| 1. |
- Baldetorp, Bo, et al.
(author)
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Analysis of protein expression in pure cell nuclei populations isolated from human breast cancer tissue by DNA flow cytometric sorting.
- 2010
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In: Journal of Proteomics. - : Elsevier BV. - 1874-3919. ; 73, s. 1111-1116
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Journal article (peer-reviewed)abstract
- In this study, cell nuclei from aneuploid breast cancer samples were sorted with respect to DNA content into pure diploid and aneuploid fractions using flow cytometry. The nuclear proteins were then separated by one-dimensional gel electrophoresis (1D-PAGE) and differences in protein expression patterns, between diploid and aneuploid nuclei from the same tumours, were compared. Using a combination of peptide finger printing and peptide identification by MALDI-TOF mass spectrometry, we identified proteins and confirmed that the proteins were of nuclear origins. The results in this study add further information to the knowledge about the breast cancer disease complexity and heterogeneity at molecular level. For some of the tumours studied different nuclei protein patterns were obtained, in the diploid respective aneuploid nuclei populations, whilst other tumours did not show these differences.
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| 2. |
- Sugihara, Yutaka, et al.
(author)
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A New Look at Drugs Targeting Malignant Melanoma – An Application for Mass Spectrometry Imaging
- 2014
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In: Proteomics. - : Wiley. - 1615-9861 .- 1615-9853. ; 14:17-18, s. 1963-1970
-
Research review (peer-reviewed)abstract
- Malignant melanoma (MM) patients are being treated with an increasing number of personalized medicine (PM) drugs, several of which are small molecule drugs developed to treat patients with specific disease genotypes and phenotypes. In particular, the clinical application of protein kinase inhibitors (PKI) has been highly effective for certain subsets of MM patients. Vemurafenib, a PKI targeting BRAF mutated protein, has shown significant efficacy in slowing disease progression. In this paper we provide an overview of this new generation of targeted drugs, and demonstrate the first data on localization of personalized medicine drugs within tumor compartments. In this study, we have introduced matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) to provide new information on one of the drugs currently used in the PM treatment of MM, vemurafenib. In a proof-of-concept in vitro study, MALDI-MSI was used to identify vemurafenib applied to metastatic lymph nodes tumors of subjects attending the regional hospital network of Southern Sweden. The paper provides evidence of BRAF overexpression in tumors isolated from MM patients and localization of the specific drug targeting BRAF, vemurafenib, using mass spectrometry fragment ion signatures. Our ability to determine drug uptake at the target sites of directed therapy provides important opportunity for increasing our understanding about the mode of action of drug activity within the disease environment.
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| 3. |
- Welinder, Charlotte, et al.
(author)
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A protein deep sequencing evaluation of metastatic melanoma tissues.
- 2015
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:4
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Journal article (peer-reviewed)abstract
- Malignant melanoma has the highest increase of incidence of malignancies in the western world. In early stages, front line therapy is surgical excision of the primary tumor. Metastatic disease has very limited possibilities for cure. Recently, several protein kinase inhibitors and immune modifiers have shown promising clinical results but drug resistance in metastasized melanoma remains a major problem. The need for routine clinical biomarkers to follow disease progression and treatment efficacy is high. The aim of the present study was to build a protein sequence database in metastatic melanoma, searching for novel, relevant biomarkers. Ten lymph node metastases (South-Swedish Malignant Melanoma Biobank) were subjected to global protein expression analysis using two proteomics approaches (with/without orthogonal fractionation). Fractionation produced higher numbers of protein identifications (4284). Combining both methods, 5326 unique proteins were identified (2641 proteins overlapping). Deep mining proteomics may contribute to the discovery of novel biomarkers for metastatic melanoma, for example dividing the samples into two metastatic melanoma "genomic subtypes", ("pigmentation" and "high immune") revealed several proteins showing differential levels of expression. In conclusion, the present study provides an initial version of a metastatic melanoma protein sequence database producing a total of more than 5000 unique protein identifications. The raw data have been deposited to the ProteomeXchange with identifiers PXD001724 and PXD001725.
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| 4. |
- Welinder, Charlotte, et al.
(author)
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Analysis of Alpha-Synuclein in Malignant Melanoma - Development of a SRM Quantification Assay.
- 2014
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:10
-
Journal article (peer-reviewed)abstract
- Globally, malignant melanoma shows a steady increase in the incidence among cancer diseases. Malignant melanoma represents a cancer type where currently no biomarker or diagnostics is available to identify disease stage, progression of disease or personalized medicine treatment. The aim of this study was to assess the tissue expression of alpha-synuclein, a protein implicated in several disease processes, in metastatic tissues from malignant melanoma patients. A targeted Selected Reaction Monitoring (SRM) assay was developed and utilized together with stable isotope labeling for the relative quantification of two target peptides of alpha-synuclein. Analysis of alpha-synuclein protein was then performed in ten metastatic tissue samples from the Lund Melanoma Biobank. The calibration curve using peak area ratio (heavy/light) versus concentration ratios showed linear regression over three orders of magnitude, for both of the selected target peptide sequences. In support of the measurements of specific protein expression levels, we also observed significant correlation between the protein and mRNA levels of alpha-synuclein in these tissues. Investigating levels of tissue alpha-synuclein may add novel aspect to biomarker development in melanoma, help to understand disease mechanisms and ultimately contribute to discriminate melanoma patients with different prognosis.
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| 5. |
- Welinder, Charlotte, et al.
(author)
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Establishing a Southern Swedish Malignant Melanoma OMICS and Biobank Clinical Capability
- 2013
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In: Clinical and Translational Medicine. - : Wiley. - 2001-1326. ; 2:1
-
Journal article (peer-reviewed)abstract
- Background: The Southern Swedish Malignant Melanoma (SSMM) research team is a truly cross functional group with members from oncology, clinical, surgery, bioinformatics, proteomics, and genomics initiatives. The SSMM’s objectives and goals are to develop, build and utilize cutting edge biobanks and OMICS platforms to better understand disease pathology and drug mechanisms. Within the research team there are members who daily diagnose patients with suspect melanomas, do follow-ups on malignant melanoma patients and remove primary or metastatic lesions by surgery. This inter-disciplinary clinical patient care ensures a competence build as well as a best practice procedure where the patient benefits. The science output in these resulting study outcomes further strengthens the build of healthcare benefit in the complex challenges of malignant melanoma pathophysiology that is addressed by the novel personalized medicines entering the market. These patient biobank archives will be fully automated with novel ultralow temperature biobank storage units and used as a clinical resource. Methods: Clinical materials from patients before, during and after treatments, with clinical end points are being collected. Tissue samples as well as bio-fluid samples such as blood fractions, plasma, serum and whole blood will be archived in 384-high density sample tube formats. We are developing standardized approaches for patient selections, patient sampling, sample-processing and analysis platforms with dedicated protein assays and genomics platforms that will hold value for the research community. Results: An IT-infrastructure using a laboratory information management system (LIMS) has been established, that will be the key interface for the research teams in order to share and explore data generated within the project. The cross-site data repository in Lund will form the basis for sample processing, together with biological samples in southern Sweden, including blood fractions and tumor tissues. Clinical registries are being associated with the biobank materials, including pathology reports on disease diagnosis on the MM patients. Conclusions: We provide data on the developments of protein profiling and targeted protein target assays on isolated melanoma tumors, as well as reference blood standards that is used by the team members in the respective laboratories. These pilot data show biobank access and feasibility of performing quantitative proteomics in MM biobank repositories collected in southern Sweden.
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| 6. |
- Welinder, Charlotte, et al.
(author)
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Feasibility Study on Measuring Selected Proteins in Malignant Melanoma Tissue by SRM Quantification.
- 2014
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In: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 13:3, s. 1315-1326
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Journal article (peer-reviewed)abstract
- Currently there are no clinically recognized molecular biomarkers for malignant melanoma (MM) for either diagnosing disease stage or measuring response to therapy. The aim of this feasibility study was to develop targeted selected reaction monitoring (SRM) assays for identifying candidate protein biomarkers in metastatic melanoma tissue lysate. In a pilot study applying the SRM assay, the tissue expression of nine selected proteins [complement 3 (C3), T-cell surface glycoprotein CD3 epsilon chain E (CD3E), dermatopontin, minichromosome maintenance complex component (MCM4), premelanosome protein (PMEL), S100 calcium binding protein A8 (S100A8), S100 calcium binding protein A13 (S100A13), transgelin-2 and S100B] was quantified in a small cohort of metastatic malignant melanoma patients. The SRM assay was developed using a TSQ Vantage triple quadrupole mass spectrometer that generated highly accurate peptide quantification. Repeated injection of internal standards spiked into matrix showed relative standard deviation (RSD) from 6% to 15%. All nine target proteins were identified in tumor lysate digests spiked with heavy peptide standards. The multiplex SRM peptide assay panel was then measured and quantified on a set of frozen MM tissue samples obtained from the Malignant Melanoma Biobank collected in Lund, Sweden. All nine proteins could be accurately quantified using the new SRM assay format. This study provides preliminary data on the heterogeneity of biomarker expression within MM patients. The S100B protein, which is clinically used as the pathology identifier of MM, was identified in 9 out of 10 MM tissue lysates. The use of the targeted SRM assay provides potential advancements in the diagnosis of MM that can aid in future assessments of disease in melanoma patients.
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| 7. |
- Abolfathi, Bela, et al.
(author)
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The Fourteenth Data Release of the Sloan Digital Sky Survey : First Spectroscopic Data from the Extended Baryon Oscillation Spectroscopic Survey and from the Second Phase of the Apache Point Observatory Galactic Evolution Experiment
- 2018
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In: Astrophysical Journal Supplement Series. - : IOP Publishing Ltd. - 0067-0049 .- 1538-4365. ; 235:2
-
Journal article (peer-reviewed)abstract
- The fourth generation of the Sloan Digital Sky Survey (SDSS-IV) has been in operation since 2014 July. This paper describes the second data release from this phase, and the 14th from SDSS overall (making this Data Release Fourteen or DR14). This release makes the data taken by SDSS-IV in its first two years of operation (2014-2016 July) public. Like all previous SDSS releases, DR14 is cumulative, including the most recent reductions and calibrations of all data taken by SDSS since the first phase began operations in 2000. New in DR14 is the first public release of data from the extended Baryon Oscillation Spectroscopic Survey; the first data from the second phase of the Apache Point Observatory (APO) Galactic Evolution Experiment (APOGEE-2), including stellar parameter estimates from an innovative data-driven machine-learning algorithm known as "The Cannon"; and almost twice as many data cubes from the Mapping Nearby Galaxies at APO (MaNGA) survey as were in the previous release (N = 2812 in total). This paper describes the location and format of the publicly available data from the SDSS-IV surveys. We provide references to the important technical papers describing how these data have been taken (both targeting and observation details) and processed for scientific use. The SDSS web site (www.sdss.org) has been updated for this release and provides links to data downloads, as well as tutorials and examples of data use. SDSS-IV is planning to continue to collect astronomical data until 2020 and will be followed by SDSS-V.
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| 8. |
- Andersen, Mette K., et al.
(author)
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Association of variants in HLA-DQA1-DQB1, PTPN22, INS, and CTLA4 with GAD autoantibodies and insulin secretion in nondiabetic adults of the Botnia Prospective Study
- 2012
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In: European Journal of Endocrinology. - 1479-683X. ; 167:1, s. 27-33
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Journal article (peer-reviewed)abstract
- Objective: Previously, we observed an association between family history of type 1 diabetes and development of non-insulin-dependent diabetes. The aims of this study were to assess whether type 1 diabetes susceptibility gene variants explain this association and investigate the effect of the variants on insulin secretion and presence of glutamic acid decarboxylase autoantibodies (GADA) in nondiabetic adults. Design and methods: Polymorphisms in INS (rs689), PTPN22 (rs2476601), CTLA4 (rs3087243), and the HLA-DQA1-DQB1 regions (rs2187668 and rs7454108 tagging HLA-DQ2.5 and HLA-DQ8 respectively) were genotyped in the Botnia Prospective Study (n=2764), in which initially nondiabetic participants were followed for a mean of 8.1 years. Results: The variants did not explain the association between family history of type 1 diabetes and development of non-insulin-dependent diabetes. In these nondiabetic adults, HLA-DQ and PTPN22 risk genotypes were associated with GADA (HLA-DQ2.5/HLA-DQ8 or HLA-DQ8: OR (95% CI): 1.7 (1.3-2.3), P=0.0004; PTPN22 CT/TT: OR: 1.6 (1.2-2.2), P=0.003; P values were adjusted for sex, age, BMI, and follow-up time). A higher genetic risk score was associated with lower insulin secretion (insulinogenic index: 13.27 (16.27) vs 12.69 (15.27) vs 10.98 (13.06), P=0.02) and better insulin sensitivity index (risk score of 0-1 vs 2-3 vs 4-6: 142 (111) vs 144 (118) vs 157 (127), P=0.01) at baseline and a poorer capacity to compensate for the increased insulin demand after follow-up. Conclusions: In nondiabetic adults, HLA-DQ2.5/HLA-DQ8 and PTPN22 CT/TT genotypes were associated with GADA.
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| 9. |
- Andersen, Mette K., et al.
(author)
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Latent Autoimmune Diabetes in Adults Differs Genetically From Classical Type 1 Diabetes Diagnosed After the Age of 35 Years
- 2010
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In: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 33:9, s. 2062-2064
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Journal article (peer-reviewed)abstract
- OBJECTIVE- We studied differences between patients with latent autoimmune diabetes in adults (LADA), type 2 diabetes, and classical type 1 diabetes diagnosed after age 35 years. RESEARCH DESIGN AND METHODS- Polymorphisms in HLA-DQB1, INS, PTPN22, and CTLA4 were genotyped in patients with LADA (n = 213), type 1 diabetes diagnosed at >35 years of age (T1D(>35y); n = 257) or <20 years of age (T1D(<20y); n = 158), and type 2 diabetes. RESULTS- Although patients with LADA had an increased frequency of HLA-DQB1 and PTPN22 risk genotypes and alleles compared with type 2 diabetic subjects, the frequency was significantly lower compared with T1D(>35y) patients. Genotype frequencies, measures of insulin secretion, and metabolic traits within LADA differed according to GAD antibody (GADA) quartiles, but even the highest quartile differed from type 1 diabetes. Having two or more risk genotypes was associated with lower C-peptide concentrations in LADA. CONCLUSIONS- LADA patients differed genetically and phenotypically from both T1D(>35y) and type 2 diabetic patients in a manner dependent on GADA levels.
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| 10. |
- Ardesjö Lundgren, Brita, et al.
(author)
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Identification of complement C3 as an autoantigen in inflammatory bowel disease.
- 2010
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In: European journal of gastroenterology & hepatology. - 1473-5687 .- 0954-691X. ; 22:4, s. 429-436
-
Journal article (peer-reviewed)abstract
- OBJECTIVE: Autoantibodies against goblet cells in the gastrointestinal mucosa have been described in patients with inflammatory bowel disease (IBD) but a corresponding autoantigen has not yet been identified. The aim of this study was to identify such an antigen. METHODS: First, 10 candidate autoantigens were discarded based on double stainings of appendiceal sections and a mucin-producing cell line (HT29-mtx). Second, an appendiceal cDNA library was immunoscreened with IBD sera. RESULTS: Three out of 48 positive clones were identified as complement C3. Using immunoprecipitation of in vitro transcribed and translated C3, seven of 17 primary sclerosing cholangitis patient sera, 15 of 65 IBD sera, and none out of 54 sera from healthy blood donors showed C3 immunoreactivity. The results were confirmed using western blot and an enzyme-linked immunosorbent assay with alternative sources of C3 protein. CONCLUSION: In conclusion, we have identified complement C3 as a potential autoantigen in IBD and primary sclerosing cholangitis.
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| 11. |
- Arvidsson, Alf, et al.
(author)
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För Sverige i tiden?
- 2009
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In: Kulturella perspektiv - Svensk etnologisk tidskrift. - Umeå. - 1102-7908. ; 18:2, s. 2-8
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Journal article (peer-reviewed)
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| 12. |
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| 13. |
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| 14. |
- Berlin, Marie, et al.
(author)
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Dental health care utilization among young adults who were in societal out-of-home care as children : a Swedish national cohort study
- 2018
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In: International Journal of Social Welfare. - : John Wiley & Sons. - 1369-6866 .- 1468-2397. ; 27:4, s. 325-336
-
Journal article (peer-reviewed)abstract
- We used Swedish national registers to analyse dental health care among young adults with childhood experience of out‐of‐home care (OHC), in Cox regression analyses. All 1.7 million Swedish residents born in 1980–1994 were included, of whom 4% had been in OHC. The population was followed up in the Dental Health Register from age 20 to 29, during the period 2009–2014. We found that persons with short or long OHC experience made emergency dental care visits more often than their majority‐population peers: 17–23% versus 9–10%, (adjusted Hazard ratios [HR:s] 1.60–2.02); they more often had tooth extractions, 9–12% versus 3% (HR:s 2.33–3.03); but less regularly visited a dentist for planned check‐ups, 61–77% versus 80–87% (HR:s 0.76–0.78). Since dental health in young adulthood reflects dental health and dental care in childhood, the findings of this study call for improved preventive dental health care for children in OHC.
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| 15. |
- Betancourt, Lazaro Hiram, et al.
(author)
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Improved survival prognostication of node-positive malignant melanoma patients utilizing shotgun proteomics guided by histopathological characterization and genomic data
- 2019
-
In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1
-
Journal article (peer-reviewed)abstract
- Metastatic melanoma is one of the most common deadly cancers, and robust biomarkers are still needed, e.g. to predict survival and treatment efficiency. Here, protein expression analysis of one hundred eleven melanoma lymph node metastases using high resolution mass spectrometry is coupled with in-depth histopathology analysis, clinical data and genomics profiles. This broad view of protein expression allowed to identify novel candidate protein markers that improved prediction of survival in melanoma patients. Some of the prognostic proteins have not been reported in the context of melanoma before, and few of them exhibit unexpected relationship to survival, which likely reflects the limitations of current knowledge on melanoma and shows the potential of proteomics in clinical cancer research.
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| 16. |
- Betancourt, Lazaro Hiram, et al.
(author)
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The hidden story of heterogeneous B-raf V600E mutation quantitative protein expression in metastatic melanoma—association with clinical outcome and tumor phenotypes
- 2019
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In: Cancers. - : MDPI AG. - 2072-6694. ; 11:12
-
Journal article (peer-reviewed)abstract
- In comparison to other human cancer types, malignant melanoma exhibits the greatest amount of heterogeneity. After DNA-based detection of the BRAF V600E mutation in melanoma patients, targeted inhibitor treatment is the current recommendation. This approach, however, does not take the abundance of the therapeutic target, i.e., the B-raf V600E protein, into consideration. As shown by immunohistochemistry, the protein expression profiles of metastatic melanomas clearly reveal the existence of inter-and intra-tumor variability. Nevertheless, the technique is only semi-quantitative. To quantitate the mutant protein there is a fundamental need for more precise techniques that are aimed at defining the currently non-existent link between the levels of the target protein and subsequent drug efficacy. Using cutting-edge mass spectrometry combined with DNA and mRNA sequencing, the mutated B-raf protein within metastatic tumors was quantitated for the first time. B-raf V600E protein analysis revealed a subjacent layer of heterogeneity for mutation-positive metastatic melanomas. These were characterized into two distinct groups with different tumor morphologies, protein profiles and patient clinical outcomes. This study provides evidence that a higher level of expression in the mutated protein is associated with a more aggressive tumor progression. Our study design, comprised of surgical isolation of tumors, histopathological characterization, tissue biobanking, and protein analysis, may enable the eventual delineation of patient responders/non-responders and subsequent therapy for malignant melanoma.
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| 17. |
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| 18. |
- Betancourt, Lazaro Hiram, et al.
(author)
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The human melanoma proteome atlas-Defining the molecular pathology
- 2021
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In: Clinical and Translational Medicine. - : Wiley. - 2001-1326. ; 11:7, s. 1-20
-
Journal article (peer-reviewed)abstract
- The MM500 study is an initiative to map the protein levels in malignant melanoma tumor samples, focused on in-depth histopathology coupled to proteome characterization. The protein levels and localization were determined for a broad spectrum of diverse, surgically isolated melanoma tumors originating from multiple body locations. More than 15,500 proteoforms were identified by mass spectrometry, from which chromosomal and subcellular localization was annotated within both primary and metastatic melanoma. The data generated by global proteomic experiments covered 72% of the proteins identified in the recently reported high stringency blueprint of the human proteome. This study contributes to the NIH Cancer Moonshot initiative combining detailed histopathological presentation with the molecular characterization for 505 melanoma tumor samples, localized in 26 organs from 232 patients.
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| 19. |
- Blanton, Michael R., et al.
(author)
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Sloan Digital Sky Survey IV : Mapping the Milky Way, Nearby Galaxies, and the Distant Universe
- 2017
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In: Astronomical Journal. - : IOP Publishing Ltd. - 0004-6256 .- 1538-3881. ; 154:1
-
Journal article (peer-reviewed)abstract
- We describe the Sloan Digital Sky Survey IV (SDSS-IV), a project encompassing three major spectroscopic programs. The Apache Point Observatory Galactic Evolution Experiment 2 (APOGEE-2) is observing hundreds of thousands of Milky Way stars at high resolution and. high signal-to-noise ratios in the near-infrared. The Mapping Nearby Galaxies at Apache Point Observatory (MaNGA) survey is obtaining spatially resolved spectroscopy for thousands of nearby galaxies (median z similar to 0.03). The extended Baryon Oscillation Spectroscopic Survey (eBOSS) is mapping the galaxy, quasar, and neutral gas distributions between z similar to 0.6 and 3.5 to constrain cosmology using baryon acoustic oscillations, redshift space distortions, and the shape of the power spectrum. Within eBOSS, we are conducting two major subprograms: the SPectroscopic IDentification of eROSITA Sources (SPIDERS), investigating X-ray AGNs. and galaxies in X-ray clusters, and the Time Domain Spectroscopic Survey (TDSS), obtaining spectra of variable sources. All programs use the 2.5 m Sloan Foundation Telescope at the. Apache Point Observatory; observations there began in Summer 2014. APOGEE-2 also operates a second near-infrared spectrograph at the 2.5 m du Pont Telescope at Las Campanas Observatory, with observations beginning in early 2017. Observations at both facilities are scheduled to continue through 2020. In keeping with previous SDSS policy, SDSS-IV provides regularly scheduled public data releases; the first one, Data Release 13, was made available in 2016 July.
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| 20. |
- Bratt, Ola, et al.
(author)
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Metaphase cytogenetics and DNA flow cytometry with analysis of S-phase fraction in prostate cancer: influence on prognosis
- 1996
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In: Urology. - 1527-9995. ; 47:2, s. 218-224
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Journal article (peer-reviewed)abstract
- OBJECTIVES: To compare the prognostic significance of chromosome aberrations, DNA ploidy, and S-phase fraction (SPF) in prostate adenocarcinomas and to compare the sensitivity of metaphase cytogenetics with flow cytometry (FCM) in detecting abnormal tumor clones. METHODS: Prostate adenocarcinomas from 57 men were previously successfully analyzed with metaphase cytogenetics. Archival material from these tumors were further analyzed with FCM for DNA content and SPF. RESULTS: The patients were followed for 4.5 to 7.7 years. DNA ploidy was analyzed in 51, and SPF in 45 of the 57 tumors. Clonal chromosomal aberrations, DNA aneuploidy, and high SPF were all significantly associated with poor survival. Of these three variables, SPF was the best predictor of survival, but compared with tumor stage and grade in multivariate analysis, SPF was not an independent prognostic factor. Patients with locally advanced tumors or metastatic disease with SPF less than 8% had a median survival of 5.9 years, compared with only 1.3 years for those with SPF more than 8%. Twenty-eight abnormal clones were detected with FCM and 20 with cytogenetic analysis, but only for two of these clones could the results from the two different methods be regarded as concordant. CONCLUSIONS: SPF was superior to karyotype and ploidy in predicting death in prostate cancer, but it remains to be shown whether SPF analysis adds prognostic information to tumor stage and grade. The cytogenetic analyses correlated poorly with results of FCM, indicating low sensitivity of both methods.
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| 21. |
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| 22. |
- Cabric, Sanja, et al.
(author)
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Islet Surface Heparinization Prevents the Instant-Blood Mediated Inflammatory Reaction in Islet Transplantation
- 2007
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In: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 56:8, s. 2008-2015
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Journal article (peer-reviewed)abstract
- OBJECTIVE—In clinical islet transplantation, the instant blood-mediated inflammatory reaction (IBMIR) is a major factor contributing to the poor initial engraftment of the islets. This reaction is triggered by tissue factor and monocyte chemoattractant protein (MCP)-1, expressed by the transplanted pancreatic islets when the islets come in contact with blood in the portal vein. All currently identified systemic inhibitors of the IBMIR are associated with a significantly increased risk of bleeding or other side effects. To avoid systemic treatment, the aim of the present study was to render the islet graft blood biocompatible by applying a continuous heparin coating to the islet surface.RESEARCH DESIGN AND METHODS—A biotin/avidin technique was used to conjugate preformed heparin complexes to the surface of pancreatic islets. This endothelial-like coating was achieved by conjugating barely 40 IU heparin per full-size clinical islet transplant.RESULTS—Both in an in vitro loop model and in an allogeneic porcine model of clinical islet transplantation, this heparin coating provided protection against the IBMIR. Culturing heparinized islets for 24 h did not affect insulin release after glucose challenge, and heparin-coated islets cured diabetic mice in a manner similar to untreated islets.CONCLUSIONS—This novel pretreatment procedure prevents intraportal thrombosis and efficiently inhibits the IBMIR without increasing the bleeding risk and, unlike other pretreatment procedures (e.g., gene therapy), without inducing acute or chronic toxicity in the islets.
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| 23. |
- Carreras-Puigvert, Jordi, et al.
(author)
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A comprehensive structural, biochemical and biological profiling of the human NUDIX hydrolase family
- 2017
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In: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 8:1
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Journal article (peer-reviewed)abstract
- The NUDIX enzymes are involved in cellular metabolism and homeostasis, as well as mRNA processing. Although highly conserved throughout all organisms, their biological roles and biochemical redundancies remain largely unclear. To address this, we globally resolve their individual properties and inter-relationships. We purify 18 of the human NUDIX proteins and screen 52 substrates, providing a substrate redundancy map. Using crystal structures, we generate sequence alignment analyses revealing four major structural classes. To a certain extent, their substrate preference redundancies correlate with structural classes, thus linking structure and activity relationships. To elucidate interdependence among the NUDIX hydrolases, we pairwise deplete them generating an epistatic interaction map, evaluate cell cycle perturbations upon knockdown in normal and cancer cells, and analyse their protein and mRNA expression in normal and cancer tissues. Using a novel FUSION algorithm, we integrate all data creating a comprehensive NUDIX enzyme profile map, which will prove fundamental to understanding their biological functionality.
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| 24. |
- Eich, Torsten, et al.
(author)
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Positron emission tomography : A real-time tool to quantify early islet engraftment in a preclinical large animal model
- 2007
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In: Transplantation. - : Ovid Technologies (Wolters Kluwer Health). - 0041-1337 .- 1534-6080. ; 84:7, s. 893-898
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Journal article (peer-reviewed)abstract
- Background. Clinical islet transplantation is currently being explored as a therapeutic option for persons with type I diabetes and hypoglycemic unawareness. Techniques to monitor graft survival are urgently needed to optimize the procedure. Therefore, the objective of the present study was to develop a technique for imaging survival of transplanted islets in the peritransplant and early posttransplant phase.Methods. Isolated porcine islets were labeled in vitro with 2-deoxy-2[18F]fluoro-D-glucose ([18F]FDG) and infused intraportally into anesthetized pigs (n=10). Dynamic examination was performed on a positron emission tomography/computed tomography hybrid system.Results. More than 95% of the radioactivity was confined to the islets at the time of transplantation. The peak percentage of infused radioactivity within the liver, quantified at the end of the islet infusion, was only 54±5.1%. The distribution of the radioactivity in the liver was found to be heterogeneous. A whole-body examination showed no accumulation in the lungs or brain; extrahepatic radioactivity was, except urinary excretion, evenly distributed in the pig body.Conclusions. Our results imply that almost 50% of the islets were damaged to the extent that the FDG contained was release within minutes after intraportal transplantation. The distribution of radioactivity without accumulation in the brain indicates that the activity is released from lysed islet cells in the form of [18F]FDG-6P rather than native [18F]FDG. The presented technique shows promise to become a powerful and quantitative tool, readily available in the clinic, to evaluate initial islet engraftment and survival.
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| 25. |
- El-Tawil, Asmaa A., et al.
(author)
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Influence of Bio-Coal Properties on Carbonization and Bio-Coke Reactivity
- 2021
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In: Metals. - : Minerals, Metals & Materials Society. - 2075-4701. ; 11:11
-
Journal article (peer-reviewed)abstract
- Coke corresponds to 2/3–3/4 of the reducing agents in BF, and by the partial replacement of coking coals with 5–10% of bio-coal, the fossil CO2 emissions from the BF can be lowered by ~4–8%. Coking coal blends with 5% and 10% additions of bio-coals (pre-treated biomass) of different origins and pre-treatment degrees were carbonized at laboratory scale and with a 5% bio-coal addition at technical scale, aiming to understand the impact on the bio-coal properties (ash amount and composition, volatile matter content) and the addition of bio-coke reactivity. A thermogravimetric analyzer (TGA) connected to a quadrupole mass spectroscope monitored the residual mass and off-gases during carbonization. To explore the effect of bio-coal addition on plasticity, optical dilatometer tests were conducted for coking coal blends with 5% and 10% bio-coal addition. The plasticity was lowered with increasing bio-coal addition, but pyrolyzed biomass had a less negative effect on the plasticity compared to torrefied biomasses with a high content of oxygen. The temperature for starting the gasification of coke was in general lowered to a greater extent for bio-cokes produced from coking coal blends containing bio-coals with higher contents of catalyzing oxides. There was no significant difference in the properties of laboratory and technical scale produced coke, in terms of reactivity as measured by TGA. Bio-coke produced with 5% of high temperature torrefied pelletized biomass showed a similar coke strength as reference coke after reaction.
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| 26. |
- El-Tawil, Asmaa, et al.
(author)
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Influence of Modified Bio-Coals on Carbonization and Bio-Coke Reactivity
- 2021
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In: Metals. - : MDPI. - 2075-4701. ; 12:1
-
Journal article (peer-reviewed)abstract
- Substitution of coal in coking coal blend with bio-coal is a potential way to reduce fossil CO2 emissions from iron and steelmaking. The current study aims to explore possible means to counteract negative influence from bio-coal in cokemaking. Washing and kaolin coating of bio-coals were conducted to remove or bind part of the compounds in the bio-coal ash that catalyzes the gasification of coke with CO2. To further explore how the increase in coke reactivity is related to more reactive carbon in bio-coal or catalytic oxides in bio-coal ash, ash was produced from a corresponding amount of bio-coal and added to the coking coal blend for carbonization. The reaction behavior of coals and bio-coals under carbonization conditions was studied in a thermogravimetric analyzer equipped with a mass spectrometer during carbonization. The impact of the bio-coal addition on the fluidity of the coking coal blend was studied in optical dilatometer tests for coking coal blends with and without the addition of bio-coal or bio-coal ash. The result shows that the washing of bio-coal will result in lower or even negative dilatation. The washing of bio-coals containing a higher amount of catalytic components will reduce the negative effect on bio-coke reactivity, especially with acetic acid washing when the start of gasification temperature is less lowered. The addition of bio-coal coated with 5% kaolin do not significantly lower the dilatation-relative reference coking coal blend. The reactivity of bio-cokes containing bio-coal coated with kaolin-containing potassium oxide was higher in comparison to bio-coke containing the original bio-coal. The addition of ash from 5% of torrefied bio-coals has a moderate effect on lowering the start of gasification temperature, which indicates that the reactive carbon originating from bio-coal has a larger impact.
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| 27. |
- El-Tawil, Asmaa, et al.
(author)
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The Effect of Bio-Coal Agglomeration and High-Fluidity Coking Coal on Bio-Coke Quality
- 2023
-
In: Metals. - : MDPI. - 2075-4701. ; 13:1
-
Journal article (peer-reviewed)abstract
- Metallurgical coke with high strength and low reactivity is used in the ironmaking blast furnace. Replacement of some coking coal with bio-coal was shown to result in lower strength and higher reactivity of produced coke due to introduction of reactive bio-coal carbon and ash components catalyzing the Boudouard reaction, but also due to lowering of the coking coal blend fluidity, which influences coke strength and reactivity negatively. The current study aims to investigate the possibility to counteract negative impact from bio-coal addition on fluidity and coke reactivity by using high-fluidity coking coal and by agglomeration of bio-coal before addition. Original bio-coal and micro-agglomerate of bio-coal was added at 10%, 15% and 20% to the coking coal blend. The influence of bio-coals on the coke reactivity was measured by using CO2 in a thermogravimetric analyzer. Selected cokes and bio-cokes were produced in technical scale, and their reactivity and strength were measured in standard tests. The effect on dilatation of adding bio-coal or crushed agglomerates of bio-coal to the coking coal blends was measured in an optical dilatometer. The results show that by using a coking coal blend containing high-fluidity coal with agglomerated bio-coal, the max. contraction is increased, whereas the opposite occurs by using original bio-coal. The results show overlapping between contraction occurring before dilatation and during dilation, which affects max. dilatation. The bio-coke containing high-fluidity coal with agglomerated bio-coal has lower reactivity in comparison to bio-cokes with original bio-coal or bio-coke with agglomerated bio-coal produced from a coking coal blend without high-fluidity coal. The reactivity of coke produced in technical scale, as measured in CRI/CSR tests, shows a similar trend regarding reactivity, as measured by thermogravimetric analysis, on coke produced in laboratory scale.
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| 28. |
- Engström, Terese, et al.
(author)
-
Hormone receptor mRNA and protein levels as predictors of premenopausal tamoxifen benefit
- 2024
-
In: Acta Oncologica. - 0284-186X. ; 63, s. 125-136
-
Journal article (peer-reviewed)abstract
- Background and purpose: Tamoxifen remains an important adjuvant treatment in premenopausal patients with hormone receptor-positive breast cancer. Thus, determination of hormone receptors is important. Here, we compare cytosol-based methods, immunohistochemistry (IHC), and gene expression (GEX) analysis for determining hormone receptor status in premenopausal breast cancer patients from a randomised tamoxifen trial, to evaluate their performance in identifying patients that benefit from tamoxifen. Patients and Methods: Premenopausal patients (n=564) were randomised to 2 years of tamoxifen or no systemic treatment. Estrogen receptor (ER) and progesterone receptor (PR) status by protein expression measured by cytosol-based methods and IHC, and mRNA by GEX analysis were compared in 313 patients with available data from all methods. Kaplan Meier estimates and Cox regression were used to evaluate the treatment-predictive value for recurrence-free interval (RFi) and overall survival (OS). Median follow-up for event-free patients was 26 (RFi) and 33 (OS) years. Results: The mRNA data of ESR1 and PGR distributed bimodally, patterns confirmed in an independent cohort. Kappa-values between all methods were 0.76 and 0.79 for ER and PR, respectively. Tamoxifen improved RFi in patients with ER-positive (ER+) or PR-positive (PR+) tumours (Hazard Ratio [HR] and 95% confidence interval [CI]), cytosol-ER+ 0.53 [0.36–0.79]; IHC-ER+ 0.55 [0.38–0.79]; GEX-ER+ 0.54 [0.37–0.77]; cytosol-PR+ 0.49 [0.34–0.72]; IHC-PR+ 0.58 [0.40–0.85]; GEX-PR+ 0.55 [0.38–0.80]). Results were similar for OS. Interpretation: These methods can all identify patients that benefit from 2 years of tamoxifen with equal performance, indicating that GEX data might be used to guide adjuvant tamoxifen therapy.
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| 29. |
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| 30. |
- Ericsson, Olle, et al.
(author)
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Clinical validation of a novel automated cell-free DNA screening assay for trisomies 21, 13, and 18 in maternal plasma.
- 2019
-
In: Prenatal diagnosis. - : Wiley. - 1097-0223 .- 0197-3851. ; 39:11, s. 1011-1015
-
Journal article (peer-reviewed)abstract
- To evaluate clinical performance of a new automated cell-free (cf)DNA assay in maternal plasma screening for trisomies 21, 18, and 13, and to determine fetal sex.Maternal plasma samples from 1200 singleton pregnancies were analyzed with a new non-sequencing cfDNA method, which is based on imaging and counting specific chromosome targets. Reference outcomes were determined by either cytogenetic testing, of amniotic fluid or chorionic villi, or clinical examination of neonates.The samples examined included 158 fetal aneuploidies. Sensitivity was 100% (112/112) for trisomy 21, 89% (32/36) for trisomy 18, and 100% (10/10) for trisomy 13. The respective specificities were 100%, 99.5%, and 99.9%. There were five first pass failures (0.4%), all in unaffected pregnancies. Sex classification was performed on 979 of the samples and 99.6% (975/979) provided a concordant result.The new automated cfDNA assay has high sensitivity and specificity for trisomies 21, 18, and 13 and accurate classification of fetal sex, while maintaining a low failure rate. The study demonstrated that cfDNA testing can be simplified and automated to reduce cost and thereby enabling wider population-based screening.
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| 31. |
- Ericzon, Bo-Göran, et al.
(author)
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Liver Transplantation for Transthyretin Amyloidosis
- 2009
-
In: Recent Advances in Transthyretin Evolution, Structure and Biological Functions. - New York : Springer Berlin/Heidelberg. - 9783642006456 - 9783642006463 ; , s. 239-260
-
Book chapter (other academic/artistic)abstract
- Liver transplantation has until now proved to be the only treatment available that halts the progression of hereditary transthyretin (TTR) associated amyloidosis. The rationale behind the procedure is to replace the liver producing variant TTR with one that produces wild type TTR only, and thereby cease the production of amyloidogenic TTR (ATTR). Even though the transplantation does not improve the patient's symptoms, the progression of the disease comes to a halt for a majority of patients. However, unforeseen complications after the transplantation have emerged, in particular a continuous amyloid formation in the heart observed in non-ATTR Val30Met mutations. Thus, combined liver and heart transplantation has been performed in selected cases. Since the ATTR liver functions normally apart from a synthesis of the variant TTR, utilisation of ATTR-amyloid patients' livers for transplantation of liver disease patients has been performed. In a few patients, development of amyloid disease has been reported, but the procedure remains an important source of organs, especially for patients with hepatocellular cancer.
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| 32. |
- Eriksson, Olof, et al.
(author)
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Distribution of adoptively transferred porcine T-lymphoblasts tracked by (18)F-2-fluoro-2-deoxy-D-glucose and position emission tomography
- 2011
-
In: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 38:6, s. 827-833
-
Journal article (peer-reviewed)abstract
- Introduction: Autologous or allogeneic transfer of tumor-infiltrating T-Iymphocytes is a promising treatment for metastatic cancers, but a major concern is the difficulty in evaluating cell trafficking and distribution in adoptive cell therapy. This study presents a method of tracking transfusion of T-Iymphoblasts in a porcine model by (18)F-2-fluoro-2-deoxy-D-glucose ([(18)F]FDG) and positron emission tomography. Methods: T-Iymphoblasts were labeled with the positron-emitting tracer [(18)F]FDG through incubation. The T-Iymphoblasts were administered into the bloodstream, and the distribution was followed by positron emission tomography for 120 min. The cells were administered either intravenously into the internal jugular vein (n=5) or intraarterially into the ascending aorta (n=1). Two of the pigs given intravenous administration were pretreated with low-molecular-weight dextran sulphate. Results: The cellular kinetics and distribution were readily quantifiable for up to 120 min. High (78.6% of the administered cells) heterogeneous pulmonary uptake was found after completed intravenous transfusion. The pulmonary uptake was decreased either by preineubating and coadministrating the T-Iymphoblasts with low-molecular-weight dextran sulphate or by administrating them intraarterially. Conclusions: The present work shows the feasibility of quantitatively monitoring and evaluating cell trafficking and distribution following administration of [(18)F]FDG-labeled T-Iymphoblasts. The protocol can potentially be transferred to the clinical setting with few modifications.
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| 33. |
- Eriksson, Olof, et al.
(author)
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Positron emission tomography in clinical islet transplantation
- 2009
-
In: American Journal of Transplantation. - : Elsevier BV. - 1600-6135 .- 1600-6143. ; 9:12, s. 2816-2824
-
Journal article (peer-reviewed)abstract
- The fate of islets in clinical transplantation is unclear. To elude on this positron emission tomography combined with computed tomography (PET/CT) was performed for 60 min during islet transplantation in five patients receiving six transplants. A fraction of the islets (23%) were labeled with 18F-fluorodeoxyglucose ([(18)F]FDG) and carefully mixed with unlabeled islets just prior to intraportal transplantation. The peak radioactivity concentration in the liver was found at 19 min after start of islet infusion and corresponded to only 75% of what was expected, indicating that islets are lost during the transplantation procedure. No accumulation of radioactivity was found in the lungs. A nonphysiological peak of C-peptide was found in plasma during and immediately after transplantation in all subjects. Distribution in the liver was heterogeneous with wide variations in location and concentration. Islets found in areas with concentrations of >400 IEQ/cc liver tissue varied between 1% and 32% of the graft in different subjects. No side effects attributed to the PET/CT procedure were found. Clinical outcome in all patients was comparable to that previously observed indicating that the [(18)F]FDG labeling procedure did not harm the islets. The technique has potential to be used to assess approaches to enhance islet survival and engraftment in clinical transplantation.
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| 34. |
- Espmark, Kristina, 1975-
(author)
-
Utanför gränserna : En vetenskapshistorisk biografi om Astrid Cleve von Euler
- 2012
-
Doctoral thesis (other academic/artistic)abstract
- This dissertation is a scientific biography of Astrid Cleve von Euler. She was Sweden’s first female Ph.D. graduate in the natural sciences (1898) and pursued a scientific career in spite of formal and cultural limitations. Though she failed to secure a professional position as a scientist, she published numerous papers throughout her life. The dissertation studies her life in general and analyses her research in particular. How did her research change over time in relation to the rest of her life? How did established scientists receive her research? How did her status as a woman on the fringes of academia affect her research? Sociologist Thomas F. Gieryn’s concepts of boundary-work and credibility contests are important analytical tools in the interpretation of these questions, as Cleve’sresearch was regulated by various boundaries: between professionals and amateurs, between men and women and between different academic disciplines.The study is divided into seven chapters. The first chapter introduces the dissertation, its objective and theoretical framework. The remaining chapters follow Cleve’s life in a chronological and sometimes thematic order and the source material is continually analysed. Chapter two accounts for Cleve’s childhood and student years in Uppsala, ending with her Ph.D. graduation. Chapter tree focuses on her research as a chemist and her ten years of marriage to a fellow researcher, Hans von Euler-Chelpin, a marriage that was closely intertwined with their academic studies. The fourth chapter studies Cleve’s controversy with some of the leading quaternary geologists in Sweden at the time, regarding the level changes of the Scandinavian land mass following the latest Ice Age. The fifth chapter diverges slightly from Cleve’s research, and investigates her undertakings in popular science and her political standpoints. Chapter six analyses her archaeological studies as part of the scientific controversy she was involved in, but also as influenced by political and religious views. Finally, the seventh chapter begins with a closer look at Cleve’s diatom studies, already part of most of the study but thus far not focused on as such, and ends with the main conclusions of the entire dissertation project.The dissertation shows that while science was part of Cleve’s life from childhood to death, factors other than her personal desire to uncover scientific truths governed her research opportunities and the topics of her studies. While she was consistently highly regarded as a diatom expert and gained some success as a chemist, disciplines she was formally educated in, she was met with scepticism and eventually silence when she tried to make an impact in quaternary geology and archaeology, fields of research in which she had no formal training. This demonstrates a possibility to simultaneously be regarded as credible and non-credible as a scientist, as credibility is not necessarily attached to the individual, but to his or her formal expertise in a particular area.
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| 35. |
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| 36. |
- Friberg, Andrew S, et al.
(author)
-
Transplantable functional islet mass – predictive biomarkers of graft function in islet after kidney transplanted patients
-
Other publication (other academic/artistic)abstract
- The ability to predict clinical function of a specific islet batch released for clinical transplantation using standardized variables remains an elusive goal. Analysis of donor, islet isolation, quality control and recipient variables was undertaken in 110 islet after kidney (IAK) transplants and correlated to the pre- to 28-day posttransplant change in C-peptide to glucose and creatinine ratio (ΔCP/GCr). Using backward multiple regression the variables positively associated to ΔCP/GCr were islet volume transplanted (p<0.001) and glucose stimulated insulin secretion (SI) (p=0.009). Factors negatively associated to ΔCP/GCr were cold ischemia time (CIT) (p=0.002) and total tissue volume (p=0.009). Donor age, donor body mass index, number of retrieved organs from the donor, preservation solution, islet insulin content, body weight of the recipient of the islets had no influence on transplant function. The transplantable functional islet mass (TFIM), accounting for islet volume transplanted, SI, CIT, and total tissue volume explained 39% of the variance of the clinical outcome in the IAK data set. Therefore, the TFIM provides a straightforward and potent tool to guide the decision to utilize a specific islet preparation for clinical transplantation.
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| 37. |
- Friberg, Andrew S., et al.
(author)
-
Transplanted functional islet mass : donor islet preparation, and recipitent factors influence early graft function in islet-after-kidney patients
- 2012
-
In: Transplantation. - 0041-1337 .- 1534-6080. ; 93:6, s. 632-638
-
Journal article (peer-reviewed)abstract
- Background.The ability to predict clinical function of a specific islet batch released for clinical transplantation using standardized variables remains an elusive goal.Methods. Analysis of 10 donor, 7 islet isolation, 3 quality control, and 6 recipient variables was undertaken in 110 islet-after-kidney transplants and correlated to the pre- to 28-day posttransplant change in C-peptide to glucose and creatinine ratio ([DELTA]CP/GCr).Results.Univariate analysis yielded islet volume transplanted (Spearman r=0.360, P<0.001) and increment of insulin secretion (r=0.377, P<0.001) as variables positively associated to [DELTA]CP/GCr. A negative association to [DELTA]CP/GCr was cold ischemia time (r=-0.330, P<0.001). A linear, backward-selection multiple regression was used to obtain a model for the transplanted functional islet mass (TFIM). The TFIM model, composed of islet volume transplanted, increment of insulin secretion, cold ischemia time, and exocrine tissue volume transplanted, accounted for 43% of the variance of the clinical outcome in the islet-after-kidney data set.Conclusion.The TFIM provides a straightforward and potent tool to guide the decision to use a specific islet preparation for clinical transplantation.
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| 38. |
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| 39. |
- Gad, Helge, et al.
(author)
-
MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
- 2014
-
In: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
-
Journal article (peer-reviewed)abstract
- Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
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| 40. |
- Gil, Jeovanis, et al.
(author)
-
Clinical protein science in translational medicine targeting malignant melanoma
- 2019
-
In: Cell Biology and Toxicology. - : Springer Science and Business Media LLC. - 0742-2091 .- 1573-6822. ; 35:4, s. 293-332
-
Journal article (peer-reviewed)abstract
- Melanoma of the skin is the sixth most common type of cancer in Europe and accounts for 3.4% of all diagnosed cancers. More alarming is the degree of recurrence that occurs with approximately 20% of patients lethally relapsing following treatment. Malignant melanoma is a highly aggressive skin cancer and metastases rapidly extend to the regional lymph nodes (stage 3) and to distal organs (stage 4). Targeted oncotherapy is one of the standard treatment for progressive stage 4 melanoma, and BRAF inhibitors (e.g. vemurafenib, dabrafenib) combined with MEK inhibitor (e.g. trametinib) can effectively counter BRAFV600E-mutated melanomas. Compared to conventional chemotherapy, targeted BRAFV600E inhibition achieves a significantly higher response rate. After a period of cancer control, however, most responsive patients develop resistance to the therapy and lethal progression. The many underlying factors potentially causing resistance to BRAF inhibitors have been extensively studied. Nevertheless, the remaining unsolved clinical questions necessitate alternative research approaches to address the molecular mechanisms underlying metastatic and treatment-resistant melanoma. In broader terms, proteomics can address clinical questions far beyond the reach of genomics, by measuring, i.e. the relative abundance of protein products, post-translational modifications (PTMs), protein localisation, turnover, protein interactions and protein function. More specifically, proteomic analysis of body fluids and tissues in a given medical and clinical setting can aid in the identification of cancer biomarkers and novel therapeutic targets. Achieving this goal requires the development of a robust and reproducible clinical proteomic platform that encompasses automated biobanking of patient samples, tissue sectioning and histological examination, efficient protein extraction, enzymatic digestion, mass spectrometry–based quantitative protein analysis by label-free or labelling technologies and/or enrichment of peptides with specific PTMs. By combining data from, e.g. phosphoproteomics and acetylomics, the protein expression profiles of different melanoma stages can provide a solid framework for understanding the biology and progression of the disease. When complemented by proteogenomics, customised protein sequence databases generated from patient-specific genomic and transcriptomic data aid in interpreting clinical proteomic biomarker data to provide a deeper and more comprehensive molecular characterisation of cellular functions underlying disease progression. In parallel to a streamlined, patient-centric, clinical proteomic pipeline, mass spectrometry–based imaging can aid in interrogating the spatial distribution of drugs and drug metabolites within tissues at single-cell resolution. These developments are an important advancement in studying drug action and efficacy in vivo and will aid in the development of more effective and safer strategies for the treatment of melanoma. A collaborative effort of gargantuan proportions between academia and healthcare professionals has led to the initiation, establishment and development of a cutting-edge cancer research centre with a specialisation in melanoma and lung cancer. The primary research focus of the European Cancer Moonshot Lund Center is to understand the impact that drugs have on cancer at an individualised and personalised level. Simultaneously, the centre increases awareness of the relentless battle against cancer and attracts global interest in the exceptional research performed at the centre.
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| 41. |
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| 42. |
- Hjälm, Göran, et al.
(author)
-
Cloning and sequencing of human gp330, a Ca2+ -binding receptor with potential intracellular signaling properties
- 1996
-
In: European Journal of Biochemistry. - : Wiley. - 0014-2956 .- 1432-1033. ; 239:1, s. 132-137
-
Journal article (peer-reviewed)abstract
- We present here the complete primary structure of human gp330, the human variant of the principal kidney autoantigen causing Heymann membranous glomerulonephritis in rats. The deduced 4655 amino acid residues give a calculated molecular mass of 519636 Da for the mature protein and consists of a probable 25-amino-acid N-terminal signal peptide sequence, an extracellular region of 4398 amino acids, a single transmembrane-spanning domain of 23 amino acids, and an intracellular C-terminal region of 209 amino acid residues. Three types of cysteine-rich repeats characteristic of the low density lipoprotein receptor (LDLR) superfamily are present in human gp330. In the extracellular region, there are a total of 36 LDLR ligand-binding repeats, comprising four distinct domains, 16 growth factor repeats separated by eight YWTD spacer regions, and one epidermal growth factor-like repeat. No consensus cleavage sequence for the processing endoprotease furin is detected in human gp330. The intracellular tail contains not only two copies of the F(X)NPXY coated-pit mediated internalization signal characteristic of LDLR superfamily members, but also intriguing and potentially functional motifs including several Src-homology 3 recognition motifs, one Src-homology 2 recognition motif for the p85 regulatory subunit of phosphatidylinositol 3-kinase, and additional sites for protein kinase C, casein kinase II and cAMP-/cGMP-dependent protein kinase. There is approximately 77% amino acid identity between human and rat gp330 with minor differences between the extracellular and intracellular regions. Recently gp330 has been implicated in Ca2+ regulation in the parathyroid, the placenta, and the renal tubule, but its overall physiological and pathological role still remains uncertain.
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| 43. |
- Johansson, Henrik J., et al.
(author)
-
Retinoic acid receptor alpha is associated with tamoxifen resistance in breast cancer
- 2013
-
In: Nature Communications. - : Nature Publishing Group: Nature Communications. - 2041-1723. ; 4:3175
-
Journal article (peer-reviewed)abstract
- About one-third of oestrogen receptor alpha-positive breast cancer patients treated with tamoxifen relapse. Here we identify the nuclear receptor retinoic acid receptor alpha as a marker of tamoxifen resistance. Using quantitative mass spectrometry-based proteomics, we show that retinoic acid receptor alpha protein networks and levels differ in a tamoxifen-sensitive (MCF7) and a tamoxifen-resistant (LCC2) cell line. High intratumoural retinoic acid receptor alpha protein levels also correlate with reduced relapse-free survival in oestrogen receptor alpha-positive breast cancer patients treated with adjuvant tamoxifen solely. A similar retinoic acid receptor alpha expression pattern is seen in a comparable independent patient cohort. An oestrogen receptor alpha and retinoic acid receptor alpha ligand screening reveals that tamoxifen-resistant LCC2 cells have increased sensitivity to retinoic acid receptor alpha ligands and are less sensitive to oestrogen receptor alpha ligands compared with MCF7 cells. Our data indicate that retinoic acid receptor alpha may be a novel therapeutic target and a predictive factor for oestrogen receptor alpha-positive breast cancer patients treated with adjuvant tamoxifen.
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| 44. |
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| 45. |
- Johansson, Helena, et al.
(author)
-
Tissue factor produced by the endocrine cells of the islets of Langerhans is associated with a negative outcome of clinical islet transplantation
- 2005
-
In: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 54:6, s. 1755-62
-
Journal article (peer-reviewed)abstract
- There are strong indications that only a small fraction of grafts successfully engraft in clinical islet transplantation. One explanation may be the instant blood-mediated inflammatory reaction (IBMIR) elicited by tissue factor, which is produced by the endocrine cells. In the present study, we show that islets intended for islet transplantation produce tissue factor in both the transmembrane and the alternatively spliced form and that the membrane-bound form is released as microparticles often associated with both insulin and glucagon granules. A low-molecular mass factor VIIa (FVIIa) inhibitor that indirectly blocks both forms of tissue factor was shown in vitro to be a promising drug to eliminate the IBMIR. Thrombin-antithrombin complex (TAT) and FVIIa-antithrombin complex (FVIIa-AT) were measured in nine patients who together received 20 infusions of isolated human islets. Both the TAT and FVIIa-AT complexes increased rapidly within 15-60 min after infusion. When the initial TAT and FVIIa-AT levels were plotted against the increase in C-peptide concentration after 7 days, patients with an initially strong IBMIR showed no significant increase in insulin synthesis after 7 days. In conclusion, tissue factor present in both the islets and the culture medium and elicits IBMIR, which affects the function of the transplanted islets.
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| 46. |
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| 47. |
- Johansson, Patrik, et al.
(author)
-
A Patient-Derived Cell Atlas Informs Precision Targeting of Glioblastoma
- 2020
-
In: Cell Reports. - : Elsevier BV. - 2211-1247. ; 32:2
-
Journal article (peer-reviewed)abstract
- Glioblastoma (GBM) is a malignant brain tumor with few therapeutic options. The disease presents with a complex spectrum of genomic aberrations, but the pharmacological consequences of these aberrations are partly unknown. Here, we report an integrated pharmacogenomic analysis of 100 patient-derived GBM cell cultures from the human glioma cell culture (HGCC) cohort. Exploring 1,544 drugs, we find that GBM has two main pharmacological subgroups, marked by differential response to proteasome inhibitors and mutually exclusive aberrations in TP53 and CDKN2A/B. We confirm this trend in cell and in xenotransplantation models, and identify both Bcl-2 family inhibitors and p53 activators as potentiators of proteasome inhibitors in GBM cells, We can further predict the responses of individual cell cultures to several existing drug classes, presenting opportunities for drug repurposing and design of stratified trials. Our functionally profiled biobank provides a valuable resource for the discovery of new treatments for GBM.
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| 48. |
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| 49. |
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| 50. |
- Kim, Yonghyo, et al.
(author)
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Protein Expression in Metastatic Melanoma and the Link to Disease Presentation in a Range of Tumor Phenotypes
- 2020
-
In: Cancers. - : MDPI AG. - 2072-6694. ; 12:3
-
Research review (peer-reviewed)abstract
- Malignant melanoma is among the most aggressive skin cancers and it has among the highest metastatic potentials. Although surgery to remove the primary tumor is the gold standard treatment, once melanoma progresses and metastasizes to the lymph nodes and distal organs, i.e., metastatic melanoma (MM), the usual outcome is decreased survival. To improve survival rates and life span, advanced treatments have focused on the success of targeted therapies in the MAPK pathway that are based on BRAF (BRAF V600E) and MEK. The majority of patients with tumors that have higher expression of BRAF V600E show poorer prognosis than patients with a lower level of the mutated protein. Based on the molecular basis of melanoma, these findings are supported by distinct tumor phenotypes determined from differences in tumor heterogeneity and protein expression profiles. With these aspects in mind, continued challenges are to: (1) deconvolute the complexity and heterogeneity of MM; (2) identify the signaling pathways involved; and (3) determine protein expression to develop targeted therapies. Here, we provide an overview of the results from protein expression in MM and the link to disease presentation in a variety of tumor phenotypes and how these will overcome the challenges of clinical problems and suggest new promising approaches in metastatic melanoma and cancer therapy.
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