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- de Ståhl, Teresita Diaz, et al.
(author)
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The Swedish childhood tumor biobank : systematic collection and molecular characterization of all pediatric CNS and other solid tumors in Sweden
- 2023
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In: Journal of Translational Medicine. - : BioMed Central (BMC). - 1479-5876. ; 21
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Journal article (peer-reviewed)abstract
- The Swedish Childhood Tumor Biobank (BTB) is a nonprofit national infrastructure for collecting tissue samples and genomic data from pediatric patients diagnosed with central nervous system (CNS) and other solid tumors. The BTB is built on a multidisciplinary network established to provide the scientific community with standardized biospecimens and genomic data, thereby improving knowledge of the biology, treatment and outcome of childhood tumors. As of 2022, over 1100 fresh-frozen tumor samples are available for researchers. We present the workflow of the BTB from sample collection and processing to the generation of genomic data and services offered. To determine the research and clinical utility of the data, we performed bioinformatics analyses on next-generation sequencing (NGS) data obtained from a subset of 82 brain tumors and patient blood-derived DNA combined with methylation profiling to enhance the diagnostic accuracy and identified germline and somatic alterations with potential biological or clinical significance. The BTB procedures for collection, processing, sequencing, and bioinformatics deliver high-quality data. We observed that the findings could impact patient management by confirming or clarifying the diagnosis in 79 of the 82 tumors and detecting known or likely driver mutations in 68 of 79 patients. In addition to revealing known mutations in a broad spectrum of genes implicated in pediatric cancer, we discovered numerous alterations that may represent novel driver events and specific tumor entities. In summary, these examples reveal the power of NGS to identify a wide number of actionable gene alterations. Making the power of NGS available in healthcare is a challenging task requiring the integration of the work of clinical specialists and cancer biologists; this approach requires a dedicated infrastructure, as exemplified here by the BTB.
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| 2. |
- Mohanty, Chitralekha, et al.
(author)
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Predicting the sensitivity to ion therapy based on the response to photon irradiation - experimental evidence and mathematical modelling
- 2014
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In: Anticancer Research. - 0250-7005 .- 1791-7530. ; 34:6, s. 2801-2806
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Journal article (peer-reviewed)abstract
- Background/Aim: The use of ion radiation therapy is growing due to the continuously increasing positive clinical experience obtained. Therefore, there is a high interest in radio-biological experiments comparing the relative efficiency in cell killing of ions and photons as the photons are currently the main radiation modality used for cancer treatment. This comparison is particularly important since the treatment planning systems (TPSs) used at the main ion therapy centres make use of parameters describing the cellular response to photons, respectively ions, determined in vitro. It was therefore the aim of this paper to compare the effects of high LET ion radiation with low LET photons and determine whether the cellular response to low LET could predict the response to high LET irradiation. Materials and Methods: Clonogenic cell survival data of five tumor cell lines irradiated with different ion beams of similar, clinically-relevant, LET were studied in relation to the response to low LET photons. Two mathematical models were used to fit the data, the repairable-conditionally repairable damage (RCR) model and the linear quadratic (LQ) model. Results: The results indicate that the relative biological efficiency of the high LET radiation assessed with the RCR model could be predicted based only on the response to the low LET irradiation. Conclusion: The particular features of the RCR model indicate thus that tumor cells showing a large capacity for repairing the damage will have the larger benefit from radiation therapy with ions beams.
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| 3. |
- Zielinska-Chomej, Katarzyna
(author)
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Analysis and characterization of chemo- and radiation therapy sensitizing strategies in tumours with focus on effects of phenothiazines on DNA damage response signalling
- 2015
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Doctoral thesis (other academic/artistic)abstract
- Cancer is, despite rapid progress in development of new targeted therapies, still mainly treated with surgery, chemotherapy and/or radiation therapy. The last two mentioned conventional therapies often meet general obstacles such as normal cell toxicity and tumour cell resistance. Further efforts are, hence, required to increase efficacy of both radiotherapy and chemotherapy in order to increase patients survival. In this thesis, we analysed and characterised strategies to improve chemotherapy and radiation therapy sensitivity in tumours, with focus on lung cancer. Particle radiation therapy offers an opportunity to overcome tumours' resistance to conventional photon irradiation. Unfortunately, treatment planning systems describing parameters for ion irradiations, used in particle therapy centres worldwide, are still based on the survival data from conventional radiation. In Paper I, we used two mathematical models, the linear-quadratic (LQ) and the repairable-conditionally repairable damage (RCR), to compare the effects of high LET accelerated ions with those elicited by conventional low LET photons, in different types of tumour cells. We show that the data on response to low LET irradiation can be used to create models that can predict cellular response to high LET with radiobiological parameters assessed with the RCR model. Moreover, results achieved with the RCR - but not with LQ model, suggest that tumour cells with high DNA repair capacity can benefit from radiation therapy with accelerated particles. Another cancer treatment strategy presented in this thesis is focused on the use of phenothiazines, alone or as sensitizers to chemotherapy. Phenothiazines are drugs clinically used for psychiatric disorders, but which also have been shown to possess cytotoxic activity in various regimens and tumours. In Paper II, we uncovered that monotherapy with phenothiazines caused decreased cell viability and cell death of small cell lung cancer (SCLC) cells. Furthermore, we showed that lysosomal dysfunction induced by phenothiazines was responsible for the observed higher responsiveness of SCLC cells. Our studies presented a new context of use and activity of phenothiazines in tumour cells and allow for a potential treatment opportunity for SCLC. In Paper III, we showed that phenothiazines interfere with DNA damage response (DDR) machinery in tumour cells by inhibition of one of the DNA double strand breaks (DBSs) repair pathways - the nonhomologous end joining (NHEJ). We demonstrated that this phenothiazine-mediated inhibition of DNA repair was associated with increased chromatin-centred DNA-PK/ATM signalling, resulting in augmented substrate phosphorylation and protracted checkpoint arrest. This novel tumour cell selective feature of phenothiazines preferentially caused chemosensitization to genotoxic agents that induce DNA DSBs, but also opens up for possible combinations with DNA repair inhibitors. In Paper IV, in silico gene expression analysis suggested similarities in mode of action between phenothiazines and epigenetic signalling modulators. Accordingly, we showed that phenothiazines can be used to treat SCLC or the epigenetically deregulated tumour cells, neuroblastoma (NB) and acute myeloid leukemia (AML), either alone or in combination with chromatin-modifying drugs. The cytotoxicity, cell death signalling and hyperactivation of DNA repair signals observed with phenothiazines in tumour cells, were comparable in magnitude with the effect of the chromatin-modifying drugs, pan-HDACi panobinostat or the BRD4 antagonist JQ1. Moreover, the model phenothiazine compound trifluoperazine, TFP, was also found to prolong phosphorylation of DNA-PKcs in chromatin fractions of SCLC cells. The tandem treatment with TFP and either panobinostat or JQ1 was also demonstrated to increase cytotoxicity and triggered both apoptotic and autophagic cell death signalling in SCLC and NB cells. Thus, our findings in Paper IV suggest a novel therapeutic utility of phenothiazines and chromatin-modifying drugs in cancer therapy.
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