| 1. |
- Munthe, Christian, 1962, et al.
(author)
-
The Return of Lombroso? Ethical Aspects of (Visions of) Preventive Forensic Screening
- 2015
-
In: Public Health Ethics. - : Oxford University Press (OUP). - 1754-9973 .- 1754-9981. ; 8:3, s. 270-283
-
Journal article (peer-reviewed)abstract
- The vision of legendary criminologist Cesare Lombroso to use scientific theories of individual causes of crime as a basis for screening and prevention programmes targeting individuals at risk for future criminal behaviour has resurfaced, following advances in genetics, neuroscience and psychiatric epidemiology. This article analyses this idea and maps its ethical implications from a public health ethical standpoint. Twenty-seven variants of the new Lombrosian vision of forensic screening and prevention are distinguished, and some scientific and technical limitations are noted. Some lures, biases and structural factors, making the application of the Lombrosian idea likely in spite of weak evidence are pointed out and noted as a specific type of ethical aspect. Many classic and complex ethical challenges for health screening programmes are shown to apply to the identified variants and the choice between them, albeit with peculiar and often provoking variations. These variations are shown to actualize an underlying theoretical conundrum in need of further study, pertaining to the relationship between public health ethics and the ethics and values of criminal law policy.
|
|
| 2. |
- Munthe, Christian, 1962
(author)
-
Etiska aspekter på regenerativ medicin : Ethical aspects on regenerative medicine
- 2003
-
In: SNIB-konferensen 2003, Chalmers tekniska högskola, Göteborg, 16-18 maj 2003.
-
Conference paper (other academic/artistic)abstract
- Inom den regenerativa medicinen strävar man efter att ersätta skadat eller sjukligt biologiskt mänskligt material (celler, organ, kroppsdelar) med nya biologiska komponenter. Området aktualiserar en rad etiska frågeställningar vad gäller (1) produktionen av ersättningsmaterialet (t.ex. embryonala stamceller eller införskaffande av transplantationsvävnad från donatorer), (2) risker i samband med försök på människa (genmodifierat material, material från djur), samt (3) gränserna för hur långt man bör gå i denna slags försök att förlänga människans livsspann. Föredraget ger en kort översikt över dessa frågeställningar, ståndpunkter och argument i debatten kring dem.
|
|
| 3. |
- Falk Erhag, Hanna, et al.
(author)
-
Concluding Remarks
- 2022
-
In: A Multidisciplinary Approach to Capability in Age and Ageing. - Chem : Springer. - 9783030780654 ; 18:2, s. 143-144
-
Book chapter (other academic/artistic)
|
|
| 4. |
- Palmquist, Anders, 1977, et al.
(author)
-
Complex geometry and integrated macro-porosity: Clinical applications of electron beam melting to fabricate bespoke bone-anchored implants
- 2023
-
In: Acta Biomaterialia. - : Elsevier BV. - 1742-7061 .- 1878-7568. ; 156, s. 125-145
-
Research review (peer-reviewed)abstract
- The last decade has witnessed rapid advancements in manufacturing technologies for biomedical implants. Additive manufacturing (or 3D printing) has broken down major barriers in the way of producing complex 3D geometries. Electron beam melting (EBM) is one such 3D printing process applicable to metals and alloys. EBM offers build rates up to two orders of magnitude greater than comparable laser-based technologies and a high vacuum environment to prevent accumulation of trace elements. These features make EBM particularly advantageous for materials susceptible to spontaneous oxidation and nitrogen pick-up when exposed to air (e.g., titanium and titanium-based alloys). For skeletal reconstruction(s), anatomical mimickry and integrated macro-porous architecture to facilitate bone ingrowth are undoubtedly the key features of EBM manufactured implants. Using finite element modelling of physiological loading conditions, the design of a prosthesis may be further personalised. This review looks at the many unique clinical applications of EBM in skeletal repair and the ground-breaking innovations in prosthetic rehabilitation. From a simple acetabular cup to the fifth toe, from the hand-wrist complex to the shoulder, and from vertebral replacement to cranio-maxillofacial reconstruction, EBM has experienced it all. While sternocostal reconstructions might be rare, the repair of long bones using EBM manufactured implants is becoming exceedingly frequent. Despite the various merits, several challenges remain yet untackled. Nevertheless, with the capability to produce osseointegrating implants of any conceivable shape/size, and permissive of bone ingrowth and functional loading, EBM can pave the way for numerous fascinating and novel applications in skeletal repair, regeneration, and rehabilitation. Statement of significance: Electron beam melting (EBM) offers unparalleled possibilities in producing contaminant-free, complex and intricate geometries from alloys of biomedical interest, including Ti6Al4V and CoCr. We review the diverse range of clinical applications of EBM in skeletal repair, both as mass produced off-the-shelf implants and personalised, patient-specific prostheses. From replacing large volumes of disease-affected bone to complex, multi-material reconstructions, almost every part of the human skeleton has been replaced with an EBM manufactured analog to achieve macroscopic anatomical-mimickry. However, various questions regarding long-term performance of patient-specific implants remain unaddressed. Directions for further development include designing personalised implants and prostheses based on simulated loading conditions and accounting for trabecular bone microstructure with respect to physiological factors such as patient's age and disease status.
|
|
| 5. |
|
|
| 6. |
|
|
| 7. |
- Darmanis, Spyros, et al.
(author)
-
Identification of Candidate Serum Proteins for Classifying Well-Differentiated Small Intestinal Neuroendocrine Tumors
- 2013
-
In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:11, s. e81712-
-
Journal article (peer-reviewed)abstract
- BackgroundPatients with well-differentiated small intestine neuroendocrine tumors (WD-SI-NET) are most often diagnosed at a metastatic stage of disease, which reduces possibilities for a curative treatment. Thus new approaches for earlier detection and improved monitoring of the disease are required.Materials and methodsSuspension bead arrays targeting 124 unique proteins with antibodies from the Human Protein Atlas were used to profile biotinylated serum samples. Discoveries from a cohort of 77 individuals were followed up in a cohort of 132 individuals both including healthy controls as well as patients with untreated primary WD-SI-NETs, lymph node metastases and liver metastases.Results A set of 20 antibodies suggested promising proteins for further verification based on technically verified statistical significance. Proceeding, we assessed the classification performance in an independent cohort of patient serum, achieving, classification accuracy of up to 85% with different subsets of antibodies in respective pairwise group comparisons. The protein profiles of nine targets, namely IGFBP2, IGF1, SHKBP1, ETS1, IL1α, STX2, MAML3, EGR3 and XIAP were verified as significant contributors to tumor classification.ConclusionsWe propose new potential protein biomarker candidates for classifying WD-SI-NET at different stage of disease. Further evaluation of these proteins in larger sample sets and with alternative approaches is needed in order to further improve our understanding of their functional relation to WD-SI-NET and their eventual use in diagnostics.
|
|
| 8. |
- Bin Kaderi, Mohamed Arifin, 1978-
(author)
-
Assessment of Novel Molecular Prognostic Markers in Chronic Lymphocytic Leukemia
- 2010
-
Doctoral thesis (other academic/artistic)abstract
- The clinical course of chronic lymphocytic leukemia (CLL) is highly heterogeneous, which has prompted the search for biomarkers that can predict prognosis in this disease. The IGHV gene mutation status and certain genomic aberrations have been identified as reliable prognostic markers of clinical outcome for this disorder. However, the search for more feasible prognostic markers in CLL is still being pursued. Recently, certain single nucleotide polymorphisms (SNPs) in the GNAS1, BCL2 and MDM2 genes and the RNA expression levels of the LPL, ZAP70, TCL1, CLLU1 and MCL1 genes were suggested as novel prognostic markers in CLL. In papers I-III, we performed genotyping analyses of the GNAS1 T393C, BCL2 -938C>A and MDM2 SNP309 polymorphisms in 268-418 CLL patients and related the genotypes with clinical data. Association studies between the polymorphisms and established prognostic markers (i.e. IGHV mutation status, genomic aberrations, CD38 expression) were also performed. Our studies did not find any significant relationship between these SNPs with either clinical outcome or other known prognostic markers in CLL. In paper IV, we measured the RNA expression levels of LPL, ZAP70, TCL1, CLLU1 and MCL1 in 252 CLL cases and correlated these levels with clinical outcome. Here, we verified that high expression of all these RNA-based markers, except MCL1, were associated with an unfavourable prognosis. We also confirmed a close relationship between IGHV mutation status and the RNA-based markers, especially for LPL and CLLU1 expression. Among the RNA-based markers, multivariate analysis revealed LPL expression as the strongest independent prognostic marker for overall survival and time to treatment. Furthermore, the RNA-based markers could add further prognostic information to established markers in subgroups of patients, with LPL expression status giving the most significant results. In summary, data from papers I-III could not verify the GNAS1 T393C, BCL2 -938C>A and MDM2 SNP309 polymorphisms as prognostic markers in CLL. Future SNP markers must hence be confirmed in large, independent cohorts before being proposed as prognostic marker in CLL. In paper IV, we conclude that LPL expression appears to be the strongest among the RNA-based markers for CLL prognostication. Further efforts to standardize LPL quantification are required before it can be applied in the clinical laboratory to predict clinical outcome in this disease.
|
|
| 9. |
- Jing, Yujia, 1985
(author)
-
Hyperthermia-responsive liposomal systems
- 2015
-
Doctoral thesis (other academic/artistic)abstract
- Abstract Sophisticated liposomal systems are emerging at an increasing rate to meet the demands for multifunctional drug carriers in chemotherapies in combined with hyperthermia. For example, liposomal drug carriers for temperature-controlled drug release under hyperthermic conditions have recently been tested in clinical trials. More advanced designs of liposomes are expected to release encapsulated contents and activate hidden surface-functions in response to heat stimulus. Towards this aim, the present thesis is focused on formulating asymmetric lipid systems that can preserve functional moieties, and reactivate the targeted function as well as release the encapsulated compounds upon local heating. The design of the asymmetric liposomal systems utilizes the heat-activated transmembrane lipid diffusion during gel to liquid-crystalline phase transitions of the lipid membranes.Rational design of advanced liposomal drug-delivery systems will require understanding of the physicochemical properties of lipid membranes under, e.g., hyperthermic conditions. Here, supported lipid membranes on planar solid surfaces were used for model studies of lipid composition yielding a gel to liquid crystalline phase-transition temperature in the range 40 – 45 °C. It was found that the liposome-to-membrane formation process is not only size-dependent but also governed by temperature. Two methods of preparing supported asymmetric lipid membranes were investigated. As a proof-of-concept, the upper leaflets were either replaced or chemically transformed by enzymatic hydrolysis. The processes were monitored using surface sensitive techniques such as quartz crystal microbalance with dissipation (QCM-D) and dual polarization interferometry (DPI). The asymmetric structures were stable at a room temperature, while lipid flip-flop was induced upon increasing of the temperature. Transmembrane lipid exchange in the asymmetric structure under hyperthermic conditions was demonstrated by detecting, through streptavidin binding, biotinylated lipids appearing at the top leaflet which were first located in the lower leaflet. The protocols developed for the supported lipid systems were adapted for the preparation of asymmetric liposomes. Biotinylated asymmetric liposomes were used as a model system to demonstrate the principle of heat-activated targeting of asymmetric liposomes to streptavidin-coated surfaces. More biologically relevant interaction was utilized to replace the biotin-streptavidin function, where asymmetric cationic liposomes were binding to anionic supported membrane immobilized surfaces upon heating. The described strategies for assembly of asymmetric supported membranes provide a guide to the development of multifunctional drug carriers. The protocols used in experiments with supported membranes were readily adapted to the preparation of asymmetric liposomes. The ongoing study tests the asymmetric liposomes in vitro, which is designed to demonstrate hyperthermia treatment can enhance accumulation of liposomes in FaDu cells, and at the same time activate release of the encapsulated components. The results of in vitro tests can be used to analyze the feasibility of utilizing the asymmetric liposomes as a platform in vivo to explore further improvement in their functions upon microwave hyperthermia.
|
|
| 10. |
|
|
| 11. |
- Munthe, Christian, 1962
(author)
-
Will IVF ever be the norm?
- 2014
-
In: Future of IVF - A Brave New World? ESHRE symposium, September 26-27, Stockholm.
-
Conference paper (other academic/artistic)
|
|
| 12. |
- Senkowski, Wojciech
(author)
-
High-throughput screening using multicellular tumor spheroids to reveal and exploit tumor-specific vulnerabilities
- 2017
-
Doctoral thesis (other academic/artistic)abstract
- High-throughput drug screening (HTS) in live cells is often a vital part of the preclinical anticancer drug discovery process. So far, two-dimensional (2D) monolayer cell cultures have been the most prevalent model in HTS endeavors. However, 2D cell cultures often fail to recapitulate the complex microenvironments of in vivo tumors. Monolayer cultures are highly proliferative and generally do not contain quiescent cells, thought to be one of the main reasons for the anticancer therapy failure in clinic. Thus, there is a need for in vitro cellular models that would increase predictive value of preclinical research results. The utilization of more complex three-dimensional (3D) cell cultures, such as multicellular tumor spheroids (MCTS), which contain both proliferating and quiescent cells, has therefore been proposed. However, difficult handling and high costs still pose significant hurdles for application of MCTS for HTS.In this work, we aimed to develop novel assays to apply MCTS for HTS and drug evaluation. We also set out to identify cellular processes that could be targeted to selectively eradicate quiescent cancer cells. In Paper I, we developed a novel MCTS-based HTS assay and found that nutrient-deprived and hypoxic cancer cells are selectively vulnerable to treatment with inhibitors of mitochondrial oxidative phosphorylation (OXPHOS). We also identified nitazoxanide, an FDA-approved anthelmintic agent, to act as an OXPHOS inhibitor and to potentiate the effects of standard chemotherapy in vivo. Subsequently, in Paper II we applied the high-throughput gene-expression profiling method for MCTS-based drug screening. This led to discovery that quiescent cells up-regulate the mevalonate pathway upon OXPHOS inhibition and that the combination of OXPHOS inhibitors and mevalonate pathway inhibitors (statins) results in synergistic toxicity in this cell population. In Paper III, we developed a novel spheroid-based drug combination-screening platform and identified a set of molecules that synergize with nitazoxanide to eradicate quiescent cancer cells. Finally, in Paper IV, we applied our MCTS-based methods to evaluate the effects of phosphodiesterase (PDE) inhibitors in PDE3A-expressing cell lines.In summary, this work illustrates how MCTS-based HTS yields potential to reveal and exploit previously unrecognized tumor-specific vulnerabilities. It also underscores the importance of cell culture conditions in preclinical drug discovery endeavors.
|
|
| 13. |
- Wang, Xi, et al.
(author)
-
Comparison of the major cell populations among osteoarthritis, Kashin-Beck disease and healthy chondrocytes by single-cell RNA-seq analysis
- 2021
-
In: Cell Death and Disease. - : Springer Nature. - 2041-4889. ; 12:6
-
Journal article (peer-reviewed)abstract
- Chondrocytes are the key target cells of the cartilage degeneration that occurs in Kashin-Beck disease (KBD) and osteoarthritis (OA). However, the heterogeneity of articular cartilage cell types present in KBD and OA patients and healthy controls is still unknown, which has prevented the study of the pathophysiology of the mechanisms underlying the roles of different populations of chondrocytes in the processes leading to KBD and OA. Here, we aimed to identify the transcriptional programmes and all major cell populations in patients with KBD, patients with OA and healthy controls to identify the markers that discriminate among chondrocytes in these three groups. Single-cell RNA sequencing was performed to identify chondrocyte populations and their gene signatures in KBD, OA and healthy cells to investigate their differences as related to the pathogenetic mechanisms of these two osteochondral diseases. We performed immunohistochemistry and quantitative reverse-transcription PCR (qRT-PCR) assays to validate the markers for chondrocyte population. Ten clusters were labelled by cell type according to the expression of previously described markers, and one novel population was identified according to the expression of a new set of markers. The homeostatic and mitochondrial chondrocyte populations, which were identified by the expression of the unknown markers MT1X and MT2A and MT-ND1 and MT-ATP6, were markedly expanded in KBD. The regulatory chondrocyte population, identified by the expression of CHI3L1, was markedly expanded in OA. Our study allows us to better understand the heterogeneity of chondrocytes in KBD and OA and provides new evidence of differences in the pathogenetic mechanisms between these two diseases.
|
|
| 14. |
- Almstedt, Elin, 1988-
(author)
-
New targeted therapies for malignant neural tumors : From systematic discovery to zebrafish models
- 2020
-
Doctoral thesis (other academic/artistic)abstract
- Cancers in the neural system presents a major health challenge. The most aggressive brain tumor in adults, glioblastoma, has a median survival of 15 months and few therapeutic options. High-risk neuroblastoma, a childhood tumor originating in the sympathetic nervous system, has a 5-year survival under 50%, despite extensive therapy. Molecular characterization of these tumors has had some, but so far limited, clinical impact. In neuroblastoma, patients with ALK mutated tumors can benefit from treatment with ALK inhibitors. In glioblastoma, molecular subgroups have not yet revealed any subgroup-specific gene dependencies due to tumor heterogeneity and plasticity. In this thesis, we identify novel treatment candidates for neuroblastoma and glioblastoma. In paper I, we discover novel drug targets for high-risk neuroblastoma by integrating patient data, large-scale pharmacogenomic profiles, and drug-protein interaction maps. Using a novel algorithm, TargetTranslator, we identify more than 80 targets for this patient group. Activation of cannabinoid receptor 2 (CNR2) or inhibition of mitogen-activated protein kinase 8 (MAPK8) reduces tumor growth in zebrafish and mice models of neuroblastoma, establishing TargetTranslator as a useful tool for target discovery in cancer. In paper II, we screen approximately 1500 compounds across 100 molecularly characterized cell lines from patients to uncover heterogeneous responses to drugs in glioblastoma. We identify several connections between pathway activities and drug response. Sensitivity to proteasome inhibition is linked to oxidative stress response and p53 activity in cells, and can be predicted using a gene signature. We also discover sigma receptors as novel drug targets for glioblastoma and find a synergistic vulnerability in targeting cholesterol homeostasis.In paper III, we systematically explore novel targets for glioblastoma using an siRNA screen. Downregulation of ZBTB16 decreases cell cycle-related proteins and transcripts in patient-derived glioblastoma cells. Using a zebrafish assay, we find that ZBTB16 promotes glioblastoma invasion in vivo. In paper IV, we characterized the growth of seven patient-derived glioblastoma cell lines in orthotopic zebrafish xenografts. Using automated longitudinal imaging, we find that tumor engraftment strongly correlates with tumor initiation capacity in mice xenografts and that the heterogeneous response to proteasome inhibitors is maintained in vivo. In summary, this thesis identifies novel targets for glioblastoma and neuroblastoma using systematic approaches. Treatment candidates are evaluated in novel zebrafish xenograft models that are developed for high-throughput glioblastoma and neuroblastoma drug evaluation. Together, this thesis provides promising evidence of new therapeutic options for malignant neural tumors.
|
|
| 15. |
- Bakidou, Anna, 1996, et al.
(author)
-
On Scene Injury Severity Prediction (OSISP) model for trauma developed using the Swedish Trauma Registry
- 2023
-
In: BMC Medical Informatics and Decision Making. - 1472-6947. ; 23:1
-
Journal article (peer-reviewed)abstract
- Background: Providing optimal care for trauma, the leading cause of death for young adults, remains a challenge e.g., due to field triage limitations in assessing a patient’s condition and deciding on transport destination. Data-driven On Scene Injury Severity Prediction (OSISP) models for motor vehicle crashes have shown potential for providing real-time decision support. The objective of this study is therefore to evaluate if an Artificial Intelligence (AI) based clinical decision support system can identify severely injured trauma patients in the prehospital setting. Methods: The Swedish Trauma Registry was used to train and validate five models – Logistic Regression, Random Forest, XGBoost, Support Vector Machine and Artificial Neural Network – in a stratified 10-fold cross validation setting and hold-out analysis. The models performed binary classification of the New Injury Severity Score and were evaluated using accuracy metrics, area under the receiver operating characteristic curve (AUC) and Precision-Recall curve (AUCPR), and under- and overtriage rates. Results: There were 75,602 registrations between 2013–2020 and 47,357 (62.6%) remained after eligibility criteria were applied. Models were based on 21 predictors, including injury location. From the clinical outcome, about 40% of patientswere undertriaged and 46% were overtriaged. Models demonstrated potential for improved triaging and yielded AUC between 0.80–0.89 and AUCPR between 0.43–0.62. Conclusions: AI based OSISP models have potential to provide support during assessment of injury severity. The findings may be used for developing tools to complement field triage protocols, with potential to improve prehospital trauma care and thereby reduce morbidity and mortality for a large patient population.
|
|
| 16. |
- Juth, Niklas, 1973, et al.
(author)
-
The Ethics of Screening in Health Care and Medicine: Serving Society or Serving the Patient?
- 2012
-
Book (other academic/artistic)abstract
- Medical or health-oriented screening programs are amongst the most debated aspects of health care and public health practices in health care and public health ethics, as well as health policy discussions. In spite of this, most treatments of screening in the research literature restrict themselves to isolated scientific aspects, sometimes complemented by economic analyses or loose speculations regarding policy aspects. At the same time, recent advances in medical genetics and technology, as well as a rapidly growing societal focus on public health concerns, inspires an increase in suggested or recently started screening programs. This book involves an in-depth analysis of the ethical, political and philosophical issues related to health-oriented screening programs. It explores the considerations that arise when heath care interacts with other societal institutions on a large scale, as is the case with screening: What values may be promoted or compromised by screening programs? What conflicts of values do typically arise – both internally and in relation to the goals of health care, on the one hand, and the goals of public health and the general society, on the other? What aspects of screening are relevant for determining whether it should be undertaken or not and how it should be organised in order to remain defensible? What implications does the ethics of screening have for health care ethics as a whole? These questions are addressed by applying philosophical methods of conceptual analysis, as well as models and theories from moral and political philosophy, medical ethics, and public health ethics, to a large number of ongoing and proposed screening programs which makes this book the first comprehensive work on the ethics of screening. Analyses and suggestions are made that are of potential interest to health care staff, medical researchers, policy makers and the general public.
|
|
| 17. |
- Cardemil, Carina, et al.
(author)
-
Strontium-doped calcium phosphate and hydroxyapatite granules promote different inflammatory and bone remodelling responses in normal and ovariectomised rats.
- 2013
-
In: PLosOne. - : Public Library of Science (PLoS). - 1932-6203. ; 8:12
-
Journal article (peer-reviewed)abstract
- The healing of bone defects may be hindered by systemic conditions such as osteoporosis. Calcium phosphates, with or without ion substitutions, may provide advantages for bone augmentation. However, the mechanism of bone formation with these materials is unclear. The aim of this study was to evaluate the healing process in bone defects implanted with hydroxyapatite (HA) or strontium-doped calcium phosphate (SCP) granules, in non-ovariectomised (non-OVX) and ovariectomised (OVX) rats. After 0 (baseline), six and 28d, bone samples were harvested for gene expression analysis, histology and histomorphometry. Tumour necrosis factor-α (TNF-α), at six days, was higher in the HA, in non-OVX and OVX, whereas interleukin-6 (IL-6), at six and 28d, was higher in SCP, but only in non-OVX. Both materials produced a similar expression of the receptor activator of nuclear factor kappa-B ligand (RANKL). Higher expression of osteoclastic markers, calcitonin receptor (CR) and cathepsin K (CatK), were detected in the HA group, irrespective of non-OVX or OVX. The overall bone formation was comparable between HA and SCP, but with topological differences. The bone area was higher in the defect centre of the HA group, mainly in the OVX, and in the defect periphery of the SCP group, in both non-OVX and OVX. It is concluded that HA and SCP granules result in comparable bone formation in trabecular bone defects. As judged by gene expression and histological analyses, the two materials induced different inflammatory and bone remodelling responses. The modulatory effects are associated with differences in the spatial distribution of the newly formed bone.
|
|
| 18. |
|
|
| 19. |
- Bauzá-Thorbrügge, Marco, et al.
(author)
-
NRF2 is essential for adaptative browning of white adipocytes.
- 2023
-
In: Redox biology. - : Elsevier. - 2213-2317. ; 68
-
Journal article (peer-reviewed)abstract
- White adipose tissue browning, defined by accelerated mitochondrial metabolism and biogenesis, is considered a promising mean to treat or prevent obesity-associated metabolic disturbances. We hypothesize that redox stress acutely leads to increased production of reactive oxygen species (ROS), which activate electrophile sensor nuclear factor erythroid 2-Related Factor 2 (NRF2) that over time results in an adaptive adipose tissue browning process. To test this, we have exploited adipocyte-specific NRF2 knockout mice and cultured adipocytes and analyzed time- and dose-dependent effect of NAC and lactate treatment on antioxidant expression and browning-like processes. We found that short-term antioxidant treatment with N-acetylcysteine (NAC) induced reductive stress as evident from increased intracellular NADH levels, increased ROS-production, reduced oxygen consumption rate (OCR), and increased NRF2 levels in white adipocytes. In contrast, and in line with our hypothesis, longer-term NAC treatment led to a NRF2-dependent browning response. Lactate treatment elicited similar effects as NAC, and mechanistically, these NRF2-dependent adipocyte browning responses in vitro were mediated by increased heme oxygenase-1 (HMOX1) activity. Moreover, this NRF2-HMOX1 axis was also important for β3-adrenergic receptor activation-induced adipose tissue browning in vivo. In conclusion, our findings show that administration of exogenous antioxidants can affect biological function not solely through ROS neutralization, but also through reductive stress. We also demonstrate that NRF2 is essential for white adipose tissue browning processes.
|
|
| 20. |
- Aulin, Cecilia, 1979-
(author)
-
Extracellular Matrix Based Materials for Tissue Engineering
- 2010
-
Doctoral thesis (other academic/artistic)abstract
- The extracellular matrix is (ECM) is a network of large, structural proteins and polysaccharides, important for cellular behavior, tissue development and maintenance. Present thesis describes work exploring ECM as scaffolds for tissue engineering by manipulating cells cultured in vitro or by influencing ECM expression in vivo. By culturing cells on polymer meshes under dynamic culture conditions, deposition of a complex ECM could be achieved, but with low yields. Since the major part of synthesized ECM diffused into the medium the rate limiting step of deposition was investigated. This quantitative analysis showed that the real rate limiting factor is the low proportion of new proteins which are deposited as functional ECM. It is suggested that cells are pre-embedded in for example collagen gels to increase the steric retention and hence functional deposition. The possibility to induce endogenous ECM formation and tissue regeneration by implantation of growth factors in a carrier material was investigated. Bone morphogenetic protein-2 (BMP-2) is a growth factor known to be involved in growth and differentiation of bone and cartilage tissue. The BMP-2 processing and secretion was examined in two cell systems representing endochondral (chondrocytes) and intramembranous (mesenchymal stem cells) bone formation. It was discovered that chondrocytes are more efficient in producing BMP-2 compared to MSC. The role of the antagonist noggin was also investigated and was found to affect the stability of BMP-2 and modulate its effect. Finally, an injectable gel of the ECM component hyaluronan has been evaluated as delivery vehicle in cartilage regeneration. The hyaluronan hydrogel system showed promising results as a versatile biomaterial for cartilage regeneration, could easily be placed intraarticulary and can be used for both cell based and cell free therapies.
|
|
| 21. |
|
|
| 22. |
- Yu, Di, 1985-
(author)
-
Adenovirus for Cancer Therapy : With a Focus on its Surface Modification
- 2013
-
Doctoral thesis (other academic/artistic)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.
|
|
| 23. |
- Abdellah, Tebani, et al.
(author)
-
Integration of molecular profiles in a longitudinal wellness profiling cohort.
- 2020
-
In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
-
Journal article (peer-reviewed)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.
|
|
| 24. |
- Matthiesen, Isabelle, et al.
(author)
-
Continuous Monitoring Reveals Protective Effects of N‐Acetylcysteine Amide on an Isogenic Microphysiological Model of the Neurovascular Unit
- 2021
-
In: Small. - : Wiley. - 1613-6810 .- 1613-6829. ; 17:32, s. 2101785-
-
Journal article (peer-reviewed)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.
|
|
| 25. |
- Visuttijai, Kittichate, 1979-, et al.
(author)
-
Lowered Expression of Tumor Suppressor Candidate MYO1C Stimulates Cell Proliferation, Suppresses Cell Adhesion and Activates AKT
- 2016
-
In: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 11:10
-
Journal article (peer-reviewed)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.
|
|
