| 1. |
- Bastard, P, et al.
(author)
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Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1
- 2021
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In: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 218:7
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Journal article (peer-reviewed)abstract
- Patients with biallelic loss-of-function variants of AIRE suffer from autoimmune polyendocrine syndrome type-1 (APS-1) and produce a broad range of autoantibodies (auto-Abs), including circulating auto-Abs neutralizing most type I interferons (IFNs). These auto-Abs were recently reported to account for at least 10% of cases of life-threatening COVID-19 pneumonia in the general population. We report 22 APS-1 patients from 21 kindreds in seven countries, aged between 8 and 48 yr and infected with SARS-CoV-2 since February 2020. The 21 patients tested had auto-Abs neutralizing IFN-α subtypes and/or IFN-ω; one had anti–IFN-β and another anti–IFN-ε, but none had anti–IFN-κ. Strikingly, 19 patients (86%) were hospitalized for COVID-19 pneumonia, including 15 (68%) admitted to an intensive care unit, 11 (50%) who required mechanical ventilation, and four (18%) who died. Ambulatory disease in three patients (14%) was possibly accounted for by prior or early specific interventions. Preexisting auto-Abs neutralizing type I IFNs in APS-1 patients confer a very high risk of life-threatening COVID-19 pneumonia at any age.
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| 4. |
- Ahlgren, Sara, et al.
(author)
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Targeting of HER2-expressing tumors with a site-specifically 99mTc-labeled recombinant affibody molecule, ZHER2:2395, with C-terminally engineered cysteine
- 2009
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In: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 50:5, s. 781-789
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Journal article (peer-reviewed)abstract
- The detection of human epidermal growth factor receptor type 2 (HER2) expression in malignant tumors provides important information influencing patient management. Radionuclide in vivo imaging of HER2 may permit the detection of HER2 in both primary tumors and metastases by a single noninvasive procedure. Small (7 kDa) high-affinity anti-HER2 Affibody molecules may be suitable tracers for SPECT visualization of HER2-expressing tumors. The use of generator-produced (99m)Tc as a label would facilitate the prompt translation of anti-HER2 Affibody molecules into use in clinics. METHODS: A C-terminal cysteine was introduced into the Affibody molecule Z(HER2:342) to enable site-specific labeling with (99m)Tc. Two recombinant variants, His(6)-Z(HER2:342)-Cys (dissociation constant [K(D)], 29 pM) and Z(HER2:2395)-Cys, lacking a His tag (K(D), 27 pM), were labeled with (99m)Tc in yields exceeding 90%. The binding specificity and the cellular processing of Affibody molecules were studied in vitro. Biodistribution and gamma-camera imaging studies were performed in mice bearing HER2-expressing xenografts. RESULTS: (99m)Tc-His(6)-Z(HER2:342)-Cys was capable of targeting HER2-expressing SKOV-3 xenografts in SCID mice, but the liver radioactivity uptake was high. A series of comparative biodistribution experiments indicated that the presence of the His tag caused elevated accumulation in the liver. (99m)Tc-Z(HER2:2395)-Cys, not containing a His tag, showed low uptake in the liver and high and specific uptake in HER2-expressing xenografts. Four hours after injection, the radioactivity uptake values (percentage of injected activity per gram of tissue [%IA/g]) were 6.9 +/- 2.5 (mean +/- SD) %IA/g in LS174T xenografts (moderate level of HER2 expression) and 15 +/- 3 %IA/g in SKOV-3 xenografts (high level of HER2 expression). The corresponding tumor-to-blood ratios were 88 +/- 24 and 121 +/- 24, respectively. Both LS174T and SKOV-3 xenografts were clearly visualized with a clinical gamma-camera 1 h after injection of (99m)Tc-Z(HER2:2395)-Cys. CONCLUSION: The Affibody molecule (99m)Tc-Z(HER2:2395)-Cys is a promising tracer for SPECT visualization of HER2-expressing tumors.
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| 5. |
- Bragina, O. D., et al.
(author)
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Possibilities of radionuclide diagnostics of Her2-positive breast cancer using technetium-99m-labeled target molecules : the first experience of clinical use
- 2021
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In: Bûlleten' sibirskoj mediciny. - : Siberian State Medical University. - 1682-0363 .- 1819-3684. ; 20:1, s. 23-30
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Journal article (peer-reviewed)abstract
- Background. The main purpose of the Her2/neu status determination in clinical practice is to determine the indications for the appointment of targeted therapy. The main methods for detecting the Her2/neu status are the immunohistochemical method (IHC) and the fluorescence in situ hybridization (FISH); however, despite their widespread use, they have a number of significant disadvantages. Over the past few years, radionuclide diagnostics using a new class of alternative scaffold proteins that meet all the requirements for optimal delivery of radionuclides to tumor cells has become widespread.Aim. To study the possibility of clinical use of a radiopharmaceutical based on technetium-99m-labeled target molecules for the diagnosis of breast cancer with the Her2/neu overexpression in humans.Materials and methods. The study included 11 patients with breast cancer (T1–4N0–2M0) before systemic therapy: 5 with Her2/neu overexpression; expression of the marker was not detected in 6. In all cases, morphologicaland immunohistochemical studies were performed. In case of Her2/neu 2+, FISH analysis was performed. The radiopharmaceutical was prepared immediately before administration, after which it was slowly injected intravenously into the patient. Scintigraphic studies in the “WholeBody” mode and SPECT of the chest organs were performed 2, 4, 6 and 24 hours after injection.Results. Radiochemical yield, radiochemical purity and activity before administration were (80 ± 4)%, (98 ± 1)% and (434 ± 19.5) MBq, respectively. The greatest uptake by normal organs was observed at a time interval of 6 hours in the kidneys and at a moderate activity in the liver and lungs at the same time interval. The organ with the highest absorbed dose was the kidneys; significant accumulation was also detected in the adrenal glands, gallbladder, liver, pancreas and spleen. The smallest accu mulation of the studied drug was observed in the brain (0.001 ± 0.000) mGy and skin (0.001 ± 0.000) mGy. The effective dose was (0.009 ± 0.002) mGy. The difference between tumors with positive and negative Her2-neu expression was found at all time points. In this case, the best indicator was determined after 2 hours of drug injection (р < 0.05).Conclusion. Based on the results obtained, it can be indicated that the investigated radiopharmaceutical can be considered as a new additional method for the diagnosis of Her2-positive breast tumors.
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| 6. |
- Hasnowo, Lutfi A., et al.
(author)
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Synthesis, I-123-Radiolabeling Optimization, and Initial Preclinical Evaluation of Novel Urea-Based PSMA Inhibitors with a Tributylstannyl Prosthetic Group in Their Structures
- 2023
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In: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 24:15
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Journal article (peer-reviewed)abstract
- Prostate-specific membrane antigen (PSMA) has been identified as a target for the development of theranostic agents. In our current work, we describe the design and synthesis of novel N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-(S)-L-lysine (DCL) urea-based PSMA inhibitors with a chlorine-substituted aromatic fragment at the lysine & epsilon;-nitrogen atom, a dipeptide including two phenylalanine residues in the L-configuration as the peptide fragment of the linker, and 3- or 4-(tributylstannyl)benzoic acid as a prosthetic group in their structures for radiolabeling. The standard compounds [I-127]PSMA-m-IB and [I-127]PSMA-p-IB for comparative and characterization studies were first synthesized using two alternative synthetic approaches. An important advantage of the alternative synthetic approach, in which the prosthetic group (NHS-activated esters of compounds) is first conjugated with the polypeptide sequence followed by replacement of the Sn(Bu)(3) group with radioiodine, is that the radionuclide is introduced in the final step of synthesis, thereby minimizing operating time with iodine-123 during the radiolabeling process. The obtained DCL urea-based PSMA inhibitors were radiolabeled with iodine-123. The radiolabeling optimization results showed that the radiochemical yield of [I-123]PSMA-p-IB was higher than that of [I-123]PSMA-m-IB, which were 74.9 & PLUSMN; 1.0% and 49.4 & PLUSMN; 1.2%, respectively. The radiochemical purity of [I-123]PSMA-p-IB after purification was greater than 99.50%. The initial preclinical evaluation of [I-123]PSMA-p-IB demonstrated a considerable affinity and specific binding to PC-3 PIP (PSMA-expressing cells) in vitro. The in vivo biodistribution of this new radioligand [I-123]PSMA-p-IB showed less accumulation than [Lu-177]Lu-PSMA-617 in several normal organs (liver, kidney, and bone). These results warrant further preclinical development, including toxicology evaluation and experiments in tumor-bearing mice.
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| 7. |
- Ivanov, I. I., et al.
(author)
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Investigation of catalytic hydrogen sensors with platinum group catalysts
- 2021
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In: Sensors and actuators. B, Chemical. - : Elsevier. - 0925-4005 .- 1873-3077. ; 346
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Journal article (peer-reviewed)abstract
- Environmental deterioration and limited resources of hydrocarbons push the development of alternative power sources. One of the most promising energy carriers is hydrogen. However, handling hydrogen is more hazardous than the use of hydrocarbons because it has a significantly wider flammable range. Thus the development of new sensors for preventing hydrogen leakage is the actual task of modern materials science and chemical engineering. In this work, the response of catalytic sensors to hydrogen with different catalysts of platinum group (Pt, Pd, Ir, Rh, Pt + Pd, Pt + Pd + Rh, Pt + Pd + Ir) in the pre-explosion concentration range is studied. Temperature dependencies of sensitivity are discussed. A hysteresis in sensor response is observed during the cycling of the supply voltage. This phenomenon can be explained by partial transformation of platinum group metal oxides into metallic phase at a temperature of more than 500 °C and reverse metal oxidation at temperatures less than 400 °C. It has been shown that the sensors with catalysts containing Ir and Rh demonstrate more preferable characteristics for practical applications. © 2021 Elsevier B.V.
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| 8. |
- Klaholz, B.P, Pape, T, Zavialov, A.V, Myasnikov, A.G., Orlova, E.V., Vestergaard, B, Ehrenberg, M and van Heel, M.
(author)
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Structure of the E.coli ribosomal termination complex with release factor 2
- 2003
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In: journal. - : Nature. ; 421, s. 90-94
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Journal article (peer-reviewed)
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| 9. |
- Klaholz, B.P., Pape, T.,. Zavialov, A.V., Myasnikov, A.G., Orlova, E.V., Vestergaard, B., Ehrenberg, M. and van Heel, M.
(author)
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. Structure of the E. coli ribosomal termination complex with release factor 2.
- 2003
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In: Nature. ; 421, s. 90-94
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Journal article (peer-reviewed)
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| 10. |
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