| 1. |
- Munthe, Christian, 1962, et al.
(author)
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The Return of Lombroso? Ethical Aspects of (Visions of) Preventive Forensic Screening
- 2015
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In: Public Health Ethics. - : Oxford University Press (OUP). - 1754-9973 .- 1754-9981. ; 8:3, s. 270-283
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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.
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| 2. |
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| 3. |
- Darmanis, Spyros, et al.
(author)
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Identification of Candidate Serum Proteins for Classifying Well-Differentiated Small Intestinal Neuroendocrine Tumors
- 2013
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:11, s. e81712-
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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.
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| 4. |
- Bin Kaderi, Mohamed Arifin, 1978-
(author)
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Assessment of Novel Molecular Prognostic Markers in Chronic Lymphocytic Leukemia
- 2010
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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.
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| 5. |
- Jing, Yujia, 1985
(author)
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Hyperthermia-responsive liposomal systems
- 2015
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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.
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| 6. |
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| 7. |
- Munthe, Christian, 1962
(author)
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Will IVF ever be the norm?
- 2014
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In: Future of IVF - A Brave New World? ESHRE symposium, September 26-27, Stockholm.
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Conference paper (other academic/artistic)
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| 8. |
- Senkowski, Wojciech
(author)
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High-throughput screening using multicellular tumor spheroids to reveal and exploit tumor-specific vulnerabilities
- 2017
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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.
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| 9. |
- Juth, Niklas, 1973, et al.
(author)
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The Ethics of Screening in Health Care and Medicine: Serving Society or Serving the Patient?
- 2012
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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.
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| 10. |
- Cardemil, Carina, et al.
(author)
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Strontium-doped calcium phosphate and hydroxyapatite granules promote different inflammatory and bone remodelling responses in normal and ovariectomised rats.
- 2013
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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.
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| 11. |
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| 12. |
- Aulin, Cecilia, 1979-
(author)
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Extracellular Matrix Based Materials for Tissue Engineering
- 2010
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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.
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| 13. |
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| 14. |
- Yu, Di, 1985-
(author)
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Adenovirus for Cancer Therapy : With a Focus on its Surface Modification
- 2013
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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.
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| 15. |
- Visuttijai, Kittichate, 1979-, et al.
(author)
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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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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.
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| 16. |
- Klingström, Tomas, et al.
(author)
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Legal & ethical compliance when sharing biospecimen
- 2018
-
In: Briefings in Functional Genomics & Proteomics. - Oxford : Oxford University Press. - 2041-2649 .- 2041-2657. ; 17:1, s. 1-7
-
Research review (peer-reviewed)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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| 17. |
- Mondal, Tanmoy, 1981, et al.
(author)
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Sense-antisense lncRNA pair encoded by locus 6p22.3 determines neuroblastoma susceptibility via the USP36-CHD7-SOX9 regulatory axis
- 2018
-
In: Cancer Cell. - : Elsevier BV. - 1535-6108 .- 1878-3686. ; 33:3
-
Journal article (peer-reviewed)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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| 18. |
- Orru, Anna Maria, 1976, et al.
(author)
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AHA! festival 2015
- 2015
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Other publication (other academic/artistic)abstract
- The AHA festival investigates the borders between art and science in a three-day event at the Chalmers University of Technology hosted by the Department of Architecture. An international festival intended to provide enlightening experiences, staging surprises, new thoughts and displaced perspectives that lead to alternative modes of thinking about the space between art and science. We invite scientists (physicists, historians, mathematicians, medical students), artists (dancers, musicians, painters, poets, chefs) and not least architects, who reside in these borderlands and wish to share their vision and work. The key intention is to celebrate both art and science as key knowledge building devices.
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| 19. |
- Orre, Lukas Minus, et al.
(author)
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SubCellBarCode : Proteome-wide Mapping of Protein Localization and Relocalization
- 2019
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In: Molecular Cell. - : Elsevier BV. - 1097-2765 .- 1097-4164. ; 73:1, s. 166-182.e7
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Journal article (peer-reviewed)abstract
- Subcellular localization is a main determinant of protein function; however, a global view of cellular proteome organization remains relatively unexplored. We have developed a robust mass spectrometry-based analysis pipeline to generate a proteome-wide view of subcellular localization for proteins mapping to 12,418 individual genes across five cell lines. Based on more than 83,000 unique classifications and correlation profiling, we investigate the effect of alternative splicing and protein domains on localization, complex member co-localization, cell-type-specific localization, as well as protein relocalization after growth factor inhibition. Our analysis provides information about the cellular architecture and complexity of the spatial organization of the proteome; we show that the majority of proteins have a single main subcellular location, that alternative splicing rarely affects subcellular location, and that cell types are best distinguished by expression of proteins exposed to the surrounding environment. The resource is freely accessible via www.subcellbarcode.org.
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| 20. |
- Chaudhari, Aditi, et al.
(author)
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p110α hot spot mutations E545K and H1047R exert metabolic reprogramming independently of p110α kinase activity
- 2015
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In: Molecular and Cellular Biology. - : American Society for Microbiology. - 0270-7306 .- 1098-5549. ; 35:19, s. 3258-3273
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Journal article (peer-reviewed)abstract
- The phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) catalytic subunit p110α is the most frequently mutated kinase in human cancer, and the hot spot mutations E542K, E545K, and H1047R are the most common mutations in p110α. Very little is known about the metabolic consequences of the hot spot mutations of p110α in vivo. In this study, we used adenoviral gene transfer in mice to investigate the effects of the E545K and H1047R mutations on hepatic and whole-body glucose metabolism. We show that hepatic expression of these hot spot mutations results in rapid hepatic steatosis, paradoxically accompanied by increased glucose tolerance, and marked glycogen accumulation. In contrast, wild-type p110α expression does not lead to hepatic accumulation of lipids or glycogen despite similar degrees of upregulated glycolysis and expression of lipogenic genes. The reprogrammed metabolism of the E545K and H1047R p110α mutants was surprisingly not dependent on altered p110α lipid kinase activity.
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| 21. |
- Memedi, Mevludin, et al.
(author)
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Validity and responsiveness of at-home touch-screen assessments in advanced Parkinson's disease
- 2015
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In: IEEE journal of biomedical and health informatics. - : Institute of Electrical and Electronics Engineers (IEEE). - 2168-2194 .- 2168-2208. ; 19:6, s. 1829-1834
-
Journal article (peer-reviewed)abstract
- The aim of this study was to investigate if a telemetry test battery can be used to measure effects of Parkinson’s disease (PD) treatment intervention and disease progression in patients with fluctuations. Sixty-five patients diagnosed with advanced PD were recruited in an open longitudinal 36-month study; 35 treated with levodopa-carbidopa intestinal gel (LCIG) and 30 were candidates for switching from oral PD treatment to LCIG. They utilized a test battery, consisting of self-assessments of symptoms and fine motor tests (tapping and spiral drawings), four times per day in their homes during week-long test periods. The repeated measurements were summarized into an overall test score (OTS) to represent the global condition of the patient during a test period. Clinical assessments included ratings on Unified PD Rating Scale (UPDRS) and 39-item PD Questionnaire (PDQ-39) scales. In LCIG-naïve patients, mean OTS compared to baseline was significantly improved from the first test period on LCIG treatment until month 24. In LCIG-non-naïve patients, there were no significant changes in mean OTS until month 36. The OTS correlated adequately with total UPDRS (rho = 0.59) and total PDQ-39 (0.59). Responsiveness measured as effect size was 0.696 and 0.536 for OTS and UPDRS respectively. The trends of the test scores were similar to the trends of clinical rating scores but dropout rate was high. Correlations between OTS and clinical rating scales were adequate indicating that the test battery contains important elements of the information of well-established scales. The responsiveness and reproducibility were better for OTS than for total UPDRS.
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| 22. |
- Lagging, Martin, 1965, et al.
(author)
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Treatment of hepatitis C virus infection in adults and children: Updated Swedish consensus recommendations
- 2012
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In: Scandinavian Journal of Infectious Diseases. - : Informa UK Limited. - 0036-5548 .- 1651-1980. ; 44:7, s. 502-521
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Journal article (peer-reviewed)abstract
- Swedish recommendations for the treatment of hepatitis C virus (HCV) infection were updated at a recent expert meeting. Therapy for acute HCV infection should be initiated if spontaneous resolution does not occur within 12 weeks. The recommended standard-of-care therapy for chronic HCV genotype 1 infection is an HCV protease inhibitor in combination with peginterferon (peg-IFN) and ribavirin. Treatment is strongly recommended in patients with bridging fibrosis and cirrhosis, whereas in patients with less advanced fibrosis, deferring therapy may be preferential in light of likely therapeutic improvements in the near future. Patients with chronic genotype 2/3 infection should generally be treated with peg-IFN and ribavirin for 24 weeks. In patients with a very rapid viral response (i.e. HCV RNA below 1000 IU/ml on day 7), or favourable baseline characteristics and undetectable HCV RNA week 4, treatment can be shortened to 12 - 16 weeks, provided that no dose reductions are needed.
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| 23. |
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| 24. |
- Huijbers, Elisabeth J. M, 1979-
(author)
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Development of a Cancer Vaccine Targeting Tumor Blood Vessels
- 2012
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Doctoral thesis (other academic/artistic)abstract
- A treatment strategy for cancer is the suppression of tumor growth by directing an immune response to the tumor vessels, which will destroy the tissue.In this thesis we describe the development of a vaccine that targets antigens expressed around angiogenic vasculature in most solid tumors. These antigens are alternative spliced extra domains of glycoproteins present in the extracellular matrix; e.g. the extra domain-B (ED-B) and extra domain-A (ED-A) of fibronectin and the C-domain of tenascin-C (TNCC).We show that it is possible to break self-tolerance and induce a strong antibody response against ED-B by vaccination. Furthermore, tumor growth was inhibited and the changes observed in the tumor tissue were consistent with an attack of the tumor vasculature by the immune system.For clinical development of therapeutic vaccines, targeting self-molecules like ED-B, a potent but non-toxic biodegradable adjuvant is required. The squalene-based Montanide ISA 720 (M720) in combination with CpG DNA fulfilled these requirements and induced an equally strong anti-self immune response as the preclinical golden standard Freund’s adjuvant. We have further characterized the immune response against ED-B generated with the adjuvant M720/GpG. The ED-B vaccine also inhibited tumor growth in a therapeutic setting in a transgenic mouse model of pancreatic insulinoma in which tumorigenesis was already initiated. Furthermore, antibodies against ED-A and TNCC could be induced in mice and rabbits. We analyzed the expression of ED-A in breast tumors of transgenic MMTV-PyMT mice, a metastatic breast cancer model, with the aim to use this model to study the effect of an ED-A vaccine on metastasis. We also detected ED-B in canine mammary tumor tissue. Therefore vascular antigens might also represent potential therapeutic targets in dogs. All together our preclinical data demonstrate that a vaccine targeting tumor blood vessels is a promising new approach for cancer treatment.
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| 25. |
- Bondesson, Johan, 1991, et al.
(author)
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Definition of Tubular Anatomic Structures from Arbitrary Stereo Lithographic Surface
- 2017
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In: Initiative Seminar Engineering Health, 8-9 November 2017, Chalmers.
-
Conference paper (other academic/artistic)abstract
- An accurate description of anatomies and dynamics of vessels is crucial to understand their characteristics and improve surgical techniques, thus it is the basis, in addition to surgeon experience, on which stent design and operation procedures rely. The process of producing this description is user intensive, and recent improvement in image processing of medical3D imaging allows for a more automated workflow. However, there is a need to bridge the gap from a processed geometry to a robust mathematical computational grid. By sequentially segmenting a tubular anatomic structure, here defined by a stereo lithographic (STL) surface, an initial centerline is formed by connecting centroids of orthogonal cross-sectional contours along the length of the structure. Relying on the initial centerline, a set of non-overlapping 2D cross sectional contours are defined along the centerline, a centerline which is updated after the 2D contours are produced. After a second iteration of producing 2D contours and updating the centerline, a full description of the structure is created. Our method for describing vessel geometry shows good coherence to existing method. The main advantages of our method include the possibility of having arbitrary triangulated STL surface input, automated centerline definition, safety against intersecting cross-sectional contours and automatic clean-up of local kinks and wrinkles.
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| 26. |
- Webb, Dominic-Luc, et al.
(author)
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The type 2 CCK/gastrin receptor antagonist YF476 acutely prevents NSAID-induced gastric ulceration while increasing iNOS expression
- 2013
-
In: Naunyn-Schmiedeberg's Archives of Pharmacology. - : Springer Verlag (Germany). - 0028-1298 .- 1432-1912. ; 386:1, s. 41-49
-
Journal article (peer-reviewed)abstract
- YF476 differs from the proton pump inhibitor (PPI) esomeprazole in mode of action by antagonizing the type 2 receptor of cholecystokinin/gastrin (CCK-2R). YF476 protection against diclofenac-induced gastric ulcers was compared to esomeprazole and correlated with plasma levels of hormones related to gastric pH (gastrin, ghrelin, and somatostatin), gastric gene expression of these hormones, their receptors, and inducible nitric oxide synthase (iNOS). YF476 or esomeprazole pretreatments were followed by diclofenac. Four hours later, gastric tissue was excised and analyzed for ulcer index. An intragastrically implanted Bravo capsule measured pH for 5 days during YF476 plus pentagastrin treatment. Changes in gene expression were assayed for gastrin, ghrelin, and somatostatin; their receptors; and iNOS. YF476 acutely (within 4 h) protected against diclofenac-induced gastric ulcers equivalent to esomeprazole. Gastric pH recorded during 5 days in the presence of pentagastrin was 1.83 (+/- 0.06). YF476 raised pH to 3.67 (+/- 0.09) and plasma ghrelin, gastrin, and somatostatin increased. YF476 increased gene expression of somatostatin receptor and gastrin, while ghrelin receptor decreased; transcripts coding ghrelin, somatostatin, and CCK-2R remained unchanged. In the presence of diclofenac, esomeprazole increased expression of all these transcripts and that of iNOS, while YF476 yielded only decreased CCK-2R and increased iNOS transcripts. YF476 is a potential new preventative treatment for patients at risk of nonsteroidal antiinflammatory drug (NSAID)-induced ulceration. Gastric gene expressions of ghrelin, gastrin, and somatostatin and their receptors differ between esomeprazole and YF476. Despite these differences and different modes of action to raise gastric pH, both drugs acutely increase iNOS, suggesting iNOS expression parallels pH.
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| 27. |
- Hamrin Senorski, Eric, 1989, et al.
(author)
-
Concomitant injuries may not reduce the likelihood of achieving symmetrical muscle function oneyear after anterior cruciate ligament reconstruction: a prospective observational study based on 263 patients.
- 2018
-
In: Knee surgery, sports traumatology, arthroscopy : official journal of the ESSKA. - : Springer Science and Business Media LLC. - 1433-7347. ; 26:10, s. 2966-2977
-
Journal article (peer-reviewed)abstract
- A better understanding of patient characteristics and the way common concomitant injuries affect the recovery of muscle function after surgery should help providers to treat patients with anterior cruciate ligament (ACL) injuries. The aim of this study was to determine whether patient characteristics, concomitant injuries and graft choice at ACL reconstruction were associated with symmetrical knee muscle function at one year. The hypothesis was that the presence of concomitant injuries would negatively influence the opportunity to achieve symmetrical knee function at the one-year follow-up.Data was extracted from the Swedish National Knee Ligament Register and a rehabilitation outcome register between August 2012 and December 2016. The patients had been evaluated with a battery of tests comprising knee extension and flexion strength, vertical jump, hop for distance and the side-hop test one year after ACL reconstruction. Univariable and multivariable logistic regression analyses were performed with achieving a limb symmetry index (LSI) of ≥90% in all tests of muscle function as primary outcome.A total of 263 patients with a mean age of 26.7±10.3years were included in the study (47% females). No patient demographic or intra-operative predictors were found to be significant when attempting to predict the achievement of a symmetrical muscle function. Lateral meniscus injury and a patellar tendon autograft reduced the odds of achieving an LSI of ≥90% in knee extension strength, OR=0.49 [(95% CI 0.25-0.97), p=0.039] and OR=0.30 [(95% CI 0.14-0.67), p=0.0033] respectively. In addition, reduced odds of recovering knee extension strength were found in older patients, OR=0.76 [(95% CI 0.60-0.98), p=0.034]. A higher pre-injury level of physical activity increased the odds of recovering knee flexion strength, OR=1.14 [(95% CI 1.01-1.29), p=0.037].Intra-operatively identified concomitant injuries or graft choice did not affect the likelihood of recovering symmetrical performance in five different tests of muscle function one year after ACL reconstruction. However, fewer than one in four patients achieved an LSI of ≥90% in all tests.Prospective observational study: Level 2.
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| 28. |
- Krupic, Ferid, et al.
(author)
-
Ethnic differences in the perception of pain: a systematic review of qualitative and quantitative research.
- 2019
-
In: Medicinski glasnik : official publication of the Medical Association of Zenica-Doboj Canton, Bosnia and Herzegovina. - 1840-2445. ; 16:1, s. 108-114
-
Research review (peer-reviewed)abstract
- Aim To investigate existence of scientific support for linking differences in the experience of pain to ethnicity. Methods The study was designed as a systematic literature review of qualitative and quantitative studies. The inclusion criteria were scientific studies published in scientific journals and written in English. Studies that described children's experiences and animals were excluded. There were 10 studies, one qualitative and nine quantitative. Results The result was divided into two main sections. The first section presents the results of investigated material regarding different ethnic groups, the groups' different experiences with regard to pain and its treatment focusing entirely on the patients' perspective. Several studies have revealed major differences in the way individuals perceive their pain, using various pain evaluation tools. The second section explained different coping strategies depending on ethnicity and showed that different ethnic groups handle their pain in different ways. Conclusion Healthcare professionals have a duty to pay attention to and understand the patients' experience of their disease and suffering and, as far as possible, mitigate this using appropriate measures. For this purpose, ethnic, cultural and religious differences between different patients need to be understood. It is necessary to continue to study ethnic differences in reporting and predicting pain and its consequences, including the assessment of variables associated with pain, as well as examining the use of prayer as a form of dealing with pain, with an evaluation of various effects of such different influences.
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| 29. |
- Mordenfeld, Arne, et al.
(author)
-
Histological and histomorphometrical analyses of biopsies harvested 11 years after maxillary sinus floor augmentation with deproteinized bovine and autogenous bone
- 2010
-
In: Clinical Oral Implants Research. - : Wiley. - 0905-7161 .- 1600-0501. ; 21:9, s. 961-970
-
Journal article (peer-reviewed)abstract
- Objective The purpose of the present study was to histologically and histomorphometrically evaluate the long-term tissue response to deproteinized bovine bone (DPBB) particles used in association with autogenous bone and to compare particle size after 6 months and 11 years, in the same patients, in order to determine possible resorption. Material and methods Twenty consecutive patients (14 women and six men) with a mean age of 62 years (range 48-69 years) with severe atrophy of the posterior maxilla were included in this study. Thirty maxillary sinuses with < 5 mm subantral alveolar bone were augmented with a mixture of 80% DPBB and 20% autogenous bone. Eleven years (mean 11.5 years) after augmentation, biopsies were taken from the grafted areas of the 11 patients who volunteered to participate in this new surgical intervention. The following histomorphometrical measurements were performed in these specimens: total bone area in percentage, total area of the DPBB, total area of marrow space, the degree of DPBB-bone contact (percentage of the total surface length for each particle), the length of all DPBB particles and the area of all DPBB particles. The length and the area of the particles were compared with samples harvested from the same patients at 6 months (nine samples) and pristine particles from the manufacturer. Results The biopsies consisted of 44.7 +/- 16.9% lamellar bone, 38 +/- 16.9% marrow space and 17.3 +/- 13.2% DPBB. The degree of DPBB to bone contact was 61.5 +/- 34%. There were no statistically significant differences between the length and area of the particles after 11 years compared with those measured after 6 months in the same patients or to pristine particles from the manufacturer. Conclusion DPBB particles were found to be well integrated in lamellar bone, after sinus floor augmentation in humans, showing no significant changes in particle size after 11 years.
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| 30. |
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| 31. |
- Tobe, Brian T. D., et al.
(author)
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Probing the lithium-response pathway in hiPSCs implicates the phosphoregulatory set-point for a cytoskeletal modulator in bipolar pathogenesis
- 2017
-
In: Proceedings of the National Academy of Sciences of the United States of America. - Washington DC, USA : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 114:22, s. E4462-E4471
-
Journal article (peer-reviewed)abstract
- The molecular pathogenesis of bipolar disorder (BPD) is poorly understood. Using human-induced pluripotent stem cells (hiPSCs) to unravel such mechanisms in polygenic diseases is generally challenging. However, hiPSCs from BPD patients responsive to lithium offered unique opportunities to discern lithium's target and hence gain molecular insight into BPD. By profiling the proteomics of BDP-hiPSC-derived neurons, we found that lithium alters the phosphorylation state of collapsin response mediator protein-2 (CRMP2). Active non-phosphorylated CRMP2, which binds cytoskeleton, is present throughout the neuron; inactive phosphorylated CRMP2, which dissociates from cytoskeleton, exits dendritic spines. CRMP2 elimination yields aberrant dendritogenesis with diminished spine density and lost lithium responsiveness (LiR). The "set-point" for the ratio of pCRMP2: CRMP2 is elevated uniquely in hiPSC-derived neurons from LiR BPD patients, but not with other psychiatric (including lithium-nonresponsive BPD) and neurological disorders. Lithium (and other pathway modulators) lowers pCRMP2, increasing spine area and density. Human BPD brains show similarly elevated ratios and diminished spine densities; lithium therapy normalizes the ratios and spines. Consistent with such "spine-opathies," human LiR BPD neurons with abnormal ratios evince abnormally steep slopes for calcium flux; lithium normalizes both. Behaviorally, transgenic mice that reproduce lithium's postulated site-of-action in dephosphorylating CRMP2 emulate LiR in BPD. These data suggest that the " lithium response pathway" in BPD governs CRMP2's phosphorylation, which regulates cytoskeletal organization, particularly in spines, modulating neural networks. Aberrations in the posttranslational regulation of this developmentally critical molecule may underlie LiR BPD pathogenesis. Instructively, examining the proteomic profile in hiPSCs of a functional agent-even one whose mechanism-of-action is unknown-might reveal otherwise inscrutable intracellular pathogenic pathways.
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| 32. |
- Schöll, Michael, 1980, et al.
(author)
-
Biomarkers for tau pathology.
- 2019
-
In: Molecular and cellular neurosciences. - : Elsevier BV. - 1095-9327 .- 1044-7431. ; 97, s. 18-33
-
Research review (peer-reviewed)abstract
- The aggregation of fibrils of hyperphosphorylated and C-terminally truncated microtubule-associated tau protein characterizes 80% of all dementia disorders, the most common neurodegenerative disorders. These so-called tauopathies are hitherto not curable and their diagnosis, especially at early disease stages, has traditionally proven difficult. A keystone in the diagnosis of tauopathies was the development of methods to assess levels of tau protein in vivo in cerebrospinal fluid, which has significantly improved our knowledge about these conditions. Tau proteins have also been measured in blood, but the importance of tau-related changes in blood is still unclear. The recent addition of positron emission tomography ligands to visualize, map and quantify tau pathology has further contributed with information about the temporal and spatial characteristics of tau accumulation in the living brain. Together, the measurement of tau with fluid biomarkers and positron emission tomography constitutes the basis for a highly active field of research. This review describes the current state of biomarkers for tau biomarkers derived from neuroimaging and from the analysis of bodily fluids and their roles in the detection, diagnosis and prognosis of tau-associated neurodegenerative disorders, as well as their associations with neuropathological findings, and aims to provide a perspective on how these biomarkers might be employed prospectively in research and clinical settings.
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| 33. |
- Landegren, Nils, et al.
(author)
-
Transglutaminase 4 as a prostate autoantigen in male subfertility
- 2015
-
In: Science Translational Medicine. - : American Association for the Advancement of Science. - 1946-6234 .- 1946-6242. ; 7:292
-
Journal article (peer-reviewed)abstract
- Autoimmune polyendocrine syndrome type 1 (APS1), a monogenic disorder caused by AIRE gene mutations, features multiple autoimmune disease components. Infertility is common in both males and females with APS1. Although female infertility can be explained by autoimmune ovarian failure, the mechanisms underlying male infertility have remained poorly understood. We performed a proteome-wide autoantibody screen in APS1 patient sera to assess the autoimmune response against the male reproductive organs. By screening human protein arrays with male and female patient sera and by selecting for gender-imbalanced autoantibody signals, we identified transglutaminase 4 (TGM4) as a male-specific autoantigen. Notably, TGM4 is a prostatic secretory molecule with critical role in male reproduction. TGM4 autoantibodies were detected in most of the adult male APS1 patients but were absent in all the young males. Consecutive serum samples further revealed that TGM4 autoantibodies first presented during pubertal age and subsequent to prostate maturation. We assessed the animal model for APS1, the Aire-deficient mouse, and found spontaneous development of TGM4 autoantibodies specifically in males. Aire-deficient mice failed to present TGM4 in the thymus, consistent with a defect in central tolerance for TGM4. In the mouse, we further link TGM4 immunity with a destructive prostatitis and compromised secretion of TGM4. Collectively, our findings in APS1 patients and Aire-deficient mice reveal prostate autoimmunity as a major manifestation of APS1 with potential role in male subfertility.
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| 34. |
- Baskaran, Sathishkumar, 1988-
(author)
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New Molecular Approaches to Glioblastoma Therapy
- 2017
-
Doctoral thesis (other academic/artistic)abstract
- Glioblastoma (GBM) is the most common high-grade brain tumor diagnosed in patients who are more than 50 years of age. The standard of care treatment is surgery, followed by radiotherapy and chemotherapy. The median life expectancy of patients is only between 12 to 15 months after receiving current treatment regimes. Hence, identification of new therapeutic compounds and gene targets are highly warranted. This thesis describes four interlinked studies to attain this goal. In study 1, we explored drug combination effects in a material of 41 patient-derived GBM cell (GC) cultures. Synergies between three compounds, pterostilbene, gefitinib, and sertraline, resulted in effective killing of GC and can be predicted by biomarkers. In study 2, we performed a large-scale screening of FDA approved compounds (n=1544) in a larger panel of GCs (n=106). By combining the large-scale drug response data with GCs genomics data, we built a novel computational model to predict the sensitivity of each compound for a given GC. A notable finding was that GCs respond very differently to proteasome inhibitors in both in-vitro and in-vivo. In study 3, we explored new gene targets by RNAi (n=1112) in a panel of GC cells. We found that loss of transcription factor ZBTB16/PLZF inhibits GC cell viability, proliferation, migration, and invasion. These effects were due to downregulation of c-MYC and Cyclin B1 after the treatment. In study 4, we tested the genomic stability of three GCs upon multiple passaging. Using molecular and mathematical analyses, we showed that the GCs undergo both systematic adaptations and sequential clonal takeovers. Such changes tend to affect a broad spectrum of pathways. Therefore, a systematic analysis of cell culture stability will be essential to make use of primary cells for translational oncology.Taken together, these studies deepen our knowledge of the weak points of GBM and provide several targets and biomarkers for further investigation. The work in this thesis can potentially facilitate the development of targeted therapies and result in more accurate tools for patient diagnostics and stratification.
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| 35. |
- Cepeda, D., et al.
(author)
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CDK-mediated activation of the SCFFBXO28 ubiquitin ligase promotes MYC-driven transcription and tumourigenesis and predicts poor survival in breast cancer
- 2013
-
In: EMBO Molecular Medicine. - : EMBO. - 1757-4676 .- 1757-4684. ; 5:7, s. 999-1018
-
Journal article (peer-reviewed)abstract
- SCF (Skp1/Cul1/F-box) ubiquitin ligases act as master regulators of cellular homeostasis by targeting key proteins for ubiquitylation. Here, we identified a hitherto uncharacterized F-box protein, FBXO28 that controls MYC-dependent transcription by non-proteolytic ubiquitylation. SCFFBXO28 activity and stability are regulated during the cell cycle by CDK1/2-mediated phosphorylation of FBXO28, which is required for its efficient ubiquitylation of MYC and downsteam enhancement of the MYC pathway. Depletion of FBXO28 or overexpression of an F-box mutant unable to support MYC ubiquitylation results in an impairment of MYC-driven transcription, transformation and tumourigenesis. Finally, in human breast cancer, high FBXO28 expression and phosphorylation are strong and independent predictors of poor outcome. In conclusion, our data suggest that SCFFBXO28 plays an important role in transmitting CDK activity to MYC function during the cell cycle, emphasizing the CDK-FBXO28-MYC axis as a potential molecular drug target in MYC-driven cancers, including breast cancer. FBXO28 is identified as part of a SCF complex acting as a regulator of tumor cell proliferation and an important modifier of MYC function. FBXO28 may be a new prognostic factor in breast cancer and a new potential drug target in MYC- driven tumors.
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| 36. |
- Nawaz, Muhammad
(author)
-
Extracellular vesicle-mediated transport of non-coding RNAs between stem cells and cancer cells: implications in tumor progression and therapeutic resistance.
- 2017
-
In: Stem cell investigation. - : AME Publishing Company. - 2306-9759 .- 2313-0792. ; 4
-
Research review (peer-reviewed)abstract
- Recent years have witnessed intensive progress in studying extracellular vesicles (EVs), both for understanding their basic biology and contribution to variety of diseases, biomarker discovery, and their potential as gene delivery vectors and source of innovative therapies. As such, stem cell-derived EVs have contributed significant knowledge which led to the development of cell-free therapies in regenerative medicine. Although, the role of stem cell-derived EVs in maintaining stemness, differentiation and repairing tissue injuries is relatively well-understood; however, knowledge about the contribution of stem cell-derived EVs in cancer progression is just emerging. The aim of this review is, therefore, to discuss the recent developments in stem cell-derived EVs and tumor progression, placing a particular focus on non-coding RNA (ncRNA) mediated cancer progression and resistance against therapies. This includes the failure of normal hematopoiesis and the progression of myeloid neoplasms, enhanced capacity of cancer cells to proliferate and metastasize, and the conversion of normal cells into cancer cells, activation of angiogenic pathways and dormancy in cancer cells. These processes are shared by mesenchymal stem cells (MSCs), cancer stem like-cells and cancer cells in an intricate intratumoral network in order to create self-strengthening tumor niche. In this context, EV-ncRNAs serve as mediators to relay bystander effects of secreting cancer stem cells (CSCs) into recipient cells for priming a tumor permissive environment and relaying therapeutic resistance. Collectively, this knowledge will improve our understandings and approaches in finding new therapeutic targets in the context of CSCs, which could be benefited through engineering EVs for innovative therapies.
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| 37. |
- Ulfenborg, Benjamin, 1985-
(author)
-
Bioinformatics tools for discovery and evaluation of biomarkers : Applications in clinical assessment of cancer
- 2016
-
Doctoral thesis (other academic/artistic)abstract
- Cancer is a disease characterized by abnormal proliferation of cells in the body and ranks as the second leading cause of death worldwide. In order to improve cancer patient care, a major focus of cancer research is to discover biomarkers. A biomarker is a biological molecule found in tissues or body fluids and can be used to predict or assess disease states. The aim of this thesis is to develop bioinformatics tools for discovery and evaluation of novel biomarkers from high-throughput datasets.MicroRNAs (miRNAs) are short non-coding RNAs that function as negative regulators of gene expression. Dysregulation of miRNAs in cancer is frequently reported, making them interesting as biomarker candidates. GenoScan was developed for genome-wide discovery of miRNA-coding genes, as a first step in the identification of novel mi-RNA biomarkers.High-throughput technologies such as microarrays allow researchers to measure the expression of thousands of genes or miRNAs simultaneously. The Decision Trunk Classifier (DTC) algorithm has been developed to screen datasets from these experiments for biomarker candidates. When applied to a miRNA expression dataset for endometrial cancer (EC) samples vs. controls, a two-marker model with 98 % accuracy was generated. These miRNAs (hsa-miR-183-5p and hsa-miRPlus-C1070) are promising as biomarkers for EC screening.The miREC database was developed to store gene and miRNA data from curated expression profiling studies of EC, as well as gene-miRNA regulatory connections. Using gene-miRNA interaction networks from miREC, the roles of miRNAs in cancer hallmark acquisition can be clarified. To further support exploratory analysis of expression data, DTC was extended with partial least squares regression models. The resulting PLS-DTC algorithm can be used to gain deeper insights into the perturbation of biological processes and pathways.
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| 38. |
- Forsberg, Karin, et al.
(author)
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Novel antibodies reveal inclusions containing non-native SOD1 in sporadic ALS patients
- 2010
-
In: PLOS ONE. - : Public library of science. - 1932-6203. ; 5:7, s. e11552-
-
Journal article (peer-reviewed)abstract
- Mutations in CuZn-superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS) and are found in 6% of ALS patients. Non-native and aggregation-prone forms of mutant SOD1s are thought to trigger the disease. Two sets of novel antibodies, raised in rabbits and chicken, against peptides spaced along the human SOD1 sequence, were by enzyme-linked immunosorbent assay and an immunocapture method shown to be specific for denatured SOD1. These were used to examine SOD1 in spinal cords of ALS patients lacking mutations in the enzyme. Small granular SOD1-immunoreactive inclusions were found in spinal motoneurons of all 37 sporadic and familial ALS patients studied, but only sparsely in 3 of 28 neurodegenerative and 2 of 19 non-neurological control patients. The granular inclusions were by confocal microscopy found to partly colocalize with markers for lysosomes but not with inclusions containing TAR DNA binding protein-43, ubiquitin or markers for endoplasmic reticulum, autophagosomes or mitochondria. Granular inclusions were also found in carriers of SOD1 mutations and in spinobulbar muscular atrophy (SBMA) patients and they were the major type of inclusion detected in ALS patients homozygous for the wild type-like D90A mutation. The findings suggest that SOD1 may be involved in ALS pathogenesis in patients lacking mutations in the enzyme.
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| 39. |
- Paulsson, Johan, et al.
(author)
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High Plasma Levels of Islet Amyloid Polypeptide in Young with New-Onset of Type 1 Diabetes Mellitus
- 2014
-
In: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 9:3, s. 0093053-
-
Journal article (peer-reviewed)abstract
- Aims/Hypothesis: Islet amyloid polypeptide (IAPP) is a beta cell hormone secreted together with insulin upon glucose stimulation. IAPP participates in normal glucose regulation, but IAPP is also known for its ability to misfold and form islet amyloid. Amyloid fibrils form through smaller cell toxic intermediates and deposited amyloid disrupts normal islet architecture. Even though IAPP and amyloid formation are much discussed in type 2 diabetes, our aim was to study the significance of IAPP in type 1 diabetes. Results: Plasma IAPP levels in children and adolescents with newly diagnosed type 1 diabetes (n = 224) were analysed and concentrations exceeding 100 pmol/L (127.2 - 888.7 pmol/L) were found in 11% (25/224). The IAPP increase did not correlate with C-peptide levels. Conclusions/Interpretation: Plasma levels of IAPP and insulin deviate in a subpopulation of young with newly-diagnosed type 1 diabetes. The determined elevated levels of IAPP might increase the risk for IAPP misfolding and formation of cell toxic amyloid in beta cells. This finding add IAPP-aggregation to the list over putative pathological factors causing type 1 diabetes.
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| 40. |
- Iredahl, Fredrik, 1988-
(author)
-
Assessment of microvascular and metabolic responses in the skin
- 2016
-
Doctoral thesis (other academic/artistic)abstract
- The general aim of this project was to develop experimental in vivo models that allow for minimally invasive investigations of responses in the skin to microvascular and metabolic provocations. The cutaneous microvasculature has emerged as a valuable model and been proposed to mirror the microcirculation in other organs. Dysfunction in the cutaneous microcirculation has thus been linked to systemic diseases such as hypertension and diabetes mellitus. Models for investigating skin responses could facilitate the understanding of pathophysiological mechanisms as well as effects of drugs.In the first study, three optical measurement techniques (laser Doppler flowmetry (LDF), laser speckle contrast imaging (LSCI) and tissue viability imaging (TiVi)) were compared against each other and showed differences in their ability to detect microvascular responses to provocations in the skin. TiVi was found more sensitive for measurement of noradrenaline-induced vasoconstriction, while LSCI was more sensitive for measurement of vascular occlusion. In the second study, microvascular responses in the skin to iontophoresis of vasoactive drugs were found to depend on the drug delivery protocol. Perfusion half-life was defined and used to describe the decay in the microvascular response to a drug after iontophoresis. In the third study, the role of nitric oxide (NO) was assessed during iontophoresis of insulin. The results showed a NO-dependent vasodilation in the skin by insulin. In the fourth study the vasoactive and metabolic effects of insulin were studied after both local and endogenous administration. Local delivery of insulin increased skin blood flow, paralleled by increased skin concentrations of interstitial pyruvate and lactate, although no change in glucose concentration was observed. An oral glucose load resulted in an increased insulin concentration in the skin paralleled by an increase in blood flow, as measured using the microdialysis urea clearance technique, although no changes in perfusion was measured by LSCI.The thesis concludes that when studying skin microvascular responses, the choice of measurement technique and the drug delivery protocol has an impact on the measurement results, and should therefore be carefully considered. The thesis also concludes that insulin has metabolic and vasodilatory effects in the skin both when administered locally and as an endogenous response to an oral glucose load. The vasodilatory effect of insulin in the skin is mediated by nitric oxide.
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| 41. |
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| 42. |
- Sarve, Hamid, et al.
(author)
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Extracting 3D information on bone remodeling in the proximity of titanium implants in SRμCT image volumes.
- 2011
-
In: Computer methods and programs in biomedicine. - : Elsevier BV. - 1872-7565 .- 0169-2607. ; 102:1, s. 25-34
-
Journal article (peer-reviewed)abstract
- Bone-implant integration is measured in several ways. Traditionally and routinely, 2D histological sections of samples, containing bone and the biomaterial, are stained and analyzed using a light microscope. Such histological section provides detailed cellular information about the bone regeneration in the proximity of the implant. However, this information reflects the integration in only a very small fraction, a 10 μm thick slice, of the sample. In this study, we show that feature values quantified on 2D sections are highly dependent on the orientation and the placement of the section, suggesting that a 3D analysis of the whole sample is of importance for a more complete judgment of the bone structure in the proximity of the implant. We propose features describing the 3D data by extending the features traditionally used for 2D-analysis. We present a method for extracting these features from 3D image data and we measure them on five 3D SRμCT image volumes. We also simulate cuts through the image volume positioned at all possible section positions. These simulations show that the measurement variations due to the orientation of the section around the center line of the implant are about 30%.
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| 43. |
- Calon, Tim, et al.
(author)
-
Multimodal analysis of the tissue response to a bone-anchored hearing implant. : 11.Calon TGA, Johansson ML, Omar O, Shah FA, Budding D, Trobos M, Thomsen P, Stokroos RJ, Palmquist
- 2019
-
In: 2nd Politzer Society Meeting/2nd World Congress of Otology, 28 May - 1 June, 2019, Warsaw, Poland..
-
Conference paper (other academic/artistic)
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| 44. |
- Ebbers, Tino, 1972-
(author)
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Flow Imaging: Cardiac Applications of 3D Cine Phase-Contrast MRI
- 2011
-
In: Current Cardiovascular Imaging Reports. - : Springer Science and Business Media LLC. - 1941-9074 .- 1941-9066. ; 4:2, s. 127-133
-
Research review (peer-reviewed)abstract
- Global and regional blood flow dynamics are of pivotal importance to cardiac function. Fluid mechanical forces can affect hemolysis and platelet aggregation, as well as myocardial remodeling. In recent years, assessment of blood flow patterns based on time-resolved, three-dimensional, three-directional phase-contrast MRI (3D cine PC MRI) has become possible and rapidly gained popularity. Initially, this technique was mainly known for its intuitive and appealing visualizations of the cardiovascular blood flow. Most recently, the technique has begun to go beyond compelling images toward comprehensive and quantitative assessment of blood flow. In this article, cardiac applications of 3D cine PC MRI data are discussed, starting with a review of the acquisition and analysis techniques, and including descriptions of promising applications of cardiac 3D cine PC MRI for the clinical evaluation of myocardial, valvular, and vascular disorders.
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| 45. |
- Skiöld, Sara, et al.
(author)
-
Radiation-induced stress response in peripheral blood of breast cancer patients differs between patients with severe acute skin reactions and patients with no side effects to radiotherapy
- 2013
-
In: Mutation research. Genetic toxicology and environmental mutagenesis. - : Elsevier BV. - 1383-5718 .- 1879-3592. ; 756:1-2, s. 152-157
-
Journal article (peer-reviewed)abstract
- The aim of the study was to compare the radiation-induced oxidative stress response in blood samples from breast cancer patients that developed severe acute skin reactions during the radiotherapy, with the response in blood samples from patients with no side effects. Peripheral blood was collected from 12 breast cancer patients showing no early skin reactions after radiotherapy (RTOG grade 0) and from 14 breast cancer patients who developed acute severe skin reactions (RTOG grade 3-4). Whole blood was irradiated with 0, 5 and 2000 mGy gamma-radiation and serum was isolated. The biomarker for oxidative stress, 8-oxo-dG, was analyzed in the serum by a modified ELISA. While a significant radiation-induced increase of serum 8-oxo-dG levels was observed in serum of the RTOG 0 patients, no increase was seen in serum of the RTOG 3-4 patients. The radiation induced increase in serum 8-oxo-dG levels after 5 mGy did not differ significantly from the increase observed for 2000 mGy in the RTOG 3-4 cohort, thus no dose response relation was observed. A receiver operating characteristic (ROC) value of 0.97 was obtained from the radiation-induced increase in 8-oxo-dG indicating that the assay could be used to identify patients with severe acute adverse reactions to radiotherapy. The results show that samples of whole blood from patients, classified as highly radiosensitive (RTOG 3-4) based on their skin reactions to radiotherapy, differ significantly in their oxidative stress response to ionizing radiation compared to samples of whole blood from patients with no skin reactions (RTOG 0). Extracellular 8-oxo-dG is primarily a biomarker of nucleotide damage and the results indicate that the patients with severe acute skin reactions differ in their cellular response to ionizing radiation at the level of induction of oxidative stress or at the level of repair or both.
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| 46. |
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| 47. |
- Movérare-Skrtic, Sofia, et al.
(author)
-
Osteoblast-derived WNT16 represses osteoclastogenesis and prevents cortical bone fragility fractures.
- 2014
-
In: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 20:11, s. 1279-88
-
Journal article (peer-reviewed)abstract
- The WNT16 locus is a major determinant of cortical bone thickness and nonvertebral fracture risk in humans. The disability, mortality and costs caused by osteoporosis-induced nonvertebral fractures are enormous. We demonstrate here that Wnt16-deficient mice develop spontaneous fractures as a result of low cortical thickness and high cortical porosity. In contrast, trabecular bone volume is not altered in these mice. Mechanistic studies revealed that WNT16 is osteoblast derived and inhibits human and mouse osteoclastogenesis both directly by acting on osteoclast progenitors and indirectly by increasing expression of osteoprotegerin (Opg) in osteoblasts. The signaling pathway activated by WNT16 in osteoclast progenitors is noncanonical, whereas the pathway activated in osteoblasts is both canonical and noncanonical. Conditional Wnt16 inactivation revealed that osteoblast-lineage cells are the principal source of WNT16, and its targeted deletion in osteoblasts increases fracture susceptibility. Thus, osteoblast-derived WNT16 is a previously unreported key regulator of osteoclastogenesis and fracture susceptibility. These findings open new avenues for the specific prevention or treatment of nonvertebral fractures, a substantial unmet medical need.
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| 48. |
- Shah, Furqan A., et al.
(author)
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Bioactive glass and glass-ceramic scaffolds for bone tissue engineering
- 2018
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In: Bioactive Glasses (Second Edition). - 9780081009369 ; , s. 201-33
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Book chapter (other academic/artistic)abstract
- Bioactive glasses and glass-ceramics are a diverse group of materials possessing a unique set of physicochemical properties that make them useful for bone repair. Scaffolds for bone tissue engineering are subject to many requirements including biocompatibility, osteogenesis, biodegradability, and mechanical competence, all of which must be considered in the design features. This chapter addresses various scaffold fabrication techniques for melt-derived and sol-gel-derived compositions, polymer-based organic-inorganic composites, calcium phosphate-based inorganic-inorganic composites, bioactive bone cements, scaffolds based on glass compositions containing specific therapeutic ions, and hybrid materials where the organic and inorganic phases interact at the molecular level. The most important achievements, challenges and potential solutions, as well as the most promising areas of future research involving bioactive glasses and glass-ceramics for bone tissue engineering are presented.
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| 49. |
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| 50. |
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