206 results on '"Szigeti, K"'
Search Results
2. FLT3‐directed UniCAR T‐cell therapy of acute myeloid leukaemia.
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Peschke, J. C., Bergmann, R., Mehnert, M., Gonzalez Soto, K. E., Loureiro, L. R., Mitwasi, N., Kegler, A., Altmann, H., Wobus, M., Máthé, D., Szigeti, K., Feldmann, A., Bornhäuser, M., Bachmann, M., Fasslrinner, F., and Arndt, C.
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ACUTE myeloid leukemia ,T cells ,CHIMERIC antigen receptors ,PROTEIN-tyrosine kinases - Abstract
Summary: Adaptor chimeric antigen receptor (CAR) T‐cell therapy offers solutions for improved safety and antigen escape, which represent main obstacles for the clinical translation of CAR T‐cell therapy in myeloid malignancies. The adaptor CAR T‐cell platform 'UniCAR' is currently under early clinical investigation. Recently, the first proof of concept of a well‐tolerated, rapidly switchable, CD123‐directed UniCAR T‐cell product treating patients with acute myeloid leukaemia (AML) was reported. Relapsed and refractory AML is prone to high plasticity under therapy pressure targeting one single tumour antigen. Thus, targeting of multiple tumour antigens seems to be required to achieve durable anti‐tumour responses, underlining the need to further design alternative AML‐specific target modules (TM) for the UniCAR platform. We here present the preclinical development of a novel FMS‐like tyrosine kinase 3 (FLT3)‐directed UniCAR T‐cell therapy, which is highly effective for in vitro killing of both AML cell lines and primary AML samples. Furthermore, we show in vivo functionality in a murine xenograft model. PET analyses further demonstrate a short serum half‐life of FLT3 TMs, which will enable a rapid on/off switch of UniCAR T cells. Overall, the presented preclinical data encourage the further development and clinical translation of FLT3‐specific UniCAR T cells for the therapy of AML. [ABSTRACT FROM AUTHOR]
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- 2023
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3. A novel ACE2 decoy for both neutralization of SARS-CoV-2 variants and killing of infected cells
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Kegler, A., Drewitz, L., Arndt, C., Daglar, C., Rodrigues Loureiro, L. R., Mitwasi, N., Neuber, C., González Soto, K. E., Bartsch, T., Baraban, L., Ziehr, H., Heine, M., Nieter, A., Moreira-Soto, A., Kühne, A., Drexler, J. F., Seliger, B., Laube, M., Máthé, D., Pályi, B., Hajdrik, P., Forgách, L., Kis, Z., Szigeti, K., Bergmann, R., Feldmann, A., and Bachmann, M.
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bispecific antibody ,SARS-CoV-2 ,COVID-19 ,ACE2 decoy ,adapter CAR platform ,T cell based immunotherapy - Abstract
The COVID-19 pandemic caused by SARS-CoV-2 led to millions of infections and deaths worldwide. As this virus evolves rapidly, there is a high need for treatment options, which can win the race against new emerging variants of concern. Here, we describe a novel immunotherapeutic drug based on the SARS-CoV-2 entry receptor ACE2 and provide experimental evidence that it cannot only be used for (i) neutralization of SARS-CoV-2 in vitro and in SARS-CoV-2 infected animal models, but also for (ii) clearance of virus infected cells. For the latter purpose, we equipped the ACE2 decoy with an epitope tag. Thereby, we converted it to an adapter molecule which we successfully applied in the modular platforms UniMAB and UniCAR for retargeting of either unmodified or universal chimeric antigen receptor modified immune effector cells. Our results pave the way for a clinical application of this novel ACE2 decoy, which will clearly improve COVID-19 treatment.
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- 2023
4. Phenotypic and genetic spectrum of ATP6V1A encephalopathy:a disorder of lysosomal homeostasis
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Guerrini, R. (Renzo), Mei, D. (Davide), Kerti-Szigeti, K. (Katalin), Pepe, S. (Sara), Koenig, M. K. (Mary Kay), Von Allmen, G. (Gretchen), Cho, M. T. (Megan T), McDonald, K. (Kimberly), Baker, J. (Janice), Bhambhani, V. (Vikas), Powis, Z. (Zöe), Rodan, L. (Lance), Nabbout, R. (Rima), Barcia, G. (Giulia), Rosenfeld, J. A. (Jill A), Bacino, C. A. (Carlos A), Mignot, C. (Cyril), Power, L. H. (Lillian H), Harris, C. J. (Catharine J), Marjanovic, D. (Dragan), Møller, R. S. (Rikke S), Hammer, T. B. (Trine B), T. D. (The DDD Study), Keski Filppula, R. (Riikka), Vieira, P. (Päivi), Hildebrandt, C. (Clara), Sacharow, S. (Stephanie), U. D. (Undiagnosed Diseases Network), Maragliano, L. (Luca), Benfenati, F. (Fabio), Lachlan, K. (Katherine), Benneche, A. (Andreas), Petit, F. (Florence), de Sainte Agathe, J. M. (Jean Madeleine), Hallinan, B. (Barbara), Si, Y. (Yue), Wentzensen, I. M. (Ingrid M), Zou, F. (Fanggeng), Narayanan, V. (Vinodh), Matsumoto, N. (Naomichi), Boncristiano, A. (Alessandra), la Marca, G. (Giancarlo), Kato, M. (Mitsuhiro), Anderson, K. (Kristin), Barba, C. (Carmen), Sturiale, L. (Luisa), Garozzo, D. (Domenico), Bei, R. (Roberto), A. c. (ATP6V1A collaborators), Masuelli, L. (Laura), Conti, V. (Valerio), Novarino, G. (Gaia), and Fassio, A. (Anna)
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developmental delay ,epileptic encephalopathy ,lysosomal disorder ,ATP6V1A ,progressive brain atrophy - Abstract
Vacuolar-type H⁺-ATPase (V-ATPase) is a multimeric complex present in a variety of cellular membranes that acts as an ATP-dependent proton pump and plays a key role in pH homeostasis and intracellular signalling pathways. In humans, 22 autosomal genes encode for a redundant set of subunits allowing the composition of diverse V-ATPase complexes with specific properties and expression. Sixteen subunits have been linked to human disease. Here we describe 26 patients harbouring 20 distinct pathogenic de novo missense ATP6V1A variants, mainly clustering within the ATP synthase α/β family-nucleotide-binding domain. At a mean age of 7 years (extremes: 6 weeks, youngest deceased patient to 22 years, oldest patient) clinical pictures included early lethal encephalopathies with rapidly progressive massive brain atrophy, severe developmental epileptic encephalopathies and static intellectual disability with epilepsy. The first clinical manifestation was early hypotonia, in 70%; 81% developed epilepsy, manifested as developmental epileptic encephalopathies in 58% of the cohort and with infantile spasms in 62%; 63% of developmental epileptic encephalopathies failed to achieve any developmental, communicative or motor skills. Less severe outcomes were observed in 23% of patients who, at a mean age of 10 years and 6 months, exhibited moderate intellectual disability, with independent walking and variable epilepsy. None of the patients developed communicative language. Microcephaly (38%) and amelogenesis imperfecta/enamel dysplasia (42%) were additional clinical features. Brain MRI demonstrated hypomyelination and generalized atrophy in 68%. Atrophy was progressive in all eight individuals undergoing repeated MRIs. Fibroblasts of two patients with developmental epileptic encephalopathies showed decreased LAMP1 expression, Lysotracker staining and increased organelle pH, consistent with lysosomal impairment and loss of V-ATPase function. Fibroblasts of two patients with milder disease, exhibited a different phenotype with increased Lysotracker staining, decreased organelle pH and no significant modification in LAMP1 expression. Quantification of substrates for lysosomal enzymes in cellular extracts from four patients revealed discrete accumulation. Transmission electron microscopy of fibroblasts of four patients with variable severity and of induced pluripotent stem cell-derived neurons from two patients with developmental epileptic encephalopathies showed electron-dense inclusions, lipid droplets, osmiophilic material and lamellated membrane structures resembling phospholipids. Quantitative assessment in induced pluripotent stem cell-derived neurons identified significantly smaller lysosomes. ATP6V1A-related encephalopathy represents a new paradigm among lysosomal disorders. It results from a dysfunctional endo-lysosomal membrane protein causing altered pH homeostasis. Its pathophysiology implies intracellular accumulation of substrates whose composition remains unclear, and a combination of developmental brain abnormalities and neurodegenerative changes established during prenatal and early postanal development, whose severity is variably determined by specific pathogenic variants.
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- 2022
5. Practice Parameter: The Evaluation of Distal Symmetric Polyneuropathy: The Role ofLaboratory and Genetic Testing (An Evidence-Based Review): Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation
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England, J.D., Gronseth, G.S., Franklin, G., Carter, G.T., Kinsella, L.J., Cohen, J.A., Asbury, A.K., Szigeti, K., Lupski, J.R., Latov, N., Lewis, R.A., Low, P.A., Fisher, M.A., Herrmann, D.N., Howard, J.F., Lauria, G., Miller, R.G., Polydefkis, M., and Sumner, A.J.
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- 2009
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6. Practice Parameter: The Evaluation of Distal Symmetric Polyneuropathy: The Role of Autonomic Testing, Nerve Biopsy, and Skin Biopsy (An Evidence-Based Review): Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation
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England, J.D., Gronseth, G.S., Franklin, G., Carter, G.T., Kinsella, L.J., Cohen, J.A., Asbury, A.K., Szigeti, K., Lupski, J.R., Latov, N., Lewis, R.A., Low, P.A., Fisher, M.A., Herrmann, D., Howard, J.F., Lauria, G., Miller, R.G., Polydefkis, M., and Sumner, A.J.
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- 2009
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7. Research and Technology in Neurocritical Care
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Wijman, C. A. C., Smirnakis, S. M., Vespa, P., Szigeti, K., Ziai, W. C., Ning, M. M., Rosand, J., Hanley, D. F., Geocadin, R., Hall, C., Le Roux, P. D., Suarez, J. I., Zaidat, O. O., and For the First Neurocritical Care Research Conference Investigators
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- 2012
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8. The anti-leukemic agent dasatinib inhibits in vivo inflammatory responses in experimental mice: 324
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Futosi, K., Németh, T., Szigeti, K., Máthé, D., and Mócsai, A.
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- 2012
9. Exercise before ALPPS Improves the Functional Regeneration of the Liver in Experimental Model
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Daradics, N., Levay, K., Horvath, I., Domokos, M., Szigeti, K., Szijarto, A., and Fulop, A.
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- 2023
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10. Evaluation of distal symmetric polyneuropathy: The role of autonomic testing, nerve biopsy, and skin biopsy (an evidence-based review)
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England, J. D., Gronseth, G. S., Franklin, G., Carter, G. T., Kinsella, L. J., Cohen, J. A., Asbury, A. K., Szigeti, K., Lupski, J. R., Latov, N., Lewis, R. A., Low, P. A., Fisher, M. A., Herrmann, D., Howard, J. F., Lauria, G., Miller, R. G., Polydefkis, M., and Sumner, A. J.
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- 2009
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11. Evaluation of distal symmetric polyneuropathy: The role of laboratory and genetic testing (an evidence-based review)
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England, J. D., Gronseth, G. S., Franklin, G., Carter, G. T., Kinsella, L. J., Cohen, J. A., Asbury, A. K., Szigeti, K., Lupski, J. R., Latov, N., Lewis, R. A., Low, P. A., Fisher, M. A., Herrmann, D., Howard, J. F., Lauria, G., Miller, R. G., Polydefkis, M., and Sumner, A. J.
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- 2009
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12. Interstitial deletion of 10p and atrial septal defect in DiGeorge 2 syndrome
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Yatsenko, S A, Yatsenko, A N, Szigeti, K, Craigen, W J, Stankiewicz, P, Cheung, S W, and Lupski, J R
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- 2004
13. MNGIE with lack of skeletal muscle involvement and a novel TP splice site mutation
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Szigeti, K, Wong, L-J C, Perng, C-L, Saifi, G M, Eldin, K, Adesina, A M, Cass, D L, Hirano, M, Lupski, J R, and Scaglia, F
- Published
- 2004
14. Al(OH)3 facilitated synthesis of water-soluble, magnetic, radiolabelled and fluorescent hydroxyapatite nanoparticles† †Electronic supplementary information (ESI) available: Conjugation of NPs with dyes, radiolabelling for NPs, NMR spectra, XRD, IR, zeta potential, DLS size distribution, TEM images and TGA data of NPs, fluorescent images of NPs. See DOI: 10.1039/c5cc02259b Click here for additional data file
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Cui, X., Green, M. A., Blower, P. J., Zhou, D., Yan, Y., Zhang, W., Djanashvili, K., Mathe, D., Veres, D. S., and Szigeti, K.
- Subjects
Fluorine Radioisotopes ,Molecular Structure ,Water ,Aluminum Hydroxide ,equipment and supplies ,digestive system ,Chemistry ,Magnetics ,Durapatite ,Microscopy, Electron, Transmission ,Solubility ,Nanoparticles ,human activities ,Fluorescent Dyes - Abstract
Radiolabelling, magnetic and fluorescent properties are incorporated in one single Fe3O4@HA nanoparticle with potential application as trimodal probes., Magnetic and fluorescent hydroxyapatite nanoparticles were synthesised using Al(OH)3-stabilised MnFe2O4 or Fe3O4 nanoparticles as precursors. They were readily and efficiently radiolabelled with 18F. Bisphosphonate polyethylene glycol polymers were utilised to endow the nanoparticles with excellent colloidal stability in water and to incorporate cyclam for high affinity labelling with 64Cu.
- Published
- 2015
15. Detection of Radiation-Induced Changes in Healthy Mouse Brain Using Diffusion-weighted MRI and 18F-FDG-PET
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Máthé, D., Kovács, N., Szigeti, K., and Bergmann, R.
- Abstract
Aim: To evaluate in vivo longitudinal PET and MRI parameter changes in images can be sensitively read out with radiation‐induced tissue changes in healthy mouse brain. Materials and Methods: We irradiated a group of c57bl6 mice (n=6) with 5 Gy and another (n=6) with 20 Gy in the left hemisphere using an X‐ray tube (Yxlon Maxishot). Animals were imaged before, and 3‐7‐30 and 60 days post irradiation. For 18F‐Fluoro‐Deoxy‐Glucose (FDG) PET we injected 10 to 15 MBq FDG iv. PET and MR imaging was performed subsequently with a Mediso nanoScan PET/CT and a Bruker Biospec 7T MRI system. Arterial spin labeling (ASL) was probed using a FAIR‐EPI sequence. For DWI, a SE EPI‐based sequence was used. Standardized brain FDG‐PET uptake (SUV) values were determined for righ/left hemispheres and cerebellum using Rover software. ASL data and water apparent diffusion coefficients (ADC) were read out using a Matlab code after atlas coregistration. We determined statistical differences between readout results in both groups and between the time points in the same groups in these regions. Results: There was no significant difference in ASL values neither in ADC values in the 5 Gy group compared to baseline or between time points. If both hemisphere’s respective VOI data were taken into account we could observe significant ADC differences between early (3 days) and late (30 to 60 days) changes in almost all VOIs of the brains. Using hemisphere VOI PET data we see a change at 7 days and 60 days both compared to baseline and all other time points in both groups by a decrease in SUVs of both hemispheres at Day 7 and and an increase at Day 60. Conclusion: In our study ASL had no readout value on radiation‐induced changes. Using ADC maps, as early as 3 days and after one month post irradiation the late changes are visible throughout the brain. FDG‐PET provided us with a readable change at day 7. The direction of increased metabolism in the hemisphere 60 days read out with PET coregisters with the increase in ADC values at Day 60. These late changes are possibly due to second‐phase neuro‐inflammation and cell content increase in accordance with PET imaging results. Combined DWI MR/FDG PET is a promising means for radiation therapy side effect follow‐up. This research reading to these results has received funding from the European Union Seventh Framework Programme FP7/2007‐2013 under grant agreement n° 305311/INSERT.
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- 2014
16. PO-275 Gene expression and splicing variants changes in colorectal cancer related cell function pathways
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Wichmann, B., Nagy, Z., Barták, B., Galamb, O., Kalmár, A., Zsigrai, S., Szigeti, K., Igaz, P., Tulassay, Z., and Molnár, B.
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- 2018
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17. PO-378 Systematic miRNA expression changes in human colorectal cancer development and in animal model
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Nagy, Z.B., Bartak, B., Kalmar, A., Wichmann, B., Galamb, O., Zsigrai, S., Szigeti, K., Igaz, P., Tulassay, Z., and Molnar, B.
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- 2018
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18. PO-377 Whole transcriptome analysis reveals colorectal cancer-associated long non-coding RNAs including UCA1 already dysregulated in colorectal adenomas
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Kalmar, A., Nagy, Z.B., Galamb, O., Wichmann, B., Bartak, B.K., Valcz, G., Szigeti, K., Tulassay, Z., Igaz, P., and Molnar, B.
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- 2018
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19. In Vivo Imaging of Microglia Cells Activated by LPS-Induced Systemic Inflammation in Mouse
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Mathe, D., Futo, I., Veres, D., Horvath, I., Semjeni, M., Kovacs, N., Tóth, M., Bergmann, R. K., and Szigeti, K.
- Abstract
Introduction: The role of microglia cells in the pathogenesis of inflammations and chronic neurodegenerative disorders in the central nervous system (CNS) is an active research field in recent years. The ramified form of microglia cells is activated via inflammation markers (e.g. IL-1b, TNF-alpha). The activated form of microglia cells as a key player of the innate immune system in the CNS present MHC II and release antiinflammatory agents. The activation status of the microglial benzodiazepine (BZD) receptor system could be used to monitor the process of neuroinflammation. Methods: Healthy (n=6) and LPS induced inflamed (n=4) C57BL/6 mice were used. The activation of the microglia cells was induced by systemic injection of 0.3 g/bw kg lipopolysaccharide (LPS) 5h before the in vivo measurements. We used NanoSPECT/CT Plus and nanoScan PET/MRI (Mediso Ltd, Hungary) multimodal in vivo imaging systems. To detect dynamics and localization of microglia activation we used a micro dose partial inverse BZD agonist ( 125-I - Iomazenil). The change of the general metabolic state in the CNS was monitored by 18-F-FDG PET. 99m-Tc-HMPAO (hexamethylpropylene-amino-oxime) was used for the detection of altered regional cerebral perfusion. The segmentation of different mouse regions was first based on MRI measurements of the animals and for aims of standardization coregistered with an MRI atlas. Results: FDG uptake was increased by systemic LPS in every region of the brain (p
- Published
- 2013
20. Practice Parameter: Evaluation of distal symmetric polyneuropathy: Role of autonomic testing, nerve biopsy, and skin biopsy (an evidence-based review): Report of the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Academy of Physical Medicine and Rehabilitation
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Lauria, G., Miller, R. G., Asbury, A. K., Fisher, M. A., Lewis, R. A., Carter, G. T., Szigeti, K., Sumner, A. J., England, J. D., Latov, N., Herrmann, D. N., Cohen, J. A., Lupski, J. R., Gronseth, G. S., Polydefkis, M., Kinsella, L. J., Low, P. A., Franklin, G., and Howard, J. F.
- Abstract
BACKGROUND: Distal symmetric polyneuropathy (DSP) is the most common variety of neuropathy. Since the evaluation of this disorder is not standardized, the available literature was reviewed to provide evidence-based guidelines regarding the role of autonomic testing, nerve biopsy, and skin biopsy for the assessment of polyneuropathy. METHODS: A literature review using MEDLINE, EMBASE, and Current Contents was performed to identify the best evidence regarding the evaluation of polyneuropathy published between 1980 and March 2007. Articles were classified according to a four-tiered level of evidence scheme and recommendations were based upon the level of evidence. RESULTS AND RECOMMENDATIONS: 1) Autonomic testing should be considered in the evaluation of patients with polyneuropathy to document autonomic nervous system dysfunction (Level B). Such testing should be considered especially for the evaluation of suspected autonomic neuropathy (Level B) and distal small fiber sensory polyneuropathy (SFSN) (Level C). A battery of validated tests is recommended to achieve the highest diagnostic accuracy (Level B). 2) Nerve biopsy is generally accepted as useful in the evaluation of certain neuropathies as in patients with suspected amyloid neuropathy, mononeuropathy multiplex due to vasculitis, or with atypical forms of chronic inflammatory demyelinating polyneuropathy (CIDP). However, the literature is insufficient to provide a recommendation regarding when a nerve biopsy may be useful in the evaluation of DSP (Level U). 3) Skin biopsy is a validated technique for determining intraepidermal nerve fiber density and may be considered for the diagnosis of DSP, particularly SFSN (Level C). There is a need for additional prospective studies to define more exact guidelines for the evaluation of polyneuropathy.
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- 2009
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21. Al(OH)3 facilitated synthesis of water-soluble, magnetic, radiolabelled and fluorescent hydroxyapatite nanoparticles.
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Cui, X., Green, M. A., Blower, P. J., Zhou, D., Yan, Y., Zhang, W., Djanashvili, K., Mathe, D., Veres, D. S., and Szigeti, K.
- Subjects
FLUORESCENCE ,HYDROXYAPATITE ,NANOPARTICLES ,CHEMICAL precursors ,POLYETHYLENE ,ETHYLENE glycol - Abstract
Magnetic and fluorescent hydroxyapatite nanoparticles were synthesised using Al(OH)
3 -stabilised MnFe2 O4 or Fe3 O4 nanoparticles as precursors. They were readily and efficiently radiolabelled with18 F. Bisphosphonate polyethylene glycol polymers were utilised to endow the nanoparticles with excellent colloidal stability in water and to incorporate cyclam for high affinity labelling with64 Cu. [ABSTRACT FROM AUTHOR]- Published
- 2015
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22. Genome-Wide Scan for Copy Number Variation Association with Biomarker Quantitative Trait Loci in Aging.
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Szigeti, K., Trummer, B., Lal, D., Doody, R.S., Yan, L., Liu, S., and Ma, C.
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DNA copy number variations , *BIOMARKERS , *AGING , *METALLOPROTEINASES , *PHENOTYPES - Abstract
Biomarkers are emerging as important tools in the detection and monitoring of various diseases. A major limitation and challenge to effectively utilize biomarker signals is the limited understanding of factors contributing to their variance. As genetic variation is a major contributor to phenotypic variation, exploring genetic contributions is of great importance. Copy number variants (CNVs) offer an alternative genomic framework to understand contributions to phenotypic variance. A copy-number variation genome-wide association study was performed using 116 serum inflammatory biomarkers as quantitative trait in elderly normal controls to test the hypothesis that CNVs contribute to the phenotypic heterogeneity of serum biomarkers. Three chromosomal regions were associated with four biomarkers in trans. Transforming growth factor alpha (TG-alpha) serum levels were associated with CNV dosage at chr11:5,788 kb, soluble levels of receptor for advanced glycation endproducts (sRAGE) was associated with CNV dosage at chr8:40,183 kb and both thrombospondin-1 and tissue inhibitor of metalloproteinase 1 (TIMP-1) were associated with CNV dosage at chr11:18,961 kb. The CNV at chr11:5,788 kb harbors 2 olfactory genes and the introns of Tripartite motif-containing (TRIM) gene cluster TRIM5&22 while the CNV at chr11:18,961 includes the Mas-related G-protein coupled receptor member X1. These trans associations may identify novel relationships in the relevant pathways and suggest that genetic variation can contribute to biomarker levels. The detected trans-association between MRGPRX1 and thrombospondin-1/TIMP-1 could implicate a novel pathway between pain/itching and inflammation. Cataloguing all genetic variants with an effect on biomarkers will serve as a tool to interpret epidemiological studies and establish causal relationships through Mendelian randomization. [ABSTRACT FROM AUTHOR]
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- 2014
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23. Genome-wide scan for copy number variation association with age at onset of Alzheimer's disease.
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Szigeti K, Lal D, Li Y, Doody RS, Wilhelmsen K, Yan L, Liu S, Ma C, Szigeti, Kinga, Lal, Deepika, Li, Yanchun, Doody, Rachelle S, Wilhelmsen, Kirk, Yan, Li, Liu, Song, Ma, Changxing, and Texas Alzheimer Research and Care Consortium
- Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disease with high prevalence, which imposes a substantial public health problem. The heritability of AD is estimated at 60-80% forecasting the potential use of genetic biomarkers for risk stratification in the future. Several large scale genome-wide association studies using high frequency variants identified 10 loci accountable for only a fraction of the estimated heritability. To find the missing heritability, systematic assessment of various mutational mechanisms needs to be performed. This copy number variation (CNV) genome-wide association study with age at onset (AAO) of AD identified 5 CNV regions that may contribute to the heritability of AAO of AD. Two CNV events are intragenic causing a deletion in CPNE4. In addition, to further study the mutational load at the 10 known susceptibility loci, CNVs overlapping with these loci were also catalogued. We identified rare small events overlapping CR1 and BIN1 in AD and normal controls with opposite CNV dosage. The CR1 events are consistent with previous reports. Larger scale studies with deeper genotyping specifically addressing CNV are needed to evaluate the significance of these findings. [ABSTRACT FROM AUTHOR]
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- 2013
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24. Olfactory copy number association with age at onset of Alzheimer disease.
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Shaw CA, Li Y, Wiszniewska J, Chasse S, Zaidi SN, Jin W, Dawson B, Wilhelmsen K, Lupski JR, Belmont JW, Doody RS, Szigeti K, Shaw, C A, Li, Y, Wiszniewska, J, Chasse, S, Zaidi, S N Y, Jin, W, Dawson, B, and Wilhelmsen, K
- Published
- 2011
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25. Practice Parameter: evaluation of distal symmetric polyneuropathy: role of autonomic testing, nerve biopsy, and skin biopsy (an evidence-based review). Report of the American Academy of Neurology, American Association of Neuromuscular and...
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England JD, Gronseth GS, Franklin G, Carter GT, Kinsella LJ, Cohen JA, Asbury AK, Szigeti K, Lupski JR, Latov N, Lewis RA, Low PA, Fisher MA, Herrmann DN, Howard JF Jr, Lauria G, Miller RG, Polydefkis M, and Sumner AJ
- Published
- 2009
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26. Practice Parameter: evaluation of distal symmetric polyneuropathy: role of laboratory and genetic testing (an evidence-based review). Report of the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine,...
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England JD, Gronseth GS, Franklin G, Carter GT, Kinsella LJ, Cohen JA, Asbury AK, Szigeti K, Lupski JR, Latov N, Lewis RA, Low PA, Fisher MA, Herrmann DN, Howard JF Jr, Lauria G, Miller RG, Polydefkis M, and Sumner AJ
- Published
- 2009
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27. MFN2 mutation distribution and genotype/phenotype correlation in Charcot-Marie-Tooth type 2.
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Verhoeven K, Claeys KG, Züchner S, Schröder JM, Weis J, Ceuterick C, Jordanova A, Nelis E, De Vriendt E, Van Hul M, Seeman P, Mazanec R, Saifi GM, Szigeti K, Mancias P, Butler IJ, Kochanski A, Ryniewicz B, De Bleecker J, and Van den Bergh P
- Published
- 2006
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28. T118M PMP22 mutation causes partial loss of function and HNPP-like neuropathy.
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Shy ME, Scavina MT, Clark A, Krajewski KM, Li J, Kamholz J, Kolodny E, Szigeti K, Fischer RA, Saifi GM, Scherer SS, and Lupski JR
- Published
- 2006
29. The donor chromosome breakpoint for a jumping translocation is associated with large low-copy repeats in 21q21.3.
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Stankiewicz, P., Cheung, S. W., Shaw, C. J., Saleki, R., Szigeti, K., and Lupski, J. R.
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CHROMOSOMES ,GENETICS ,FLUORESCENCE in situ hybridization ,GENOMES ,TELOMERES - Abstract
Jumping translocations (JTs) are very rare chromosome aberrations, usually identified in tumors. We report a constitutional JT between donor chromosome 21q21.3→qter and recipients 13qter and 18qter, resulting in an ∼15.5-Mb proximal deletion 21q in a girl with mild developmental delay and minor dysmorphic features. Using fluorescence in situ hybridization (FISH) studies, we identified an ∼550-kb complex inter- and intra-chromosomal low-copy repeat (LCR) adjacent to the 21q21.3 translocation breakpoint. On the recipient chromosomes 13qter and 18qter, the telomeric sequences TTAGGG were retained. Genotyping revealed that the deletion was of maternal origin. We propose that genome architecture involving LCRs may be a major mechanism responsible for the origin of jumping translocations. Copyright © 2003 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]
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- 2003
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30. P1056 NEW EXPERIENCES BY SCREENING FAMILY MEMBERS OF CHILDREN WITH COELIAC.
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Szigeti, K., Tari, B., Várkonyi, Á., and Túri, S.
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- 2004
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31. 695 - HISTOLOGICAL EVALUATION OF THE THERAPY IN DIABETIC ANGIOPATHY
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Vértesi, Cs., Szentivánvi, M., and Szigeti, K.
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- 1978
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32. CHRFAM7A diversifies human immune adaption through Ca 2+ signalling and actin cytoskeleton reorganization.
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Szigeti K, Ihnatovych I, Notari E, Dorn RP, Maly I, He M, Birkaya B, Prasad S, Byrne RS, Indurthi DC, Nimmer E, Heo Y, Retfalvi K, Chaves L, Sule N, Hofmann WA, Auerbach A, Wilding G, Bae Y, and Reynolds J
- Subjects
- Humans, Calcium metabolism, Immunity, Innate, Monocytes metabolism, Phagocytosis, rac1 GTP-Binding Protein metabolism, rac1 GTP-Binding Protein genetics, Actin Cytoskeleton metabolism, alpha7 Nicotinic Acetylcholine Receptor metabolism, alpha7 Nicotinic Acetylcholine Receptor genetics, Calcium Signaling, Induced Pluripotent Stem Cells metabolism, Induced Pluripotent Stem Cells cytology
- Abstract
Background: Human restricted genes contribute to human specific traits in the immune system. CHRFAM7A, a uniquely human fusion gene, is a negative regulator of the α7 nicotinic acetylcholine receptor (α7 nAChR), the highest Ca
2+ conductor of the ACh receptors implicated in innate immunity. Understanding the mechanism of how CHRFAM7A affects the immune system remains unexplored., Methods: Two model systems are used, human induced pluripotent stem cells (iPSC) and human primary monocytes, to characterize α7 nAChR function, Ca2+ dynamics and decoders to elucidate the pathway from receptor to phenotype., Findings: CHRFAM7A/α7 nAChR is identified as a hypomorphic receptor with mitigated Ca2+ influx and prolonged channel closed state. This shifts the Ca2+ reservoir from the extracellular space to the endoplasmic reticulum (ER) leading to Ca2+ dynamic changes. Ca2+ decoder small GTPase Rac1 is then activated, reorganizing the actin cytoskeleton. Observed actin mediated phenotypes include cellular adhesion, motility, phagocytosis and tissue mechanosensation., Interpretation: CHRFAM7A introduces an additional, human specific, layer to Ca2+ regulation leading to an innate immune gain of function. Through the actin cytoskeleton it drives adaptation to the mechanical properties of the tissue environment leading to an ability to invade previously immune restricted niches. Human genetic diversity predicts profound translational significance as its understanding builds the foundation for successful treatments for infectious diseases, sepsis, and cancer metastasis., Funding: This work is supported in part by the Community Foundation for Greater Buffalo (Kinga Szigeti) and in part by NIH grant R01HL163168 (Yongho Bae)., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)- Published
- 2024
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33. Human restricted CHRFAM7A gene increases brain efficiency.
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Jakimovski D, Dorn RP, Regno MD, Bartnik A, Bergsland N, Ramanathan M, Dwyer MG, Benedict RHB, Zivadinov R, and Szigeti K
- Abstract
Introduction: CHRFAM7A , a uniquely human fusion gene, has been associated with neuropsychiatric disorders including Alzheimer's disease, schizophrenia, anxiety, and attention deficit disorder. Understanding the physiological function of CHRFAM7A in the human brain is the first step to uncovering its role in disease. CHRFAM7A was identified as a potent modulator of intracellular calcium and an upstream regulator of Rac1 leading to actin cytoskeleton reorganization and a switch from filopodia to lamellipodia implicating a more efficient neuronal structure. We performed a neurocognitive-MRI correlation exploratory study on 46 normal human subjects to explore the effect of CHRFAM7A on human brain., Methods: Dual locus specific genotyping of CHRFAM7A was performed on genomic DNA to determine copy number (TaqMan assay) and orientation (capillary sequencing) of the CHRFAM7A alleles. As only the direct allele is expressed at the protein level and affects α7 nAChR function, direct allele carriers and non-carriers are compared for neuropsychological and MRI measures. Subjects underwent neuropsychological testing to measure motor (Timed 25-foot walk test, 9-hole peg test), cognitive processing speed (Symbol Digit Modalities Test), Learning and memory (California Verbal Learning Test immediate and delayed recall, Brief Visuospatial Memory Test-Revised immediate and delayed recall) and Beck Depression Inventory-Fast Screen, Fatigue Severity Scale. All subjects underwent MRI scanning on the same 3 T GE scanner using the same protocol. Global and tissue-specific volumes were determined using validated cross-sectional algorithms including FSL's Structural Image Evaluation, using Normalization, of Atrophy (SIENAX) and FSL's Integrated Registration and Segmentation Tool (FIRST) on lesion-inpainted images. The cognitive tests were age and years of education-adjusted using analysis of covariance (ANCOVA). Age-adjusted analysis of covariance (ANCOVA) was performed on the MRI data., Results: CHRFAM7A direct allele carrier and non-carrier groups included 33 and 13 individuals, respectively. Demographic variables (age and years of education) were comparable. CHRFAM7A direct allele carriers demonstrated an upward shift in cognitive performance including cognitive processing speed, learning and memory, reaching statistical significance in visual immediate recall (FDR corrected p = 0.018). The shift in cognitive performance was associated with smaller whole brain volume (uncorrected p = 0.046) and lower connectivity by resting state functional MRI in the visual network (FDR corrected p = 0.027) accentuating the cognitive findings., Conclusion: These data suggest that direct allele carriers harbor a more efficient brain consistent with the cellular biology of actin cytoskeleton and synaptic gain of function. Further larger human studies of cognitive measures correlated with MRI and functional imaging are needed to decipher the impact of CHRFAM7A on brain function., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Jakimovski, Dorn, Regno, Bartnik, Bergsland, Ramanathan, Dwyer, Benedict, Zivadinov and Szigeti.)
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- 2024
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34. Translational implications of CHRFAM7A, an elusive human-restricted fusion gene.
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Ihnatovych I, Saddler RA, Sule N, and Szigeti K
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- Humans, Animals, Translational Research, Biomedical methods, alpha7 Nicotinic Acetylcholine Receptor genetics, alpha7 Nicotinic Acetylcholine Receptor metabolism
- Abstract
Genes restricted to humans may contribute to human-specific traits and provide a different context for diseases. CHRFAM7A is a uniquely human fusion gene and a negative regulator of the α7 nicotinic acetylcholine receptor (α7 nAChR). The α7 nAChR has been a promising target for diseases affecting cognition and higher cortical functions, however, the treatment effect observed in animal models failed to translate into human clinical trials. As CHRFAM7A was not accounted for in preclinical drug screens it may have contributed to the translational gap. Understanding the complex genetic architecture of the locus, deciphering the functional impact of CHRFAM7A on α7 nAChR neurobiology and utilizing human-relevant models may offer novel approaches to explore α7 nAChR as a drug target., (© 2024. The Author(s).)
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- 2024
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35. Radiolabeling of Platelets with 99m Tc-HYNIC-Duramycin for In Vivo Imaging Studies.
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Merkel K, Szöllősi D, Horváth I, Jezsó B, Baranyai Z, Szigeti K, Varga Z, Hegedüs I, Padmanabhan P, Gulyás B, Bergmann R, and Máthé D
- Subjects
- Mice, Humans, Animals, Tissue Distribution, Peptides metabolism, Tomography, Emission-Computed, Single-Photon methods, Bacteriocins metabolism
- Abstract
Following the in vivo biodistribution of platelets can contribute to a better understanding of their physiological and pathological roles, and nuclear imaging methods, such as single photon emission tomography (SPECT), provide an excellent method for that. SPECT imaging needs stable labeling of the platelets with a radioisotope. In this study, we report a new method to label platelets with
99m Tc, the most frequently used isotope for SPECT in clinical applications. The proposed radiolabeling procedure uses a membrane-binding peptide, duramycin. Our results show that duramycin does not cause significant platelet activation, and radiolabeling can be carried out with a procedure utilizing a simple labeling step followed by a size-exclusion chromatography-based purification step. The in vivo application of the radiolabeled human platelets in mice yielded quantitative biodistribution images of the spleen and liver and no accumulation in the lungs. The performed small-animal SPECT/CT in vivo imaging investigations revealed good in vivo stability of the labeling, which paves the way for further applications of99m Tc-labeled-Duramycin in platelet imaging.- Published
- 2023
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36. Correction: Synthesis and preclinical application of a Prussian blue-based dual fluorescent and magnetic contrast agent (CA).
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Hegedűs N, Forgách L, Kiss B, Varga Z, Jezsó B, Horváth I, Kovács N, Hajdrik P, Padmanabhan P, Gulyás B, Szigeti K, and Máthé D
- Abstract
[This corrects the article DOI: 10.1371/journal.pone.0264554.]., (Copyright: © 2023 Hegedűs et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
- Published
- 2023
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37. Development of Polymer-Encapsulated, Amine-Functionalized Zinc Ferrite Nanoparticles as MRI Contrast Agents.
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Ilosvai ÁM, Forgách L, Kovács N, Heydari F, Szigeti K, Máthé D, Kristály F, Daróczi L, Kaleta Z, Viskolcz B, Nagy M, and Vanyorek L
- Subjects
- Mice, Animals, Polymers, Amines, Zinc, Tissue Distribution, Magnetic Resonance Imaging methods, Ferric Compounds, Pharmaceutical Preparations, Contrast Media, Nanoparticles
- Abstract
The need for stable and well-defined magnetic nanoparticles is constantly increasing in biomedical applications; however, their preparation remains challenging. We used two different solvothermal methods (12 h reflux and a 4 min microwave, MW) to synthesize amine-functionalized zinc ferrite (ZnFe
2 O4 -NH2 ) superparamagnetic nanoparticles. The morphological features of the two ferrite samples were the same, but the average particle size was slightly larger in the case of MW activation: 47 ± 14 nm (Refl.) vs. 63 ± 20 nm (MW). Phase identification measurements confirmed the exclusive presence of zinc ferrite with virtually the same magnetic properties. The Refl. samples had a zeta potential of -23.8 ± 4.4 mV, in contrast to the +7.6 ± 6.8 mV measured for the MW sample. To overcome stability problems in the colloidal phase, the ferrite nanoparticles were embedded in polyvinylpyrrolidone and could be easily redispersed in water. Two PVP-coated zinc ferrite samples were administered (1 mg/mL ZnFe2 O4 ) in X BalbC mice and were compared as contrast agents in magnetic resonance imaging (MRI). After determining the r1/r2 ratio, the samples were compared to other commercially available contrast agents. Consistent with other SPION nanoparticles, our sample exhibits a concentrated presence in the hepatic region of the animals, with comparable biodistribution and pharmacokinetics suspected. Moreover, a small dose of 1.3 mg/body weight kg was found to be sufficient for effective imaging. It should also be noted that no toxic side effects were observed, making ZnFe2 O4 -NH2 advantageous for pharmaceutical formulations.- Published
- 2023
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38. Molecular imaging of bacterial outer membrane vesicles based on bacterial surface display.
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Szöllősi D, Hajdrik P, Tordai H, Horváth I, Veres DS, Gillich B, Shailaja KD, Smeller L, Bergmann R, Bachmann M, Mihály J, Gaál A, Jezsó B, Barátki B, Kövesdi D, Bősze S, Szabó I, Felföldi T, Oszwald E, Padmanabhan P, Gulyás BZ, Hamdani N, Máthé D, Varga Z, and Szigeti K
- Subjects
- Animals, Mice, Bacterial Outer Membrane metabolism, Tissue Distribution, Bacterial Outer Membrane Proteins metabolism, Molecular Imaging, Escherichia coli metabolism, Extracellular Vesicles metabolism
- Abstract
The important roles of bacterial outer membrane vesicles (OMVs) in various diseases and their emergence as a promising platform for vaccine development and targeted drug delivery necessitates the development of imaging techniques suitable for quantifying their biodistribution with high precision. To address this requirement, we aimed to develop an OMV specific radiolabeling technique for positron emission tomography (PET). A novel bacterial strain (E. coli BL21(DE3) ΔnlpI, ΔlpxM) was created for efficient OMV production, and OMVs were characterized using various methods. SpyCatcher was anchored to the OMV outer membrane using autotransporter-based surface display systems. Synthetic SpyTag-NODAGA conjugates were tested for OMV surface binding and
64 Cu labeling efficiency. The final labeling protocol shows a radiochemical purity of 100% with a ~ 29% radiolabeling efficiency and excellent serum stability. The in vivo biodistribution of OMVs labeled with64 Cu was determined in mice using PET/MRI imaging which revealed that the biodistribution of radiolabeled OMVs in mice is characteristic of previously reported data with the highest organ uptakes corresponding to the liver and spleen 3, 6, and 12 h following intravenous administration. This novel method can serve as a basis for a general OMV radiolabeling scheme and could be used in vaccine- and drug-carrier development based on bioengineered OMVs., (© 2023. The Author(s).)- Published
- 2023
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39. Neuronal actin cytoskeleton gain of function in the human brain.
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Szigeti K, Ihnatovych I, Rosas N, Dorn RP, Notari E, Cortes Gomez E, He M, Maly I, Prasad S, Nimmer E, Heo Y, Fuchsova B, Bennett DA, Hofmann WA, Pralle A, Bae Y, and Wang J
- Subjects
- Humans, Neurons metabolism, Actin Cytoskeleton metabolism, Actins metabolism, Gain of Function Mutation, Brain metabolism
- Abstract
Background: While advancements in imaging techniques have led to major strides in deciphering the human brain, successful interventions are elusive and represent some of the most persistent translational gaps in medicine. Human restricted CHRFAM7A has been associated with neuropsychiatric disorders., Methods: The physiological role of CHRFAM7A in human brain is explored using multiomics approach on 600 post mortem human brain tissue samples. The emerging pathways and mechanistic hypotheses are tested and validated in an isogenic hiPSC model of CHRFAM7A knock-in medial ganglionic eminence progenitors and neurons., Findings: CHRFAM7A is identified as a modulator of intracellular calcium dynamics and an upstream regulator of Rac1. Rac1 activation re-designs the actin cytoskeleton leading to dynamic actin driven remodeling of membrane protrusion and a switch from filopodia to lamellipodia. The reinforced cytoskeleton leads to an advantage to tolerate stiffer mechanical properties of the extracellular environment., Interpretation: CHRFAM7A modifies the actin cytoskeleton to a more dynamic and stiffness resistant state in an α7nAChR dependent manner. CHRFAM7A may facilitate neuronal adaptation to changes in the brain environment in physiological and pathological conditions contributing to risk or recovery. Understanding how CHRFAM7A affects human brain requires human studies in the areas of memory formation and erasure, cognitive reserve, and neuronal plasticity., Funding: This work is supported in part by the Community Foundation for Greater Buffalo (Kinga Szigeti). Also, in part by the International Society for Neurochemistry (ISN) and The Company of Biologists (Nicolas Rosas). ROSMAP is supported by NIA grants P30AG10161, P30AG72975, R01AG15819, R01AG17917. U01AG46152, and U01AG61356., Competing Interests: Declaration of interests The authors declare no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)
- Published
- 2023
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40. Erratum: 210 Preliminary Validation of the Arabic Global Neuropsychological Assessment (GNA) - ERRATUM.
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Gillies J, Olson L, Almukhtar R, Strohmeier A, Szigeti K, Schretlen D, Cadzow R, and Benedict R
- Abstract
[This corrects the article DOI: 10.1017/cts.2023.283.]., (© The Author(s) 2023.)
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- 2023
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41. A novel ACE2 decoy for both neutralization of SARS-CoV-2 variants and killing of infected cells.
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Kegler A, Drewitz L, Arndt C, Daglar C, Rodrigues Loureiro L, Mitwasi N, Neuber C, González Soto KE, Bartsch T, Baraban L, Ziehr H, Heine M, Nieter A, Moreira-Soto A, Kühne A, Drexler JF, Seliger B, Laube M, Máthé D, Pályi B, Hajdrik P, Forgách L, Kis Z, Szigeti K, Bergmann R, Feldmann A, and Bachmann M
- Subjects
- Animals, Humans, Angiotensin-Converting Enzyme 2, COVID-19 Drug Treatment, SARS-CoV-2, COVID-19
- Abstract
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to millions of infections and deaths worldwide. As this virus evolves rapidly, there is a high need for treatment options that can win the race against new emerging variants of concern. Here, we describe a novel immunotherapeutic drug based on the SARS-CoV-2 entry receptor ACE2 and provide experimental evidence that it cannot only be used for (i) neutralization of SARS-CoV-2 in vitro and in SARS-CoV-2-infected animal models but also for (ii) clearance of virus-infected cells. For the latter purpose, we equipped the ACE2 decoy with an epitope tag. Thereby, we converted it to an adapter molecule, which we successfully applied in the modular platforms UniMAB and UniCAR for retargeting of either unmodified or universal chimeric antigen receptor-modified immune effector cells. Our results pave the way for a clinical application of this novel ACE2 decoy, which will clearly improve COVID-19 treatment., Competing Interests: Author DM was employed by CROmed Translational Research Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kegler, Drewitz, Arndt, Daglar, Rodrigues Loureiro, Mitwasi, Neuber, González Soto, Bartsch, Baraban, Ziehr, Heine, Nieter, Moreira-Soto, Kühne, Drexler, Seliger, Laube, Máthé, Pályi, Hajdrik, Forgách, Kis, Szigeti, Bergmann, Feldmann and Bachmann.)
- Published
- 2023
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42. Possible use of Digital Variance Angiography in Liver Transarterial Chemoembolization: A Retrospective Observational Study.
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Lucatelli P, Rocco B, Ciaglia S, Teodoli L, Argirò R, Guiu B, Saba L, Vallati G, Spiliopoulos S, Patrone L, Gyánó M, Góg I, Osváth S, Szigeti K, Kiss JP, and Catalano C
- Subjects
- Humans, Male, Middle Aged, Aged, Female, Retrospective Studies, Angiography, Digital Subtraction methods, Carcinoma, Hepatocellular therapy, Liver Neoplasms diagnostic imaging, Liver Neoplasms therapy, Liver Neoplasms blood supply, Chemoembolization, Therapeutic methods
- Abstract
Purpose: Digital variance angiography (DVA), a recently developed image processing technology, provided higher contrast-to-noise ratio (CNR) and better image quality (IQ) during lower limb interventions than digital subtraction angiography (DSA). Our aim was to investigate whether this quality improvement can be observed also during liver transarterial chemoembolization (TACE)., Materials and Methods: We retrospectively compared the CNR and IQ parameters of DSA and DVA images from 25 patients (65% male, mean ± SD age: 67.5 ± 11.2 years) underwent TACE intervention at our institute. CNR was calculated on 50 images. IQ of every image set was evaluated by 5 experts using 4-grade Likert scales. Both single image evaluation and paired image comparison were performed in a blinded and randomized manner. The diagnostic value was evaluated based on the possibility to identify lesions and feeding arteries., Results: DVA provided significantly higher CNR (mean CNR
DVA /CNRDSA was 1.33). DVA images received significantly higher individual Likert score (mean ± SEM 3.34 ± 0,08 vs. 2.89 ± 0.11, Wilcoxon signed-rank p < 0.001) and proved to be superior also in paired comparisons (median comparison score 1.60 [IQR:2.40], one sample Wilcoxon p < 0.001 compared to equal quality level). DSA could not detect lesion and feeding artery in 28 and 36% of cases, and allowed clear detection only in 22% and 16%, respectively. In contrast, DVA failed only in 8 and 18% and clearly revealed lesions and feeding arteries in 32 and 26%, respectively., Conclusion: In our study, DVA provided higher quality images and better diagnostic insight than DSA; therefore, DVA could represent a useful tool in liver TACE interventions., Level of Evidence: III Non-consecutive study., (© 2023. The Author(s).)- Published
- 2023
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43. Radiation Exposure Reduction by Digital Variance Angiography in Lower Limb Angiography: A Randomized Controlled Trial.
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Sótonyi P, Berczeli M, Gyánó M, Legeza P, Mihály Z, Csobay-Novák C, Pataki Á, Juhász V, Góg I, Szigeti K, Osváth S, Kiss JP, and Nemes B
- Abstract
Background: digital variance angiography (DVA) provides higher image quality than digital subtraction angiography (DSA). This study investigates whether the quality reserve of DVA allows for radiation dose reduction during lower limb angiography (LLA), and compares the performance of two DVA algorithms., Methods: this prospective block-randomized controlled study enrolled 114 peripheral arterial disease patients undergoing LLA into normal dose (ND, 1.2 µGy/frame, n = 57) or low-dose (LD, 0.36 µGy/frame, n = 57) groups. DSA images were generated in both groups, DVA1 and DVA2 images were generated in the LD group. Total and DSA-related radiation dose area product (DAP) were analyzed. Image quality was assessed on a 5-grade Likert scale by six readers., Results: the total and DSA-related DAP were reduced by 38% and 61% in the LD group. The overall visual evaluation scores (median (IQR)) of LD-DSA (3.50 (1.17)) were significantly lower than the ND-DSA scores (3.83 (1.00), p < 0.001). There was no difference between ND-DSA and LD-DVA1 (3.83 (1.17)), but the LD-DVA2 scores were significantly higher (4.00 (0.83), p < 0.01). The difference between LD-DVA2 and LD-DVA1 was also significant ( p < 0.001)., Conclusions: DVA significantly reduced the total and DSA-related radiation dose in LLA, without affecting the image quality. LD-DVA2 images outperformed LD-DVA1, therefore DVA2 might be especially beneficial in lower limb interventions.
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- 2023
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44. Initial Experience Using Digital Variance Angiography in Context of Prostatic Artery Embolization in Comparison with Digital Subtraction Angiography.
- Author
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Alizadeh LS, Gyánó M, Góg I, Szigeti K, Osváth S, Kiss JP, Yel I, Koch V, Grünewald LD, Vogl TJ, and Booz C
- Subjects
- Aged, Humans, Male, Middle Aged, Angiography, Digital Subtraction methods, Arteries, Prostate diagnostic imaging, Retrospective Studies, Embolization, Therapeutic, Prostatic Hyperplasia
- Abstract
Rationale and Objectives: In previous clinical studies digital variance angiography (DVA) provided higher contrast-to-noise ratio (CNR) and better image quality in lower extremity angiography than digital subtraction angiography (DSA). Our aim was to investigate whether DVA has similar quality reserve in prostatic artery embolization (PAE). The secondary aim was to explore the potential advantages of the color-coded DVA (ccDVA) technology in PAE., Material and Methods: This retrospective study evaluated 108 angiographic acquisitions from 30 patients (mean ± SD age 68.0 ± 8.9, range 41-87) undergoing PAE between May and October 2020. DSA and DVA images were generated from the same unsubtracted acquisition, and their CNR was calculated. Visual evaluation of DVA and DSA image quality was performed by four experienced interventional radiologists in a randomized, blinded manner. The diagnostic value of DSA and ccDVA images was also evaluated using clinically relevant criteria (visibility of small [< 2.5 mm] and large arteries [> 2.5 mm], feeding arteries and tissue blush) in a paired comparison. Data were analysed by the Wilcoxon signed rank test or the binomial test, the interrater agreement was determined by the Kendall W or Fleiss Kappa analysis., Results: DVA provided 4.11 times higher median CNR than DSA (IQR: 1.72). The visual score of DVA images (4.40 ± 0.05) was significantly higher than that of DSA (3.39 ± 0.07, p < 0.001). The Kendall W analysis showed moderate but significant agreement (W
DVA = 0.38, WDSA = 0.53). The preference of ccDVA images was significantly higher in all criteria (63-89%) with an interrater agreement of 58-79%. The Fleiss Kappa range was 0.02-0.18, significant in all criteria except large vessels., Conclusion: Our data show that DVA provides higher CNR and better image quality in PAE. This quality reserve might be used for dose management (reduction of radiation dose and contrast agent volume), and ccDVA technology has also a high potential to assist PAE interventions in the future., (Copyright © 2022 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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45. A snapshot on Pestivirus A strains occurring in Central Europe.
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Kiss I, Szigeti K, Bányai K, and Dobos A
- Subjects
- Cattle, Animals, Genotype, Phylogeny, Diarrhea Virus 1, Bovine Viral genetics, Pestivirus genetics, Bovine Virus Diarrhea-Mucosal Disease, Diarrhea Viruses, Bovine Viral genetics, Cattle Diseases epidemiology
- Abstract
Seven dairy farms and a beef herd were sampled to reveal the presence of bovine viral diarrhoea viruses (BVDV) in the cattle population and provide information on the occurrence of the different genotypes of the virus in Hungary and Slovakia. Serum and organ samples, lung, and lymph nodes were collected and submitted to serological testing, RT-qPCR, nucleotide sequencing, and virus isolation. The detected viruses belonged to 1b, 1d, and 1f subtypes. No Pestivirus B was found. Serum samples of cows immunized with a live vaccine containing a subtype 1a virus (Oregon C24V) showed cross-neutralizing activity against the selected representative field strains of each subtype. An RT-qPCR, specific for the vaccine strain was developed to differentiate between vaccine and field viruses and was used to evaluate vaccine virus viraemia and shedding. The obtained data provide baseline information on the currently occurring BVDV genotypes in the region and contribute to elaborating efficient control strategies., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2022
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46. Physical prehabilitation improves the postoperative outcome of associating liver partition and portal vein ligation for staged hepatectomy in experimental model.
- Author
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Daradics N, Levay K, Horvath I, Kovacs N, Mathe D, Szigeti K, Szijarto A, and Fulop A
- Subjects
- Humans, Rats, Animals, Male, Hepatectomy methods, Portal Vein surgery, Ki-67 Antigen, Preoperative Exercise, Treatment Outcome, Rats, Wistar, Liver surgery, Liver Regeneration, Ligation, Models, Theoretical, Endotoxemia, Liver Neoplasms
- Abstract
Aiming to improve the postoperative outcome of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), the effect of physical prehabilitation (PP) was investigated in experimental model. Male Wistar rats (n = 106) divided to PP and sedentary (S) groups underwent ALPPS. Changes in liver weight, Ki67 index and liver volume by magnetic resonance imaging (MRI) were evaluated. Liver function was assessed by laboratory parameters and
99m Tc-mebrofenin single-photon emission computed tomography (SPECT) hepatobiliary scintigraphy (HBS). Utilizing endotoxemia model mortality and septic parameters were investigated. Liver mass (p < 0.001), Ki67 index (p < 0.001) and MRI liver volume (p < 0.05) increased in the PP group compared to the S group. Both standard laboratory parameters (p < 0.001) and HBS (p < 0.05) showed enhanced liver function in the PP group compared to the S group. The vulnerability of animals improved in the PP group, as mortality decreased (p < 0.001), while septic laboratory parameters improved (p < 0.05) compared to the S group in the endotoxemia model. Our study demonstrated for the first time the beneficial role of PP on not only volumetric but also functional liver regeneration and postoperative vulnerability after ALLPS., (© 2022. The Author(s).)- Published
- 2022
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47. The Utilization of Physiologically Active Molecular Components of Grape Seeds and Grape Marc.
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Hegedüs I, Andreidesz K, Szentpéteri JL, Kaleta Z, Szabó L, Szigeti K, Gulyás B, Padmanabhan P, Budan F, and Máthé D
- Subjects
- Antioxidants pharmacology, Antiviral Agents analysis, Flavonoids pharmacology, Humans, Hypoglycemic Agents analysis, Polyphenols analysis, Polyphenols pharmacology, Polyphenols therapeutic use, Quercetin analysis, Resveratrol, Seeds chemistry, Catechin, Dendrimers, Vitis chemistry
- Abstract
Nutritional interventions may highly contribute to the maintenance or restoration of human health. Grapes ( Vitis vinifera ) are one of the oldest known beneficial nutritional components of the human diet. Their high polyphenol content has been proven to enhance human health beyond doubt in statistics-based public health studies, especially in the prevention of cardiovascular disease and cancer. The current review concentrates on presenting and classifying polyphenol bioactive molecules (resveratrol, quercetin, catechin/epicatechin, etc.) available in high quantities in Vitis vinifera grapes or their byproducts. The molecular pathways and cellular signaling cascades involved in the effects of these polyphenol molecules are also presented in this review, which summarizes currently available in vitro and in vivo experimental literature data on their biological activities mostly in easily accessible tabular form. New molecules for different therapeutic purposes can also be synthesized based on existing polyphenol compound classes available in high quantities in grape, wine, and grape marc. Therefore an overview of these molecular structures is provided. Novel possibilities as dendrimer nanobioconjugates are reviewed, too. Currently available in vitro and in vivo experimental literature data on polyphenol biological activities are presented in easily accessible tabular form. The scope of the review details the antidiabetic, anticarcinogenic, antiviral, vasoprotective, and neuroprotective roles of grape-origin flavonoids. The novelty of the study lies in the description of the processing of agricultural by-products (grape seeds and skins) of industrial relevance, and the detailed description of the molecular mechanisms of action. In addition, the review of the clinical therapeutic applications of polyphenols is unique as no summary study has yet been done.
- Published
- 2022
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48. Phenotypic and genetic spectrum of ATP6V1A encephalopathy: a disorder of lysosomal homeostasis.
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Guerrini R, Mei D, Kerti-Szigeti K, Pepe S, Koenig MK, Von Allmen G, Cho MT, McDonald K, Baker J, Bhambhani V, Powis Z, Rodan L, Nabbout R, Barcia G, Rosenfeld JA, Bacino CA, Mignot C, Power LH, Harris CJ, Marjanovic D, Møller RS, Hammer TB, Keski Filppula R, Vieira P, Hildebrandt C, Sacharow S, Maragliano L, Benfenati F, Lachlan K, Benneche A, Petit F, de Sainte Agathe JM, Hallinan B, Si Y, Wentzensen IM, Zou F, Narayanan V, Matsumoto N, Boncristiano A, la Marca G, Kato M, Anderson K, Barba C, Sturiale L, Garozzo D, Bei R, Masuelli L, Conti V, Novarino G, and Fassio A
- Subjects
- Adenosine Triphosphate, Atrophy, Child, Homeostasis, Humans, Infant, Lysosomes, Phenotype, Brain Diseases, Epilepsy, Intellectual Disability, Spasms, Infantile, Vacuolar Proton-Translocating ATPases
- Abstract
Vacuolar-type H+-ATPase (V-ATPase) is a multimeric complex present in a variety of cellular membranes that acts as an ATP-dependent proton pump and plays a key role in pH homeostasis and intracellular signalling pathways. In humans, 22 autosomal genes encode for a redundant set of subunits allowing the composition of diverse V-ATPase complexes with specific properties and expression. Sixteen subunits have been linked to human disease. Here we describe 26 patients harbouring 20 distinct pathogenic de novo missense ATP6V1A variants, mainly clustering within the ATP synthase α/β family-nucleotide-binding domain. At a mean age of 7 years (extremes: 6 weeks, youngest deceased patient to 22 years, oldest patient) clinical pictures included early lethal encephalopathies with rapidly progressive massive brain atrophy, severe developmental epileptic encephalopathies and static intellectual disability with epilepsy. The first clinical manifestation was early hypotonia, in 70%; 81% developed epilepsy, manifested as developmental epileptic encephalopathies in 58% of the cohort and with infantile spasms in 62%; 63% of developmental epileptic encephalopathies failed to achieve any developmental, communicative or motor skills. Less severe outcomes were observed in 23% of patients who, at a mean age of 10 years and 6 months, exhibited moderate intellectual disability, with independent walking and variable epilepsy. None of the patients developed communicative language. Microcephaly (38%) and amelogenesis imperfecta/enamel dysplasia (42%) were additional clinical features. Brain MRI demonstrated hypomyelination and generalized atrophy in 68%. Atrophy was progressive in all eight individuals undergoing repeated MRIs. Fibroblasts of two patients with developmental epileptic encephalopathies showed decreased LAMP1 expression, Lysotracker staining and increased organelle pH, consistent with lysosomal impairment and loss of V-ATPase function. Fibroblasts of two patients with milder disease, exhibited a different phenotype with increased Lysotracker staining, decreased organelle pH and no significant modification in LAMP1 expression. Quantification of substrates for lysosomal enzymes in cellular extracts from four patients revealed discrete accumulation. Transmission electron microscopy of fibroblasts of four patients with variable severity and of induced pluripotent stem cell-derived neurons from two patients with developmental epileptic encephalopathies showed electron-dense inclusions, lipid droplets, osmiophilic material and lamellated membrane structures resembling phospholipids. Quantitative assessment in induced pluripotent stem cell-derived neurons identified significantly smaller lysosomes. ATP6V1A-related encephalopathy represents a new paradigm among lysosomal disorders. It results from a dysfunctional endo-lysosomal membrane protein causing altered pH homeostasis. Its pathophysiology implies intracellular accumulation of substrates whose composition remains unclear, and a combination of developmental brain abnormalities and neurodegenerative changes established during prenatal and early postanal development, whose severity is variably determined by specific pathogenic variants., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2022
- Full Text
- View/download PDF
49. Synthesis and preclinical application of a Prussian blue-based dual fluorescent and magnetic contrast agent (CA).
- Author
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Hegedűs N, Forgách L, Kiss B, Varga Z, Jezsó B, Horváth I, Kovács N, Hajdrik P, Padmanabhan P, Gulyás B, Szigeti K, and Máthé D
- Subjects
- Animals, Coloring Agents, Ferrocyanides chemistry, Iron, Magnetic Resonance Imaging methods, Mice, Tissue Distribution, Contrast Media chemistry, Nanoparticles chemistry
- Abstract
The aim of this study was to develop and characterize a Prussian Blue based biocompatible and chemically stable T1 magnetic resonance imaging (MRI) contrast agent with near infrared (NIR) optical contrast for preclinical application. The physical properties of the Prussian blue nanoparticles (PBNPs) (iron (II); iron (III);octadecacyanide) were characterized with dynamic light scattering (DLS), zeta potential measurement, atomic force microscopy (AFM), and transmission electron microscopy (TEM). In vitro contrast enhancement properties of PBNPs were determined by MRI. In vivo T1-weighted contrast of the prepared PBNPs was investigated by MRI and optical imaging modality after intravenous administration into NMRI-Foxn1 nu/nu mice. The biodistribution studies showed the presence of PBNPs predominantly in the cardiovascular system. Briefly, in this paper we show a novel approach for the synthesis of PBNPs with enhanced iron content for T1 MRI contrast. This newly synthetized PBNP platform could lead to a new diagnostic agent, replacing the currently used Gadolinium based substances., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2022
- Full Text
- View/download PDF
50. 3D culturing of human pluripotent stem cells-derived endothelial cells for vascular regeneration.
- Author
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Gara E, Zucchelli E, Nemes A, Jakus Z, Ajtay K, Kemecsei É, Kiszler G, Hegedűs N, Szigeti K, Földes I, Árvai K, Kósa J, Kolev K, Komorowicz E, Padmanabhan P, Maurovich-Horvat P, Dósa E, Várady G, Pólos M, Hartyánszky I, Harding SE, Merkely B, Máthé D, Szabó G, Radovits T, and Földes G
- Subjects
- Animals, Blood Vessel Prosthesis, Cell Differentiation, Dogs, Endothelial Cells metabolism, Humans, Rats, Induced Pluripotent Stem Cells metabolism, Pluripotent Stem Cells
- Abstract
Rationale: Human induced pluripotent stem cell-derived endothelial cells can be candidates for engineering therapeutic vascular grafts. Methods: Here, we studied the role of three-dimensional culture on their characteristics and function both in vitro and in vivo . Results: We found that differentiated hPSC-EC can re-populate decellularized biomatrices; they remain viable, undergo maturation and arterial/venous specification. Human PSC-EC develop antifibrotic, vasoactive and anti-inflammatory properties during recellularization. In vivo , a robust increase in perfusion was detected at the engraftment sites after subcutaneous implantation of an hPSC-EC-laden hydrogel in rats. Histology confirmed survival and formation of capillary-like structures, suggesting the incorporation of hPSC-EC into host microvasculature. In a canine model, hiPSC-EC-seeded onto decellularised vascular segments were functional as aortic grafts. Similarly, we showed the retention and maturation of hiPSC-EC and dynamic remodelling of the vessel wall with good maintenance of vascular patency. Conclusions: A combination of hPSC-EC and biomatrices may be a promising approach to repair ischemic tissues., Competing Interests: Competing Interests: DM is managing director, CROmed Research Ltd, grant-in-aid of Mediso Ltd. by providing nanoScan PET-MRI instrument usage time., (© The author(s).)
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- 2022
- Full Text
- View/download PDF
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