| 1. |
- Kurt, Semih, et al.
(författare)
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CopyVAE: a variational autoencoder-based approach for copy number variation inference using single-cell transcriptomics
- 2024
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Ingår i: Bioinformatics. - : Oxford University Press. - 1367-4803 .- 1367-4811. ; 40:5
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Tidskriftsartikel (refereegranskat)abstract
- Motivation: Copy number variations (CNVs) are common genetic alterations in tumour cells. The delineation of CNVs holds promise for enhancing our comprehension of cancer progression. Moreover, accurate inference of CNVs from single-cell sequencing data is essential for unravelling intratumoral heterogeneity. However, existing inference methods face limitations in resolution and sensitivity. Results: To address these challenges, we present CopyVAE, a deep learning framework based on a variational autoencoder architecture. Through experiments, we demonstrated that CopyVAE can accurately and reliably detect CNVs from data obtained using single-cell RNA sequencing. CopyVAE surpasses existing methods in terms of sensitivity and specificity. We also discussed CopyVAE’s potential to advance our understanding of genetic alterations and their impact on disease advancement. Availability and implementation: CopyVAE is implemented and freely available under MIT license at https://github.com/kurtsemih/copyVAE.
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| 2. |
- Chen, Shaoqing, et al.
(författare)
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Anchoring High-Concentration Oxygen Vacancies at Interfaces of CeO2–x/Cu toward Enhanced Activity for Preferential CO Oxidation
- 2015
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Ingår i: ACS Applied Materials & Interfaces. - 1944-8252 .- 1944-8244. ; 7:41, s. 22999-23007
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Tidskriftsartikel (refereegranskat)abstract
- Catalysts are urgently needed to remove the residual CO in hydrogen feeds through selective oxidation for large-scale applications of hydrogen proton exchange membrane fuel cells. We herein propose a new methodology that anchors high concentration oxygen vacancies at interface by designing a CeO2–x/Cu hybrid catalyst with enhanced preferential CO oxidation activity. This hybrid catalyst, with more than 6.1% oxygen vacancies fixed at the favorable interfacial sites, displays nearly 100% CO conversion efficiency in H2-rich streams over a broad temperature window from 120 to 210 °C, strikingly 5-fold wider than that of conventional CeO2/Cu (i.e., CeO2 supported on Cu) catalyst. Moreover, the catalyst exhibits a highest cycling stability ever reported, showing no deterioration after five cycling tests, and a super long-time stability beyond 100 h in the simulated operation environment that involves CO2 and H2O. On the basis of an arsenal of characterization techniques, we clearly show that the anchored oxygen vacancies are generated as a consequence of electron donation from metal copper atoms to CeO2 acceptor and the subsequent reverse spillover of oxygen induced by electron transfer in well controlled nanoheterojunction. The anchored oxygen vacancies play a bridging role in electron capture or transfer and drive molecule oxygen into active oxygen species to interact with the CO molecules adsorbed at interfaces, thus leading to an excellent preferential CO oxidation performance. This study opens a window to design a vast number of high-performance metal-oxide hybrid catalysts via the concept of anchoring oxygen vacancies at interfaces.
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| 3. |
- Chen, Xinsong, et al.
(författare)
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Breast cancer patient-derived whole-tumor cell culture model for efficient drug profiling and treatment response prediction
- 2023
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 120:1
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer (BC) is a complex disease comprising multiple distinct subtypes with different genetic features and pathological characteristics. Although a large number of antineoplastic compounds have been approved for clinical use, patient-to-patient variability in drug response is frequently observed, highlighting the need for efficient treatment prediction for individualized therapy. Several patient-derived models have been established lately for the prediction of drug response. However, each of these models has its limitations that impede their clinical application. Here, we report that the whole-tumor cell culture (WTC) ex vivo model could be stably established from all breast tumors with a high success rate (98 out of 116), and it could reassemble the parental tumors with the endogenous microenvironment. We observed strong clinical associations and predictive values from the investigation of a broad range of BC therapies with WTCs derived from a patient cohort. The accuracy was further supported by the correlation between WTC-based test results and patients' clinical responses in a separate validation study, where the neoadjuvant treatment regimens of 15 BC patients were mimicked. Collectively, the WTC model allows us to accomplish personalized drug testing within 10 d, even for small-sized tumors, highlighting its potential for individualized BC therapy. Furthermore, coupled with genomic and transcriptomic analyses, WTC-based testing can also help to stratify specific patient groups for assignment into appropriate clinical trials, as well as validate potential biomarkers during drug development.
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| 4. |
- Chen, Xinsong
(författare)
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Studies on early cellular responses during Epstein-Barr virus infection
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The human gamma-herpesvirus Epstein-Barr virus (EBV) has been implicated in the pathogenesis of a broad spectrum of lymphoid and epithelial cell malignancies. A characteristic property of the virus is the capacity to establish a non-productive growthpromoting infection in B-lymphocytes. Although the induction of cell proliferation is a key feature in oncogenesis, it is not sufficient for full malignancy. In the work presented in this thesis my colleagues and I have asked whether the virus might contribute to oncogenesis by triggering additional events that are required for tumor progression. Replicative immortality is dependent on the activation of mechanisms that maintain the integrity of telomeres. Malignant cells achieve this by activating telomerase or a recombination-dependent pathway known as alternative lengthening of telomeres (ALT). We observed multiple signs of telomere dysfunction consistent with the activation of ALT in newly EBV infected Blymphocytes. These include accumulation of telomere-associated promyelocytic leukemia nuclear bodies (APBs), telomeric-sister chromatid exchange (T-SCE), and low expression of telomere associated proteins such as TRF1, TRF2, POT1, and ATRX, pointing to telomere de-protection as possible cause of telomere damage. The early phase of EBV induced B-cell immortalization is characterized by the accumulation of DNA damage and activation of a DNA damage response (DDR) that limits the efficiency of growth transformation. By comparing the response of B-lymphocytes infected with EBV or stimulated with a potent Bcell mitogen, we found that significant higher levels of damage occur in EBV infected blasts due to stronger and sustained accumulation of reactive oxygen species (ROS). Quenching of ROS did not affect the kinetics and magnitude of viral gene expression but dramatically decreased the efficiency of B-cell transformation, which correlated with selective downregulation of the viral LMP1 and the phosphorylated form of the cellular transcription factor STAT3. Analysis of the mechanism by which high levels of ROS support LMP1 expression revealed selective inhibition of viral microRNAs that target the LMP1 transcript. Viral products that are delivered to the infected cells by the incoming virions are likely to play important roles in regulating the cellular response to infection. One of such products, the large tegument protein BPLF1, is a cysteine protease with potent ubiquitin and NEDD8-specific deconjugase activities. We found that targeting of the deneddylase activity of BPLF1 to nucleus of productively infected cells requires processing of the catalytic N-terminus by caspase-1. Inhibition of caspase-1 severely impairs viral DNA synthesis and the release of infectious viruses. Collectively, the findings summarized in this thesis provide new insights on the capacity of EBV to contribute to tumor initiation and progression by triggering events, such as oxidative stress and ALT, that favor the acquisition of both genomic instability and replicative immortality. Regulation of viral functions by the cellular response to danger signals delivered by incoming virions may further contribute to the remodeling of the host cell environment allowing successful infection.
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| 5. |
- Collodet, Caterina, et al.
(författare)
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Development and characterization of a recombinant silk network for 3D culture of immortalized and fresh tumor-derived breast cancer cells
- 2023
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Ingår i: Bioengineering and Translational Medicine. - : Wiley. - 2380-6761. ; 8:5
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Tidskriftsartikel (refereegranskat)abstract
- Traditional cancer models rely on 2D cell cultures or 3D spheroids, which fail to recapitulate cell-extracellular matrix (ECM) interactions, a key element of tumor development. Existing hydrogel-based 3D alternatives lack mechanical support for cell growth and often suffer from low reproducibility. Here we report a novel strategy to make 3D models of breast cancer using a tissue-like, well-defined network environment based on recombinant spider silk, functionalized with a cell adhesion motif from fibronectin (FN-silk). With this approach, the canonical cancer cells SK-BR-3, MCF-7, and MDA-MB-231, maintain their characteristic expression of markers (i.e., ERα, HER2, and PGR) while developing distinct morphology. Transcriptomic analyses demonstrate how culture in the FN-silk networks modulates the biological processes of cell adhesion and migration while affecting physiological events involved in malignancy, such as inflammation, remodeling of the ECM, and resistance to anticancer drugs. Finally, we show that integration in FN-silk networks promotes the viability of cells obtained from the superficial scraping of patients' breast tumors.
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| 6. |
- Engblom, Camilla, et al.
(författare)
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Spatial transcriptomics of B cell and T cell receptors reveals lymphocyte clonal dynamics
- 2023
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 382:6675, s. 8486-
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Tidskriftsartikel (refereegranskat)abstract
- The spatial distribution of lymphocyte clones within tissues is critical to their development, selection, and expansion. We have developed spatial transcriptomics of variable, diversity, and joining (VDJ) sequences (Spatial VDJ), a method that maps B cell and T cell receptor sequences in human tissue sections. Spatial VDJ captures lymphocyte clones that match canonical B and T cell distributions and amplifies clonal sequences confirmed by orthogonal methods. We found spatial congruency between paired receptor chains, developed a computational framework to predict receptor pairs, and linked the expansion of distinct B cell clones to different tumor-associated gene expression programs. Spatial VDJ delineates B cell clonal diversity and lineage trajectories within their anatomical niche. Thus, Spatial VDJ captures lymphocyte spatial clonal architecture across tissues, providing a platform to harness clonal sequences for therapy.
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| 7. |
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| 8. |
- Hases, Linnea, et al.
(författare)
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The importance of sex in colorectal cancer biomarker discovery
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Colorectal cancer (CRC) is the third leading cause for cancer deaths, indicating the needfor new diagnostic and prognostic biomarkers. The advances in omics technologies andbioinformatics can speed up and improve current biomarker discovery strategies.Machine learning has been integrated for analysis of transcriptomic data for severalcancers. However, in addition to improved data-analysis, there is a need to investigate theimpact of sex in the biomarker discovery since there are several sex-differences in theincidence, mortality, prognosis and tumor characteristics of CRC. First we investigated ifthere are any sex-differences in the transcriptome of normal colon and CRC andinvestigated if there are any sex-differences in the differentially expressed genes betweenpaired-normal and CRC. In an attempt to study sex-specific biomarkers we used TCGAdata and performed feature selection with Vita, Boruta and MRMR in combination withmachine learning to identify top CRC biomarkers. Interestingly, we found stronger sexdifferencesin the normal colon compared to in CRC. Although the sex-differences werestronger in normal colon, sex showed to have a significant impact of the prognostic valueof the biomarkers. 13 of the selected features showed a sex-specific prognostic value. Thepreviously proposed prognostic biomarkers ESM1 and GUCA2A showed a male-specificprognostic value whereas CLDN1 was specific for females. Additionally, we found somenovel prognostic biomarkers including TSPAN7 (females), SLC25A23 (females) andC2orf88 (males). In conclusion, our data show the importance of sex in the discovery ofCRC biomarkers and proposes 13 sex-specific CRC prognostic biomarkers.
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| 9. |
- Hases, Linnea, et al.
(författare)
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The Importance of Sex in the Discovery of Colorectal Cancer Prognostic Biomarkers
- 2021
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 22:3
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer (CRC) is the third leading cause of cancer deaths. Advances within bioinformatics, such as machine learning, can improve biomarker discovery and ultimately improve CRC survival rates. There are clear sex differences in CRC characteristics, but the impact of sex has not been considered with regards to CRC biomarkers. Our aim here was to investigate sex differences in the transcriptome of a normal colon and CRC, and between paired normal and tumor tissue. Next, we attempted to identify CRC diagnostic and prognostic biomarkers and investigate if they are sex-specific. We collected paired normal and tumor tissue, performed RNA-seq, and applied feature selection in combination with machine learning to identify the top CRC diagnostic biomarkers. We used The Cancer Genome Atlas (TCGA) data to identify sex-specific CRC diagnostic biomarkers and performed an overall survival analysis to identify sex-specific prognostic biomarkers. We found transcriptomic sex differences in both the normal colon tissue and in CRC. Forty-four of the top-ranked biomarkers were sex-specific and 20 biomarkers showed a sex-specific prognostic value. Our data show the importance of sex in the discovery of CRC biomarkers. We propose 20 sex-specific CRC prognostic biomarkers, including ESM1, GUCA2A, and VWA2 for males and CLDN1 and FUT1 for females.
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| 10. |
- Jun, Seong-Hwan, et al.
(författare)
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Reconstructing clonal tree for phylo-phenotypic characterization of cancer using single-cell transcriptomics
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Functional characterization of the cancer clones can shed light on the evolutionary mechanisms driving cancer's proliferation and relapse mechanisms. Single-cell RNA sequencing data provide grounds for understanding the functional state of cancer as a whole; however, much research remains to identify and reconstruct clonal relationships toward characterizing the changes in functions of individual clones. We present PhylEx that integrates bulk genomics data with co-occurrences of mutations from single-cell RNA sequencing data to reconstruct high-fidelity clonal trees. We evaluate PhylEx on synthetic and well-characterized high-grade serous ovarian cancer cell line datasets. PhylEx outperforms the state-of-the-art methods both when comparing capacity for clonal tree reconstruction and for identifying clones. We analyze high-grade serous ovarian cancer and breast cancer data to show that PhylEx exploits clonal expression profiles beyond what is possible with expression-based clustering methods and clear the way for accurate inference of clonal trees and robust phylo-phenotypic analysis of cancer. The functional changes of individual clones in single cell RNA sequencing (scRNA-seq) data remain elusive. Here, the authors develop PhylEx that integrates bulk genomics data with co-occurrences of mutations revealed by scRNA-seq data and apply it to high-grade serous ovarian cancer cell line and breast cancer datasets.
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