| 1. |
- Byrling, Johannes, et al.
(författare)
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Mass spectrometry-based analysis of formalin-fixed, paraffin-embedded distal cholangiocarcinoma identifies stromal thrombospondin-2 as a potential prognostic marker
- 2020
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Ingår i: Journal of Translational Medicine. - : Springer Science and Business Media LLC. - 1479-5876. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Distal cholangiocarcinoma is an aggressive malignancy with a dismal prognosis. Diagnostic and prognostic biomarkers for distal cholangiocarcinoma are lacking. The aim of the present study was to identify differentially expressed proteins between distal cholangiocarcinoma and normal bile duct samples. Methods: A workflow utilizing discovery mass spectrometry and verification by parallel reaction monitoring was used to analyze surgically resected formalin-fixed, paraffin-embedded samples from distal cholangiocarcinoma patients and normal bile duct samples. Bioinformatic analysis was used for functional annotation and pathway analysis. Immunohistochemistry was performed to validate the expression of thrombospondin-2 and investigate its association with survival. Results: In the discovery study, a total of 3057 proteins were identified. Eighty-seven proteins were found to be differentially expressed (q < 0.05 and fold change ≥ 2 or ≤ 0.5); 31 proteins were upregulated and 56 were downregulated in the distal cholangiocarcinoma samples compared to controls. Bioinformatic analysis revealed an abundance of differentially expressed proteins associated with the tumor reactive stroma. Parallel reaction monitoring verified 28 proteins as upregulated and 18 as downregulated in distal cholangiocarcinoma samples compared to controls. Immunohistochemical validation revealed thrombospondin-2 to be upregulated in distal cholangiocarcinoma epithelial and stromal compartments. In paired lymph node metastases samples, thrombospondin-2 expression was significantly lower; however, stromal thrombospondin-2 expression was still frequent (72%). Stromal thrombospondin-2 was an independent predictor of poor disease-free survival (HR 3.95, 95% CI 1.09-14.3; P = 0.037). Conclusion: Several proteins without prior association with distal cholangiocarcinoma biology were identified and verified as differentially expressed between distal cholangiocarcinoma and normal bile duct samples. These proteins can be further evaluated to elucidate their biomarker potential and role in distal cholangiocarcinoma carcinogenesis. Stromal thrombospondin-2 is a potential prognostic marker in distal cholangiocarcinoma.
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| 2. |
- Kelemen, Olga, et al.
(författare)
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Proteomic analysis enables distinction of early- versus advanced-stage lung adenocarcinomas
- 2020
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Ingår i: Clinical and Translational Medicine. - : Wiley. - 2001-1326. ; 10:2, s. 106-106
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: A gel-free proteomic approach was utilized to perform in-depth tissue protein profiling of lung adenocarcinoma (ADC) and normal lung tissues from early and advanced stages of the disease. The long-term goal of this study is to generate a large-scale, label-free proteomics dataset from histologically well-classified lung ADC that can be used to increase further our understanding of disease progression and aid in identifying novel biomarkers.METHODS AND RESULTS: Cases of early-stage (I-II) and advanced-stage (III-IV) lung ADCs were selected and paired with normal lung tissues from 22 patients. The histologically and clinically stratified human primary lung ADCs were analyzed by liquid chromatography-tandem mass spectrometry. From the analysis of ADC and normal specimens, 4863 protein groups were identified. To examine the protein expression profile of ADC, a peak area-based quantitation method was used. In early- and advanced-stage ADC, 365 and 366 proteins were differentially expressed, respectively, between normal and tumor tissues (adjusted P-value < .01, fold change ≥ 4). A total of 155 proteins were dysregulated between early- and advanced-stage ADCs and 18 were suggested as early-specific stage ADC. In silico functional analysis of the upregulated proteins in both tumor groups revealed that most of the enriched pathways are involved in mRNA metabolism. Furthermore, the most overrepresented pathways in the proteins that were unique to ADC are related to mRNA metabolic processes.CONCLUSIONS: Further analysis of these data may provide an insight into the molecular pathways involved in disease etiology and may lead to the identification of biomarker candidates and potential targets for therapy. Our study provides potential diagnostic biomarkers for lung ADC and novel stage-specific drug targets for rational intervention.
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| 3. |
- Kim, Yonghyo, et al.
(författare)
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Protein Expression in Metastatic Melanoma and the Link to Disease Presentation in a Range of Tumor Phenotypes
- 2020
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 12:3
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Forskningsöversikt (refereegranskat)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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| 4. |
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| 5. |
- Sahlin, K. Barbara, et al.
(författare)
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Short-term effect of pharmacologically induced alterations in testosterone levels on common blood biomarkers in a controlled healthy human model
- 2020
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Ingår i: Scandinavian Journal of Clinical and Laboratory Investigation. - : Informa UK Limited. - 0036-5513 .- 1502-7686. ; 80:1, s. 25-31
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Tidskriftsartikel (refereegranskat)abstract
- Testosterone deficiency in males is associated with serious comorbidities such as cardiovascular disease, diabetes type two, and also an increased risk of premature death. The pathogenetic mechanism behind this association, however, has not yet been clarified and is potentially bidirectional. The aim of this clinical trial was to gain insight into the short-term effect of changes in testosterone on blood analytes in healthy young men. Thirty healthy young male volunteers were recruited and monitored in our designed human model. Blood sampling was performed prior to and 3 weeks after pharmacological castration with a gonadotropin-releasing hormone antagonist. Subsequently, testosterone replacement with 1000 mg testosterone undecanoate was given and additional blood samples were collected 2 weeks later. The alterations in the levels of 37 routine biomarkers were statistically analysed. Eight biomarkers changed significantly in a similar manner as testosterone between the time points (e.g. prostate specific antigen, creatinine and magnesium), whereas seven other markers changed in the inverse manner as testosterone, including sexual hormone-binding globulin, urea, aspartate aminotransferase and alanine aminotransferase. Most of our results were supported by data from other studies. The designed controlled human model yielded changes in known biomarkers suggesting that low testosterone has a negative effect on health in young healthy men.
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| 6. |
- Sanchez, Aniel, et al.
(författare)
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Novel functional proteins coded by the human genome discovered in metastases of melanoma patients
- 2020
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Ingår i: Cell Biology and Toxicology. - : Springer Science and Business Media LLC. - 0742-2091 .- 1573-6822. ; 36:3, s. 261-272
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Tidskriftsartikel (refereegranskat)abstract
- In the advanced stages, malignant melanoma (MM) has a very poor prognosis. Due to tremendous efforts in cancer research over the last 10 years, and the introduction of novel therapies such as targeted therapies and immunomodulators, the rather dark horizon of the median survival has dramatically changed from under 1 year to several years. With the advent of proteomics, deep-mining studies can reach low-abundant expression levels. The complexity of the proteome, however, still surpasses the dynamic range capabilities of current analytical techniques. Consequently, many predicted protein products with potential biological functions have not yet been verified in experimental proteomic data. This category of ‘missing proteins’ (MP) is comprised of all proteins that have been predicted but are currently unverified. As part of the initiative launched in 2016 in the USA, the European Cancer Moonshot Center has performed numerous deep proteomics analyses on samples from MM patients. In this study, nine MPs were clearly identified by mass spectrometry in MM metastases. Some MPs significantly correlated with proteins that possess identical PFAM structural domains; and other MPs were significantly associated with cancer-related proteins. This is the first study to our knowledge, where unknown and novel proteins have been annotated in metastatic melanoma tumour tissue.
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