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- Hober, Sophia, Professor, 1965-, et al.
(författare)
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Systematic evaluation of SARS-CoV-2 antigens enables a highly specific and sensitive multiplex serological COVID-19 assay
- 2021
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Ingår i: Clinical & Translational Immunology. - : Wiley. - 2050-0068. ; 10:7
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Tidskriftsartikel (refereegranskat)abstract
- Objective. The COVID-19 pandemic poses an immense need for accurate, sensitive and high-throughput clinical tests, and serological assays are needed for both overarching epidemiological studies and evaluating vaccines. Here, we present the development and validation of a high-throughput multiplex bead-based serological assay. Methods. More than 100 representations of SARS-CoV-2 proteins were included for initial evaluation, including antigens produced in bacterial and mammalian hosts as well as synthetic peptides. The five best-performing antigens, three representing the spike glycoprotein and two representing the nucleocapsid protein, were further evaluated for detection of IgG antibodies in samples from 331 COVID-19 patients and convalescents, and in 2090 negative controls sampled before 2020. Results. Three antigens were finally selected, represented by a soluble trimeric form and the S1-domain of the spike glycoprotein as well as by the C-terminal domain of the nucleocapsid. The sensitivity for these three antigens individually was found to be 99.7%, 99.1% and 99.7%, and the specificity was found to be 98.1%, 98.7% and 95.7%. The best assay performance was although achieved when utilising two antigens in combination, enabling a sensitivity of up to 99.7% combined with a specificity of 100%. Requiring any two of the three antigens resulted in a sensitivity of 99.7% and a specificity of 99.4%. Conclusion. These observations demonstrate that a serological test based on a combination of several SARS-CoV-2 antigens enables a highly specific and sensitive multiplex serological COVID-19 assay.
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| 2. |
- Engstrand, Thomas, et al.
(författare)
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Development of a bioactive implant for repair and potential healing of cranial defects
- 2014
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Ingår i: Journal of Neurosurgery. - 0022-3085 .- 1933-0693. ; 120:1, s. 273-277
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Tidskriftsartikel (refereegranskat)abstract
- The repair of complex craniofacial bone defects is challenging and a successful result is dependent on the size of the defect, quality of the soft tissue covering the defect, and choice of reconstruction method. The objective of this study was to develop a bioactive cranial implant that could provide a permanent reconstructive solution to the patient by stimulating bone healing of the defect. In this paper the authors report on the feasibility and clinical results of using such a newly developed device for the repair of a large traumatic and therapy-resistant cranial bone defect. The patient had undergone numerous attempts at repair, in which established methods had been tried without success. A mosaic-designed device was manufactured and implanted, comprising interconnected ceramic tiles with a defined calcium phosphate composition. The clinical outcome 30 months after surgery revealed a restored cranial vault without postoperative complications. Computed tomography demonstrated signs of bone ingrowth. Examination with combined 18F-fluoride PET and CT provided further evidence of bone healing of the cranial defect.
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| 3. |
- Ibarra, Cristian, et al.
(författare)
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BCG-induced cytokine release in bladder cancer cells is regulated by Ca2+ signaling
- 2019
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Ingår i: Molecular Oncology. - : WILEY. - 1574-7891 .- 1878-0261. ; 13:2, s. 202-211
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Tidskriftsartikel (refereegranskat)abstract
- Bacillus Calmette-Guerin (BCG) is widely used in the clinic to effectively treat superficial urinary bladder cancer. However, a significant proportion of patients who fail to respond to BCG risk cystectomy or death. Though more than 3 million cancer treatments with BCG occur annually, surprisingly little is known about the initial signaling cascades activated by BCG. Here, we report that BCG induces a rapid intracellular Ca2+ (calcium ion) signal in bladder cancer cells that is essential for activating the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) and for synthesizing and secreting proinflammatory cytokines, including interleukin 8 (IL-8). A similar Ca2+ response was observed when cells were exposed to the supernatant of BCG. Studying cellular molecular mechanisms involved in the BCG signaling event, we found pivotal roles for phospholipase C and the Toll-like receptor 4. Further assessment revealed that this signaling pathway induces synthesis of IL-8, whereas exocytosis appeared to be controlled by global Ca2+ signaling. These results shed new light on the molecular mechanisms underlying BCG treatment of bladder cancer, which can help in improving therapeutic efficacy and reducing adverse side effects.
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| 4. |
- Lundgren, T Kalle
(författare)
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Rewiring ret : PTB-adaptor regulated signaling and cell biology
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The Ret receptor belongs to a group of transmembrane tyrosine kinase receptors that serve to transduce environmental signals into cellular responses. Upon extracellular ligand activation the receptors dimerize and their structural conformation is altered into one that allows for interaction with proteins in the cell cytosol. Among the most proximal interactors are PTBadaptor molecules that dock to Ret tyrosine residues. As several PTB-adaptors compete for interaction with the same receptor-sequence the molecule that successfully binds to Ret excludes binding of any other PTB-adaptor at that time. Hence, the resulting signals are dependent on which adaptor that successfully engaged the receptor. In this work, Ret has been rewired to preferentially bind one PTB-adaptor on the expense of others to tyrosine 1062. This makes it possible to experimentally assign biochemical events as well as cell biological outcomes to one specific adaptor and so increasingly reveal how one common receptor may serve a plethora of functions depending on the subcellular milieu in which it operates. In paper I the important residues for Ret interaction with the Shc and Frs2alpha adaptors were investigated. Based on data from the effect on adaptor affinity for Ret by specifically substituting amino acids around tyrosine 1062, mutants could be established with selective recruitment of either Shc or Frs2alpha to this tyrosine. Ret interaction with Shc resulted in capacity for the receptor to mediate ligand dependent survival in the setting of apoptotic stimuli or severe starvation while Frs2alpha mediated signaling was insufficient to do so. In paper II the Frs2alpha adaptor docked to Ret were found to be essential for chemotactic directional migration towards Ret ligands. The molecular basis for Ret promoted migration depended on the membrane associated Src family of kinases that bind to Ret at a different tyrosine than Frs2alpha such that these two residues are cooperatively involved in assembling the molecular framework required to execute a migratory response downstream of Ret. In paper III the Dok adaptors, which were recently found to interact with Ret, were investigated. Dok selective Ret mutants could be created and were expressed in neuronally derived cells. Dok binding resulted in prolonged phosphorylation of MAP kinases and allowed for Cdc42 activation. The cellular response was enhanced microspike formation as determined morphologically. In paper IV local membranous Ret interaction with Shc and Frs2alpha were investigated. While Frs2alpha overexpression recruited Ret to distinct lipid raft like partitions of the plasma membrane Shc expression led to Ret being found outside these fractions. A Shc molecule with an appendage forcing its association to lipid rafts resembled Frs2alpha characteristics in terms of downstream biochemical profile and dependence of ordered cholesterol species in the membrane for signaling, suggesting the importance of adaptors for appropriate relocation of Ret. Moreover, the Frs2alpha dependent migration was indeed disrupted by cholesterol oxidation while the survival response promoted via Shc showed little dependence on disruption of membrane architecture.
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| 5. |
- Neovius, Erik, et al.
(författare)
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Long-term sensory disturbances after orbitozygomatic fractures
- 2017
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Ingår i: Journal of Plastic, Reconstructive & Aesthetic Surgery. - : Elsevier. - 1748-6815 .- 1878-0539. ; 70, s. 120-126
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Tidskriftsartikel (refereegranskat)abstract
- Background: Orbitozygomatic fractures often lead to infraorbital nerve (ION) injury, and affected sensibility is a common long-term complaint within this patient group. We present a long-term follow-up study where the validated von Frey filament system was used for testing ION sensibility. Furthermore, we examined the incidence of persistent nerve injury and whether more complex fractures led to more pronounced ION sensibility disturbances. Methods: Patients treated for facial fractures involving the orbitozygomatic complex were included and the follow-up time was 3 years or more. Depending on the location and severity of the fractures, the patients were divided into 4 groups. The patients answered a questionnaire before ION sensibility testing with von Frey filaments. Results: Eighty-one patients were examined: 65 males (80%) and 16 females (20%). Examinations were conducted between 3.0 and 7.6 years (mean 4.9 years) after injury. Sixteen patients (20%) had affected and 6 patients (7.4%) had severely affected ION sensibility according to von Frey testing. No statistically significant differences were found in terms of questionnaire score between the groups. There was also no statistically significant correlation between questionnaire results and log von Frey values. Although the effect of groups could not be statistically verified using the log von Frey values, a larger proportion of patients with complex fractures had higher log von Frey values than the other groups
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| 6. |
- Neovius, Erik, et al.
(författare)
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Persistent diplopia after fractures involving the orbit related to nerve injury
- 2015
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Ingår i: Journal of Plastic, Reconstructive & Aesthetic Surgery. - : Elsevier BV. - 1748-6815 .- 1878-0539. ; 68:2, s. 219-225
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Tidskriftsartikel (refereegranskat)abstract
- Background: Fractures in the facial skeleton are common and may lead to orbital sequelae caused by the injury and/or the surgery. In this long-term follow-up, we examined the nature of sequelae after facial fractures involving the orbit and whether a higher complexity of the fractures produced more sequelae compared to simpler fracture patterns, and if so, to what extent. Methods: Patients surgically treated for facial fractures involving the orbit at the Karolinska University Hospital with a follow-up duration of >= 3 years were included in this retrospective study and were examined by a neuro-ophthalmologist. Based on the location and severity of the fractures, the patients were divided into four groups according to fracture complexity: 1) isolated zygomatic fracture, 2) isolated orbital floor blowout fracture, 3) zygomatic fracture combined with blowout fracture and 4) bilateral or multiple fracture patterns. Results: Out of 154 patients, 81 patients (53%) attended follow-up examinations, 65 male (80%) and 16 female (20%). The duration of follow-up was 3.0-7.6 years (mean of 4.9 years). The incidence of diplopia was 3.7%, visual loss 2.5%, dystopia 4.9% and visible enophthalmos (>2 mm) 8.6%. Severe diplopia (2.5%) was due to nerve injuries. Visual loss was encountered only in group 4 with complex fractures. Fracture complexity had an effect on the presence of any sequelae, with group 4 presenting a higher percentage of patients with sequelae than the other three groups. However, no statistically significant effect of group could be found on the individual, quantitative output values of dystopia and enophthalmos. Conclusions: In this study, severe persistent diplopia in patients was due to nerve injuries, which emphasizes the need for preoperative ophthalmologic examinations, in all patients with fractures involving the orbit. A higher fracture complexity was found to lead to a higher percentage of patients presenting sequelae. (C) 2014 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.
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