| 1. |
- Parris, Toshima Z, 1978, et al.
(author)
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Additive effect of the AZGP1, PIP, S100A8, and UBE2C molecular biomarkers improves outcome prediction in breast carcinoma
- 2014
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In: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 134:7, s. 1617-1629
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Journal article (peer-reviewed)abstract
- The deregulation of key cellular pathways is fundamental for the survival and expansion of neoplastic cells, which in turn can have a detrimental effect on patient outcome. To develop effective individualized cancer therapies, we need to have a better understanding of which cellular pathways are perturbed in a genetically defined subgroup of patients. Here, we validate the prognostic value of a 13-marker signature in independent gene expression microarray datasets (n = 1,141) and immunohistochemistry with full-faced FFPE samples (n = 71). The predictive performance of individual markers and panels containing multiple markers was assessed using Cox regression analysis. In the external gene expression dataset, six of the 13 genes (AZGP1, NME5, S100A8, SCUBE2, STC2, and UBE2C) retained their prognostic potential and were significantly associated with disease-free survival (P < 0.001). Protein analyses refined the signature to a four-marker panel (AZGP1, PIP, S100A8, and UBE2C) significantly correlated with cycling, high grade tumors and lower disease-specific survival rates. AZGP1 and PIP were found in significantly lower levels in invasive breast tissue compared with adjacent normal tissue, whereas elevated levels of S100A8 and UBE2C were observed. A predictive model containing the four-marker panel in conjunction with established clinical variables outperformed a model containing the clinical variables alone. Our findings suggest that deregulated AZGP1, PIP, S100A8, and UBE2C are critical for the aggressive breast cancer phenotype, which may be useful as novel therapeutic targets for drug development to complement established clinical variables. © 2013 Wiley Periodicals, Inc.
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| 2. |
- Parris, Toshima Z, 1978, et al.
(author)
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Clinical relevance of breast cancer-related genes as potential biomarkers for oral squamous cell carcinoma
- 2014
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In: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 14
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Journal article (peer-reviewed)abstract
- Background: Squamous cell carcinoma of the oral cavity (OSCC) is a common cancer form with relatively low 5-year survival rates, due partially to late detection and lack of complementary molecular markers as targets for treatment. Molecular profiling of head and neck cancer has revealed biological similarities with basal-like breast and lung carcinoma. Recently, we showed that 16 genes were consistently altered in invasive breast tumors displaying varying degrees of aggressiveness. Methods: To extend our findings from breast cancer to another cancer type with similar characteristics, we performed an integrative analysis of transcriptomic and proteomic data to evaluate the prognostic significance of the 16 putative breast cancer-related biomarkers in OSCC using independent microarray datasets and immunohistochemistry. Predictive models for disease-specific (DSS) and/or overall survival (OS) were calculated for each marker using Cox proportional hazards models. Results: We found that CBX2, SCUBE2, and STK32B protein expression were associated with important clinicopathological features for OSCC (peritumoral inflammatory infiltration, metastatic spread to the cervical lymph nodes, and tumor size). Consequently, SCUBE2 and STK32B are involved in the hedgehog signaling pathway which plays a pivotal role in metastasis and angiogenesis in cancer. In addition, CNTNAP2 and S100A8 protein expression were correlated with DSS and OS, respectively. Conclusions: Taken together, these candidates and the hedgehog signaling pathway may be putative targets for drug development and clinical management of OSCC patients.
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| 3. |
- Biermann, Jana, et al.
(author)
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A novel 18-marker panel predicting clinical outcome in breast cancer
- 2017
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In: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. - 1538-7755. ; 26:11, s. 1619-28
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Journal article (peer-reviewed)abstract
- Gene expression profiling has made considerable contributions to our understanding of cancer biology and clinical care. This study describes a novel gene expression signature for breast cancer-specific survival that was validated using external datasets. Gene expression signatures for invasive breast carcinomas (mainly Luminal B subtype) corresponding to 136 patients were analysed using Cox regression and the effect of each gene on disease-specific survival (DSS) was estimated. Iterative Bayesian Model Averaging was applied on multivariable Cox regression models resulting in an 18-marker panel, which was validated using three external validation datasets. The 18 genes were analysed for common pathways and functions using the Ingenuity Pathway Analysis software. This study complied with the REMARK criteria. The 18-gene multivariable model showed a high predictive power for DSS in the training and validation cohort and a clear stratification between high- and low-risk patients. The differentially expressed genes were predominantly involved in biological processes such as cell cycle, DNA replication, recombination, and repair. Furthermore, the majority of the 18 genes were found to play a pivotal role in cancer. Our findings demonstrated that the 18 molecular markers were strong predictors of breast cancer-specific mortality. The stable time-dependent area under the ROC curve function (AUC(t)) and high C-indices in the training and validation cohorts were further improved by fitting a combined model consisting of the 18-marker panel and established clinical markers. Our work supports the applicability of this 18-marker panel to improve clinical outcome prediction for breast cancer patients.
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| 4. |
- Biermann, Jana, et al.
(author)
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A 17-marker panel for global genomic instability in breast cancer.
- 2020
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In: Genomics. - : Elsevier BV. - 0888-7543 .- 1089-8646. ; 112:2, s. 1151-1161
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Journal article (peer-reviewed)abstract
- Genomic instability is a hallmark of cancer that plays a pivotal role in breast cancer development and evolution. A number of existing prognostic gene expression signatures for breast cancer are based on proliferation-related genes. Here, we identified a 17-marker panel associated with genome stability. A total of 136 primary breast carcinomas were stratified by genome stability. Matched gene expression profiles showed an innate segregation based on genome stability. We identified a 17-marker panel stratifying the training and validation cohorts into high- and low-risk patients. The 17 genes associated with genomic instability strongly impacted clinical outcome in breast cancer. Pathway analyses determined chromosome organisation, cell cycle regulation, and RNA processing as the underlying biological processes, thereby offering options for drug development and treatment tailoring. Our work supports the applicability of the 17-marker panel to improve clinical outcome prediction for breast cancer patients based on a signature accounting for genomic instability.
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| 5. |
- Biermann, Jana, et al.
(author)
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Radiation-induced genomic instability in breast carcinomas of the Swedish haemangioma cohort.
- 2019
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In: Genes, chromosomes & cancer. - : Wiley. - 1098-2264 .- 1045-2257. ; 58:9, s. 627-35
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Journal article (peer-reviewed)abstract
- Radiation-induced genomic instability (GI) is hypothesized to persist after exposure and ultimately promote carcinogenesis. Based on the absorbed dose to the breast, an increased risk of developing breast cancer was shown in the Swedish haemangioma cohort that was treated with radium-226 for skin haemangioma as infants. Here, we screened 31 primary breast carcinomas for genetic alterations using the OncoScan CNV Plus Assay to assess GI and chromothripsis-like patterns associated with the absorbed dose to the breast. Higher absorbed doses were associated with increased numbers of copy number alterations (CNAs) in the tumour genome and thus a more unstable genome. Hence, the observed dose-dependent GI in the tumour genome is a measurable manifestation of the long-term effects of irradiation. We developed a highly predictive Cox regression model for overall survival based on the interaction between absorbed dose and GI. The Swedish haemangioma cohort is a valuable cohort to investigate the biological relationship between absorbed dose and GI in irradiated humans. This work gives a biological basis for improved risk assessment to minimize carcinogenesis as a secondary disease after radiation therapy. This article is protected by copyright. All rights reserved.
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| 6. |
- Biermann, Jana, et al.
(author)
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Tumour clonality in paired invasive breast carcinomas
- 2019
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In: Cancer Research. - 0008-5472.
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Conference paper (other academic/artistic)abstract
- Background: Multiple invasive breast tumours may represent either independent primary tumours or clonal recurrences of the first tumour, where the same progenitor cell gives rise to all of the detected tumours. Consequently, the driver events for the progenitor cell need to have been identical in early tumour development. Molecular classification of tumour clonality is not currently evaluated in multiple invasive breast carcinomas, despite evidence suggesting common clonal origins. Furthermore, there is no consensus about which type of biological data (e.g. copy number, mutation, histology) and especially which statistical method is most suitable to distinguish clonal recurrences from independent primary tumours. Methods: Thirty-seven invasive breast tumour pairs were stratified by laterality (bilateral vs. ipsilateral) and the time interval between the diagnoses of the first and second tumours (synchronous vs. metachronous). Both tumours from the same patient were analysed by integrating clinical characteristics (n = 37), DNA copy number (n = 37), DNA methylation (n = 8), gene expression microarray (n = 7), RNA sequencing (n = 3), and SNP genotyping data (n = 3). Different statistical methods, e.g. the diagnostic similarity index (SI), distance measure, shared segment analysis etc., were used to classify the tumours from the same patient as clonally related recurrences or independent primary tumours. Results: The SI applied on DNA copy numbers derived from aCGH (array comparative genomic hybridization) data was determined as the strongest indicator of clonal relatedness as it showed the highest concordance with all other methods. The distance measure was the most conservative method and the shared segment analysis most liberal. Concordant evidence for tumour clonality was found in 46% (17/37) of the patients. Notably, no significant association was found between the clinical characteristics and molecular tumour features. Conclusions: A more accurate classification of clonal relatedness between multiple breast tumours may help to mitigate treatment failure and relapse by integrating tumour-associated molecular features, clinical parameters, and statistical methods. In cases of extremely similar or different tumour pairs, the results showed consistency regardless of the method used. The SI can be easily integrated into clinical routine using FFPE samples to obtain copy number data. However, clinical guidelines with exact thresholds need to be defined to standardize clonality testing in a routine diagnostic setting.
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| 7. |
- Karlsson, Mattias, 1981-, et al.
(author)
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Substances released from probiotic Lactobacillus rhamnosus GR-1 potentiate NF-κB activity in Escherichia coli-stimulated urinary bladder cells
- 2012
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In: FEMS Immunology and Medical Microbiology. - Hoboken, USA : Wiley-Blackwell. - 0928-8244 .- 1574-695X. ; 66:2, s. 147-156
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Journal article (peer-reviewed)abstract
- Lactobacillus rhamnosus GR-1 is a probiotic bacterium used to maintain urogenital health. The putative mechanism for its probiotic effect is by modulating the host immunity. Urinary tract infections (UTI) are often caused by uropathogenic Escherichia coli that frequently evade or suppress immune responses in the bladder and can target pathways, including nuclear factor-kappaB (NF-κB). We evaluated the role of L. rhamnosus GR-1 on NF-κB activation in E. coli-stimulated bladder cells. Viable L. rhamnosus GR-1 was found to potentiate NF-κB activity in E. coli-stimulated T24 bladder cells, whereas heat-killed lactobacilli demonstrated a marginal increase in NF-κB activity. Surface components released by trypsin- or LiCl treatment, or the resultant heat-killed shaved lactobacilli, had no effect on NF-κB activity. Isolation of released products from L. rhamnosus GR-1 demonstrated that the induction of NF-κB activity was owing to released product(s) with a relatively large native size. Several putative immunomodulatory proteins were identified, namely GroEL, elongation factor Tu and NLP/P60. GroEL and elongation factor Tu have previously been shown to elicit immune responses from human cells. Isolating and using immune-augmenting substances produced by lactobacilli is a novel strategy for the prevention or treatment of UTI caused by immune-evading E. coli.
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| 8. |
- Lachmann, Florina, et al.
(author)
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Marine plastic litter on Small Island Developing States (SIDS): Impacts and measures.
- 2017
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Reports (other academic/artistic)abstract
- This report was commissioned by the Swedish Agency for Marine and Water management and written by analysts at the Swedish Institute for the Marine Environment (affiliated with the University of Gothenburg, Lund University, and Chalmers University of Technology). This report documents how marine plastic litter reaches even the most remote parts of the oceans with small island states, and how SIDS are especially vulnerable to its impact. The origin and composition of marine plastic litter and its impacts are described. Measures are discussed, both from state agencies and private corporations. Measures from existing RAPs on marine litter are reviewed and examples of private initiatives are mentioned. Also, the corresponding legal framework is given and side effects of marine litter measures on the Sustainable Development Goals of the UN are debated. THE VULNERABILITY OF SIDS SIDS are a set of island nations in the Caribbean Sea, the Pacific Ocean, the Atlantic, Indian Ocean, and the South China Sea. SIDS are exposed to disproportionate concentrations of plastic litter due to their location near the ocean gyres where marine litter accumulates and to often sub-performing waste management systems. ORIGINS AND COMPOSITION OF MARINE PLASTIC LITTER Because plastic make up most marine debris, the focus here is on plastic litter. Marine plastic litter washed ashore on SIDS originates from both distant countries overseas and the SIDS themselves. Buoyant plastic litter is globally distributed by ocean currents and is washed ashore on beach lines around the globe where it negatively impacts ecological and human systems. Plastics end up in the marine environment through leaks from the global value chains that run from the oil industry through various other industries to local retailers and consumers. A smaller but significant stream of plastic litter follows from the difficulties of many SIDS to establish and maintain efficient waste management systems. IMPACT OF PLASTIC LITTER ON ECOLOGICAL, SOCIAL, AND ECONOMIC VALUES Marine litter impacts the environment and organisms therein in various ways, including entanglement, ingestion, transfer of chemicals, or by otherwise altering habitats. The extent of the social and economic impact that plastic on countries is not currently well known. However, the dependence of SIDS on their natural resources through tourism and fisheries, make them economically vulnerable to plastic litter. MITIGATION AND REMEDIATION STRATEGIES For plastic that reaches SIDS, both remediation and mitigation, especially through waste management and recycling, become necessary. LEGAL AND POLITICAL FRAMEWORKS The legal framework for preventing and managing marine litter is present on all levels of governance. A declaration particularly relevant to marine litter on SIDS is the SAMOA Pathway, a declaration from the 3rd International Conference on Small Island Developing States in 2014 calling for measures to manage waste, including marine plastic litter. Multilateral agreements require party states to take actions, but these requirements are often generally formulated, and their achievements depend on the choices and participation of all parties. POLICY MEASURES PROPOSED BY REGIONAL ACTION PLANS There are 18 Regional Seas programmes under the United Nations Environmental Program for the protection of the marine environment. Some Regional Seas programmes have written strategies to guide their actions, the RAPs, i.e. a political agenda for marine litter management agreed on by member governments of the region. The contents of different RAPs show strong similarities. The analyses conducted here show that most measures suggested by RAPs are aimed at downstream processes, while fewer address the problem upstream. Additional measures are needed to solve such a global problem. VOLUNTARY AND COMMERCIAL INITIATIVES Marine litter requires an array of actions from local to global level, and is thus a matter of governance. Most measures suggested in RAPs and other work against marine litter involve government managers as well as businesses, NGOs, and voluntary initiatives. RECOMMENDATION: FUTURE COOPERATION Competence and enthusiasm for the issue on SIDS and elsewhere is growing, but more is needed. Solutions require international cooperation. Four recommendations for cooperation are highlighted here: 1. Prevent litter from entering the ocean and thus reaching SIDS: Support cooperation in regional and international agreements 2. Plastic material reaching SIDS should not be released into the environment: Technical cooperation and support for local waste management 3. If waste reaches the environment, collect it where appropriate: Support beach clean-up campaigns and other remediation measures 4. When waste has been collected, ensure that is has a value: Develop recycling markets and opportunities
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| 9. |
- Larsson, Peter, et al.
(author)
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Optimization of cell viability assays to improve replicability and reproducibility of cancer drug sensitivity screens.
- 2020
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Journal article (peer-reviewed)abstract
- Cancer drug development has been riddled with high attrition rates, in part, due to poor reproducibility of preclinical models for drug discovery. Poor experimental design and lack of scientific transparency may cause experimental biases that in turn affect data quality, robustness and reproducibility. Here, we pinpoint sources of experimental variability in conventional 2D cell-based cancer drug screens to determine the effect of confounders on cell viability for MCF7 and HCC38 breast cancer cell lines treated with platinum agents (cisplatin and carboplatin) and a proteasome inhibitor (bortezomib). Variance component analysis demonstrated that variations in cell viability were primarily associated with the choice of pharmaceutical drug and cell line, and less likely to be due to the type of growth medium or assay incubation time. Furthermore, careful consideration should be given to different methods of storing diluted pharmaceutical drugs and use of DMSO controls due to the potential risk of evaporation and the subsequent effect on dose-response curves. Optimization of experimental parameters not only improved data quality substantially but also resulted in reproducible results for bortezomib- and cisplatin-treated HCC38, MCF7, MCF-10A, and MDA-MB-436 cells. Taken together, these findings indicate that replicability (the same analyst re-performs the same experiment multiple times) and reproducibility (different analysts perform the same experiment using different experimental conditions) for cell-based drug screens can be improved by identifying potential confounders and subsequent optimization of experimental parameters for each cell line.
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| 10. |
- Parris, Toshima Z, 1978, et al.
(author)
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Frequent MYC coamplification and DNA hypomethylation of multiple genes on 8q in 8p11-p12-amplified breast carcinomas
- 2014
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In: Oncogenesis. - : Springer Science and Business Media LLC. - 2157-9024. ; 3
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Journal article (peer-reviewed)abstract
- Genetic and epigenetic (DNA methylation, histone modifications, microRNA expression) crosstalk promotes inactivation of tumor suppressor genes or activation of oncogenes by gene loss/hypermethylation or duplications/hypomethylation, respectively. The 8p11-p12 chromosomal region is a hotspot for genomic aberrations (chromosomal rearrangements, amplifications and deletions) in several cancer forms, including breast carcinoma where amplification has been associated with increased proliferation rates and reduced patient survival. Here, an integrative genomics screen (DNA copy number, transcriptional and DNA methylation profiling) performed in 229 primary invasive breast carcinomas identified substantial coamplification of the 8p11-p12 genomic region and the MYC oncogene (8q24.21), as well as aberrant methylation and transcriptional patterns for several genes spanning the 8q12.1-q24.22 genomic region (ENPP2, FABP5, IMPAD1, NDRG1, PLEKHF2, RRM2B, SQLE, TAF2, TATDN1, TRPS1, VPS13B). Taken together, our findings suggest that MYC activity and aberrant DNA methylation may also have a pivotal role in the aggressive tumor phenotype frequently observed in breast carcinomas harboring 8p11-p12 regional amplification.
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