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- Betancourt, Lazaro Hiram, et al.
(författare)
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The human melanoma proteome atlas-Defining the molecular pathology
- 2021
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Ingår i: Clinical and Translational Medicine. - : Wiley. - 2001-1326. ; 11:7, s. 1-20
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Tidskriftsartikel (refereegranskat)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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- Uhlén, Mathias, et al.
(författare)
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The human secretome
- 2019
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Ingår i: Science Signaling. - : American Association for the Advancement of Science (AAAS). - 1945-0877 .- 1937-9145. ; 12:609
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Tidskriftsartikel (refereegranskat)abstract
- The proteins secreted by human cells (collectively referred to as the secretome) are important not only for the basic understanding of human biology but also for the identification of potential targets for future diagnostics and therapies. Here, we present a comprehensive analysis of proteins predicted to be secreted in human cells, which provides information about their final localization in the human body, including the proteins actively secreted to peripheral blood. The analysis suggests that a large number of the proteins of the secretome are not secreted out of the cell, but instead are retained intracellularly, whereas another large group of proteins were identified that are predicted to be retained locally at the tissue of expression and not secreted into the blood. Proteins detected in the human blood by mass spectrometry-based proteomics and antibody-based immuno-assays are also presented with estimates of their concentrations in the blood. The results are presented in an updated version 19 of the Human Protein Atlas in which each gene encoding a secretome protein is annotated to provide an open-access knowledge resource of the human secretome, including body-wide expression data, spatial localization data down to the single-cell and subcellular levels, and data about the presence of proteins that are detectable in the blood.
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| 6. |
- Abbasiverki, Roghayeh
(författare)
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Numerical modelling considerations for analysis of concrete hydraulic structures subjected to high-frequency seismic loads
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Concrete hydraulic structures are of great importance in today's society. When situated in areas with hard bedrock, these structures may become extra vulnerable to seismic excitations as these here are dominated by high-frequency vibrations which can have disastrous consequences for slender structures. The aim of this thesis was to investigate special considerations that must be made when conducting analyses of such hydraulic structures during high-frequency excitations. Underground and on the ground structures were investigated separately. Underground concrete pipelines and concrete buttress dams were selected for the study because their behaviour when exposed to seismic excitations is dominated by their stiffness. The most effective models and modelling methods for the seismic analyses of such structures were implemented and evaluated. Two-dimensional finite element (FE) models were developed for the dynamic analysis of underground concrete pipelines loaded by seismic waves propagating from bedrock through soil. The interaction between the bedrock and the surrounding soil was investigated with respect to rock geometry and soil properties. The surface of dam foundations is commonly irregular, resulting in nonuniform motions at the dam-foundation interface. The free-field modelling methods for concrete dam foundations were adapted in order to accurately describe the propagation of earthquake vibrations from the source to the ground surface. The implementation of a threedimensional FE model for concrete buttress dams was investigated. Two different methods for free-field modelling are presented, which can be implemented independently of the software used. The seismic loads are applied as effective earthquake forces at non-reflecting boundaries. In the first method, the free-field motions at the non-reflecting boundaries are determined by the so-called domain reduction method using the direct FE calculation. In the second method, the free-field motions are analytically determined based on the onedimensional wave propagation theory. The results are also compared with the massless foundation modelling approach, in which the topographical amplifications are neglected. It was demonstrated that a two-dimensional model can effectively account for pipeline behaviour. The most important aspect of the models is the ability to capture bending deformations, as segmented structures such as pipelines are vulnerable in this respect. Nonuniform bedrock reduces the safety of concrete pipeline, especially because of bending deformations in the pipe and joints. The massless method gave unreliable results for analyses of dams, especially for high-frequency excitations. The analytical method was also unreliable in estimating the non-linear behaviour of the dams. But, a new time domain deconvolution method was developed to transform the earthquake motion from the foundation surface to the corresponding input motion at depth. It wasfound that free-field modelling of foundations using the direct FE method can accurately capture the topographic amplifications of the seismic excitations. It was shown that a three-dimensional model is required for seismic evaluation of concrete buttress dams. The topographic amplification of high-frequency waves at the surface of canyons had a significant effect on the response of this type of dam.
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| 8. |
- Betancourt, Lazaro Hiram, et al.
(författare)
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Improved survival prognostication of node-positive malignant melanoma patients utilizing shotgun proteomics guided by histopathological characterization and genomic data
- 2019
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1
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Tidskriftsartikel (refereegranskat)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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| 9. |
- Betancourt, Lazaro Hiram, et al.
(författare)
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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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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 11:12
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Tidskriftsartikel (refereegranskat)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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| 10. |
- Brahm, Carl-Otto, et al.
(författare)
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Patients with head and neck cancer treated with radiotherapy : Their experiences after 6 months of prophylactic tooth extractions and temporary removable dentures
- 2021
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Ingår i: Clinical and Experimental Dental Research. - : John Wiley & Sons. - 2057-4347. ; 7:5, s. 894-902
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: The impact of dental occlusion on the experiences of head and neck cancer patients and their oral, social and psychological functioning has been sparsely investigated. There is a lack of knowledge regarding the experience of tooth loss and dentures among patients treated for head and neck cancer. The aim of this study was to describe the experiences of head and neck cancer patients of prophylactic tooth extractions and temporary removable dentures, 6 months after radiotherapy treatment. Material and methods: An individual interview with 25 patients 6 months after radiotherapy was subjected to a qualitative content analysis. Results: Two categories, Impaired oral function and Belief in the future, and seven subcategories described the patients' experiences of temporary removable dentures during the first 6 months after prophylactic tooth extractions. The temporary removable dentures affected the patients' ability to chew, swallow and speak, caused pain, and were experienced as an enemy. Despite that, the patients were hopeful and had a wish for recovery, which gave them the energy to live. Conclusion: Prophylactic tooth extractions and temporary removable dentures 6 months after radiotherapy treatment affect head and neck cancer patients' recovery and everyday life. However, they have the will to take on these challenges, pertaining not only to themselves, but also to relatives and health professionals. At the individual level, the patient needs individualized professional support to get through the arduous procedure, from the acute situation until the end of the rehabilitation phase.
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