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| 2. |
- Asif, Sana, et al.
(author)
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Heparinization of cell surfaces with short peptide-conjugated PEG-lipid regulates thromboinflammation in transplantation of human MSCs and hepatocytes
- 2016
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In: Acta Biomaterialia. - : Elsevier BV. - 1742-7061 .- 1878-7568. ; 35, s. 194-205
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Journal article (peer-reviewed)abstract
- Infusion of therapeutic cells into humans is associated with immune responses, including thromboinflammation, which result in a large loss of transplanted cells\ To address these problems, heparinization of the cell surfaces was achieved by a cell-surface modification technique using polyethylene glycol conjugated phospholipid (PEG-lipid) derivatives. A short heparin-binding peptide was conjugated to the PEG-lipid for immobilization of heparin conjugates on the surface of human mesenchymal stem cells (hMSCs) and human hepatocytes. Here three kinds of heparin-binding peptides were used for immobilizing heparin conjugates and examined for the antithrombogenic effects on the cell surface. The heparinized cells were incubated in human whole blood to evaluate their hemocompatibility by measuring blood parameters such as platelet count, coagulation markers, complement markers, and Factor Xa activity. We found that one of the heparin-binding peptides did not show cytotoxicity after the immobilization with heparin conjugates. The degree of binding of the heparin conjugates on the cell surface (analyzed by flow cytometer) depended on the ratio of the active peptide to control peptide. For both human MSCs and hepatocytes in whole-blood experiments, no platelet aggregation was seen in the heparin conjugate-immobilized cell group vs. the controls (non-coated cells or control peptide). Also, the levels of thrombin-antithrombin complex (TAT), C3a, and sC5b-9 were significantly lower than those of the controls, indicating a lower activation of coagulation and complement. Factor Xa analysis indicated that the heparin conjugate was still active on the cell surface at 24 h post-coating. It is possible to immobilize heparin conjugates onto hMSC and human hepatocyte surfaces and thereby protect the cell surfaces from damaging thromboinflammation. Statement of Signigficance We present a promising approach to enhance the biocompatibility of therapeutic cells. Here we used short peptide-conjugated PEG-lipid for cell surface modification and heparin conjugates for the coating of human hepatocytes and MSCs. We screened the short peptides to find higher affinity for heparinization of cell surface and performed hemocompatibility assay of heparinized human hepatocytes and human MSCs in human whole blood. Using heparin-binding peptide with higher affinity, not only coagulation activation but also complement activation was significantly suppressed. Thus, it was possible to protect human hepatocytes and human MSCs from the attack of thromboinflammatory activation, which can contribute to the improvement graft survival. (C) 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
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| 3. |
- Asif, Sana, M.D, PhD student, et al.
(author)
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Immuno-Modulatory Effects of Dexamethasone in Severe COVID-19 : A Swedish Cohort Study
- 2023
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In: Biomedicines. - : MDPI. - 2227-9059. ; 11:1
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Journal article (peer-reviewed)abstract
- Dexamethasone (Dex) has been shown to decrease mortality in severe coronavirus disease 2019 (COVID-19), but the mechanism is not fully elucidated. We aimed to investigate the physiological and immunological effects associated with Dex administration in patients admitted to intensive care with severe COVID-19. A total of 216 adult COVID-19 patients were included-102 (47%) received Dex, 6 mg/day for 10 days, and 114 (53%) did not. Standard laboratory parameters, plasma expression of cytokines, endothelial markers, immunoglobulin (Ig) IgA, IgM, and IgG against SARS-CoV-2 were analyzed post-admission to intensive care. Patients treated with Dex had higher blood glucose but lower blood lactate, plasma cortisol, IgA, IgM, IgG, D-dimer, cytokines, syndecan-1, and E-selectin and received less organ support than those who did not receive Dex (Without-Dex). There was an association between Dex treatment and IL-17A, macrophage inflammatory protein 1 alpha, syndecan-1 as well as E-selectin in predicting 30-day mortality. Among a subgroup of patients who received Dex early, within 14 days of COVID-19 debut, the adjusted mortality risk was 0.4 (95% CI 0.2-0.8), i.e., 40% compared with Without-Dex. Dex administration in a cohort of critically ill COVID-19 patients resulted in altered immunological and physiologic responses, some of which were associated with mortality.
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| 4. |
- Asif, Sana, et al.
(author)
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Oxygen-charged HTK-F6H8 emulsion reduces ischemia : reperfusion injury in kidneys from brain-dead pigs
- 2012
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In: Journal of Surgical Research. - : Elsevier BV. - 0022-4804 .- 1095-8673. ; 178:2, s. 959-967
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Journal article (peer-reviewed)abstract
- Background:Prolonged cold ischemia is frequently associated with a greater risk of delayed graft function and enhanced graft failure. We hypothesized that media, combining a high oxygen-dissolving capacity with specific qualities of organ preservation solutions, would be more efficient in reducing immediate ischemia-reperfusion injury from organs stored long term compared with standard preservation media.Methods:Kidneys retrieved from brain-dead pigs were flushed using either cold histidine-tryptophan-ketoglutarate (HTK) or oxygen-precharged emulsion composed of 75% HTK and 25% perfluorohexyloctane. After 18 h of cold ischemia the kidneys were transplanted into allogeneic recipients and assessed for adenosine triphosphate content, morphology, and expression of genes related to hypoxia, environmental stress, inflammation, and apoptosis.Results:Compared with HTK-flushed kidneys, organs preserved using oxygen-precharged HTK-perfluorohexyloctane emulsion had increased elevated adenosine triphosphate content and a significantly lower gene expression of hypoxia inducible factor-1 alpha, vascular endothelial growth factor, interleukin-1 alpha, tumor necrosis factor-alpha, interferon-alpha, JNK-1, p38, cytochrome-c, Bax, caspase-8, and caspase-3 at all time points assessed. In contrast, the mRNA expression of Bcl-2 was significantly increased.Conclusions:The present study has demonstrated that in brain-dead pigs the perfusion of kidneys with oxygen-precharged HTK-perfluorohexyloctane emulsion results in significantly reduced inflammation, hypoxic injury, and apoptosis and cellular integrity and energy content are well maintained. Histologic examination revealed less tubular, vascular, and glomerular changes in the emulsion-perfused tissue compared with the HTK-perfused counterparts. The concept of perfusing organs with oxygen-precharged emulsion based on organ preservation media represents an efficient alternative for improved organ preservation.
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| 5. |
- Asif, Sana, M.D, PhD student, et al.
(author)
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Plasma endostatin correlates with hypoxia and mortality in COVID-19-associated acute respiratory failure
- 2021
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In: Biomarkers in Medicine. - : Future Medicine. - 1752-0363 .- 1752-0371. ; 15:16, s. 1509-1517
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Journal article (peer-reviewed)abstract
- Background: The contribution of endothelial injury in the pathogenesis of COVID-19-associated acute respiratory distress syndrome (ARDS) and resulting respiratory failure remains unclear. Plasma endostatin, an endogenous inhibitor of angiogenesis and endothelial dysfunction is upregulated during hypoxia, inflammation and progress of pulmonary disease.Aim: To investigate if plasma endostatin is associated to hypoxia, inflammation and 30-day mortality in patients with severe COVID-19 infection.Method: Samples for blood analysis and plasma endostatin quantification were collected from adult patients with ongoing COVID-19 (n = 109) on admission to intensive care unit (day 1). Demographic characteristics and 30-day mortality data were extracted from medical records. The ability of endostatin to predict mortality was analyzed using receiving operating characteristics and Kaplan-Meier analysis with a cutoff at 46.2 ng/ml was used to analyze the association to survival.Results: Plasma endostatin levels correlated with; PaO2/FiO2 (r = -0.3, p < 0.001), arterial oxygen tension (r = -0.2, p = 0.01), lactate (r = 0.2, p = 0.04), C-reactive protein (r = 0.2, p = 0.04), ferritin (r = 0.2, p = 0.09), D-dimer (r = 0.2, p = 0.08) and IL-6 (r = 0.4, p < 0.001). Nonsurvivors at 30 days had higher plasma endostatin levels than survivors (72 ± 26 vs 56 ± 16 ng/ml, p = 0.01). Receiving operating characteristic curve (area under the curve 0.7) showed that plasma endostatin >46.2 ng/ml predicts mortality with a sensitivity of 92% and specificity of 71%. In patients with plasma endostatin >46.2 ng/ml probability of survival was lower (p = 0.02) in comparison to those with endostatin <46.2 ng/ml.Conclusion: Our results suggest that plasma endostatin is an early biomarker for disease severity in COVID-19.
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| 6. |
- Asif, Sana, M.D, PhD student
(author)
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Regulation of thromboinflammation in therapeutic medicine : Special focus on surface coating strategies
- 2019
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Doctoral thesis (other academic/artistic)abstract
- Biomaterials are an integral part of modern health care and offer potential treatment modalities to diseases and conditions otherwise intractable. However, the critical issue herein is incompatibility reactions.Our innate immune system is fundamental in protection against pathogens and foreign intruders and controls the discrimination between self and non-self. Biomaterials come in contact with blood upon implantation where they are sensed by innate immune mediators which through a cascade of complex, multifaceted reactions induce inflammation as well as thrombosis which may induce biomaterial dysfunction and rejection. This explains why patients undergoing haemodialysis therapy exhibit an increased incidence of whole-body inflammation and other thrombotic events. Similarly, therapeutic cells such as hepatocytes upon implantation initiate an instant blood mediated inflammatory reaction, responsible for cell damage and death via apoptosis.In order to achieve safer and more efficient therapeutic interventions, engineering of materials and cells that can avoid these adverse reactions is essential. Fabrication of biomaterials consisting of coating of bioinert polymers to avoid immune recognition and activation is a promising approach to modulate immune reactions.In this thesis, we have employed a PEG-lipid polymer coating, which intercalates in to biomembranes via hydrophobic interactions and thus shields from immune rejection. Treatment with PEG-lipid not only makes the surface “invisible” to immune cells but it also acts as a filter which prevents entry of immune cells without inducing cytotoxicity. Results from this thesis illustrate that fabrication of bio-surfaces by bio-inert PEG-lipid polymer is a harmless procedure which not only attenuates thrombo-inflammation but also assist in design of self-tailored materials for a wide range of biomedical applications.
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| 7. |
- Asif, Sana, M.D, PhD student, et al.
(author)
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Severe obstetric lacerations associated with postpartum depression among women with low resilience : a Swedish birth cohort study
- 2020
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In: British Journal of Obstetrics and Gynecology. - : Wiley. - 1470-0328 .- 1471-0528. ; 127:11, s. 1382-1390
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Journal article (peer-reviewed)abstract
- OBJECTIVE: Women's levels of resilience and attitudes towards perineal lacerations vary greatly. Some women see them as part of the birthing process, while others react with anger, depressed mood or even self-harm thoughts. A previous study has reported increased risk of postpartum depressive (PPD) symptoms in women with severe perineal lacerations. The aim of this study was to assess the association between severe obstetric perineal lacerations and PPD. A secondary objective was to assess this association among women with low resilience.DESIGN: Nested cohort study.SETTING: Uppsala, Sweden.SAMPLE: Vaginally delivered women with singleton pregnancies (n = 2,990).METHODS: The main exposure was obstetric perineal lacerations. Resilience was assessed in gestational week 32 using the Swedish version of the Sense of Coherence Scale (SOC-29). A digital acyclic graph (DAG) was used to identify possible confounders and mediators. Logistic regression was used to estimate odds ratios and 95% confidence intervals. A sub-analysis was run after excluding women with normal or high resilience.MAIN OUTCOME MEASURES: Postpartum depression, assessed with the Depression Self-Reporting Scale (DSRS), completed at six weeks postpartum.RESULTS: There was no significant association between severe obstetric perineal lacerations and PPD at six weeks postpartum. However, a significant association was found between severe lacerations and PPD in women with low resilience (OR =4.8 95% CI = 1.2-20), persisting even after adjusting for confounding factors.CONCLUSION: Health care professionals might need to identify women with low resilience, as they are at increased risk for PPD after a severe perineal laceration.
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| 8. |
- Asif, Sana, M.D, PhD student, et al.
(author)
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Validation of an MPC polymer coating to attenuate surface- induced cross-talk between the complement and coagulation systems in whole blood in in vitro and in vivo models
- 2019
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In: Macromolecular Bioscience. - : Wiley-VCH Verlagsgesellschaft. - 1616-5187 .- 1616-5195. ; 19:5
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Journal article (peer-reviewed)abstract
- Artificial surfaces that come into contact with blood induce an immediate activation of the cascade systems of the blood, leading to a thrombotic and/or inflammatory response that can eventually cause damage to the biomaterial or the patient, or to both. Heparin coating has been used to improve hemocompatibility, and another approach is 2-methacryloyloxyethyl phosphorylcholine (MPC)-based polymer coatings. Here, the aim is to evaluate the hemocompatibility of MPC polymer coating by studying the interactions with coagulation and complement systems using human blood in vitro model and pig in vivo model. The stability of the coatings is investigated in vitro and MPC polymer-coated catheters are tested in vivo by insertion into the external jugular vein of pigs to monitor the catheters' antithrombotic properties. There is no significant activation of platelets or of the coagulation and complement systems in the MPC polymer-coated one, which was superior in hemocompatibility to non-coated matrix surfaces. The protective effect of the MPC polymer coat does not decline after incubation in human plasma for up to 2 weeks. With MPC polymer-coated catheters, it is possible to easily draw blood from pig for 4 days in contrast to the case for non-coated catheters, in which substantial clotting is seen.
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| 9. |
- Asif, Sana, M.D, PhD student, et al.
(author)
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Validation of an MPC polymer coating to reduce surface-induced cascade system activation in whole blood in in vitroand in vivo models
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Other publication (other academic/artistic)abstract
- ABSTRACTBackground: Artificial surfaces that come into contact with blood (e.g., when used in various forms of biomedical device) induce an immediate activation of the cascade systems of the blood, the coagulation and complement systems. These reactions may lead to a thrombotic and/or inflammatory response that can eventually cause damage to the biomaterial or the patient, or to both. Multiple strategies to dampen these reactions have been employed, with heparin conjugation to the material surface being the most successfulthus far. Another approach to improving hemocompatibility is to use 2-methacryloyloxyethyl phosphorylcholine (MPC)-based polymer coatings.Experimental: In the present study, we evaluated the effectiveness of MPC polymer coating and compared it to a commercially available heparin coating in various in vitromodels using fresh human blood with the aim to replace the costly heparin-coated equipment with the more economic MPC. We then investigated the stability of the various coatings in human plasma in vitrofor 2 weeks. Finally, we inserted MPC polymer-coated catheters into the external jugular vein of pigs and monitored the catheters’ antithrombotic properties for 4 days.Results: 1) There was no significant activation of platelets and of the coagulation and complement systems on the MPC polymer-coated or the commercially available heparin surface. 2) Both coats were superior in hemocompatibility to non-coated matrix surfaces. 3) The protective effect of the MPC polymer coat did not decline after incubation in plasma for up to 2 weeks. 4) With MPC polymer-coated catheters, it was possible to easily draw blood from experimental animals for 4 days, in contrast to the case for heparin-flushed commercially available non-coated catheters, in which substantial clotting was seen.
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