| 1. |
- Engert, Andreas, et al.
(författare)
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The European Hematology Association Roadmap for European Hematology Research : a consensus document
- 2016
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Ingår i: Haematologica. - Pavia, Italy : Ferrata Storti Foundation (Haematologica). - 0390-6078 .- 1592-8721. ; 101:2, s. 115-208
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Tidskriftsartikel (refereegranskat)abstract
- The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at (sic)23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine 'sections' in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients.
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| 2. |
- Cockell, Charles S., et al.
(författare)
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Subsurface scientific exploration of extraterrestrial environments (MINAR 5) : analogue science, technology and education in the Boulby Mine, UK
- 2019
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Ingår i: International Journal of Astrobiology. - : Cambridges Institutes Press. - 1473-5504 .- 1475-3006. ; 18:2, s. 157-182
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Tidskriftsartikel (refereegranskat)abstract
- The deep subsurface of other planetary bodies is of special interest for robotic and human exploration. The subsurface provides access to planetary interior processes, thus yielding insights into planetary formation and evolution. On Mars, the subsurface might harbour the most habitable conditions. In the context of human exploration, the subsurface can provide refugia for habitation from extreme surface conditions. We describe the fifth Mine Analogue Research (MINAR 5) programme at 1 km depth in the Boulby Mine, UK in collaboration with Spaceward Bound NASA and the Kalam Centre, India, to test instruments and methods for the robotic and human exploration of deep environments on the Moon and Mars. The geological context in Permian evaporites provides an analogue to evaporitic materials on other planetary bodies such as Mars. A wide range of sample acquisition instruments (NASA drills, Small Planetary Impulse Tool (SPLIT) robotic hammer, universal sampling bags), analytical instruments (Raman spectroscopy, Close-Up Imager, Minion DNA sequencing technology, methane stable isotope analysis, biomolecule and metabolic life detection instruments) and environmental monitoring equipment (passive air particle sampler, particle detectors and environmental monitoring equipment) was deployed in an integrated campaign. Investigations included studying the geochemical signatures of chloride and sulphate evaporitic minerals, testing methods for life detection and planetary protection around human-tended operations, and investigations on the radiation environment of the deep subsurface. The MINAR analogue activity occurs in an active mine, showing how the development of space exploration technology can be used to contribute to addressing immediate Earth-based challenges. During the campaign, in collaboration with European Space Agency (ESA), MINAR was used for astronaut familiarization with future exploration tools and techniques. The campaign was used to develop primary and secondary school and primary to secondary transition curriculum materials on-site during the campaign which was focused on a classroom extra vehicular activity simulation.
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| 3. |
- Friboulet, Luc, et al.
(författare)
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Molecular Characteristics of ERCC1-Negative versus ERCC1-Positive Tumors in Resected NSCLC
- 2011
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 17:17, s. 5562-5572
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Excision repair cross-complementation group 1 (ERCC1) is a protein involved in repair of DNA platinum adducts and stalled DNA replication forks. We and others have previously shown the influence of ERCC1 expression upon survival rates and benefit of cisplatin-based chemotherapy in patients with resected non-small-cell lung cancer (NSCLC). However, little is known about the molecular characteristics of ERCC1-positive and ERCC1-negative tumors. Experimental Design: We took advantage of a cohort of 91 patients with resected NSCLC, for which we had matched frozen and paraffin-embedded samples to explore the comparative molecular portraits of ERCC1-positive and ERCC1-negative tumors of NSCLC. We carried out a global molecular analysis including assessment of ERCC1 expression levels by using both immunohistochemistry (IHC) and quantitative reverse transcriptase PCR (qRT-PCR), genomic instability, global gene and miRNA expression, and sequencing of selected key genes involved in lung carcinogenesis. Results: ERCC1 protein and mRNA expression were significantly correlated. However, we observed several cases with clear discrepancies. We noted that ERCC1-negative tumors had a higher rate of genomic abnormalities versus ERCC1-positive tumors. ERCC1-positive tumors seemed to share a common DNA damage response (DDR) phenotype with the overexpression of seven genes linked to DDR. The miRNA expression analysis identified miR-375 as significantly underexpressed in ERCC1-positive tumors. Conclusions: Our data show inconsistencies in ERCC1 expression between IHC and qRT-PCR readouts. Furthermore, ERCC1 status is not linked to specific mutational patterns or frequencies. Finally, ERCC1negative tumors have a high rate of genomic aberrations that could consequently influence prognosis in patients with resected NSCLC. Clin Cancer Res; 17(17); 5562-72.
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| 4. |
- Galluzzi, Lorenzo, et al.
(författare)
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Prognostic Impact of Vitamin B6 Metabolism in Lung Cancer
- 2012
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Ingår i: Cell Reports. - Cambridge : Cell press. - 2211-1247. ; 2:2, s. 257-269
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Tidskriftsartikel (refereegranskat)abstract
- Patients with non-small cell lung cancer (NSCLC) are routinely treated with cytotoxic agents such as cisplatin. Through a genome-wide siRNA-based screen, we identified vitamin B6 metabolism as a central regulator of cisplatin responses in vitro and in vivo. By aggravating a bioenergetic catastrophe that involves the depletion of intracellular glutathione, vitamin B6 exacerbates cisplatin-mediated DNA damage, thus sensitizing a large panel of cancer cell lines to apoptosis. Moreover, vitamin B6 sensitizes cancer cells to apoptosis induction by distinct types of physical and chemical stress, including multiple chemotherapeutics. This effect requires pyridoxal kinase (PDXK), the enzyme that generates the bioactive form of vitamin B6. In line with a general role of vitamin B6 in stress responses, low PDXK expression levels were found to be associated with poor disease outcome in two independent cohorts of patients with NSCLC. These results indicate that PDXK expression levels constitute a biomarker for risk stratification among patients with NSCLC.
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| 5. |
- Lazar, Vladimir, et al.
(författare)
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Integrated molecular portrait of non-small cell lung cancers
- 2013
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Ingår i: BMC Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 6:1, s. 53-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Non-small cell lung cancer (NSCLC), a leading cause of cancer deaths, represents a heterogeneous group of neoplasms, mostly comprising squamous cell carcinoma (SCC), adenocarcinoma (AC) and large-cell carcinoma (LCC). The objectives of this study were to utilize integrated genomic data including copy-number alteration, mRNA, microRNA expression and candidate-gene full sequencing data to characterize the molecular distinctions between AC and SCC. Methods: Comparative genomic hybridization followed by mutational analysis, gene expression and miRNA microarray profiling were performed on 123 paired tumor and non-tumor tissue samples from patients with NSCLC. Results: At DNA, mRNA and miRNA levels we could identify molecular markers that discriminated significantly between the various histopathological entities of NSCLC. We identified 34 genomic clusters using aCGH data; several genes exhibited a different profile of aberrations between AC and SCC, including PIK3CA, SOX2, THPO, TP63, PDGFB genes. Gene expression profiling analysis identified SPP1, CTHRC1and GREM1 as potential biomarkers for early diagnosis of the cancer, and SPINK1 and BMP7 to distinguish between AC and SCC in small biopsies or in blood samples. Using integrated genomics approach we found in recurrently altered regions a list of three potential driver genes, MRPS22, NDRG1 and RNF7, which were consistently over-expressed in amplified regions, had wide-spread correlation with an average of similar to 800 genes throughout the genome and highly associated with histological types. Using a network enrichment analysis, the targets of these potential drivers were seen to be involved in DNA replication, cell cycle, mismatch repair, p53 signalling pathway and other lung cancer related signalling pathways, and many immunological pathways. Furthermore, we also identified one potential driver miRNA hsa-miR-944. Conclusions: Integrated molecular characterization of AC and SCC helped identify clinically relevant markers and potential drivers, which are recurrent and stable changes at DNA level that have functional implications at RNA level and have strong association with histological subtypes.
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| 6. |
- Michels, Judith, et al.
(författare)
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Cisplatin Resistance Associated with PARP Hyperactivation
- 2013
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Ingår i: Cancer Research. - Philadelphia : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 73:7, s. 2271-2280
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Tidskriftsartikel (refereegranskat)abstract
- Non-small cell lung carcinoma patients are frequently treated with cisplatin (CDDP), most often yielding temporary clinical responses. Here, we show that PARP1 is highly expressed and constitutively hyperactivated in a majority of human CDDP-resistant cancer cells of distinct histologic origin. Cells manifesting elevated intracellular levels of poly(ADP-ribosyl)ated proteins (PAR(high)) responded to pharmacologic PARP inhibitors as well as to PARP1-targeting siRNAs by initiating a DNA damage response that translated into cell death following the activation of the intrinsic pathway of apoptosis. Moreover, PARP1-overexpressing tumor cells and xenografts displayed elevated levels of PAR, which predicted the response to PARP inhibitors in vitro and in vivo more accurately than PARP1 expression itself. Thus, a majority of CDDP-resistant cancer cells appear to develop a dependency to PARP1, becoming susceptible to PARP inhibitor-induced apoptosis. Cancer Res; 73(7); 2271-80.
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| 7. |
- 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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