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  • 1
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    Abstract 833: S100A4 interacts with p53 in the nucleus promoting its degradation.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 833-833
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 833-833
    Abstract: Background. S100A4 is a calcium binding protein which has no known enzymatic activity, but it exerts its function by binding and regulating other molecules, among which have been described Myosin and p53. S100A4 has been shown to be upregulated in several types of cancers, correlating with poor prognosis and metastasis. In a previous study (Orre et al., 2007), S100A4 has been shown to be involved the cellular response to ionizing irradiation in a p53 dependent manner; our aim here was therefore to investigate the cellular interaction partners of S100A4 in response to p53 and then, based on this data, to further elucidate the cellular function of S100A4. Observations. Nutlin-3A is a compound that specifically stabilizes p53 through inhibiting the interaction between p53 and mdm2. We could show an interaction between S100A4 and p53 via immunoprecipitation in the NSCLC cell line A549 (which has a high expression of S100A4 and a wild-type p53), and that this interaction is increased after Nutlin-3A treatment. The interaction has been independently confirmed via Proximity Ligation Assay, showing as well that the protein complexes are localized in the nucleus. Since this interaction increased after inhibition of the mdm2-p53 interaction, we hypothesized that S100A4 could be involved in regulation of p53 degradation; therefore we generated two cell lines from A549, infected with S100A4 shRNA (shS100A4) or an Empty Vector shRNA (shEV) as a control. Knockdown of S100A4 resulted in stabilization of p53 and transactivation of p53 transcriptional targets; it also resulted in higher sensitivity to cisplatin-mediated apoptotic cell death, measured as a drop in mitochondrial membrane potential, caspase-3 activation and AV/PI assay. We confirmed this finding by an independent method using transient S100A4 down regulation via siRNA; this resulted in an increase in p53 level and of p21 and MDM2 level in A549 adenocarcinoma cells. S100A4 siRNA resulted also in p53-dependent growth arrest, that was reversed after co-transfecting p53 siRNA. Conclusions. Our data show that S100A4 interacts with p53 increasing its degradation, resulting in higher cell viability and lower apoptosis after cisplatin treatment. A possible correlation in patients between S100A4 overexpression and cisplatin resistance could be used to drive treatment selection. Citation Format: Lukas Orre, Elena Panizza, Vitaliy Kaminskyy, Torbjörn Gräslund, Boris Zhivotovsky, Janne Lehtiö. S100A4 interacts with p53 in the nucleus promoting its degradation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 833. doi:10.1158/1538-7445.AM2013-833
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-833
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 2
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    Optimizing Analytical Depth and Cost Efficiency of IEF-LC/MS Proteomics
    Institute of Electrical and Electronics Engineers (IEEE) ; 2017
    In:  IEEE/ACM Transactions on Computational Biology and Bioinformatics Vol. 14, No. 2 ( 2017-3-1), p. 272-281
    Details
    In: IEEE/ACM Transactions on Computational Biology and Bioinformatics, Institute of Electrical and Electronics Engineers (IEEE), Vol. 14, No. 2 ( 2017-3-1), p. 272-281
    Type of Medium: Online Resource
    ISSN: 1545-5963 , 1557-9964 , 2374-0043
    URL: Article
    DOI: 10.1109/TCBB.2015.2452901
    Language: Unknown
    Publisher: Institute of Electrical and Electronics Engineers (IEEE)
    Publication Date: 2017
    detail.hit.zdb_id: 2158957-4
    SSG: 12
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  • 3
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    Abstract 3881: Breast cancer proteogenomics landscape defines subtype specific protein level regulations and reveals proteins coded by pseudogenic loci
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. 3881-3881
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 3881-3881
    Abstract: The advancement of mass spectrometry (MS) based proteomics has been tremendous in recent years and is expected to continue due to the rapid developments in instrument technology and bioinformatic analysis. These methods have enabled us to discover predictive protein markers for anti-estrogen treatment of estrogen receptor positive breast cancer 1, 2. Recently proteogenomics has emerged as an exciting area, combining proteomics with genomics and transcriptomics. We have published a proteogenomics workflow which can be used to discover new protein coding loci via an unbiased 6 reading frame translation (6-FT) search even in well-annotated higher eukaryotes such as human and mouse3. Herein we present a quantitative proteomics and proteogenomics analysis, using our high resolution isoelectric focusing (HiRIEF) aided proteogenomics method3,4, on breast tumors obtained from five breast cancer subtypes. Protein products from 12645 genes are identified and roughly 10000 proteins are quantified across the entire cohort of 45 breast cancer tissues. The resulting quantitative proteome landscape recapitulates the PAM50 subtypes. The breast cancer proteome defines clusters indicative of stroma, immune response, basal, adipocyte, proliferation, and steroid response related components. Additionally, a proteogenomics search of the 6-FT of the entire human genome reveals novel pseudogenic protein coding regions (n = 150) as well as peptides derived from lncRNA (n = 79). Finally, customized databases including variant peptides derived from SNPs, mutations, and splice junction peptides are used to analyze protein level events related to variants. This proteogenomics analysis for both new open reading frames and sequence variants reveals novel proteins expressed in a tumor specific manner in several studied individuals, with some being related to known sub-types. Taken together, this study reveals the proteome profiles are related to transcriptomics, copy number, and metabolic activity in specific tumors, proving our proteogenomics workflow provides novel information on the breast cancer molecular landscape. 1. Johansson, H.J. et al. Proteomics profiling identify CAPS as a potential predictive marker of tamoxifen resistance in estrogen receptor positive breast cancer. Clinical proteomics 12, 8 (2015). 2. Johansson, H.J. et al. Retinoic acid receptor alpha is associated with tamoxifen resistance in breast cancer. Nat Commun 4, 2175 (2013). 3. Branca, R.M. et al. HiRIEF LC-MS enables deep proteome coverage and unbiased proteogenomics. Nature methods 11, 59-62 (2014). 4. Boekel J, et.al. Multi-omic data analysis using Galaxy. Nature Biotechnol. 2015 Feb 6;33(2):137-9. Citation Format: Henrik Johansson, Yafeng Zhu, Mads Haugland, Kristine Sahlberg, Erik Fredlund, Mikael Huss, Nathaniel Vacanti, Miriam Range Aure, Bengt Sennblad, Sanela Kjellqvist, Lukas Orre, Ola Christian Lingjaerde, Anne-Lise Borresen-Dale, Janne Lehtio. Breast cancer proteogenomics landscape defines subtype specific protein level regulations and reveals proteins coded by pseudogenic loci. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3881.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-3881
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 4
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    Generation of Metal-Binding Staphylococci through Surface Display of Combinatorially Engineered Cellulose-Binding Domains
    American Society for Microbiology ; 2001
    In:  Applied and Environmental Microbiology Vol. 67, No. 10 ( 2001-10), p. 4678-4684
    Details
    In: Applied and Environmental Microbiology, American Society for Microbiology, Vol. 67, No. 10 ( 2001-10), p. 4678-4684
    Abstract: Ni 2+ -binding staphylococci were generated through surface display of combinatorially engineered variants of a fungal cellulose-binding domain (CBD) from Trichoderma reesei cellulase Cel7A. Novel CBD variants were generated by combinatorial protein engineering through the randomization of 11 amino acid positions, and eight potentially Ni 2+ -binding CBDs were selected by phage display technology. These new variants were subsequently genetically introduced into chimeric surface proteins for surface display on Staphylococcus carnosus cells. The expressed chimeric proteins were shown to be properly targeted to the cell wall of S. carnosus cells, since full-length proteins could be extracted and affinity purified. Surface accessibility for the chimeric proteins was demonstrated, and furthermore, the engineered CBDs, now devoid of cellulose-binding capacity, were shown to be functional with regard to metal binding, since the recombinant staphylococci had gained Ni 2+ -binding capacity. Potential environmental applications for such tailor-made metal-binding bacteria as bioadsorbents in biofilters or biosensors are discussed.
    Type of Medium: Online Resource
    ISSN: 0099-2240 , 1098-5336
    URL: Article
    DOI: 10.1128/AEM.67.10.4678-4684.2001
    RVK:
    WA 15000
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2001
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    SSG: 12
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  • 5
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    Systematic Analysis of Native Membrane Protein Complexes in Escherichia coli
    American Chemical Society (ACS) ; 2011
    In:  Journal of Proteome Research Vol. 10, No. 4 ( 2011-04), p. 1848-1859
    Details
    In: Journal of Proteome Research, American Chemical Society (ACS), Vol. 10, No. 4 ( 2011-04), p. 1848-1859
    Type of Medium: Online Resource
    ISSN: 1535-3893 , 1535-3907
    URL: Article
    DOI: 10.1021/pr101105c
    Language: English
    Publisher: American Chemical Society (ACS)
    Publication Date: 2011
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    SSG: 12
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  • 6
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    Plasma proteomic analyses and treatment predictive biomarker candidates in melanoma patients receiving immune checkpoint blockade or targeted therapy.
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 15_suppl ( 2019-05-20), p. 9574-9574
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. 9574-9574
    Abstract: 9574 Background: The introduction of immune checkpoint inhibitors (ICIs) or therapies targeting the MAPK-pathway (MAPKis) has significantly improved clinical outcomes in metastatic melanoma patients. Still, a large proportion of the patients become resistant to therapy and there is a need for treatment predictive biomarkers. The aim of this study was to analyze the treatment predictive biomarkers based on the plasma proteome of patients with metastatic melanoma treated with ICIs or MAPKis. Methods: We analyzed serial plasma samples from 48 patients with metastatic melanoma collected; 24 patients were treated with ICIs and with MAPKis, respcetively. A non-biased, high-resolution isoelectric focusing of peptides-liquid chromatography-mass spectrometry (HiRIEFLC-MS/MS)-based method, and with proximity ligation assays (PEA) targeting 92 immuno-oncology-related proteins were used.We analyzed the change in protein levels during treatment with a paired t-test, and their association with progression free survival (PFS) with Cox proportional hazards models. Results: HiRIEFLC-MS/MS detected 1,835 proteins.We detected statistically-significant log2-fold-changes in 109 protein levels out of 1,160 proteins tested (not corrected for multiple testing). PDCD-1 had the highest log2-fold change (FC = 1.27) after treatment (p = 0.02). After stratifying for treatment type, PDCD-1 levels increased in patients treated with ICIs (FC = 2.13, p= 0.0008), but not in MAPKis-treated patients. PEA analyses confirmed this observation. The PEA panel showed association between 44 proteins and shorter PFS (pcoefficient 〈 0.05, pLRT 〈 0.05, qLRT 〈 0.05), among them: LGALS1, CSF1, VEGFA, CASP8, CCL2, TNFSF14, ANGPT2, IL10, IL6, and ADGRG1. Of these, increase in plasma levels during treatment of LGALS1, CCL2 and ADGRG1 were associated with longer PFS. HiRIEF LC-MS/MS detected 69 proteins associated with PFS (pcoefficient 〈 0.05, pLRT 〈 0.05, qLRT 〈 0.05). Conclusions: By using HiRIEFLC-MS/MS, we could detect putative treatment predictive proteins in plasma from patients with metastatic melanoma treated with ICIs or MAPKis. Our findings require further validation.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.15_suppl.9574
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
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  • 7
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    Detection of Proteins Related to Therapeutic Outcome, Including Drug Resistance, in Acute Myeloid Leukemia Using Mass Spectrometry and Gel Based Proteomic Profiling.
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 2367-2367
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 2367-2367
    Abstract: To further improve and individualize curative treatment approaches for patients with AML, novel proteins and protein functions need to be discovered. In particular, the mechanisms responsible for chemotherapy resistance appear essential to unravel. Clinical proteomics may help to provide such information. We have used a chip-based technique, surface enhanced laser desorption/ionization mass spectrometry (SELDI-MS), to compare protein expression profiles in AML. With this technique proteins in the molecular weight area of 2–40 kDa can be spotted. For selected samples, a two-dimensional electrophoresis (2DE) method was employed, allowing detection of proteins between 15–120kDa. In the first part of the study, mononuclear peripheral blood cells were obtained from 8 AML patients clinically sensitive to and 7 patients clinically resistant to doxorubicin-containing induction chemotherapy. The clinical outcome correlated to results from parallel in vitro drug testing using the FMCA method. In addition, two variants of the human leukemic cell line CEM, one sensitive and one resistant to teniposide (CEM/VMI), were analysed. In the second part of the study, global proteomic profiles from 24 selected AML patients with good vs. poor clinical outcome (remission duration) were investigated. A total of 812 proteins were detected in the mononuclear cells obtained from the 15 doxorubicin-treated patients. Twenty of these proteins were distinguished as different between the sensitive vs. resistant patient groups. Assessing the CEM cell lines by utilizing four different affinity surfaces on ProteinChip™ arrays, approximately 450 peptides and proteins were detected. Between 29 and up to 65 proteins were detected as differentially expressed between the sensitive and the resistant CEM variants. Using the 2DE technology, approximately 1000 spots were matched on the CEM cell lines, with 47 clear expression level differences between the sub cell lines. In clustering analysis using the protein profile data we could demonstrate clear clustering of sensitive and resistant patient and cell line cells according to sensitivity measurements (IC50). Using these methods we have selected a panel of putative resistance related proteins, which are currently being identified and validated. Data from the second phase of the study, derived from 24 selected AML cell populations, are presently being analyzed. In conclusion, significant differences in protein profile expression were observed between cells obtained from AML patients with clinically divergent treatment responses. Further studies aim at identifying key proteins and protein functions to allow for improved therapeutic efficacy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.2367.2367
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
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  • 8
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    Global Proteomics in AML: Using SELDI-TOF MS on Diagnostic Samples To Identify Spectra and Protein Biomarkers Indicative of Prognosis.
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-16), p. 4436-4436
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 4436-4436
    Abstract: With the object to identify key proteins related to treatment response in acute myeloid leukemia (AML), and to eventually elucidate new targets for therapy, we have investigated protein spectra from diagnostic AML samples. Surface-enhanced laser desorption ionization time-of-flight mass spectrometry (SELDI-TOF MS) was used to spot proteins in the molecular weight area of 2–40 kDa. The samples were applied to two different chip surfaces (CM10 and Q10) for selective protein binding, avoiding the necessity of extensive purification and separation procedures prior to analysis. Peripheral blood samples from a total of 67 acute leukemia patients at diagnosis were analyzed. The cells were collected, frozen and stored in biobanks between 1988 and 2003. This provided a good basis for correlating detected protein peaks to a large number of clinical diagnostic and therapeutic variables and outcomes. Among the patients, aged 18 to 86 yrs, response to induction therapy was observed with complete remission (CR) durations ranging between 12 and 3701 days. The duration of first CR was used as a dichotomic variable in order to compare protein spectra from groups of patients with “good” and “bad” response, respectively, to chemotherapy. A peak detection and annotation software was developed in-house1,2 and employed. The software will be presented and a comparison to commercially available MS-spectral analysis methods will be provided. Initial results from MS profiling of the two response groups showed 18 significantly (p & gt;0.01) differently expressed peaks on anion exchange chips and 22 peaks on cation exchange surfaces. Ongoing work is focused on further development of the RS peak detection method, including the influence of normalisation and filtering of the SELDI data and supervised linear and non-linear modelling. In addition, identification of selected peaks and their relation to various clinical variables is in progress.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.4436.4436
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
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  • 9
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    Abstract 4956: Proteomics-based characterization of pathways involved in tamoxifen resistance in breast cancer cells
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. 4956-4956
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 4956-4956
    Abstract: Background: Although the introduction of tamoxifen (tam) has contributed to the improved survival of breast cancer patients there are those that relapse despite treatment due to de novo or acquired resistance to the drug. Since the mechanisms involved in tam resistance likely involve various pathways, techniques like mass spectrometry allowing simultaneous analyses of multiple proteins are of great value. Our aim is to identify pathways involved in tam resistance by using a mass spectrometry. Material and methods: Mass spectrometry based proteomics was used to investigate the proteomic changes associated with tam exposure using a tam-responsive and resistant cell line, MCF7 and MCF7/LCC2, respectively. Cytosolic and nuclear fractions were subjected to a shotgun proteomics approach. This included immobilised pH gradient-isoelectric focusing (IPG-IEF) of trypsinized peptides followed by Maldi-TOF/TOF mass spectrometry. Advanced biostatistics was applied to narrow identified targets to those which were significantly deregulated. Results: Preliminary results indicate a clear distinction between the nuclear and cytosolic fractions in regards to proteins. Various proteins were differentially deregulated in MCF7 compared to the resistant cell line both at the basal level and following tam treatment. At basal level, glucose-6-phosphate dehydrogenase, fatty acid synthase and keratin 18 were significantly upregulated in resistant cells as compared to parental MCF7 cells. Interestingly, tam treatment in MCF7 cells induced a significant increase in expression of several proteins involved in the p53 pathway and related to Huntingtin (HTT) while downregulating other proteins related to Retinoic Acid Receptor alpha (RARA). In contrast, resistant cells showed upregulation of proteins involved with RARA without exhibiting any specific deregulated proteins related to HTT or p53. Conclusions: Basal differences in protein expression were observed between the tam-sensitive and resistant cell line. Our results indicate that there are potentially deregulated proteins in the tam-sensitive cell line involved in p53, RARA, and HTT pathways in a manner that differs from the resistant one. The expression of the identified proteins will be further characterized. Understanding of the mechanisms involved in tam resistance can potentially aid in the development of new drugs and serve as prognostic biomarkers. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4956.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM10-4956
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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