Publikationer från Uppsala Universitet
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Plasma H3Cit-DNA Discriminates Between Cancer and Inflammation in a Cohort of Patients with Unspecific Cancer Symptoms
No full textCancer detection is challenging, especially in patients with unspecific cancer symptoms. Biomarkers could identify patients at high risk of cancer. Prior studies indicate that neutrophil extracellular traps (NETs) are associated with cancer, but also with autoimmune and infectious diseases. The objective of this prospective study was to investigate markers associated with NET formation (nucleosomal citrullinated histone 3 [H3Cit-DNA], cell free DNA [cfDNA] and neutrophil elastase [NE]), and c-reactive protein (CRP) in patients with unspecific cancer symptoms, such as fatigue, weight loss or radiological sign of malignancy without an apparent primary tumor, referred to the Diagnostic Center at Danderyd Hospital in Sweden. Blood samples were drawn on admission, before cancer diagnosis. Out of 475 patients, 160 (34%) were diagnosed with cancer, 56 (12%) with autoimmune disease, 32 (7%) with infectious disease, 71 (15%) with other diseases and 156 (33%) received no diagnosis. H3Cit-DNA, cfDNA, NE and CRP were significantly higher in patients with cancer compared to patients without cancer (p < 0.0001, p < 0.0001, p = 0.004, and p = 0.0002 respectively). H3Cit-DNA, but not cfDNA, NE or CRP, was significantly elevated in patients with cancer compared to patients with autoimmune disease (p = 0.0001). H3Cit-DNA, cfDNA, NE or CRP did not differ between cancer and infectious disease. In conclusion, H3Cit-DNA is elevated in patients diagnosed with cancer compared to non-cancer patients with the same symptomatology. Further studies should evaluate if H3Cit-DNA could aid in selecting patients that would benefit the most from a rapid cancer diagnostic work-up
Ultra-Fine 3D Bioprinting of Dynamic Hyaluronic Acid Hydrogel for in Vitro Modeling
No full text3D bioprinting bridges tissue engineering and additive manufacturing, however developing bioinks with balanced biological and physical properties remains a challenge. Hyaluronic acid (HA) is a promising base material due to its biocompatibility and cell-recognition features. An HA-based bioink is designed using dynamic disulfide-crosslinking at physiological pH by modifying HA with cysteine moieties. To overcome the slow gelation kinetics typical of disulfide-crosslinked hydrogels, potassium iodide (KI) is introduced, accelerating gelation in a concentration-dependent manner. KI not only enhances gelation but also provides radical scavenging properties while maintaining hydrogel integrity. A low KI concentration (50 mm) offers more than a 3 h printing window, ensures cell viability, and facilitates the use of fine needles (32G, 108 μm inner diameter). This enables the fabrication of large (>3 cm) and complex 3D structures. Using this bioink, an osteoarthritis disease model is developed to investigate interactions between human mesenchymal stromal cells (hMSCs) and chondrocytes, demonstrating the immunomodulatory effect of hMSCs on inflammation-induced chondrocytes. Overall, the HA-based bioink addresses critical challenges in 3D bioprinting, providing a robust platform for constructing innovative in vitro models and supporting advancements in disease modeling and precision medicine
Quantitative Mass Spectrometry Imaging Protocols for Spatially Heterogeneous Samples
No full textMatrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) is a promising tool for the spatial quantitation of endogenous and exogenous compounds directly in biological tissue sections. However, precise quantitation may be hampered due to matrix effects and variations in ionization efficiency, especially in spatially heterogeneous samples such as brain tissue. In this study, we developed and implemented two advanced MALDI-MSI protocols to address these limitations by employing a standard addition approach. The protocols involved the homogeneous spraying of standard solutions onto tissue sections to minimize the matrix effects associated with heterogeneous samples. The first method utilized spraying of deuterated analogues of neurotransmitters across all tissue sections for normalization, while calibration standards were applied in a quantitative manner to consecutive tissue sections. The second method employed two stable isotope-labeled compounds: one for calibration and the other for normalization. Both methods were applied to quantify neurotransmitters and their metabolites, e.g., dopamine, norepinephrine, and 3-methoxytyramine, in rodent brain tissue. The results showed strong linearity between signal intensities and analyte concentrations across brain tissue sections with values comparable to those obtained using high-performance liquid chromatography-electrochemical detection. The standard addition approach significantly enhanced the quantitation accuracy by accounting for tissue-specific matrix effects, providing a robust method for the spatial quantification of neurotransmitters in complex brain tissue environments
Until Time do Us Part : An Analysis of the Reflection Period Prior to Divorce and Its Function in Light of Contemporary Needs
No full textCorrelations in Magnetic Sub-Domains as an Unconventional Phase Diagram for van der Waals Ferromagnets
No full textTraditional magnetic phase diagram represents a transition between the ferromagnetic and paramagnetic states of a material under the influence of varied temperature, magnetic field, and pressure. So far, the ferromagnetic phase has been considered predominantly as a single type of magnetization texture extending macroscopically in the bulk of a crystal, existing as a ground state determined by the interactions between localized magnetic moments arranged in a lattice. Here, it is demonstrated that an unconventional magnetic order composed of vertically correlated planar magnetic sub-domains occurs intrinsically in mechanically exfoliated layers of van der Waals ferromagnet CrBr3. Based on the visualization of the magnetic textures through magnetic force microscopy in conjunction with the ab initio calculations of the crystal structure in the magnetic phase and micromagnetic simulations, the origin of the magnetic sub-domains is attributed to stacking faults isolating a van der Waals ferromagnetic well from the bulk film due to modifications in the interlayer exchange coupling. This enables to create a phase diagram describing the magnetic states unique to van der Waals ferromagnets in terms of the degree of correlation between the magnetic sub-domains, dependent on the exchange coupling constants and tuneable by magnetic field and temperature
Förekomst och riskfaktorer för persisterande hyperparatyreoidismefter kirurgi: En kvalitetsuppföljning vid Akademiska sjukhuset.
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Development and Calibration of Battery Cell Models for Simulation of Fast Charging Events-Methodology
No full textVascular permeability: Regulatory mechanisms and spatio-temporal patterns
No full textThe endothelial cell (EC) barrier maintains tissue-fluid homeostasis by controlling the exchange of solutes between blood and tissues. Active disruption of the barrier is required for passage of macromolecules, such as albumin, fibrinogen and immunoglobulins. Endothelial barrier dysfunction is a hallmark in several pathological conditions such as inflammation, cancer and retinopathies, contributing to disease progression. This thesis aims to uncover regulatory mechanisms and patterns of vascular leakage. Paper-I explores how endothelial heterogeneity impacts barrier integrity within vessel subtypes. We demonstrate that sites of leakage are predetermined, with certain ECs being more sensitive to stimulation with leakage agonists such as vascular endothelial growth factor A (VEGFA) and histamine. These leakage sites exhibit lower levels of basement membrane protein laminin α5 and show increased VE-cadherin phosphorylation at tyrosine site Y685, providing a molecular basis for increased sensitivity. Paper-II aims to uncover the distinct expression patterns of tight junction protein Claudin5, which displays diminished expression along the arteriovenous axis, correlating with a parallel increased susceptibility to barrier disruption. In addition, Claudin5 regulates leakage in an organ-specific manner in response to histamine. Paper-III investigates the role of the VEGF receptor 2 (VEGFR2) coreceptor, Neuropilin-1 (NRP1) in VEGFA- induced vascular permeability. Here, we show that EC NRP1 regulates VEGFA-mediated vascular permeability in an organ-specific manner. Perivascular NRP1 modifies downstream VEGFA signalling by trans (across adjacent cells) complex formation with VEGFR2. The ratio of cis to trans complexes dictates NRP1’s impact on VEGFA-mediated vascular permeability. Paper-IV studies the role of vascular endothelial tyrosine phosphatase (VEPTP) in regulation of VEGFR2 signalling. Using in vitro cell-based assays, we find that VEPTP-deficiency leads to increased phosphorylation of VEGFR2 and its downstream substrates. However, in vivo, all EC responses controlled by VEGFR2; proliferation, permeability and development, are suppressed in mouse models of EC-specific VEPTP knockdown, possibly through a negative feedback mechanism. Collectively, our studies provide novel understanding of organ- and vessel-specific modulation of vascular leakage. Additionally, the findings shed light on the functions of NRP1 and VEPTP in regulating VEGFR2 signaling and offer potential targets for alleviation of barrier dysfunction and exaggerated vascular leakage in pathological conditions
Non-Invasive Respiratory Support in Anesthesia and Critical Care : Clinical Perspectives on High-Flow Nasal Oxygen and Awake Prone Positioning
No full textRecently, novel non-invasive respiratory support strategies have emerged in perioperative and intensive care medicine. In anesthesia, the use of high-flow nasal oxygen (HFNO) for preoxygenation and postoperative oxygen supplementation has been increasingly reported. During the COVID-19 pandemic, awake prone positioning (APP) combined with HFNO, continuous positive airway pressure (CPAP), or non-invasive ventilation (NIV) was widely implemented as a pragmatic strategy to improve oxygenation and delay or avoid intubation in spontaneously breathing patients. While these techniques show potential, their physiological effects and clinical utility remain incompletely understood. This thesis aimed to evaluate the clinical and physiological impact of non-invasive respiratory support strategies in two distinct high-risk populations: bariatric patients undergoing general anesthesia and patients with COVID-19-associated hypoxemic respiratory failure. In Studies I and II, HFNO was evaluated against standard care in obese patients scheduled for elective laparoscopic bariatric surgery. Study I compared preoxygenation with HFNO to face mask with positive end-expiratory pressure (PEEP). Face mask with PEEP achieved higher end-tidal oxygen after five minutes, but the absolute difference was modest. All patients achieved clinically acceptable denitrogenation. Study II found no difference in postoperative arterial oxygenation between HFNO and conventional low-flow nasal cannula therapy after one hour of postoperative care. Studies III and IV investigated APP in patients with moderate to severe COVID-19–associated hypoxemic respiratory failure requiring HFNO, CPAP, or NIV. In Study III, a structured APP protocol did not reduce intubation rates compared to standard care, but was safe, feasible, and increased APP duration. In Study IV, the physiological effects of APP were assessed using electrical impedance tomography. A transient increase in end-expiratory lung impedance and oxygenation was observed during APP, while ventilation distribution and homogeneity remained unchanged. In summary, this thesis supports the continued use of face mask preoxygenation with PEEP and suggests no added benefit of HFNO in routine postoperative care for bariatric patients. Although APP did not reduce intubation rates, it appears safe and feasible, improving oxygenation and potentially promoting lung recruitment in patients with COVID-19