| 21. |
- Andersson, Sören, 1957-, et al.
(författare)
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CHIMERIC MOMP ANTIGEN
- 2015
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Patent (populärvet., debatt m.m.)
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| 22. |
- Yu, Di, 1985-
(författare)
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Adenovirus for Cancer Therapy : With a Focus on its Surface Modification
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Adenovirus serotype 5 (Ad5) is widely used as an oncolytic agent for cancer therapy. However, its infectivity is highly dependent on the expression level of coxsackievirus-adenovirus receptor (CAR) on the surface of tumor cells. We engineered Ad5 virus with the protein transduction domain (PTD) from the HIV-1 Tat protein (Tat-PTD) inserted in the hypervariable region 5 (HVR5) of the hexon protein in the virus capsid. Tat-PTD-modified Ad5 shows a dramatically increased transduction level of CAR-negative cells and bypassed fiber-mediated transduction. It also overcomes the fiber-masking problem, which is caused by release of excess fiber proteins from infected cells. To achieve specific viral replication in neuroblastoma and neuroendocrine tumor cells, we identified the secretogranin III (SCG3) promoter and constructed an adenovirus Ad5PTD(ASH1-SCG3-E1A) wherein E1A gene expression is controlled by the SCG3 promoter and the achaete-scute complex homolog 1 (ASH1) enhancer. This virus shows selective and efficient killing of neuroblastoma cell lines in vitro, and delays human neuroblastoma xenograft tumor growth on nude mice. To further enhance the viral oncolytic efficacy, we also switched the fiber 5 to fiber 35 to generate Ad5PTDf35. This vector shows dramatically increased transduction capacity of primary human cell cultures including hematopoietic cells and their derivatives, pancreatic islets and exocrine cells, mesenchymal stem cells and primary tumor cells including primary cancer initiating cells. Ad5PTDf35-based adenovirus could be a useful platform for gene delivery and oncolytic virus development. Viral oncolysis alone cannot completely eradicate tumors. Therefore, we further armed the Ad5PTDf35-D24 virus with a secreted form of Helicobacter pylori Neutrophil Activating Protein (HP-NAP). Expression of HP-NAP recruits neutrophils to the site of infection, activates an innate immune response against tumor cells and provokes a Th1-type adaptive immune response. Established tumor on nude mice could be completely eradicated in some cases after treatment with this virus and the survival of mice was significantly prolonged.
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| 23. |
- Abdellah, Tebani, et al.
(författare)
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Integration of molecular profiles in a longitudinal wellness profiling cohort.
- 2020
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- An important aspect of precision medicine is to probe the stability in molecular profiles among healthy individuals over time. Here, we sample a longitudinal wellness cohort with 100 healthy individuals and analyze blood molecular profiles including proteomics, transcriptomics, lipidomics, metabolomics, autoantibodies andimmune cell profiling, complementedwith gut microbiota composition and routine clinical chemistry. Overall, our results show high variation between individuals across different molecular readouts, while the intra-individual baseline variation is low. The analyses show that each individual has a unique and stable plasma protein profile throughout the study period and that many individuals also show distinct profiles with regards to the other omics datasets, with strong underlying connections between the blood proteome and the clinical chemistry parameters. In conclusion, the results support an individual-based definition of health and show that comprehensive omics profiling in a longitudinal manner is a path forward for precision medicine.
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| 24. |
- Matthiesen, Isabelle, et al.
(författare)
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Continuous Monitoring Reveals Protective Effects of N‐Acetylcysteine Amide on an Isogenic Microphysiological Model of the Neurovascular Unit
- 2021
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Ingår i: Small. - : Wiley. - 1613-6810 .- 1613-6829. ; 17:32, s. 2101785-
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Tidskriftsartikel (refereegranskat)abstract
- Microphysiological systems mimic the in vivo cellular ensemble and microenvironment with the goal of providing more human-like models for biopharmaceutical research. In this study, the first such model of the blood-brain barrier (BBB-on-chip) featuring both isogenic human induced pluripotent stem cell (hiPSC)-derived cells and continuous barrier integrity monitoring with <2 min temporal resolution is reported. Its capabilities are showcased in the first microphysiological study of nitrosative stress and antioxidant prophylaxis. Relying on off-stoichiometry thiol–ene–epoxy (OSTE+) for fabrication greatly facilitates assembly and sensor integration compared to the prevalent polydimethylsiloxane devices. The integrated cell–substrate endothelial resistance monitoring allows for capturing the formation and breakdown of the BBB model, which consists of cocultured hiPSC-derived endothelial-like and astrocyte-like cells. Clear cellular disruption is observed when exposing the BBB-on-chip to the nitrosative stressor linsidomine, and the barrier permeability and barrier-protective effects of the antioxidant N-acetylcysteine amide are reported. Using metabolomic network analysis reveals further drug-induced changes consistent with prior literature regarding, e.g., cysteine and glutathione involvement. A model like this opens new possibilities for drug screening studies and personalized medicine, relying solely on isogenic human-derived cells and providing high-resolution temporal readouts that can help in pharmacodynamic studies.
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| 25. |
- Visuttijai, Kittichate, 1979-, et al.
(författare)
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Lowered Expression of Tumor Suppressor Candidate MYO1C Stimulates Cell Proliferation, Suppresses Cell Adhesion and Activates AKT
- 2016
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 11:10
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Tidskriftsartikel (refereegranskat)abstract
- Myosin-1C (MYO1C) is a tumor suppressor candidate located in a region of recurrent losses distal to TP53. Myo1c can tightly and specifically bind to PIP2, the substrate of Phosphoinositide 3-kinase (PI3K), and to Rictor, suggesting a role for MYO1C in the PI3K pathway. This study was designed to examine MYO1C expression status in a panel of well-stratified endometrial carcinomas as well as to assess the biological significance of MYO1C as a tumor suppressor in vitro. We found a significant correlation between the tumor stage and lowered expression of MYO1C in endometrial carcinoma samples. In cell transfection experiments, we found a negative correlation between MYO1C expression and cell proliferation, and MYO1C silencing resulted in diminished cell migration and adhesion. Cells expressing excess of MYO1C had low basal level of phosphorylated protein kinase B (PKB, a.k.a. AKT) and cells with knocked down MYO1C expression showed a quicker phosphorylated AKT (pAKT) response in reaction to serum stimulation. Taken together the present study gives further evidence for tumor suppressor activity of MYO1C and suggests MYO1C mediates its tumor suppressor function through inhibition of PI3K pathway and its involvement in loss of contact inhibition.
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| 26. |
- Lind, Anne-Li, et al.
(författare)
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Affinity Proteomics Applied to Patient CSF Identifies Protein Profiles Associated with Neuropathic Pain and Fibromyalgia
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Objective: Today, there are no biological tests on which to base pain diagnoses, treatment choices or to understand the biological processes underlying and accompanying chronic pain for the individual pain patient. Relevant biological markers would greatly aid in diagnosis and treatment of patients with chronic pain. Our study aimed to find proteins in CSF associated with fibromyalgia and neuropathic pain, two common and poorly understood chronic pain conditions.Methods: We have performed CSF protein profiling of 55 proteins using a 100-plex antibody suspension bead array. We collected, analyzed and compared CSF samples from 25 patients with neuropathic pain (two independent sets, n=14 patients for discovery and n=11 for verification), 40 patients with fibromyalgia and 135 controls without neurological disease from two different populations.Results: We found significant differences in CSF protein levels between patients and controls (p<0.05). Among these proteins, Apolipoprotein C1 (APOC1) was found to be increased in CSF of neuropathic pain patients compared to controls and there was a non-significant trend for increased levels also in fibromyalgia patient CSF. Ectonucleotide pyrophosphatase (ENPP2, Autotaxin) was increased in the CSF of fibromyalgia patients compared to all other groups including neuropathic pain patients. Multivariate analysis revealed partially overlapping and partially distinct CSF profiles in neuropathic pain patients compared with fibromyalgia and controls for several other proteins including angiotensinogen (AGT), prostaglandin-H2 D-isomerase (PTGDS), neurexin-1 (NRXN1), superoxide dismutase 1 (SOD1) and superoxide dismutase 3 (SOD3).Conclusions: Our results, suggest that the CSF protein profiles of neuropathic pain and fibromyalgia patients may be different from each other and from those of controls. CSF levels of APOC1, ENPP2, AGT, PTGDS, NRXN1, SOD1 and SOD3 should be further investigated for their potential to serve as biomarkers of different kinds of pain pathophysiology.
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| 27. |
- Blust, Kelly
(författare)
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Advancing 3D Cell Cultures of Stem-Cell Derived Pancreatic Islets and Breast Cancer Cells Using Recombinant Functionalized Spider Silk : Insights into cellular composition using bioinformatic methods
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The culture of cells in 3D creates a more physiologically relevant cell environment than conventional 2D cultures. Interactions of cells with the extracellular matrix induce important cellular signalling that regulates cell adhesion, migration, proliferation, differentiation, and survival. This is crucial for modelling cell development and disease. This thesis aims to develop and analyse improved 3D cell culture methods for stem cell-derived pancreatic islets (SC-islets) and breast cancer cell lines using a functionalized recombinant spider silk. Spider silk is a natural protein-based material with remarkable mechanical properties of high strength and elasticity. It is also biodegradable and cytocompatible. FN-silk, the recombinant spider silk protein utilized in this thesis, is functionalized with a cell binding motif (RGD) from fibronectin, to improve cell adhesion. Notably, FN-silk self-assembles at the liquid-air interface into a fibrillar structure, making it favourable as support for cell culture. In this thesis, bioinformatic methods were used to discover how the FN-silk supported environment affects the gene expression of cells and the cellular heterogeneity of SC-islets during a differentiation process. Additionally, bioinformatical analysis of the effect of 3D cell culture of breast cancer cell lines in FN-silk networks was performed. The first part of the thesis addresses serval challenges in pancreatic islet transplantation, by presenting an optimized protocol for pancreatic differentiation from human pluripotent stem cells, improving in vitro cultivation, and developing a cryopreservation method for SC-islets. The differentiation protocol presented in Paper 1 resulted in pure endocrine cell populations, avoiding unwanted proliferating and non-endocrine cells. It was also demonstrated that these SC-islets matured in vivo, and could effectively reverse diabetes in a diabetic mouse model. Single-cell RNA sequencing analysis provided new insights into the cellular composition and gene expression of the SC-islets before and after transplantation. In Paper 2, an innovative method for 3D in vitro cultivation of SC-islets using FN-silk networks mimicking the extracellular matrix was established. The FN-silk networks provided structural support for in vitro cultivation and handling during in vivo transplantation. The viability and functionality of free and FN-silk incorporated SC-islets were evaluated and compared. Single-cell RNA sequencing analyses confirmed maintenance of cellular composition, with a slightly improved beta cell maturation for SC-islets supported by FN-silk. In Paper 3, a novel strategy for cryopreservation of SC-islets was explored. The twisted vitrification method, previously employed for 2D cultures, was adapted for 3D cultures by utilizing integration into FN-silk networks to facilitate handling during the vitrification process. The second part of the thesis aimed to develop a method for 3D culture of breast cancer cells to better replicate the complexity of the tumour microenvironment. In Paper 4, FN-silk networks were used to generate a 3D environment for breast cancer cells where crucial cell-ECM interactions can be established. Proliferation rates and key marker expression of the cells cultured in 2D versus in the FN-silk network environment were investigated. Bioinformatic analysis of bulk RNA sequencing data was used to compare breast cancer cells in conventional 2D cell cultures with those cultured in 3D with the support of FNsilk. In conclusion, the work conducted in this thesis presents significant advancements in the development and analyses of 3D cell cultures of both SCislets and breast cancer cell lines, potentially enhancing therapeutic applications, disease modeling, and drug testing.
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| 28. |
- Klingström, Tomas, et al.
(författare)
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Legal & ethical compliance when sharing biospecimen
- 2018
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Ingår i: Briefings in Functional Genomics & Proteomics. - Oxford : Oxford University Press. - 2041-2649 .- 2041-2657. ; 17:1, s. 1-7
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Forskningsöversikt (refereegranskat)abstract
- When obtaining samples from biobanks, resolving ethical and legal concerns is a time-consuming task where researchers need to balance the needs of privacy, trust and scientific progress. The Biobanking and Biomolecular Resources Research Infrastructure-large Prospective Cohorts project has resolved numerous such issues through intense ommunication between involved researchers and experts in its mission to unite large rospective study sets in Europe. To facilitate efficient communication, it is useful for onexperts to have an at least basic understanding of the regulatory systemformanaging biological samples. Laws regulating research oversight are based on national law and normally share core principles founded on international charters. In interview studies among donors, chief concerns are privacy, efficient sample utilization and access to information generated fromtheir samples. Despite a lack of clear evidence regarding which concern takes precedence, scientific as well as public discourse has largely focused on privacy concerns and the right of donors to control the usage of their samples. It is therefore important to roactively deal with ethical and legal issues to avoid complications that delay or prevent samples from being accessed. To help biobank professionals avoid making unnecessary mistakes, we have developed this basic primer covering the relationship between ethics and law, the concept of informed consent and considerations for returning findings to donors.
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| 29. |
- Mahale, Sagar, et al.
(författare)
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HnRNPK maintains single strand RNA through controlling double-strand RNA in mammalian cells.
- 2022
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Although antisense transcription is a widespread event in the mammalian genome, double-stranded RNA (dsRNA) formation between sense and antisense transcripts is very rare and mechanisms that control dsRNA remain unknown. By characterizing the FGF-2 regulated transcriptome in normal and cancer cells, we identified sense and antisense transcripts IER3 and IER3-AS1 that play a critical role in FGF-2 controlled oncogenic pathways. We show that IER3 and IER3-AS1 regulate each other's transcription through HnRNPK-mediated post-transcriptional regulation. HnRNPK controls the mRNA stability and colocalization of IER3 and IER3-AS1. HnRNPK interaction with IER3 and IER3-AS1 determines their oncogenic functions by maintaining them in a single-stranded form. hnRNPK depletion neutralizes their oncogenic functions through promoting dsRNA formation and cytoplasmic accumulation. Intriguingly, hnRNPK loss-of-function and gain-of-function experiments reveal its role in maintaining global single- and double-stranded RNA. Thus, our data unveil the critical role of HnRNPK in maintaining single-stranded RNAs and their physiological functions by blocking RNA-RNA interactions.
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| 30. |
- Mondal, Tanmoy, 1981, et al.
(författare)
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Sense-antisense lncRNA pair encoded by locus 6p22.3 determines neuroblastoma susceptibility via the USP36-CHD7-SOX9 regulatory axis
- 2018
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Ingår i: Cancer Cell. - : Elsevier BV. - 1535-6108 .- 1878-3686. ; 33:3
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Tidskriftsartikel (refereegranskat)abstract
- Trait-associated loci often map to genomic regions encoding long noncoding RNAs (lncRNAs), but the role of these lncRNAs in disease etiology is largely unexplored. We show that a pair of sense/antisense lncRNA (6p22lncRNAs) encoded by CASC15 and NBAT1 located at the neuroblastoma (NB) risk-associated 6p22.3 locus are tumor suppressors and show reduced expression in high-risk NBs. Loss of functional synergy between 6p22lncRNAs results in an undifferentiated state that is maintained by a gene-regulatory network, including SOX9 located on 17q, a region frequently gained in NB. 6p22lncRNAs regulate SOX9 expression by controlling CHD7 stability via modulating the cellular localization of USP36, encoded by another 17q gene. This regulatory nexus between 6p22.3 and 17q regions may lead to potential NB treatment strategies.
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