| 1. |
- Bekele, Maheteme, et al.
(författare)
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Tumor and immune cell profiling in breast cancer using highly multiplexed imaging mass cytometry single-cell technology demonstrates tumor heterogeneity and immune phenotypic abnormality in Ethiopian women
- 2020
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Ingår i: Cancer Research. - : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 80:21 Suppl.
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Tumor heterogeneity represents a complex challenge to cancer treatment, disease recurrence, and patient survival. Imaging mass cytometry (IMC) is an emerging proteomic tool for cancer profiling in tumor tissue samples. IMC enables digital image analysis by multiplexed immunostaining of cells and proteins within tissue and preserves spatial relations within tumor environment. We have applied IMC based approach to study the heterogeneity of invasive breast carcinoma protein expression pattern in formalin fixed paraffin embedded tissues.Methods: A total of 10 region of interest (ROI) derived from 5 patients with primary invasive breast carcinoma representing three molecular subclasses (HR+/HER2-,HER2+/HR- and TNBC) were stained with a 30-marker IMC metal labeled antibody panel (α-SMA, EGFR, p53, CD33, CD16, CD163, CD11b, PDL1, CD31, CD45, D44,Vimentin, FoxP3, CD4, ECadherin, CD68, CD20, CD8a, Cytokeratin7, PD1, GranzymeB, Ki67, ColTypeI, CD3, CD45RO, HLADR, DARC & CD11c). Tissue imaging was done by quantifying the abundance of bound antibody with a Hyperion IMC. MCD Viewer was used for visualization purpose and to export raw 16-bit tiff images for segmentation on CellProfiler. Segmentation masks were combined with the individual tiff files to extract single-cell information from each individual image. HistoCAT was applied to perform unbiased clustering of cell populations using the PhenoGraph algorithm and clustered cell populations was overlaid on t-SNE plot. The relative marker expression was used to generate heat-maps and each cluster was manually assigned a phenotype based on its expression profile.Results: The t-SNE generated from each ROI revealed different distinct cell populations and we report the presence of diverse tumor and immune cell populations in our samples. The (min, max) number of PhenoGraph clustered tumor cell populations in HR+/HER2-, HER2+ and TNBC Cases were (5,8) (7,9) and (5,7) respectively. Similarly, the (min, max) number of PhenoGraph clustered immune cell populations in HR+/HER2-, HER2+ and TNBC Cases were (5,8) (7,9) and (5,7) respectively. We also document the presence of inter and intra-tumor heterogeniety in expression of PD1 and PDL1 in all the tumor subtypes studied. Additionally, we report a phenotypic abnormality in the immune cell populations identified with dual or triple markers expression of the canonical CD antigens of T-Cells, B-Cells and macrophages.Conclusion: The current study demonstrates high-dimensional visualization with the simultaneous analysis of epithelial, immune, and stromal components using IMC can be used to explore cell populations in tumor tissue to quantify tumor heterogeneity or identification of novel clustering patterns that has potential for translational research and clinical practice. Significance: This study presents the potential of Imaging Mass Cytometry and single cell analysis algorithms in multiplex high throughput tumor tissue studies.
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| 2. |
- Botling, Johan, et al.
(författare)
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Biomarker Discovery in Non-Small Cell Lung Cancer : Integrating Gene Expression Profiling, Meta-analysis, and Tissue Microarray Validation
- 2013
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 19:1, s. 194-204
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Global gene expression profiling has been widely used in lung cancer research to identify clinically relevant molecular subtypes as well as to predict prognosis and therapy response. So far, the value of these multigene signatures in clinical practice is unclear, and the biologic importance of individual genes is difficult to assess, as the published signatures virtually do not overlap.Experimental Design: Here, we describe a novel single institute cohort, including 196 non-small lung cancers (NSCLC) with clinical information and long-term follow-up. Gene expression array data were used as a training set to screen for single genes with prognostic impact. The top 450 probe sets identified using a univariate Cox regression model (significance level P < 0.01) were tested in a meta-analysis including five publicly available independent lung cancer cohorts (n = 860).Results: The meta-analysis revealed 14 genes that were significantly associated with survival (P < 0.001) with a false discovery rate < 1%. The prognostic impact of one of these genes, the cell adhesion molecule 1 (CADM1), was confirmed by use of immunohistochemistry on tissue microarrays from 2 independent NSCLC cohorts, altogether including 617 NSCLC samples. Low CADM1 protein expression was significantly associated with shorter survival, with particular influence in the adenocarcinoma patient subgroup.Conclusions: Using a novel NSCLC cohort together with a meta-analysis validation approach, we have identified a set of single genes with independent prognostic impact. One of these genes, CADM1, was further established as an immunohistochemical marker with a potential application in clinical diagnostics. Clin Cancer Res; 19(1); 194-204. (c) 2012 AACR.
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| 3. |
- Gebregzabher, Endale, et al.
(författare)
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Detection of High- and Low-Risk HPV DNA in Archived Breast Carcinoma Tissues from Ethiopian Women
- 2021
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Ingår i: International Journal of Breast Cancer. - : Hindawi Publishing Corporation. - 2090-3170 .- 2090-3189. ; 2021
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Tidskriftsartikel (refereegranskat)abstract
- Background: Human papilloma virus (HPV) is involved in the development of cancer of the cervix, mouth and throat, anus, penis, vulva, or vagina, but it has not been much considered as a cause of breast cancer. Recently, a number of investigations have linked breast cancer to viral infections. High-risk HPV types, predominantly HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59, are established as carcinogens in humans. In this study we aimed to detect 19 high-risk and 9 low-risk HPVs from archived breast tumor tissue among Ethiopian women.Methods: In this study, 75 breast cancer patients from Tikur Anbassa Specialized Hospital in Addis Ababa (Ethiopia) were included. HPV detection and genotyping were done using the novel Anyplex™ II HPV28 Detection Assay at the Orebro University Hospital, Sweden. The Anyplex™ II PCR System detects 19 high-risk HPV types (16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 69, 73, and 82) and 9 low-risk HPV types (6, 11, 40, 42, 43, 44, 54, 61, and 70). IHC for p16 was done using an automated system, the Dako Autostainer Link.Results: Out of the 75 valid tests, two were found to be positive (2.7%) for HPV. One of the cases was positive for the high-risk HPV16 genotype while the other was positive both for the high-risk HPV39 and the low-risk HPV6. The cell cycle protein p16 was highly expressed in the case positive for the high-risk HPV16, but it was not expressed in the case positive for HPV39.Conclusion: The prevalence of HPV is low in Ethiopian breast cancer patients, but the role played by HPV in breast carcinogenesis among Ethiopian breast cancer patients cannot be commented based on these observations.
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| 4. |
- Hadgu, Endale, et al.
(författare)
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Breast cancer in Ethiopia : evidence for geographic difference in the distribution of molecular subtypes in Africa
- 2018
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Ingår i: BMC Women's Health. - : BioMed Central. - 1472-6874. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Breast cancer is a heterogeneous disease with several morphological and molecular subtypes. Widely accepted molecular classification system uses assessment of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and proliferation marker Ki67. Few studies have been conducted on the incidence and molecular types of breast cancer in Sub-Saharan Africa. Previous studies mainly from Western and Central Africa, showed breast cancer to occur at younger ages and to present with aggressive features, such as high-grade, advanced stage and triple-negative phenotype (negative for ER, PR and HER2). Limited data from East Africa including Ethiopia however shows hormone receptor negative tumors to account for a lower proportion of all breast cancers than has been reported from elsewhere in Africa.METHODS: In this study from Tikur Anbessa Specialized Hospital, 114 breast cancer patients diagnosed between 2012 and 2015 were enrolled. ER, PR, Ki67 and HER2 receptor status were assessed using immunohistochemistry from tissue microarrays. FISH was used for assessment of gene amplification in all equivocal tumor samples and for confirmation in HER2-enriched cases.RESULTS: The distribution of molecular subtypes was: Luminal A: 40%; Luminal B: 26%; HER2-enriched: 10%; TNBC: 23%. ER were positive in 65% of all tumors and 43% the cases were positive for PR. There was statistically significant difference in median age at diagnosis between the molecular subtypes (P < 0.05). There was a bimodal distribution of molecular subtypes in different age ranges with Luminal B subtype being more common at younger ages (median = 36) and Luminal A subtype more prevalent at older ages (median = 42). There were no statistically significant differences in tumor grade, histology, and stage between the molecular subtypes of breast cancer.CONCLUSION: The present study detected Luminal A breast cancer to be the most common subtype and reveals a relatively low rate of hormone receptor negative and TNBC. Our findings and results from other East African studies suggest geographic variability in the distribution of the molecular subtypes of breast cancer in Africa and hence have important clinical and policy implications for breast cancer control and treatment in Ethiopia.
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| 5. |
- Hadgu, Endale, et al.
(författare)
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Distribution and characteristics of androgen receptor (AR) in breast cancer among women in Addis Ababa, Ethiopia : A cross sectional study
- 2020
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Ingår i: PLOS ONE. - : Public Library Science. - 1932-6203. ; 15:5
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Tidskriftsartikel (refereegranskat)abstract
- Evaluation of the role of androgen receptor (AR) in the biology of breast cancer is an emerging area of research. There are compelling evidences that AR expression may be used to further refine breast cancer molecular subtyping with prognostic and therapeutic implications. Many studies indicated co-expression of AR with the hormonal receptors in breast cancer has a favorable prognosis. AR is also investigated by many researchers as a potential therapeutic target in treatment of breast cancer. Studies on the frequency and distribution of AR in breast cancer among Africans is barely available. Given the heightened interest to understand its role in breast cancer, we determined AR expression and assessed its association with clinicopathological parameters among Ethiopian women. In this study, 112 newly diagnosed patient with invasive breast cancer at Tikur Anbessa Specialized Hospital were enrolled. Immunohistochemical assessment of AR, ER, PR, Ki67 and HER2 were performed using tissue microarrays (TMA) constructed from their primary tumor block. Out of the 112 participants, 91 (81%) were positive for AR expression and the remaining 21 participants (19%) were negative for AR expression. Expression of AR in ER+, HER2+ and TNBC cases were 93%, 83% and 48% respectively. Our study reveals AR is expressed in a significant number of breast cancers patients and this may indicate that breast cancers cases in Ethiopia have favorable prognosis and could benefit from progresses in AR targeted treatments. Since AR expression has important consequences on the prognosis and treatment of breast cancer, further studies with an increased number of participants is necessary to confirm our reports.
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| 6. |
- Hellquist, H. B., et al.
(författare)
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Bcl-2 immunoreactivity in salivary gland neoplasms is unrelated to the expression of mRNA for natural killer cell stimulatory cytokines interleukin (IL)-2 and IL-12
- 1996
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Ingår i: Virchows Archiv. - New York, USA : Springer. - 0945-6317 .- 1432-2307. ; 429:2-3, s. 149-158
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Tidskriftsartikel (refereegranskat)abstract
- Certain cytokines are involved in the generation of natural killer (NK) cells and participate in the regulation of the proto-oncogene bcl-2. We aimed to study the mRNA expression of interleukin (IL)-2, IL-4 and IL-5, the composition of the tumour infiltrating lymphocytes (TIL), and the expression of bcl-2 in 14 benign and malignant human parotid tumours. T IL were predominantly composed of T lymphocytes and NK cells. We found evidence for the homing of T cells, and for generation of NK cells in the vicinity of the tumours. mRNA for IL-2 and IL-12, were identified but IL-4 mRNA was not found. The cytokine profiles and the composition of TIL of the two tumour categories were indistinguishable, suggesting that these host-response variables do not explain the differences in biological behaviour of these particular tumours. The results support a shift towards Th 1 (T helper 1) cells and interferon-gamma production, and that IL-12 also in vivo may play an important role in the regulatory interaction between innate resistance and adaptive immunity in tumour diseases. Most infiltrating lymphocytes showed strong expression of bcl-2; an interesting observation with regard to lymphocytic apoptosis in neoplastic diseases. The immunoreactivity for the bcl-2 protein varied considerably between and within tumours, and almost all benign tumours showed strong bcl-2 positively whereas several of the malignant tumours showed weak or absent staining. The variable expression of bcl-2 protein suggests a different susceptibility of tumour cells to apoptosis. The results also indicate that bcl-2 cannot pla a major role as protective agent in the specific apoptotic pathway induced by NK cells.
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| 7. |
- Karlsson, Christina, 1968-, et al.
(författare)
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Oestrogen receptor ss in NSCLC : prevalence, proliferative influence, prognostic impact and smoking
- 2012
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Ingår i: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS). - Malden, USA : Wiley-Blackwell. - 0903-4641 .- 1600-0463. ; 120:6, s. 451-458
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Tidskriftsartikel (refereegranskat)abstract
- In non-small-cell lung carcinoma (NSCLC) there are gender differences. The female gender is associated with more adenocarcinomas (ADCA), among both smokers and non-smokers compared to men. Women with NSCLC have a better prognosis compared to men, regardless of other factors. A possible role for oestrogen receptor (ER) signalling has been proposed. The role for ER beta in NSCLC is still not clear, especially concerning the impact of smoking. In a material of NSCLC (n = 262), ER beta and cyclins A1 and A2 were studied by immunohistochemistry on formalin-fixed paraffin embedded tissue. In 137 of those cases, frozen material was available, on which expression analysis of ESR2 (ER beta) and cyclin A1 were performed. Data were correlated to histology, gender, smoking habits, stage and clinical outcome. ER beta was expressed in 86% of the cases. ER beta was most frequently expressed in Stage I ADCAs, especially in male subjects. A correlation between ER beta expression and cyclins was observed in ADCA, also with a male predominance. ER beta transcripts had a positive prognostic impact in ADCA. ER beta transcripts were increased in NSCLC among smokers compared to non-smokers. In conclusion, our data support a role for ER beta in lung ADCAs, proposing a role for ER beta in lungcarcinogenesis, especially among smokers.
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| 8. |
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| 9. |
- Mattsson, Johanna Sofia Margareta, 1985-, et al.
(författare)
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Inconsistent results in the analysis of ALK rearrangements in non-small cell lung cancer
- 2016
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Ingår i: BMC Cancer. - London, United Kingdom : Springer Science and Business Media LLC. - 1471-2407. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- Background: Identification of targetable EML4-ALK fusion proteins has revolutionized the treatment of a minor subgroup of non-small cell lung cancer (NSCLC) patients. Although fluorescence in situ hybridization (FISH) is regarded as the gold standard for detection of ALK rearrangements, ALK immunohistochemistry (IHC) is often used as screening tool in clinical practice. In order to unbiasedly analyze the diagnostic impact of such a screening strategy, we compared ALK IHC with ALK FISH in three large representative Swedish NSCLC cohorts incorporating clinical parameters and gene expression data.Methods: ALK rearrangements were detected using FISH on tissue microarrays (TMAs), including tissue from 851 NSCLC patients. In parallel, ALK protein expression was detected using IHC, applying the antibody clone D5F3 with two different protocols (the FDA approved Ventana CDx assay and our in house Dako IHC protocol). Gene expression microarray data (Affymetrix) was available for 194 patients.Results: ALK rearrangements were detected in 1.7% in the complete cohort and 2.0% in the non-squamous cell carcinoma subgroup. ALK protein expression was observed in 1.9% and 1.5% when applying the Ventana assay or the in house Dako protocol, respectively. The specificity and accuracy of IHC was high (>99%), while the sensitivity was between 69% (Ventana) and 62% (in house Dako protocol). Furthermore, only 67% of the ALK IHC positive cases were positive in both IHC assays. Gene expression analysis revealed that 6/194 (3%) tumors showed high ALK gene expression (≥6AU) and of them only three were positive by either FISH or IHC.Conclusion: The overall frequency of ALK rearrangements based on FISH was lower than previously reported. The sensitivity of both IHC assays was low, and the concordance between the FISH and the IHC assays poor, questioning current strategies to screen with IHC prior to FISH or completely replace FISH by IHC.
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| 10. |
- Mattsson, Johanna Sofia Margareta, 1985-, et al.
(författare)
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Prognostic impact of COX-2 in non-small cell lung cancer : a comprehensive compartment-specific evaluation of tumor and stromal cell expression
- 2015
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Ingår i: Cancer Letters. - : Elsevier BV. - 0304-3835 .- 1872-7980. ; 356:2, s. 837-845
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Tidskriftsartikel (refereegranskat)abstract
- Cyclooxygenase-2 (COX-2) is an enzyme that has been extensively investigated as a prognostic marker in cancer. In non-small cell lung cancer (NSCLC) previous results regarding the prognostic impact of COX-2 expression are inconsistent. Therefore we evaluated the association between transcript levels and overall survival in nine publicly available gene expression data sets (total n = 1337) and determined in situ compartment-specific tumor and stromal cell protein expression in two independent cohorts (n = 616). Gene expression did not show any correlation with clinical parameters or with overall survival. Protein expression in tumor and stromal cells did not correlate with any clinical parameter or with overall survival in one of the analyzed cohorts, while a significant association of high stromal expression with longer survival was observed in both univariate and multivariate analysis in the other cohort. Stromal expression of COX-2 has not been separately evaluated in NSCLC previously and may be a subject of further investigation, whereas the presented findings from this comprehensive compartment specific evaluation clearly reject the hypothesis of COX-2 tumor cell expression having a prognostic value in NSCLC. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
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| 11. |
- Stjernström, Annika, et al.
(författare)
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Alterations of INPP4B, PIK3CA and pAkt of the PI3K pathway are associated with squamous cell carcinoma of the lung
- 2014
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Ingår i: Cancer Medicine. - : John Wiley & Sons. - 2045-7634. ; 3:2, s. 337-348
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the study was to investigate how alterations in the PI3K pathway correlate with non-small cell lung cancer subtypes squamous cell carcinoma (SSC) and adenocarcinoma (ADCA). We analyzed copy number variation and protein expression of INPP4B, protein expression of pAkt, PDPK1, and PTEN and mutational status of PIK3CA and PTEN in 180 cases. Nineteen% displayed loss of INPP4B copy, whereas 47% lacked expression, both showing correlation with SCC. Elevated pAkt expression was seen in 63% of all cases, also correlating to SCC. PDPK1 was expressed in 70%, more in male than female patients. Regarding PTEN, 50% displayed loss of expression, of which seven were identified with mutations in the phosphatase domain. We detected nine cases (5%) of PIK3CA mutations, all identified as the E545K hot spot mutation in the helical domain, all except one in SCC. When analyzing all PI3K pathway components together, we show that patients with at least one alteration in the PI3K pathway are twice as likely to have SCC, than ADCA. Interestingly, we also found a strong correlation between high pAkt expression and PTEN expression. As comparison, we also analyzed mitogen-activated protein kinase (MAPK) pathway genes, where we identified fifteen KRAS mutations (8%) and one BRAF mutation (1%), significantly associated to ADCA. No association was found to the Gly972Arg polymorphism of IRS-1, involved in activation of both PI3K and MAPK pathways. In conclusion, we show here that several components of the PI3K pathway, alone and in combination, are correlated to development of SCC of the lung.
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| 12. |
- Carney Almroth, Bethanie, 1974, et al.
(författare)
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Assessing the effects of textile leachates in fish using multiple testing methods: From gene expression to behavior
- 2021
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Ingår i: Ecotoxicology and Environmental Safety. - : Elsevier BV. - 0147-6513 .- 1090-2414. ; 207
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Tidskriftsartikel (refereegranskat)abstract
- The textile industry, while of major importance in the world economy, is a toxic industry utilizing and emitting thousands of chemical substances into the aquatic environment. The aim of this project was to study the potentially harmful effects associated with the leaching of chemical residues from three different types of textiles: sportswear, children’s bath towels, and denim using different fish models (cell lines, fish larvae and juvenile fish). A combination of in vitro and in vivo test systems was used. Numerous biomarkers, ranging from gene expression, cytotoxicity and biochemical analysis to behavior, were measured to detect effects of leached chemicals. Principle findings indicate that leachates from all three types of textiles induced cytotoxicity on fish cell lines (RTgill-W1). Leachates from sportswear and towels induced mortality in zebrafish embryos, and chemical residues from sportswear reduced locomotion responses in developing larval fish. Sportswear leachate increased Cyp1a mRNA expression and EROD activity in liver of exposed brown trout. Leachates from towels induced EROD activity and VTG in rainbow trout, and these effects were mitigated by the temperature of the extraction process. All indicators of toxicity tested showed that exposure to textile leachate can cause adverse reactions in fish. These findings suggested that chemical leaching from textiles from domestic households could pose an ecotoxicological threat to the health of the aquatic environment.
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| 13. |
- Hurtsén, Anna Stene, 1992-, et al.
(författare)
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A randomized porcine study of hemorrhagic shock comparing end-tidal carbon dioxide targeted and proximal systolic blood pressure targeted partial resuscitative endovascular balloon occlusion of the aorta in the mitigation of metabolic injury
- 2023
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Ingår i: Intensive Care Medicine Experimental. - : Springer. - 2197-425X. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The definition of partial resuscitative endovascular balloon occlusion of the aorta (pREBOA) is not yet determined and clinical markers of the degree of occlusion, metabolic effects and end-organ injury that are clinically monitored in real time are lacking. The aim of the study was to test the hypothesis that end-tidal carbon dioxide (ETCO2) targeted pREBOA causes less metabolic disturbance compared to proximal systolic blood pressure (SBP) targeted pREBOA in a porcine model of hemorrhagic shock.MATERIALS AND METHODS: Twenty anesthetized pigs (26-35 kg) were randomized to 45 min of either ETCO2 targeted pREBOA (pREBOAETCO2, ETCO2 90-110% of values before start of occlusion, n = 10) or proximal SBP targeted pREBOA (pREBOASBP, SBP 80-100 mmHg, n = 10), during controlled grade IV hemorrhagic shock. Autotransfusion and reperfusion over 3 h followed. Hemodynamic and respiratory parameters, blood samples and jejunal specimens were analyzed.RESULTS: ETCO2 was significantly higher in the pREBOAETCO2 group during the occlusion compared to the pREBOASBP group, whereas SBP, femoral arterial mean pressure and abdominal aortic blood flow were similar. During reperfusion, arterial and mesenteric lactate, plasma creatinine and plasma troponin concentrations were higher in the pREBOASBP group.CONCLUSIONS: In a porcine model of hemorrhagic shock, ETCO2 targeted pREBOA caused less metabolic disturbance and end-organ damage compared to proximal SBP targeted pREBOA, with no disadvantageous hemodynamic impact. End-tidal CO2 should be investigated in clinical studies as a complementary clinical tool for mitigating ischemic-reperfusion injury when using pREBOA.
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| 14. |
- Karlsson, Christina, 1968-
(författare)
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Biomarkers in non-small cell lung carcinoma : methodological aspects and influence of gender, histology and smoking habits on estrogen receptor and epidermal growth factor family receptor signalling
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Non-small cell lung carcinoma is a leading cause of cancer mortality worldwide. There are gender and smoking associated differences both in tumour types and clinical outcome. Squamous cell carcinomas (SCC) are more frequent among smoking men while females develop adenocarcinomas (ADCA). NSCLC among never smokers are mainly ADCA, and occurs mostly in females. The present thesis elucidates the role of estrogen receptor (ER) and epidermal growth factor receptor family (EGFR/HER2-4) in NSCLC in the perspective of gender and histology as well as the influence of smoking on those biomarkers. A recently developed technique, tissue micro array (TMA), was employed.The question of how much of a tumour tissue that needed to be included in a TMA for biomarker analysis was analyzed by a statistical approach. Data indicates a sample size of three cylinders of tumour tissue with a diameter of 0.6 mm each as being appropriate and cost-effective. In order to optimally use the up to thousands of different tumour samples within a TMA, it would be optimal to serially cut and store slides before performing in situ detection of proteins and nucleic acids. Applying up to date methodology, and by evaluation with image analysis, data are presented that shows that such handling of TMA slides would be possible without any loss of biomarker information. ERα is more frequently observed in ADCA and in females and a local estradiol synthesis is supported by the presence of aromatase. ERβ is identified as a positive prognostic marker in ADCA. Smoking is associated to increased levels of ERβ mRNA. EGFR over expression is associated with a ligand. Independent phosporylation of ERα. HER-4 intracellular domain may also act as a co-activator to ERα in ADCA, especially among neversmokers. The question of ER and EGFR family signalling crosstalk as a potential target for combined targeted therapy is raised.
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| 15. |
- Lloyd, Katy A., et al.
(författare)
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Differential ACPA Binding to Nuclear Antigens Reveals a PAD-Independent Pathway and a Distinct Subset of Acetylation Cross-Reactive Autoantibodies in Rheumatoid Arthritis
- 2019
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 9, s. 1-22
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Tidskriftsartikel (refereegranskat)abstract
- Rheumatoid arthritis (RA) associated anti-citrullinated protein autoantibodies (ACPA) target a wide range of modified proteins. Citrullination occurs during physiological processes such as apoptosis, yet little is known about the interaction of ACPA with nuclear antigens or apoptotic cells. Since uncleared apoptotic cells and neutrophil extracellular trap (NET) products have been postulated to be central sources of autoantigen and immunostimulation in autoimmune disease, we sought to characterize the anti-nuclear and anti-neutrophil reactivities of ACFA. Serology showed that a subset of anti-CCP2 seropositive RA patients had high reactivity to full-length citrullinated histones. In contrast, seronegative RA patients displayed elevated IgG reactivity to native histone compared to controls, but no citrulline-specific reactivity. Screening of 10 single B-cell derived monoclonal AGFA from RA patients revealed that four ACPA exhibited strong binding to apoptotic cells and three of these had anti-nuclear (ANA) autoantibody reactivity. Modified histones were confirmed to be the primary targets of this anti-nuclear ACPA subset following immunoprecipitation from apoptotic cell lysates. Monoclonal ACPA were also screened for reactivities against stimulated murine and human neutrophils, and all the nuclear-reactive monoclonal ACPA bound to NETs. Intriguingly, one ACPA mAb displayed a contrasting cytoplasmic perinuclear neutrophil binding and may represent a different NET-reactive ACPA subset. Notably, studies of CRISPR-Cas9 PAD4 KO cells and cells from PAD KO mice showed that the cytoplasmic NET-binding was fully dependent on PAD4, whilst nuclear- and histone-mediated NEI reactivity was largely PAD-independent. Our further analysis revealed that the nuclear binding could be explained by consensus-motif driven ACPA cross-reactivity to acetylated histones. Specific acetylated histone peptides targeted by the monoclonal antibodies were identified and the anti-modified protein autoantibody (AMPA) profile of the ACPA was found to correlate with the functional activity of the antibodies. In conclusion, when investigating monoclonal ACPA, we could group ACPA into distinct subsets based on their nuclear binding-patterns and acetylation-mediated binding to apoptotic cells, neutrophils, and NETs. Differential anti-modified protein reactivities of RA-autoantibody subsets could have an important functional impact and provide insights in RA pathogenesis.
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| 16. |
- Lovane, Lucília, et al.
(författare)
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PD-L1 expression in squamous cervical carcinomas of Mozambican women living with or without HIV
- 2024
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Programmed death-ligand 1 (PD-L1) is overexpressed in squamous cervical cancer (SCC) and can be used for targeted immunotherapy. The highest mortality rates of SCC are reported in sub-Saharan Africa, where Human immunodeficiency virus (HIV) prevalence is high. In Mozambique most SCC patients present at advanced stages. Thus, there is a need to introduce new treatment options. However, immunocompromised patients were frequently excluded in previous clinical trials. Our aim was to determine if PD-L1 expression in SCC is as prevalent among women living with HIV (WLWH) as among other patients. 575 SCC from Maputo Central Hospital were included. HIV status was available in 266 (46%) cases PD-L1 expression was scored through tumour proportion score (TPS) and combined positive score (CPS). PD-L1 was positive in 20.1% of the cases (n = 110), TPS (score ≥ 25%) and in 26.3% (n = 144), CPS (score ≥ 1). Stratifying according to the HIV status, WLWH were TPS positive in 16.7%, compared to 20.9%, p = 0.43, and concerning CPS 21.1% versus 28.7%, p = 0.19, respectively. PD-L1 status was not influenced by stage, Ki-67 or p16, CD8 expression influenced only CPS status. Our data indicates that the documented effect of PD-L1 therapy on SCC should be confirmed in randomized clinical trials in an HIV endemic milieu.
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| 17. |
- Nilsson, Christina, et al.
(författare)
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Varför vårdvetenskap?
- 2008
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Ingår i: Vårdvetenskapliga vägskäl. - Växjö : Växjö universitet. ; , s. 49-60
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Rapport (övrigt vetenskapligt/konstnärligt)
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| 18. |
- Qvick, Alvida, 1990-, et al.
(författare)
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Liquid biopsy as an option for predictive testing and prognosis in patients with lung cancer
- 2021
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Ingår i: Molecular Medicine. - : Springer. - 1076-1551 .- 1528-3658. ; 27:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The aim of this study was to investigate the clinical value of liquid biopsy as a primary source for variant analysis in lung cancer. In addition, we sought to characterize liquid biopsy variants and to correlate mutational load to clinical data.Methods: Circulating cell-free DNA was extracted from plasma from patients with lung cancer (n = 60) and controls with benign lung disease (n = 16). Variant analysis was performed using the AVENIO ctDNA Surveillance kit and the results were correlated to clinical and variant analysis data from tumor tissue or cytology retrieved from clinical routine diagnostics.Results: There were significantly more variants detected in lung cancer cases compared to controls (p = 0.011), but no difference between the histological subgroups of lung cancer was found (p = 0.465). Furthermore, significantly more variants were detected in patients with stage IIIb-IV disease compared to patients with stage I-IIIa (median 7 vs 4, p = 0.017). Plasma cfDNA mutational load was significantly associated with overall survival (p = 0.010). The association persisted when adjusted for stage and ECOG performance status (HR: 3.64, 95% CI 1.37-9.67, p = 0.009). Agreement between tumor and plasma samples significantly differed with stage; patients with stage IIIb-IV disease showed agreement in 88.2% of the cases with clinically relevant variants, compared to zero cases in stage I-IIIa (p = 0.004). Furthermore, one variant in EGFR, two in KRAS, and one in BRAF were detected in plasma but not in tumor samples.Conclusion: This study concludes that in the vast majority of advanced NSCLC patients a reliable variant analysis can be performed using liquid biopsy from plasma. Furthermore, we found that the number of variants in plasma is associated with prognosis, possibly indicating a strategy for closer follow up on this crucial patient group.
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| 19. |
- Sadeghi, M., et al.
(författare)
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Total resuscitative endovascular balloon occlusion of the aorta causes inflammatory activation and organ damage within 30 minutes of occlusion in normovolemic pigs
- 2020
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Ingår i: BMC Surgery. - : Springer Science and Business Media LLC. - 1471-2482. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Resuscitative endovascular balloon occlusion of the aorta (REBOA) causes physiological, metabolic, end-organ and inflammatory changes that need to be addressed for better management of severely injured patients. The aim of this study was to investigate occlusion time-dependent metabolic, end-organ and inflammatory effects of total REBOA in Zone I in a normovolemic animal model. Methods Twenty-four pigs (25-35 kg) were randomized to total occlusion REBOA in Zone I for either 15, 30, 60 min (REBOA15, REBOA30, and REBOA60, respectively) or to a control group, followed by 3-h reperfusion. Hemodynamic variables, metabolic and inflammatory response, intraperitoneal and intrahepatic microdialysis, and plasma markers of end-organ injuries were measured during intervention and reperfusion. Intestinal histopathology was performed. Results Mean arterial pressure and cardiac output increased significantly in all REBOA groups during occlusion and blood flow in the superior mesenteric artery and urinary production subsided during intervention. Metabolic acidosis with increased intraperitoneal and intrahepatic concentrations of lactate and glycerol was most pronounced in REBOA30 and REBOA60 during reperfusion and did not normalize at the end of reperfusion in REBOA60. Inflammatory response showed a significant and persistent increase of pro- and anti-inflammatory cytokines during reperfusion in REBOA30 and was most pronounced in REBOA60. Plasma concentrations of liver, kidney, pancreatic and skeletal muscle enzymes were significantly increased at the end of reperfusion in REBOA30 and REBOA60. Significant intestinal mucosal damage was present in REBOA30 and REBOA60. Conclusion Total REBOA caused severe systemic and intra-abdominal metabolic disturbances, organ damage and inflammatory activation already at 30 min of occlusion.
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| 20. |
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| 21. |
- Santti, Kirsi, et al.
(författare)
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Estrogen receptor beta expression correlates with proliferation in desmoid tumors
- 2019
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Ingår i: Journal of Surgical Oncology. - : Wiley-Interscience Publishers. - 0022-4790 .- 1096-9098. ; 119:7, s. 873-879
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND OBJECTIVES: Estrogen receptor signaling and cyclin D1 have a major role in tumor cell proliferation in breast cancer. Desmoid tumors are rare neoplasms that may respond to endocrine treatment. The present study aimed to investigate the expression levels and the clinical relevance of estrogen receptor beta (ERβ) and cyclin D1 in desmoid tumors.METHODS: This study consists of 83 patients with a surgically treated desmoid tumor. ERβ and cyclin D1 expression was examined by immunohistochemistry in tissue microarrays. Cyclin A and Ki67 were studied in our previous work.RESULTS: = 0.34, P = 0.004). ERβ immunoexpression showed a trend towards predictive impact for recurrence as a continuous variable. Further explorative analysis indicated that very high ERβ expression was related to high risk of relapse (hazard ratio [HR] 2.6; P = 0.02). Median cyclin D1 expression was 15.6%. High cyclin D1 expression was associated with high Ki67 and cyclin A expression. Cyclin D1 was not associated with time to recurrence.CONCLUSIONS: ERβ and cyclin D1 immunopositivity correlated with high proliferation in desmoid tumors. High ERβ expression might be predictive for postoperative recurrence.
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| 22. |
- Santti, Kirsi, et al.
(författare)
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High cyclin A expression, but not Ki67, is associated with early recurrence in desmoid tumors
- 2018
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Ingår i: Journal of Surgical Oncology. - : Wiley-Interscience Publishers. - 0022-4790 .- 1096-9098. ; 118:1, s. 192-198
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND OBJECTIVES: Desmoid tumors are soft-tissue tumors originating from myofibroblasts with a tendency to recur after surgery. High expression of proliferation markers is associated with shortened progression-free and/or overall survival in many neoplasms, including soft-tissue sarcomas. We investigated the prognostic role of cyclin A and Ki67 in desmoid tumors by immunohistochemistry.METHODS: The study included 76 patients with desmoid tumor operated at Helsinki University Hospital between 1987 and 2011. A tissue micro array (TMA) was constructed and the TMA sections were immunostained with cyclin A and Ki67 antibodies. A computer-assisted image analysis was performed.RESULTS: Cyclin A expression was evaluable in 74 and Ki67 in 70 patients. Cyclin A immunopositivity varied from 0% to 9.9%, with a mean of 1.9%. Cyclin A expression correlated significantly with Ki67. Cyclin A expression was associated with recurrence-free survival (HR 1.9, 95% CI = 1.1-3.2, P = .02), as were positive margin (HR 6.0, 95% CI = 1.6-22.5, P = .008) and extremity location (HR 5.3, 95% CI = 1.7-16.8, P = 0.005). Ki67 immunopositivity varied from 0.33% to 13.8%, with a mean of 4.6%, but had no significant prognostic impact (HR 1.1, P = .2).CONCLUSIONS: Our study indicates that cyclin A may be a new prognostic biomarker in surgically treated desmoid tumors.
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| 23. |
- Wikström, Maria B, 1972-, et al.
(författare)
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A randomized porcine study of the hemodynamic and metabolic effects of combined endovascular occlusion of the vena cava and the aorta in normovolemia and in hemorrhagic shock
- 2021
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Ingår i: Journal of Trauma and Acute Care Surgery. - : Lippincott Williams & Wilkins. - 2163-0755 .- 2163-0763. ; 90:5, s. 817-826
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Mortality from traumatic retrohepatic venous injuries is high and methods for temporary circulatory stabilization are needed. We investigated survival, and hemodynamic and metabolic effects of resuscitative endovascular balloon occlusion of the aorta (REBOA) and vena cava inferior (REBOVC) in anesthetized pigs.METHODS: Twenty-five anesthetized pigs in normovolemia or severe hemorrhagic shock (controlled arterial bleeding in blood bags targeting systolic arterial pressure of 50 mmHg, corresponding to 40-50% of the blood volume) were randomized to REBOA zone 1 or REBOA+REBOVC zone 1 (n=6-7/group) for 45 minutes occlusion, followed by 3-hour resuscitation and reperfusion. Hemodynamic and metabolic variables and markers of end-organ damage were measured regularly.RESULTS: During occlusion, both the REBOA groups had higher systemic mean arterial pressure (MAP) and cardiac output (P<0.05) compared to the two REBOA+REBOVC groups. After 60 minutes reperfusion, there were no statistically significant differences between the two REBOA groups and the two REBOA+REBOVC groups in MAP and cardiac output. The two REBOA+REBOVC groups had higher arterial lactate and potassium concentrations during reperfusion, compared to the two REBOA groups (P<0.05). There was no major difference in end-organ damage markers between REBOA and REBOA+REBOVC. Survival after one-hour reperfusion was 86% and 100% respectively in the normovolemic REBOA and REBOA+REBOVC groups, and 67% and 83% respectively in the corresponding hemorrhagic shock REBOA and REBOA+REBOVC groups.CONCLUSION: Acceptable hemodynamic stability during occlusion and short-term survival can be achieved by REBOA+REBOVC with adequate resuscitation; however, the more severe hemodynamic and metabolic impacts of REBOA+REBOVC compared to REBOA must be considered.LEVEL OF EVIDENCE: Prospective, randomized, experimental animal study. Basic science study, therapeutic.
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