| 1. |
- Björklund, Johanna, et al.
(författare)
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An evaluation of structured language modeling for automatic speech recognition
- 2017
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Ingår i: Journal of universal computer science (Online). - Graz : Graz university of technology, Institute for information systems computer media IICM. - 0948-695X .- 0948-6968. ; 23:11, s. 1019-1034
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Tidskriftsartikel (refereegranskat)abstract
- We evaluated probabilistic lexicalized tree-insertion grammars (PLTIGs) on a classification task relevant for automatic speech recognition. The baseline is a family of n-gram models tuned with Witten-Bell smoothing. The language models are trained on unannotated corpora, consisting of 10,000 to 50,000 sentences collected from the English section of Wikipedia. For the evaluation, an additional 150 random sentences were selected from the same source, and for each of these, approximately 3,200 variations were generated. Each variant sentence was obtained by replacing an arbitrary word by a similar word, chosen to be at most 2 character edits from the original. The evaluation task consisted of identifying the original sentence among the automatically constructed (and typically inferior) alternatives. In the experiments, the n-gram models outperformed the PLTIG model on the smaller data set, but as the size of data grew, the PLTIG model gave comparable results. While PLTIGs are more demanding to train, they have the advantage that they assign a parse structure to their input sentences. This is valuable for continued algorithmic processing, for example, for summarization or sentiment analysis.
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| 2. |
- Björklund, My
(författare)
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Molecular signatures of progression and chemoresistance in epithelial ovarian carcinoma
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Epithelial ovarian carcinoma (EOC) is a heterogeneous disease generally classified into five histopathological subtypes; low- and high-grade serous, endometrioid, clear cell and mucinous carcinomas. Although each subtype has distinct clinical and molecular characteristics, they are all treated with surgery and platinum/ taxane chemotherapy. Despite initial responsiveness a majority of patients relapse into platinum-resistant and disseminated disease. This, together with often late diagnosis, makes EOC the most lethal gynecological cancer. Dissemination is mainly abdominal, via exfoliated tumor cells in peritoneal ascitic fluid. The origin and phenotype of cells in malignant ascites is poorly understood. Tumor progression of carcinomas towards metastasis includes epithelial-to-mesenchymal-transition (EMT), where epithelial cells gain a mesenchymal morphology to facilitate invasion. Progression and chemoresistance have also been attributed to a small population of highly tumorigenic and chemoresistant cancer stem cells, or tumor-initiating cells (TICs). In addition, altered cellular energetics is a hallmark of cancer wherefore tumor-specific metabolic features are potential targets for overcoming chemoresistance. In Paper I cell populations in malignant ascites were found to differ significantly with respect to protein expression levels of EMT and TIC markers. We identified two potential TIC profiles, highlighting a biological heterogeneity in ascitic tumor cell populations. The indicated presence of cancer-associated fibroblasts (CAFs) may further contribute to malignant properties. We found that CAF marker α-SMA expression was increased in clinical stage IV, compared to stage IIIC. Paper II reveals that long-term repeated cisplatin treatment can select for and/or induce a multiresistant cell population with EMT and TIC features. Resistance could be linked to upregulation of VDAC and HK-II, which form an anti-apoptotic complex on mitochondria. Multiresistant cells were sensitive to the lactate/ pyruvate analogue 3-BP that dissociates this complex, and particularly sensitive to 3-BP when combined with cisplatin in low doses. In Paper III expression of mitochondrial regulators PGC1α and TFAM was found to vary between EOC subtypes. For clear cell carcinomas (CCC) a profile consisting of low or undetectable levels of PGC1α, TFAM, ERα and low Ki-67 index was identified. This CCC profile, and also glycogen accumulation, was further linked to chemoresistance development in vitro. In Paper IV we used 1H NMR-based metabolomics to identify significant differences in the intracellular polar metabolome of parental and multiresistant EOC cell lines. Furthermore, we developed a tailored and reliable protocol for metabolic profiling of adherent cells, suitable for further characterization of metabolic alterations in EOC and other pathological conditions. Taken together, this thesis identifies signatures of progression and chemoresistance in EOC and highlights the need for subtype-specific treatment.
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| 3. |
- Engskog, Mikael K R, et al.
(författare)
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Metabolic profiling of epithelial ovarian cancer cell lines : evaluation of harvesting protocols for profiling using NMR spectroscopy
- 2015
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Ingår i: Bioanalysis. - : Future Science Ltd. - 1757-6180 .- 1757-6199. ; 7:2, s. 157-166
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Metabolic profiling represents a novel technology for analyzing tumor cells. Epithelial ovarian carcinoma has a low survival rate due to the development of aggressive and chemotherapy-resistant cells. A tailored and reliable protocol is presented for profiling of chemoresistant cells using the cell line SKOV3 and a multiresistant subline SKOV3R.RESULTS: Harvesting protocols with cold methanol or MilliQ freeze/thaw cycles were compared. Increased reproducibility using MilliQ was evidenced. Importantly, both approaches resulted in similar profiles. Compared with parental SKOV3, the SKOV3R cells showed a significantly different profile.CONCLUSION: The MilliQ protocol is preferred owing to higher reproducibility and increased sample preparation options. The resulting metabolic profiles summarize metabolic alterations in chemoresistant cells consistent with a progressed and aggressive phenotype.
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| 4. |
- Mareschal, Sylvain, et al.
(författare)
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Challenging conventional karyotyping by next-generation karyotyping in 281 intensively treated patients with AML
- 2021
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 5:4, s. 1003-1016
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Tidskriftsartikel (refereegranskat)abstract
- Although copy number alterations (CNAs) and translocations constitute the backbone of the diagnosis and prognostication of acute myeloid leukemia (AML), techniques used for their assessment in routine diagnostics have not been reconsidered for decades. We used a combination of 2 next-generation sequencing-based techniques to challenge the currently recommended conventional cytogenetic analysis (CCA), comparing the approaches in a series of 281 intensively treated patients with AML. Shallow whole-genome sequencing (sWGS) outperformed CCA in detecting European Leukemia Net (ELN)-defining CNAs and showed that CCA overestimated monosomies and suboptimally reported karyotype complexity. Still, the concordance between CCA and sWGS for all ELN CNA-related criteria was 94%. Moreover, using in silico dilution, we showed that 1 million reads per patient would be enough to accurately assess ELN-defining CNAs. Total genomic loss, defined as a total loss 200 Mb by sWGS, was found to be a better marker for genetic complexity and poor prognosis compared with the CCA-based definition of complex karyotype. For fusion detection, the concordance between CCA and whole-transcriptome sequencing (WTS) was 99%. WTS had better sensitivity in identifying inv(16) and KMT2A rearrangements while showing limitations in detecting lowly expressed PML-RARA fusions. Ligation-dependent reverse transcription polymerase chain reaction was used for validation and was shown to be a fast and reliable method for fusion detection. We conclude that a next-generation sequencing-based approach can replace conventional CCA for karyotyping, provided that efforts are made to cover lowly expressed fusion transcripts.
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| 5. |
- Neddermeyer, Anne, et al.
(författare)
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A new mutant NPM1/IDH2R140- and PML-RARA-associated lncRNA MALNC plays a role in AML biology, prognosis and drug response
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Acute myeloid leukemia (AML) is a hematopoietic malignancy characterized by poor prognosis that requires better understanding of its disease biology and new tools for suitable risk stratification and effective treatments. Long non-coding RNAs (lncRNAs) are involved in numerous molecular mechanisms, are implicated in tumor biology and can serve as clinical biomarkers, yet their role remains mostly unclear in AML. In this study, the aim was to discover and characterize lncRNAs implicated in AML and to describe their role in AML biology. Further aims were to explore their use as prognostic or predictive biomarkers. Using whole-transcriptome analysis, a novel lncRNA, here named MALNC, was identified. MALNC had elevated expression in two large AML cohorts compared to normal CD34+ cells. Clinical correlation analyses indicated that MALNC was almost uniquely expressed in patients with PML-RARA fusion gene and with co-mutated isocitrate dehydrogenase-2 R140 and nucleophosmin-1 (IDH2R140/NPM1). MALNC expression was specifically high at the promyelocytic stage and decreased with maturation in leukemic and normal cells. High MALNC expression associated independently with better overall survival. CRISPR-Cas9-knockout in promyelocytic cell lines impaired proliferation, colony formation and all-trans retinoic acid (ATRA)-induced differentiation. Also, MALNC-knockout dramatically sensitized cells to arsenic trioxide (ATO), ATO-ATRA combinatorial and Bcl-2-inhibitor venetoclax treatment as well as associated with cyclin-dependent kinase (Cdk)-inhibitor resistance. In conclusion, MALNC is overexpressed in certain subgroups of AML and could play a role during normal and leukemic hematopoietic maturation. Furthermore, it correlates with response to anti-leukemic drugs, which suggests a role as a predictive marker to drug response and survival in AML.
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| 6. |
- Rizoska, Biljana, et al.
(författare)
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Disease modifying effects of the amyloid-beta protofibril-selective antibody mAb158 in aged Tg2576 transgenic mice
- 2024
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Ingår i: Molecular and Cellular Neuroscience. - : Elsevier. - 1044-7431 .- 1095-9327. ; 130
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid beta (Aβ) peptides, which aggregate to form neocortical plaques in Alzheimer's disease, exist in states that range from soluble monomers and oligomers/protofibrils to insoluble fibrillar amyloid. The present study evaluated the effects of mAb158, a mouse monoclonal antibody version of lecanemab that preferentially binds to soluble Aβ protofibrils, in aged transgenic mice (Tg2576) with Aβ pathology. Female Tg2576 mice (12 months old) received weekly intraperitoneal mAb158 (35 mg/kg) or vehicle for 4 weeks or for 18 weeks, with or without a subsequent 12-week off-treatment period. Aβ protofibril levels were significantly lower in mAb158-treated animals at both 4 and 18 weeks, while longer treatment duration (18 weeks) was required to observe significantly lower Aβ42 levels in insoluble brain fractions and lower Aβ plaque load. Following the off-treatment period, comparison of the vehicle- and mAb158-treated mice demonstrated that the Aβ protofibril levels, insoluble Aβ42 levels and Aβ plaque load remained significantly lower in mAb158-treated animals, as compared with age-matched controls. However, there was a significant increase of brain accumulation of both the Aβ protofibril levels, insoluble Aβ42 levels and Aβ plaque load after treatment cessation. Thus, repeated mAb158 treatment of aged Tg2576 mice first reduced Aβ protofibril levels within 4 weeks of treatment, which then was followed by a reduction of amyloid plaque pathology within 18 weeks of treatment. These effects were maintained 12 weeks after the final dose, indicating that mAb158 had a disease-modifying effect on the Aβ pathology in this mouse model. In addition, brain accumulation of both Aβ protofibril levels and amyloid pathology progressed after discontinuation of the treatment which supports the importance of continued treatment with mAb158 to maintain the effects on Aβ pathology.
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| 7. |
- Uhlén, Mathias, et al.
(författare)
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A human protein atlas for normal and cancer tissues based on antibody proteomics
- 2005
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Ingår i: Molecular & Cellular Proteomics. - 1535-9476 .- 1535-9484. ; 4:12, s. 1920-1932
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Tidskriftsartikel (refereegranskat)abstract
- Antibody-based proteomics provides a powerful approach for the functional study of the human proteome involving the systematic generation of protein-specific affinity reagents. We used this strategy to construct a comprehensive, antibody-based protein atlas for expression and localization profiles in 48 normal human tissues and 20 different cancers. Here we report a new publicly available database containing, in the first version, similar to 400,000 high resolution images corresponding to more than 700 antibodies toward human proteins. Each image has been annotated by a certified pathologist to provide a knowledge base for functional studies and to allow queries about protein profiles in normal and disease tissues. Our results suggest it should be possible to extend this analysis to the majority of all human proteins thus providing a valuable tool for medical and biological research.
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| 8. |
- Österroos, Albin, et al.
(författare)
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Integrated transcriptomic and genomic analysis improves prediction of complete remission and survival in elderly patients with acute myeloid leukemia
- 2020
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Ingår i: Blood Cancer Journal. - : NATURE PUBLISHING GROUP. - 2044-5385. ; 10:6
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Tidskriftsartikel (refereegranskat)abstract
- Relevant molecular tools for treatment stratification of patients >= 65 years with acute myeloid leukemia (AML) are lacking. We combined clinical data with targeted DNA- and full RNA-sequencing of 182 intensively and palliatively treated patients to predict complete remission (CR) and survival in AML patients >= 65 years. Intensively treated patients withNPM1andIDH2(R172)mutations had longer overall survival (OS), whereas mutatedTP53conferred lower CR rates and shorter OS.FLT3-ITDandTP53mutations predicted worse OS in palliatively treated patients. Gene expression levels most predictive of CR were combined with somatic mutations for an integrated risk stratification that we externally validated using the beatAML cohort. We defined a high-risk group with a CR rate of 20% in patients with mutatedTP53, compared to 97% CR in low-risk patients defined by high expression ofZBTB7AandEEPD1withoutTP53mutations. Patients without these criteria had a CR rate of 54% (intermediate risk). The difference in CR rates translated into significant OS differences that outperformed ELN stratification for OS prediction. The results suggest that an integrated molecular risk stratification can improve prediction of CR and OS and could be used to guide treatment in elderly AML patients.
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