| 1. |
- Arteta, Marianna Yanez, et al.
(author)
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Successful reprogramming of cellular protein production through mRNA delivered by functionalized lipid nanoparticles
- 2018
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 115:15
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Journal article (peer-reviewed)abstract
- © 2018 National Academy of Sciences. All Rights Reserved. The development of safe and efficacious gene vectors has limited greatly the potential for therapeutic treatments based on messenger RNA (mRNA). Lipid nanoparticles (LNPs) formed by an ionizable cationic lipid (here DLin-MC3-DMA), helper lipids (distearoylphos-phatidylcholine, DSPC, and cholesterol), and a poly(ethylene glycol) (PEG) lipid have been identified as very promising delivery ve ctors of short interfering RNA (siRNA) in different clinical phases; however, delivery of high-molecular weight RNA has been proven much more demanding. Herein we elucidate the structure of hEPO modified mRNA-containing LNPs of different sizes and show how structural differences affect transfection of human adipocytes and hepatocytes, two clinically relevant cell types. Employing small-angle scattering, we demonstrate that LNPs have a disordered inverse hexagonal internal structure with a characteristic distance around 6 nm in presence of mRNA, whereas LNPs containing no mRNA do not display this structure. Furthermore, using contrast variation small-angle neutron scattering, we show that one of the lipid components, DSPC, is localized mainly at the surface of mRNA-containing LNPs. By varying LNP size and surface composition we demonstrate that both size and structure have significant influence on intracellular protein production. As an example, in both human adipocytes and hepatocytes, protein expression levels for 130 nm LNPs can differ as much as 50-fold depending on their surface characteristics, likely due to a difference in the ability of LNP fusion with the early endosome membrane. We consider these discoveries to be fundamental and opening up new possibilities for rational design of synthetic nanoscopic vehicles for mRNA delivery.
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| 2. |
- Bockermann, Robert, et al.
(author)
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Imlifidase-generated Single-cleaved IgG : Implications for Transplantation
- 2022
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In: Transplantation. - : Ovid Technologies (Wolters Kluwer Health). - 0041-1337 .- 1534-6080. ; 106:7, s. 1485-1496
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Journal article (peer-reviewed)abstract
- Background. Imlifidase is an immunoglobulin G (IgG)-specific protease conditionally approved in the EU for desensitization in highly sensitized crossmatch positive kidney transplant patients. Imlifidase efficiently cleaves both heavy chains of IgG in a 2-step process. However, low levels of the intermediate cleavage product, single-cleaved IgG (scIgG), may persist in the circulation. The study objective was to investigate Fc-mediated effector functions of scIgG and its potential impact on common clinical immunologic assays used to assess transplant eligibility.Methods. Imlifidase-generated scIgG, obtained by in vitro cleavage of HLA-sensitized patient serum or selected antibodies, was investigated in different complement- and Fc gamma R-dependent assays and models, including clinical tests used to evaluate HLA-specific antibodies.Results. ScIgG had significantly reduced Fc-mediated effector function compared with intact IgG, although some degree of activity in complement- and Fc gamma R-dependent models was still detectable. A preparation of concentrated scIgG generated from a highly HLA-sensitized individual gave rise to a positive signal in the anti-HLA IgG LABScreen, which uses anti-Fc detection, but was entirely negative in the C1qScreen. The same high-concentration HLA-binding scIgG preparation also generated positive complement-dependent cytotoxicity responses against 80%-100% of donor T and B cells, although follow-up titrations demonstrated a much lower intrinsic activity than for intact anti-HLA IgG.Conclusions. ScIgG has a significantly reduced capacity to mediate Fc-dependent effector functions. However, remaining HLA-reactive scIgG in plasma after imlifidase treatment can cause positive assay results equivalent to intact IgG in clinical assays. Therefore, complete IgG cleavage after imlifidase treatment is essential to allow correct decision-making in relation to transplant eligibility.
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| 3. |
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| 4. |
- Evertsson, Maria, et al.
(author)
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Combined Magnetomotive ultrasound, PET/CT, and MR imaging of (68)Ga-labelled superparamagnetic iron oxide nanoparticles in rat sentinel lymph nodes in vivo
- 2017
-
In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1
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Journal article (peer-reviewed)abstract
- Current methods for intra-surgical guidance to localize metastases at cancer surgery are based on radioactive tracers that cause logistical challenges. We propose the use of a novel ultrasound-based method, magnetomotive ultrasound (MMUS) imaging that employ a nanoparticle-based contrast agent that also may be used for pre-operative PET/MRI imaging. Since MMUS is radiation free, this eliminates the dependence between pre- and intra-operative imaging and the radiation exposure for the surgical staff. This study investigates a hypothetical clinical scenario of pre-operative PET imaging, combined with intra-operative MMUS imaging, implemented in a sentinel lymph node (SLN) rat model. At one-hour post injection of (68)Ga-labelled magnetic nanoparticles, six animals were imaged with combined PET/CT. After two or four days, the same animals were imaged with MMUS. In addition, ex-vivo MRI was used to evaluate the amount of nanoparticles in each single SLN. All SLNs were detectable by PET. Four out of six SLNs could be detected with MMUS, and for these MMUS and MRI measurements were in close agreement. The MRI measurements revealed that the two SLNs undetectable with MMUS contained the lowest nanoparticle concentrations. This study shows that MMUS can complement standard pre-operative imaging by providing bedside real-time images with high spatial resolution.
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| 5. |
- Evertsson, Maria, et al.
(author)
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In vivo magnetomotive ultrasound imaging of rat lymph nodes - a pilot study
- 2015
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In: 2015 IEEE International Ultrasonics Symposium (IUS). - 1948-5719.
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Conference paper (peer-reviewed)abstract
- The drive to gain a better understanding of how diseases arise and how to provide ever-earlier detection are some of the key factors for the development of molecular imaging. Compared to other imaging modalities ultrasound has not received the same attention for molecular imaging mainly due to its limited contrast resolution, together with contrast agents confined to the intravascular space. To overcome these issues, new nano-sized contrast agents and new ultrasound imaging techniques e.g. photo acoustic imaging, have been developed. Another such imaging technique under development is magnetomotive ultrasound imaging (MMUS). We have previously developed a frequency and phase tracking algorithm which is able to detect superparamagnetic iron oxide nanoparticles (SPIO NPs) using MMUS, where our suggested first clinical application is to detect sentinel lymph nodes (SLNs) in breast cancer surgery. Recently we have shown detection of SPIO laden rat SLNs in situ. Here we present the feasibility of in vivo detection of SLNs in rats. The algorithm clearly pinpoints the NP laden SLN, even in presence of significant artefactual tissue movement. The magnetomotive displacement increased when a higher voltage was applied on the coil creating the magnetic field (e.g. 56.6% increasing the voltage from 20V to 50V). An uneven concentration distribution of NPs in the SLN was found. The maximum magnetomotive displacement difference between two different cross sections in one SLN was 9.76 times. The study also showed that for a higher concentration of NPs a lower magnetic coil excitation voltage could be used in order to create a magnetomotive displacement of a certain magnitude. The result from this in vivo study shows that the method has potential for future clinical use.
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| 6. |
- Evertsson, Maria, et al.
(author)
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Magnetomotive Ultrasound Imaging Of Rat Lymph Nodes In Situ: Assessment Of Imaging Parameters
- 2013
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In: 2013 IEEE International Ultrasonics Symposium (IUS). - 9781467356855 ; , s. 600-603
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Conference paper (peer-reviewed)abstract
- Detection and removal sentinel lymph nodes (SLN) is important in the diagnosis and treatment of breast cancer and malignant melanoma. The SLN is the first regional lymph node draining the cancer tumor and if the cancer has spread it is most likely to find cancer cells in the SLN. In this study we have been able to detect multimodal superparamagnetic iron oxide nanoparticles (SPIO-NP) in rat SLNs in situ using magnetomotive ultrasound imaging (MMUS). In MMUS a time-varying external magnetic field acts to move the NPs and, thus, the NP-laden tissue. This movement can be detected by proper processing of ultrasound data. We have recently developed an MMUS algorithm, based on quadrature detection and phase gating at the frequency of NP displacement, and this is the first study where the algorithm is evaluated in animals. For both higher NP-concentration, as well as smaller NPs, we found that the MMUS data showed a larger displacement (1.56 +/- 0.43 and 1.94 +/- 0.54 times larger, respectively). The MMUS displacement also increased with a lower excitation frequency (1.95 +/- 0.64 times larger for 5 Hz compared to 15 Hz) and higher excitation voltage (2.95 +/- 1.44 times larger for 30V compared to 10V). The results from this study show that the MMUS technique has potential to be used as bedside guidance during SLN surgery, well as being used as standalone technique in a number of other applications such as stem cell tracking and cardiovascular research.
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| 7. |
- Evertsson, Maria, et al.
(author)
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Multimodal Detection of Iron Oxide Nanoparticles in Rat Lymph Nodes Using Magnetomotive Ultrasound Imaging and Magnetic Resonance Imaging
- 2014
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In: IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control. - 0885-3010. ; 61:8, s. 1276-1283
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Journal article (peer-reviewed)abstract
- Detection and removal of sentinel lymph nodes (SLN) is important in the diagnosis and treatment of cancer. The SLN is the first regional lymph node draining the primary tumor, and if the cancer has spread, it is most likely to find metastases in the SLN. In this study, we have for the first time been able to image the very same contrast agent, superparamagnetic iron oxide nanoparticles (SPIO-NPs), in rat SLNs by using both our frequency-and phase-gated magnetomotive ultrasound (MMUS) algorithm and conventional magnetic resonance imaging (MRI); MMUS post mortem, MRI in vivo. For both higher NP-concentration and smaller NPs, we found that the MMUS data showed a larger magnetomotive displacement (1.56 +/- 0.43 and 1.94 +/- 0.54 times larger, respectively) and that the MR-images were affected to a higher degree. The MMUS displacement also increased with lower excitation frequency (1.95 +/- 0.64 times larger for 5 Hz compared with 15 Hz) and higher excitation voltage (2.95 +/- 1.44 times larger for 30 V compared with 10 V). The results show that MMUS has potential to be used as bedside guidance during SLN surgery, imaging the same particles that were used in prior staging with other imaging techniques.
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| 8. |
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| 9. |
- Han, Lu, et al.
(author)
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Silica-Based Nanoporous Materials
- 2014
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In: Zeitschrift für Anorganische und Allgemeines Chemie. - : Wiley. - 0044-2313 .- 1521-3749. ; 640:3-4, s. 521-536
-
Research review (peer-reviewed)abstract
- Ordered nanoporous structures are among the most fascinating and industrially important materials currently in use. The archetypal zeolite material has now been joined by an eclectic array of new structures that exhibit porosity over a wide range of length scales and with order/disorder expressed in a multitude of ways. This raises the bar in terms of characterization and extends a real challenge to the scientific community to fully understand the properties and potential future applications of such materials. In this review we discuss the importance of modern microscopy tools combined with diffraction in this endeavour and show how the details of even the most complex quasi-crystalline nanoporous architectures can be elucidated. We show by using the appropriate spherical aberration (C-s) corrections in scanning transmission electron microscopy it is possible to decipher all the individual silicon and aluminum atoms in a zeolite structure. Automated routines for using large electron diffraction datasets for crystal structure determination of nanocrystals is described making the need for large single crystal synthesis less-and-less important. The power of complementary combinations of surface tools such as atomic force microscopy and high-resolution scanning electron microscopy is discussed to elucidate crystal growth mechanisms. For mesoporous materials synthesized from self-organized organic mesophases electron microscopy reveals the details of the complex hierarchy of porosity so crucial for the functional performance of the structure.
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| 10. |
- Jordan, Stanley C, et al.
(author)
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IgG Endopeptidase in Highly Sensitized Patients Undergoing Transplantation.
- 2017
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In: New England Journal of Medicine. - : Massachusetts Medical Society. - 0028-4793 .- 1533-4406. ; 377:5, s. 442-453
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Donor-specific antibodies create an immunologic barrier to transplantation. Current therapies to modify donor-specific antibodies are limited and ineffective in the most highly HLA-sensitized patients. The IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS), an endopeptidase, cleaves human IgG into F(ab')2 and Fc fragments inhibiting complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity, which suggests that IdeS might be useful for desensitization. We report on the combined experience of two independently performed open-label, phase 1-2 trials (conducted in Sweden and the United States) that assessed the efficacy of IdeS with regard to desensitization and transplantation of a kidney from an HLA-incompatible donor.METHODS: We administered IdeS to 25 highly HLA-sensitized patients (11 patients in Uppsala or Stockholm, Sweden, and 14 in Los Angeles) before the transplantation of a kidney from an HLA-incompatible donor. Frequent monitoring for adverse events, outcomes, donor-specific antibodies, and renal function was performed, as were renal biopsies. Immunosuppression after transplantation consisted of tacrolimus, mycophenolate mofetil, and glucocorticoids. Patients in the U.S. study also received intravenous immune globulin and rituximab after transplantation to prevent antibody rebound.RESULTS: Recipients in the U.S. study had a significantly longer cold ischemia time (the time elapsed between procurement of the organ and transplantation), a significantly higher rate of delayed graft function, and significantly higher levels of class I donor-specific antibodies than those in the Swedish study. A total of 38 serious adverse events occurred in 15 patients (5 events were adjudicated as being possibly related to IdeS). At transplantation, total IgG and HLA antibodies were eliminated. A total of 24 of 25 patients had perfusion of allografts after transplantation. Antibody-mediated rejection occurred in 10 patients (7 patients in the U.S. study and 3 in the Swedish study) at 2 weeks to 5 months after transplantation; all these patients had a response to treatment. One graft loss, mediated by non-HLA IgM and IgA antibodies, occurred.CONCLUSIONS: IdeS reduced or eliminated donor-specific antibodies and permitted HLA-incompatible transplantation in 24 of 25 patients. (Funded by Hansa Medical; ClinicalTrials.gov numbers, NCT02224820 , NCT02426684 , and NCT02475551 .).
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| 11. |
- Jordan, Stanley C., et al.
(author)
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Imlifidase desensitization in crossmatch-positive, highly-sensitized kidney transplant recipients : Results of an international phase 2 trial (Highdes)
- 2021
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In: Transplantation. - 0041-1337 .- 1534-6080. ; 105:8, s. 1808-1817
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Journal article (peer-reviewed)abstract
- BACKGROUND: Highly-HLA sensitized patients have limited access to life-saving kidney transplantation due to a paucity of immunologically suitable donors. Imlifidase is a cysteine protease that cleaves IgG leading to a rapid decrease in antibody level and inhibition of IgG-mediated injury. This study investigates the efficacy and safety of imlifidase in converting a positive crossmatch test to negative, allowing highly sensitized patients to be transplanted with a living or deceased donor kidney.METHODS: This open-label, single arm, phase 2 trial conducted at five transplant centers, evaluated the ability of imlifidase to create a negative crossmatch test within 24 hours. Secondary endpoints included post-imlifidase DSA levels compared to pre-dose levels, renal function, and pharmacokinetic/pharmacodynamic profiles. Safety endpoints included adverse events and immunogenicity profile.RESULTS: 89.5% of the transplanted patients demonstrated conversion of baseline positive crossmatch to negative within 24 hours after imlifidase treatment. DSA most often rebounded 3-14 days post-imlifidase dose, with substantial interpatient variability. Patient survival was 100% with graft survival of 88.9% at 6 months. 38.9% had early biopsy proven antibody mediated rejection with onset 2-19 days post-transplantation. Serum IgG levels began to normalize after ~3-7 days post-transplantation. Anti-drug antibody levels were consistent with previous studies. Seven adverse events in six patients were classified as possibly or probably related to treatment and were mild-moderate in severity.CONCLUSIONS: Imlifidase was well tolerated, converted positive crossmatches to negative, and enabled patients with a median cPRA of 99.83% to undergo kidney transplantation resulting in good kidney function and graft survival at 6 months.
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| 12. |
- Järnum, S., et al.
(author)
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Effects of IdeS on HLA-SAB, C1q-SAB and CDC-XM
- 2018
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In: American Journal of Transplantation. - : John Wiley & Sons. - 1600-6135 .- 1600-6143. ; 18:S4: Oral Abstracts, s. 370-371
-
Journal article (other academic/artistic)
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| 13. |
- Kjellman, Christian, et al.
(author)
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Outcomes at 3 years posttransplant in imlifidase-desensitized kidney transplant patients
- 2021
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In: American Journal of Transplantation. - : Elsevier. - 1600-6135 .- 1600-6143. ; 21:12, s. 3907-3918
-
Journal article (peer-reviewed)abstract
- Imlifidase is a cysteine proteinase which specifically cleaves IgG, inhibiting Fc-mediated effector function within hours of administration. Imlifidase converts a positive crossmatch to a potential donor (T cell, B cell, or both), to negative, enabling transplantation to occur between previously HLA incompatible donor-recipient pairs. To date, 39 crossmatch positive patients received imlifidase prior to a kidney transplant in four single-arm, open-label, phase 2 studies. At 3 years, for patients who were AMR+ compared to AMR-, death-censored allograft survival was 93% vs 77%, patient survival was 85% vs 94%, and mean eGFR was 49 ml/min/1.73 m2 vs 61 ml/min/1.73 m2 , respectively. The incidence of AMR was 38% with most episodes occurring within the first month post-transplantation. Sub-analysis of patients deemed highly sensitized with cPRA ≥ 99.9%, and unlikely to be transplanted who received crossmatch-positive, deceased donor transplants had similar rates of patient survival, graft survival, and eGFR but a higher rate of AMR. These data demonstrate that outcomes and safety up to 3 years in recipients of imlifidase-enabled allografts is comparable to outcomes in other highly sensitized patients undergoing HLA-incompatible transplantation. Thus, imlifidase is a potent option to facilitate transplantation among patients who have a significant immunologic barrier to successful kidney transplantation.
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| 14. |
- Kjellman, Tomas, et al.
(author)
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Direct Observation of Plugs and Intrawall Pores in SBA-15 Using Low Voltage High Resolution Scanning Electron Microscopy and the Influence of Solvent Properties on Plug-Formation
- 2013
-
In: Chemistry of Materials. - : American Chemical Society (ACS). - 0897-4756 .- 1520-5002. ; 25:20, s. 4105-4112
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Journal article (peer-reviewed)abstract
- Through the use of low voltage high resolution scanning electron microscopy (LV-HRSEM) we have studied the fine details of the intricate pore structure of SBA-15. Intrawall pores and deviations from the ideal and uniform cylindrical pores are clearly observed, and we report for the first time the direct observation of plugs in the pores. N-2-sorption measurements confirm their existence. LV-HRSEM provides an opportunity to quantify the frequency of occurrence of plugs within the pore structure. The rate of mesophase formation, followed with in situ small angle X-ray scattering (SAXS) under different solvent conditions, is shown to have a significant influence on the development of plugs and how frequently they occur. We suggest a mechanism explaining the existence of the plugs, providing means for a better understanding and control over material properties.
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| 15. |
- Kjellman, Tomas, et al.
(author)
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Independent Fine-Tuning of the Intrawall Porosity and Primary Mesoporosity of SBA-15
- 2013
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In: Chemistry of Materials. - : American Chemical Society (ACS). - 0897-4756 .- 1520-5002. ; 25:9, s. 1989-1997
-
Journal article (peer-reviewed)abstract
- We present a study in which the intrawall porosity and primary mesoporosity. of SBA-15 are independently controlled by modifying the strength of the molecular interaction that governs the formation of the material. The interactions are targeted at specific times during the process of formation, which results in selective tuning of the porosity, while other characteristics of the SBA-15 material are retained. We show that the intrawall porosity can be considerably reduced by addition of NaI, but not NaCl, and that the shape of the primary mesopores can be influenced by a decrease in temperature, while while the two-dimensional hexagonal structure and the particle morphology and size remain unchanged. The timing of the "tuning event" is imperative. We show that a decrease in intrawall porosity by addition of NaI is generic to Pluronic-based mesoporous silica syntheses. This work demonstrates that the material characteristic of mesoporous silica is not necessarily restricted by the initial synthesis conditions as the material properties can be tuned by "actions" taken upon the ongoing synthesis. The triblock copolymer Pluronic P104 was used as a structure director and tetramethyl orthosilicate as a silica source. The materials have been characterized primarily with nitrogen sorption and small angle X-ray diffraction.
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| 16. |
- Kjellman, Tomas, et al.
(author)
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Influence of microporosity in SBA-15 on the release properties of anticancer drug dasatinib
- 2014
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In: Journal of materials chemistry. B. - : Royal Society of Chemistry (RSC). - 2050-750X .- 2050-7518. ; 2:32, s. 5265-5271
-
Journal article (peer-reviewed)abstract
- The release of the hydrophobic cancer drug dasatinib from two mesoporous silica materials as drug delivery vehicles has been studied. One material is a reference 2D-hexagonal SBA-15 with the typical bimodal pore system with ordered primary mesopores and disordered intrawatI pores. The other material is a modified version of the same material where the intrawall porosity in the micropore regime has been selectively removed. Material characterization shows that, with the exception of the difference in intrawall porosity, the materials have identical properties. The drug dasatinib, a tyrosine kinase inhibitor, has been loaded, to the same extent, into the pores of both materials. The two materials give rise to very different release profiles of the drug. The presence of micropores leads to desired release properties: a high initial release of the drug, which is maintained over time. The lack of micropores also leads to a high initial release but followed by a rapid drop in the concentration of released drug, a consequence of its low solubility and hence crystallisation. We suggest that the presence of micropores in the carrier material, and the resultant kinetic release profile, leads to a stabilization of dasatinib in solution and to a sustained supersaturated level of the released drug. Our findings suggest that by controlling the mesoporous host with small variation in the textural properties, the kinetic release and crystallization behaviour of a drug can be altered. It is thus potentially possible to influence the drug post-release and thereby its bioavailability.
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| 17. |
- Kjellman, Tomas
(author)
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Mesoporous Silica SBA-15 - Formation, Modification and Application
- 2013
-
Doctoral thesis (other academic/artistic)abstract
- Several aspects related to the mesoporous silica material SBA-15 have been studied through the use of a wide range of experimental techniques, including low voltage high-resolution scanning electron microscopy, small angle X-ray scattering and nitrogen sorption. This work contains three parts, which are in many ways overlapping. The first part deals with the formation of SBA-15, it is found that a mechanism of transient colloidal stability governs the growth of particles. In the second part, a modified experimental protocol is developed in order to independently fine-tune the intrawall porosity and primary mesoporosity of SBA- 15. Furthermore, the influence of solvent conditions on the development of structural details such as plugs and pore corrugations is investigated. Finally the last part deals with the use of SBA-15 material in applied problems, including controlled particle deposition and drug delivery. No matter the topic, the aim is to always base the applied strategies on a solid foundation of the understanding of the basic physiochemical processes relevant to the system under study. The work is presented in a way that there is a red line going through, showing how good understanding of fundamental processes opens up for possibilities to tune material properties, which in turn improves the material for use in application.
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| 18. |
- Kjellman, Tomas, et al.
(author)
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Orientation specific deposition of mesoporous particles
- 2014
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In: APL Materials. - : AIP Publishing. - 2166-532X. ; 2:11
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Journal article (peer-reviewed)abstract
- We present a protocol for a facile orientation specific deposition of plate-like mesoporous SBA-15 silica particles onto a surface (mesopores oriented normal to surface). A drop of an aqueous dispersion of particles is placed on the surface and water vaporizes under controlled relative humidity. Three requirements are essential for uniform coverage: particle dispersion should not contain aggregates, a weak attraction between particles and surface is needed, and evaporation rate should be low. Aggregates are removed by stirring/sonication. Weak attraction is realized by introducing cationic groups to the surface. Insight into the mechanisms of the so-called coffee stain effect is also provided. (C) 2014 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 Unported License.
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| 19. |
- Kjellman, Tomas, et al.
(author)
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The use of in situ and ex situ techniques for the study of the formation mechanism of mesoporous silica formed with non-ionic triblock copolymers.
- 2013
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In: Chemical Society Reviews. - : Royal Society of Chemistry (RSC). - 0306-0012. ; 42:9, s. 3777-3791
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Research review (peer-reviewed)abstract
- Since the discovery of the mesoporous silica material templated by ionic surfactants and the subsequent development of materials templated by non-ionic surfactants and polymers, for example SBA-15, there has been a continuous research effort towards understanding their formation. In situ methodologies, such as Small Angle X-ray Scattering (SAXS), Small Angle Neutron Scattering (SANS), spectroscopic techniques like NMR and EPR, and ex situ methodologies such as electron microscopy techniques (SEM, TEM and cryo-TEM) are powerful and important tools in the investigation of the mechanism by which these materials form. The need for a fundamental understanding of the systems is of academic concern and of great importance when developing materials for applications. In this tutorial review we aim to give the reader a comprehensive overview on the development of the field over the years and an introduction to the experimental in situ and ex situ techniques that have been used.
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| 20. |
- Kourie, Mourad, et al.
(author)
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Autoimmune Pancreatitis Type 1 with Biliary, Nasal, Testicular, and Pulmonary Involvement: A Case Report and a Systematic Review
- 2023
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In: Journal of Clinical Medicine. - : MDPI. - 2077-0383. ; 12:19
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Research review (peer-reviewed)abstract
- Introduction: Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated condition associated with fibroinflammatory lesions that can occur at almost any anatomical site. It often presents as a multiorgan disease that may mimic malignancy, infection, or other immune-mediated conditions. Autoimmune pancreatitis (AIP) type 1 is the most prominent manifestation of IgG4-RD in the digestive tract, with common extra-pancreatic inflammation. We present the first patient with AIP and involvement of the testicles and nasal cavity. Patient and methods: A case of a patient with AIP type 1 and other organ involvement (bile ducts, testicles, nasal polyps, and lungs) is described. Additionally, a systematic review of AIP type 1 with testicular and nasal involvement was conducted. Results: The systematic review found two cases of AIP type 1 with testicular involvement and 143 cases with AIP type 1 with nasal cavity involvement. None of them had both testicular and nasal involvement. Conclusions: This is the first case of AIP type 1 with other organ involvement, including testicular and nasal involvement, to be described. The number of patients with nasal and testicular involvement described in the literature is low. Creating awareness of this rare clinical condition is necessary, especially due to the very effective available treatment with corticosteroids and rituximab.
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| 21. |
- Leiding, Thom, et al.
(author)
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Precise detection of pH inside large unilamellar vesicles using membrane-impermeable dendritic porphyrin-based nanoprobes.
- 2009
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In: Analytical Biochemistry. - : Elsevier BV. - 1096-0309 .- 0003-2697. ; 388, s. 296-305
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Journal article (peer-reviewed)abstract
- Accurate real-time measurements of proton concentration gradients are pivotal to mechanistic studies of proton translocation by membrane-bound enzymes. Here we report a detailed characterization of the pH-sensitive fluorescent nanoprobe Glu(3), which is well suited for pH measurements in microcompartmentalized biological systems. The probe is a polyglutamic porphyrin dendrimer in which multiple carboxylate termini ensure its high water solubility and prevent its diffusion across phospholipid membranes. The probe's pK is in the physiological pH range, and its protonation can be followed ratiometrically by absorbance or fluorescence in the ultraviolet (UV)-visible spectral region. The usefulness of the probe was enhanced by using a semiautomatic titration system coupled to a charge-coupled device (CCD) spectrometer, enabling fast and accurate titrations and full spectral coverage of the system at millisecond time resolution. The probe's pK was measured in bulk solutions as well as inside large unilamellar vesicles in the presence of physiologically relevant ions. Glu(3) was found to be completely membrane impermeable, and its distinct spectroscopic features permit pH measurements inside closed membrane vesicles, enabling quantitative mechanistic studies of membrane-spanning proteins. Performance of the probe was demonstrated by monitoring the rate of proton leakage through the phospholipid bilayer in large vesicles with and without the uncoupler gramicidin present. Overall, as a probe for biological proton translocation measurements, Glu(3) was found to be superior to the commercially available pH indicators.
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| 22. |
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| 23. |
- Lorant, Tomas, 1975-, et al.
(author)
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Safety, immunogenicity, pharmacokinetics, and efficacy of degradation of anti-HLA antibodies by IdeS (imlifidase) in chronic kidney disease patients
- 2018
-
In: American Journal of Transplantation. - : Elsevier BV. - 1600-6135 .- 1600-6143. ; 18:11, s. 2752-2762
-
Journal article (peer-reviewed)abstract
- Safety, immunogenicity, pharmacokinetics, and efficacy of the IgG-degrading enzyme of Streptococcus pyogenes (IdeS [imlifidase]) were assessed in a single-center, open-label ascending-dose study in highly sensitized patients with chronic kidney disease. Eight patients with cytotoxic PRAs (median cytotoxic PRAs of 64%) at enrollment received 1 or 2 intravenous infusions of IdeS on consecutive days (0.12 mg/kg body weight ×2 [n = 3]; 0.25 mg/kg ×1 [n = 3], or 0.25 mg/kg ×2 [n = 2]). IgG degradation was observed in all subjects after IdeS treatment, with <1% plasma IgG remaining within 48 hours and remaining low up to 7 days. Mean fluorescence intensity values of HLA class I and II reactivity were substantially reduced in all patients, and C1q binding to anti-HLA was abolished. IdeS also cleaved the IgG-type B cell receptor on CD19+ memory B cells. Anti-IdeS antibodies developed 1 week after treatment, peaking at 2 weeks. A few hours after the second IdeS infusion, 1 patient received a deceased donor kidney offer. At enrollment, the patient had a positive serum crossmatch (HLA-B7), detected by complement-dependent cytotoxicity, flow cytometry, and multiplex bead assays. After IdeS infusion (0.12 mg/kg ×2) and when the HLA-incompatible donor (HLA-B7+) kidney was offered, the HLA antibody profile was negative. The kidney was transplanted successfully.
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| 24. |
- Marco, Maugeri, 1983, et al.
(author)
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Linkage between endosomal escape of LNP-mRNA and loading into EVs for transport to other cells
- 2019
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1
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Journal article (peer-reviewed)abstract
- RNA-based therapeutics hold great promise for treating diseases and lipid nanoparticles (LNPs) represent the most advanced platform for RNA delivery. However, the fate of the LNP-mRNA after endosome-engulfing and escape from the autophagy-lysosomal pathway remains unclear. To investigate this, mRNA (encoding human erythropoietin) was delivered to cells using LNPs, which shows, for the first time, a link between LNP-mRNA endocytosis and its packaging into extracellular vesicles (endo-EVs: secreted after the endocytosis of LNP-mRNA). Endosomal escape of LNP-mRNA is dependent on the molar ratios between ionizable lipids and mRNA nucleotides. Our results show that fractions of ionizable lipids and mRNA (1:1 molar ratio of hEPO mRNA nucleotides:ionizable lipids) of endocytosed LNPs were detected in endo-EVs. Importantly, these EVs can protect the exogenous mRNA during in vivo delivery to produce human protein in mice, detected in plasma and organs. Compared to LNPs, endo-EVs cause lower expression of inflammatory cytokines.
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