor status, this classification has considerable prognostic value but there is a large variation in patient response to therapy. Gene expression profiling has provided molecular profiles characteristic of distinct subtypes of breast cancer that reflect the divergent cellular origins and degree of progression. Methods: Here we present a large-scale proteomic and transcriptomic profiling study of 477 sporadic and hereditary breast cancer tumors with matching mRNA expression analysis. Unsupervised hierarchal clustering was performed and selected proteins from large-scale tandem mass spectrometry (MS/MS) analysis were transferred into a highly multiplexed targeted selected reaction monitoring assay to classify tumors using a hierarchal cluster and support vector machine with leave one out cross-validation. Results: The subgroups formed upon unsupervised clustering agree very well with groups found at transcriptional level; however, the classifiers (genes or their respective protein products) differ almost entirely between the two datasets. In-depth analysis shows clear differences in pathways unique to each type, which may lie behind their different clinical outcomes. Targeted mass spectrometry analysis and supervised clustering correlate very well with subgroups determined by RNA classification and show convincing agreement with clinical parameters. Conclusions: This work demonstrates the merits of protein expression profiling for breast cancer stratification. These findings have important implications for the use of genomics and expression analysis for the prediction of protein expression, such as receptor status and drug target expression. The highly multiplexed MS assay is easily implemented in standard clinical chemistry practice, allowing rapid and cheap characterization of tumor tissue suitable for directing the choice of treatment.
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