| 1. |
- de Ståhl, Teresita Diaz, et al.
(författare)
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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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Ingår i: Journal of Translational Medicine. - : BioMed Central (BMC). - 1479-5876. ; 21
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Tidskriftsartikel (refereegranskat)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. |
- Marto, João Pedro, et al.
(författare)
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Safety and Outcome of Revascularization Treatment in Patients With Acute Ischemic Stroke and COVID-19: The Global COVID-19 Stroke Registry.
- 2023
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Ingår i: Neurology. - 1526-632X. ; 100:7
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Tidskriftsartikel (refereegranskat)abstract
- COVID-19-related inflammation, endothelial dysfunction, and coagulopathy may increase the bleeding risk and lower the efficacy of revascularization treatments in patients with acute ischemic stroke (AIS). We aimed to evaluate the safety and outcomes of revascularization treatments in patients with AIS and COVID-19.This was a retrospective multicenter cohort study of consecutive patients with AIS receiving intravenous thrombolysis (IVT) and/or endovascular treatment (EVT) between March 2020 and June 2021 tested for severe acute respiratory syndrome coronavirus 2 infection. With a doubly robust model combining propensity score weighting and multivariate regression, we studied the association of COVID-19 with intracranial bleeding complications and clinical outcomes. Subgroup analyses were performed according to treatment groups (IVT-only and EVT).Of a total of 15,128 included patients from 105 centers, 853 (5.6%) were diagnosed with COVID-19; of those, 5,848 (38.7%) patients received IVT-only and 9,280 (61.3%) EVT (with or without IVT). Patients with COVID-19 had a higher rate of symptomatic intracerebral hemorrhage (SICH) (adjusted OR 1.53; 95% CI 1.16-2.01), symptomatic subarachnoid hemorrhage (SSAH) (OR 1.80; 95% CI 1.20-2.69), SICH and/or SSAH combined (OR 1.56; 95% CI 1.23-1.99), 24-hour mortality (OR 2.47; 95% CI 1.58-3.86), and 3-month mortality (OR 1.88; 95% CI 1.52-2.33). Patients with COVID-19 also had an unfavorable shift in the distribution of the modified Rankin score at 3 months (OR 1.42; 95% CI 1.26-1.60).Patients with AIS and COVID-19 showed higher rates of intracranial bleeding complications and worse clinical outcomes after revascularization treatments than contemporaneous non-COVID-19 patients receiving treatment. Current available data do not allow direct conclusions to be drawn on the effectiveness of revascularization treatments in patients with COVID-19 or to establish different treatment recommendations in this subgroup of patients with ischemic stroke. Our findings can be taken into consideration for treatment decisions, patient monitoring, and establishing prognosis.The study was registered under ClinicalTrials.gov identifier NCT04895462.
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| 3. |
- Mohanty, Chitralekha, et al.
(författare)
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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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Ingår i: Anticancer Research. - 0250-7005 .- 1791-7530. ; 34:6, s. 2801-2806
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Tidskriftsartikel (refereegranskat)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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| 4. |
- Tham, Emma, et al.
(författare)
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A novel phenotype in N-glycosylation disorders: Gillessen-Kaesbach-Nishimura skeletal dysplasia due to pathogenic variants in ALG9.
- 2015
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1476-5438 .- 1018-4813.
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Tidskriftsartikel (refereegranskat)abstract
- A rare lethal autosomal recessive syndrome with skeletal dysplasia, polycystic kidneys and multiple malformations was first described by Gillessen-Kaesbach et al and subsequently by Nishimura et al. The skeletal features uniformly comprise a round pelvis, mesomelic shortening of the upper limbs and defective ossification of the cervical spine. We studied two unrelated families including three affected fetuses with Gillessen-Kaesbach-Nishimura syndrome using whole-exome and Sanger sequencing, comparative genome hybridization and homozygosity mapping. All affected patients were shown to have a novel homozygous splice variant NM_024740.2: c.1173+2T>A in the ALG9 gene, encoding alpha-1,2-mannosyltransferase, involved in the formation of the lipid-linked oligosaccharide precursor of N-glycosylation. RNA analysis demonstrated skipping of exon 10, leading to shorter RNA. Mass spectrometric analysis showed an increase in monoglycosylated transferrin as compared with control tissues, confirming that this is a congenital disorder of glycosylation (CDG). Only three liveborn children with ALG9-CDG have been previously reported, all with missense variants. All three suffered from intellectual disability, muscular hypotonia, microcephaly and renal cysts, but none had skeletal dysplasia. Our study shows that some pathogenic variants in ALG9 can present as a lethal skeletal dysplasia with visceral malformations as the most severe phenotype. The skeletal features overlap with that previously reported for ALG3- and ALG12-CDG, suggesting that this subset of glycosylation disorders constitutes a new diagnostic group of skeletal dysplasias.European Journal of Human Genetics advance online publication, 13 May 2015; doi:10.1038/ejhg.2015.91.
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| 5. |
- Tykesson, Emil, et al.
(författare)
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Dermatan sulfate epimerase 1 and dermatan 4-O-sulfotransferase 1 form complexes that generate long epimerized 4-O-sulfated blocks
- 2018
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Ingår i: Journal of Biological Chemistry. - 0021-9258. ; 293:35, s. 13725-13735
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Tidskriftsartikel (refereegranskat)abstract
- During the biosynthesis of chondroitin/dermatan sulfate (CS/ DS), a variable fraction of glucuronic acid is converted to iduronic acid through the activities of two epimerases, dermatan sulfate epimerases 1 (DS-epi1) and 2 (DS-epi2). Previous in vitro studies indicated that without association with other enzymes, DS-epi1 activity produces structures that have only a few adjacent iduronic acid units. In vivo, concomitant with epimerization, dermatan 4-O-sulfotransferase 1 (D4ST1) sulfates the GalNAc adjacent to iduronic acid. This sulfation facilitates DS-epi1 activity and enables the formation of long blocks of sulfated iduronic acid– containing domains, which can be major components of CS/DS. In this report, we used recombinant enzymes to confirm the concerted action of DS-epi1 and D4ST1. Confocal microscopy revealed that these two enzymes colocalize to the Golgi, and FRET experiments indicated that they physically interact. Furthermore, FRET, immunoprecipitation, and cross-linking experiments also revealed that DS-epi1, DS-epi2, and D4ST1 form homomers and are all part of a hetero-oligomeric complex where D4ST1 directly interacts with DS-epi1, but not with DS-epi2. The cooperation of DS-epi1 with D4ST1 may therefore explain the processive mode of the formation of iduronic acid blocks. In conclusion, the iduronic acid–forming enzymes operate in complexes, similar to other enzymes active in glycosaminoglycan biosynthesis. This knowledge shed light on regulatory mechanisms controlling the biosynthesis of the structurally diverse CS/DS molecule.
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| 6. |
- Vajro, Pietro, et al.
(författare)
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Three unreported cases of TMEM199-CDG, a rare genetic liver disease with abnormal glycosylation
- 2018
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Ingår i: Orphanet Journal of Rare Diseases. - : Springer Science and Business Media LLC. - 1750-1172. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: TMEM199 deficiency was recently shown in four patients to cause liver disease with steatosis, elevated serum transaminases, cholesterol and alkaline phosphatase and abnormal protein glycosylation. There is no information on the long-term outcome in this disorder. Results: We here present three novel patients with TMEM199-CDG. All three patients carried the same set of mutations (c.13-14delTT (p.Ser4Serfs∗30) and c.92G > C (p.Arg31Pro), despite only two were related (siblings). One mutation (c.92G > C) was described previously whereas the other was deemed pathogenic due to its early frameshift. Western Blot analysis confirmed a reduced level of TMEM199 protein in patient fibroblasts and all patients showed a similar glycosylation defect. The patients presented with a very similar clinical and biochemical phenotype to the initial publication, confirming that TMEM199-CDG is a non-encephalopathic liver disorder. Two of the patients were clinically assessed over two decades without deterioration. Conclusion: A rising number of disorders affecting Golgi homeostasis have been published over the last few years. A hallmark finding is deficiency in protein glycosylation, both in N- and O-linked types. Most of these disorders have signs of both liver and brain involvement. However, the present and the four previously reported patients do not show encephalopathy but a chronic, non-progressive (over decades) liver disease with hypertransaminasemia and steatosis. This information is crucial for the patient/families and clinician at diagnosis, as it distinguishes it from other Golgi homeostasis disorders, in having a much more favorable course.
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| 7. |
- Zielinska-Chomej, Katarzyna
(författare)
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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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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)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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