| 1. |
- Eriksson, Hanna, et al.
(författare)
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Interobserver Variability of Histopathological Prognostic Parameters in Cutaneous Malignant Melanoma : Impact on Patient Management
- 2013
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Ingår i: Acta Dermato-Venereologica. - : Medical Journals Sweden AB. - 0001-5555 .- 1651-2057. ; 93:4, s. 411-416
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Tidskriftsartikel (refereegranskat)abstract
- Clinical management of primary cutaneous melanomas is based on histopathological staging of the tumour. The aim of this study was to investigate, in a non-selected population in clinical practice, the agreement rate between general pathologists and pathologists experienced in melanoma in terms of the evaluation of histopathological prognostic parameters in cutaneous malignant melanomas, and to what extent the putative variability affected clinical management. A total of 234 cases of invasive cutaneous malignant melanoma were included in the study from the Stockholm-Gotland Healthcare Region in Sweden. Overall interobserver variability between a general pathologist and an expert review was 68.8-84.8%. Approximately 15.5% of melanomas <= 1 mm were re-classified either as melanoma in situ or melanomas >1 mm after review. In conclusion, review by a pathologist experienced in melanoma resulted in a change in recommendations about surgical excision margins and/or sentinel node biopsy in subgroups of Ti melanomas.
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| 2. |
- Franzen, Bo, et al.
(författare)
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Protein profiling of fine-needle aspirates reveals subtype-associated immune signatures and involvement of chemokines in breast cancer
- 2019
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Ingår i: Molecular Oncology. - : WILEY. - 1574-7891 .- 1878-0261. ; 13:2, s. 376-391
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Tidskriftsartikel (refereegranskat)abstract
- There are increasing demands for informative cancer biomarkers, accessible via minimally invasive procedures, both for initial diagnostics and for follow-up of personalized cancer therapy, including immunotherapy. Fine-needle aspiration (FNA) biopsy provides ready access to relevant tissue samples; however, the minute amounts of sample require sensitive multiplex molecular analysis to be of clinical biomarker utility. We have applied proximity extension assays (PEA) to analyze 167 proteins in FNA samples from patients with breast cancer (BC; n = 25) and benign lesions (n = 32). We demonstrate that the FNA BC samples could be divided into two main clusters, characterized by differences in expression levels of the estrogen receptor (ER) and the proliferation marker Ki67. This clustering corresponded to some extent to established BC subtypes. Our analysis also revealed several proteins whose expression levels differed between BC and benign lesions (e.g., CA9, GZMB, IL-6, VEGFA, CXCL11, PDL1, and PCD1), as well as several chemokines correlating with ER and Ki67 status (e.g., CCL4, CCL8, CCL20, CXCL8, CXCL9, and CXCL17). Finally, we also identified three signatures that could predict Ki67 status, ER status, and tumor grade, respectively, based on a small subset of proteins, which was dominated by chemokines. To our knowledge, expression profiles of CCL13 in benign lesions and BC have not previously been described but were shown herein to correlate with proliferation (P = 0.00095), suggesting a role in advanced BC. Given the broad functional range of the proteins analyzed, immune-related proteins were overrepresented among the observed alterations. Our pilot study supports the emerging role of chemokines in BC progression. Due to the minimally traumatic sampling and clinically important molecular information for therapeutic decisions, this methodology is promising for future immunoscoring and monitoring of treatment efficacy in BC.
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| 3. |
- Haag, Petra, et al.
(författare)
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Caspase-2 is a mediator of apoptotic signaling in response to gemtuzumab ozogamicin in acute myeloid leukemia
- 2022
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Ingår i: Cell Death Discovery. - : Springer Nature. - 2058-7716. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- The antibody conjugate gemtuzumab ozogamicin (GO; Mylotarg((R))) provides targeted therapy of acute myeloid leukemia (AML), with recent approvals for patients with CD33-positive disease at diagnosis or relapse, as monotherapy or combined with chemotherapeutics. While its clinical efficacy is well documented, the molecular routes by which GO induces AML cell death warrant further analyses. We have earlier reported that this process is initiated via mitochondria-mediated caspase activation. Here we provide additional data, focusing on the involvement of caspase-2 in this mechanism. We show that this enzyme plays an important role in triggering apoptotic death of human AML cells after exposure to GO or its active moiety calicheamicin. Accordingly, the caspase-2 inhibitor z-VDVAD-fmk reduced GO-induced caspase-3 activation. This finding was validated with shRNA and siRNA targeting caspase-2, resulting in reduced caspase-3 activation and cleavage of poly [ADP-ribose] polymerase 1 (PARP-1). We previously demonstrated that GO-induced apoptosis included a conformational change of Bax into a pro-apoptotic state. Present data reveal that GO-treatment also induced Bid cleavage, which was partially reduced by caspase-2 specific inhibition while the effect on GO-induced Bax conformational change remained unaltered. In mononuclear cells isolated from AML patients that responded to GO treatment in vitro, processing of caspase-2 was evident, whereas in cells from an AML patient refractory to treatment no such processing was seen. When assessing diagnostic samples from 22 AML patients, who all entered complete remission (CR) following anthracycline-based induction therapy, and comparing patients with long versus those with short CR duration no significant differences in baseline caspase-2 or caspase-3 full-length protein expression levels were found. In summary, we demonstrate that GO triggers caspase-2 cleavage in human AML cells and that the subsequent apoptosis of these cells in part relies on caspase-2. These findings may have future clinical implications.
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| 4. |
- Kanter-Lewensohn, Lena
(författare)
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Tumor progression in melanocytic lesions : biological and diagnostic implications
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cutaneous malignant melanoma has an annual incidence of 5% in Sweden, with about 1500 cases diagnosed yearly. In routine histopathology there are diagnostic difficulties in the analysis of pigmented lesions. In spite of useful generalizations and criteria for the diagnosis of pigmented lesions, there are clinical as well as histological difficulties. To distinguish melanoma from Spitz nevi proliferation was assessed using antibodies against Ki-67 (MIB-1) and the anti-apoptotic protein BcI-2. My results clearly show that benign and dysplastic nevi in contrast to malignant lesions have a low proliferation. The majority (96%) of the mm expressed Ki-67 as well as Bcl-2, while this was only seen in 6% of the Spitz nevi. IGF-1R is required for the establishment and maintenance of the transformed phenotype and is also important as an anti-apoptotic regulator in melanoma cells. By Western blotting and binding analysis I could confirm IGF-1R expression in 4 several melanoma cell lines. Two ways of blocking the IGF-1R function were used. For the translocation of the receptor to the cell surface N-linked glycosylation is essential. Cell growth arrest and cell death were induced by the N-linked glycosylation blocker Tunicamycin. A similar effect was obtained by the [alpha]IR-3 antibody, which blocks the binding domain of IGF-1R. These treatments resulted in apoptosis. Primary melanoma tissues and tissues from melanoma metastases, obtained from lymph nodes of patients with advanced mm, were also found to express the IGF-1R. However, none of benign nevi used for comparison stained positive. I also noted that there was an inverse correlation between the expression of IGF-1R. and the frequency of apoptotic cells, which suggest that IGF-1R. has also an anti-apoptotic effect in vivo. Cdk inhibitors may be important in controlling cellular proliferation. To evaluate other possible mechanisms in IGF-1R. dependent control of proliferation, the influence of p27 Kip1 and its related cyclins were of interest as my analyses have revealed an inverse relation between p27 Kip1 and expression of IGF-1R. in melanoma cells. Both Tunicamycin and [alpha]IR-3 caused substantial redistribution of p27 from cyclin DI to cyclin E and cyclin A. These effects may underlie the growth-inhibitory and apoptotic; effect of inhibition of IGF-1R. in melanoma cells. Previous clinical studies have indicated that the estrogen receptor blocker, Tamoxifen (TAM) has some favorable effects on the clinical outcome of mm. There is support from studies on breast cancer that TAM interferes with the IGF- 1 pathway by increasing the release of insulin-like growth factor binding proteins (IGFBPs). I showed that TAM induced cytotoxicity in several nun cell lines, which did not express ER. I could, however, confirm that TAM did not affect the IGFBPs. Instead, it seems that TAM inhibits autophosphorylation of the [beta]-subunit of the IGF- 1 receptor. This may indicate the role of TAM as an inhibitor of tyrosine kinases and a potential therapeutical approach for advanced mm.
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| 5. |
- Pernemalm, Maria, et al.
(författare)
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Quantitative Proteomics Profiling of Primary Lung Adenocarcinoma Tumors Reveals Functional Perturbations in Tumor Metabolism
- 2013
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Ingår i: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 12:9, s. 3934-3943
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Tidskriftsartikel (refereegranskat)abstract
- In this study, we have analyzed human primary lung adenocarcinoma tumors using global mass spectrometry to elucidate the biological mechanisms behind relapse post surgery. In total, we identified over 3000 proteins with high confidence. Supervised multivariate analysis was used to select 132 proteins separating the prognostic groups. Based on in-depth bioinformatics analysis, we hypothesized that the tumors with poor prognosis had a higher glycolytic activity and HIF activation. By measuring the bioenergetic cellular index of the tumors, we could detect a higher dependency of glycolysis among the tumors with poor prognosis. Further, we could also detect an up-regulation of HIF1 alpha mRNA expression in tumors with early relapse. Finally, we selected three proteins that were upregulated in the poor prognosis group (cathepsin D, ENO1, and VDAC1) to confirm that the proteins indeed originated from the tumor and not from a stromal or inflammatory component. Overall, these findings show how in-depth analysis of clinical material can lead to an increased understanding of the molecular mechanisms behind tumor progression.
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| 6. |
- Shah, Carl-Henrik, et al.
(författare)
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Vascular endothelial growth factor receptor 2, but not S100A4 or S100A6, correlates with prolonged survival in advanced urothelial carcinoma
- 2014
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Ingår i: Urologic Oncology. - : Elsevier. - 1078-1439 .- 1873-2496. ; 32:8, s. 1215-1224
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: A major challenge in muscle-invasive urothelial carcinoma (UC) is to identify biomarkers that can predict disease prognosis and treatment response after cystectomy. Therefore, we analyzed the potential prognostic value of the proteins vascular endothelial growth factor receptor 2 (VEGFR2), S100A4, and S100A6 in UC.METHODS: Retrospective outcome data and tumor specimens from 83 cystectomy patients with histologically confirmed invasive UC were included. Expression levels of VEGFR2 (also called flk-1 and KDR), S100A4, and S100A6 were analyzed in primary tumor tissue by immunohistochemistry.RESULTS: Immunohistochemical staining and analysis of VEGFR2, S100A4, and S100A6 showed localization mainly in tumor cell cytoplasm. High VEGFR2 expression and low tumor category were independent variables associated with longer overall survival (OS) and disease-free survival, revealed by a bivariate Cox proportional hazards regression model (both P<0.001). In addition, the univariate log-rank test and the Cox model demonstrated that OS beyond 2 years was significantly greater among patients with low S100A6 expression than in those with high S100A6 expression (P = 0.017 and 0.022, respectively). Differences in tumor expression of S100A4 were not significantly associated with outcome.CONCLUSION: In this study, VEGFR2 expression was significantly correlated with risk of disease relapse and OS in a defined cohort of patients with UC of the bladder treated by cystectomy.
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| 7. |
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