203Pb with High Specific Activity for Nuclear Medicine

The heavy metal pollution due to their industrial production, waste repository or accident as the cyanide spill in river Tisza in 2002, increase the scientific interest for using an ideal trace isotope for monitoring these type of events. Lead is one of the most toxic and commonly used heavy metal, its poisoning is often deadly because very difficult to recognize and identify. The neuro-scientific study of biodegradation effect of lead could be an impressive scientific field of application of 203Pb radioisotope. Furthermore, the targeted radionuclide therapy via-emitting radioisotopes is also of interest and employed tracers such as 213Bi and 212Pb [1,2]. Therefore 203Pb is a potential radioisotope for this role due to its -radiation and as heavy metal element to trace the therapy

Systematic evaluation of 99mTc-tetrofosmin versus 99mTc-sestamibi to study murine myocardial perfusion in small animal SPECT/CT

Background: The “back-translation” of clinically available protocols to measure myocardial perfusion to preclinical imaging in mouse models of human disease is attractive for basic biomedical research. With respect to singlephoton emission computed tomography (SPECT) approaches, clinical myocardial perfusion imaging protocols are established with different 99mTc-labeled perfusion tracers; however, studies evaluating and optimizing protocols for these tracers in high-resolution pinhole SPECT in mice are lacking. This study aims at evaluating two clinically available 99mTc-labeled myocardial perfusion tracers (99mTc-sestamibi vs. 99mTc-Tetrofosmin) in mice using four different imaging protocols. Methods: Adult C57BL/6 male mice were injected with 99mTc-sestamibi (MIBI) or 99mTc-Tetrofosmin (TETRO) (4 MBq/g body weight) either intravenously through the tail vein (n = 5) or retroorbitally (n = 5) or intraperitoneally (i. p.) under anesthesia (n = 3) or i.p. in an awake state (n = 3) at rest. Immediately after injection, a multi-frame singlephoton emission computed tomography/computed tomography (SPECT/CT) acquisition was initiated with six subsequent time frames of 10 min each. Reconstructed images of the different protocols were assessed and compared by visual analysis by experts and by time-activity-curves generated from regions-of-interest for various organs (normalized uptake values). Results: Visually assessing overall image quality, the best image quality was found for MIBI for both intravenous injection protocols, whereas TETRO only had comparable image quality after retroorbital injections. These results were confirmed by quantitative analysis where left ventricular (LV) uptake of MIBI after tail vein injections was found significantly higher for all time points accompanied with a significantly slower washout of 16% for MIBI vs. 33% for TETRO (p = 0.009) from 10 to 60 min post injection (PI). Interestingly, LV washout from 10 to 60 min PI was significantly higher for TETRO when applied by tail vein injections when compared to retroorbital injections (22%, p = 0.008). However, liver uptake was significant and comparable for both tracers at all time points. Radioactivity concentration in the lungs was negligible for all time points and both tracers. Conclusion: Intravenous MIBI injection (both tail vein and retroorbital) results in the best image quality for assessing myocardial perfusion of the murine heart by SPECT/CT. TETRO has a comparable image quality only for the retroorbital injection route

Új eljárás körülírt ízfelszín defektusok, valamint proliferatív synovitis gyógykezelésére mozaikplasztika valamint radiosynoviectomia segítségével lovon = Novel technique to treat circumscribed joint surface lesions and proliferative synovitis with Mosaicplasty and radiosynoviectomy in the horse.

1. Klinikai beteganyagon végzett munka 11 lovon (1-12 év), négy különböző lokalizációval sikerült SBCs eseteket összegyűjteni (femur mediális, ill. lateralis condylusán valamint a csüdízületben). A mozaikplasztikához a graftokat a femur medialis trochleájának abaxialis felszínéről vettük. A graftok implantációja miniarthrotómiából vagy artroszkópos kontroll alatt történt. Eredmények: Minden ló mozgása javult a műtétet követően; 8 ló korábbi, vagy magasabb szintű teljesítményre volt képes. Egy ló esetében négy év után tapasztaltunk recidivát. Egy esetben több együttes probléma előfordulása miatt (med meniscus sérülés) az állat tenyészértékét sikerült csak megmenteni. 2. Ló csüdízületbe végzett kísérletes beültetések 10 lovon (3-4 éves) ültettünk be 6.5 mm és 8,5 mm átmérőjű 20 mm hosszú autograftokat az elülső végtag csüdízületébe. A lovak két év elteltével kerültek végleges elaltatásra. Eredmények: a beültetett graftok tökéletesen inkorporálódtak környezetükbe, a donor areák esetében is kongruens felszínt tapasztaltunk a vizsgálatok alkalmával. Az áltültetett graftok között létrehozott porcfosztott területek két év után is csak gyengén voltak rostos porccal fedve. Ez alapján kijelenthetjük, hogy lovon is igen fontos a teherviselő ízületi felszín teljes kitöltésére törekedni. A technikai hibából kissé mélyre süllyedt graftok esetében a porckúszás különböző jelenségeit tudtuk megfigyelni. | 1. Study on clinical case log In 11 horses (1-12 years) SBCs were identified in 4 locations: medial and lateral femoral condyle, distal epiphysis of the metacarpus , or metatarsus. Osteochondral autograft transplantation (mosaic arthroplasty) was performed, taking grafts from the abaxial border of the medial femoral trochlea of the unaffected limb. Graft implantation was achieved through a small arthrotomy or by arthroscopy depending on SBC location. Results: All horses improved postoperatively; 8 horses returned to a previous or higher activity level. One horse had recurrence after 4 years of work and soundness. One stallion was used for breeding and light riding because of medial meniscal injuries on the same limb. 2. Implantations into the fetlock joint ? experimental study 10 healthy horses (3-4 years) were involved into this study. Graft, 6.5 mm and 8.5 mm in diameter and 20 mm in length were implanted into the weight bearing surface of the dist. epiphysis of the metacarpus. Horses were humanely destroyed 2 years following the first implantations. Results: Transplanted grafts were fully incorporated into the host bed; the donor areas looked congruent and smooth, without fibrillation. 2-4 mm long cartilage missing fields in-between two transplanted grafts were covered with low quality fibrillating fibrocartilage. Conclusion: even little missing hyaline cartilage on weight bearing surface has to be resurfaced even in equine species

Extended half-life target module for sustainable UniCAR T-cell treatment of STn-expressing cancers

Background: Adapter chimeric antigen receptor (CAR) approaches have emerged has promising strategies to increase clinical safety of CAR T-cell therapy. In the UniCAR system, the safety switch is controlled via a target module (TM) which is characterized by a small-size and short half-life. The rapid clearance of these TMs from the blood allows a quick steering and self-limiting safety switch of UniCAR T-cells by TM dosing. This is mainly important during onset of therapy when tumor burden and the risk for severe side effects are high. For long-term UniCAR therapy, the continuous infusion of TMs may not be an optimal setting for the patients. Thus, in later stages of treatment, single infusions of TMs with an increased half-life might play an important role in long-term surveillance and eradication of residual tumor cells. Given this, we aimed to develop and characterize a novel TM with extended half-life targeting the tumor-associated carbohydrate sialyl-Tn (STn). Methods: The extended half-life TM is composed of the STn-specific single-chain variable fragment (scFv) and the UniCAR epitope, fused to the hinge region and Fc domain of a human immunoglobulin 4 (IgG4) antibody. Specific binding and functionality of the αSTn-IgG4 TM as well as pharmacokinetic features were assessed using in vitro and in vivo assays and compared to the already established small-sized αSTn TM. Results: The novel αSTn-IgG4 TM efficiently activates and redirects UniCAR T-cells to STn-expressing tumors in a target-specific and TM-dependent manner, thereby promoting the secretion of proinflammatory cytokines and tumor cell lysis in vitro and in experimental mice. Moreover, PET-imaging results demonstrate the specific enrichment of the αSTn-IgG4 TM at the tumor site, while presenting a prolonged serum half-life compared to the short-lived αSTn TM. Conclusion: In a clinical setting, the combination of TMs with different formats and pharmacokinetics may represent a promising strategy for retargeting of UniCAR T-cells in a flexible, individualized and safe manner at particular stages of therapy. Furthermore, as these molecules can be used for in vivo imaging, they pose as attractive candidates for theranostic approaches.publishersversionpublishe

Radiolabeling of Extracellular Vesicles with (99m)Tc for Quantitative In Vivo Imaging Studies.

The biodistribution of extracellular vesicles (EVs) is a fundamental question in the field of circulating biomarkers, which has recently gained attention. Despite the capabilities of nuclear imaging methods, such as single-photon emission computed tomography, radioisotope labeling of EVs and the use of the aforementioned methods for in vivo studies hardly can be found in the literature. In this article, the authors describe a novel method for the radioisotope labeling of erythrocyte-derived EVs using the (99m)Tc-tricarbonyl complex. Moreover, the capability of the developed labeling method for in vivo biodistribution studies is demonstrated in a mouse model. The authors found that the intravenously administered (99m)Tc-labeled EVs mostly accumulated in the liver and spleen. The in vivo stability of the labeled EVs was assessed by the comparison of the obtained biodistribution of EVs with that of the free (99m)Tc-tricarbonyl. According to the authors' data, only a minor fraction of the radioactive label became detached from the EVs

Direct myosin-2 inhibition enhances cerebral perfusion resulting in functional improvement after ischemic stroke

Acute ischemic stroke treatment faces an unresolved obstacle as capillary reperfusion remains insufficient after thrombolysis and thrombectomy causing neuronal damage and poor prognosis. Hypoxia-induced capillary constriction is mediated by actomyosin contraction in precapillary smooth muscle cells (SMCs) therefore smooth muscle myosin-2 could be an ideal target with potentially high impact on reperfusion of capillaries. Methods: The myosin-2 inhibitor para-aminoblebbistatin (AmBleb) was tested on isolated human and rat arterioles to assess the effect of AmBleb on vasodilatation. Transient middle cerebral artery occlusion (MCAO) was performed on 38 male Wistar rats followed by local administration of AmBleb into the ischemic brain area. Development of brain edema and changes in cerebrovascular blood flow were assessed using MRI and SPECT. We also tested the neurological deficit scores and locomotor asymmetry of the animals for 3 weeks after the MCAO operation. Results: Our results demonstrate that AmBleb could achieve full relaxation of isolated cerebral arterioles. In living animals AmBleb recovered cerebral blood flow in 32 out of the 65 affected functional brain areas in MCAO operated rats, whereas only 8 out of the 67 affected areas were recovered in the control animals. Animals treated with AmBleb also showed significantly improved general and focal deficit scores in neurological functional tests and showed significantly ameliorated locomotor asymmetry. Conclusion: Direct inhibition of smooth muscle myosin by AmBleb in pre-capillary SMCs significantly contribute to the improvement of cerebral blood reperfusion and brain functions suggesting that smooth muscle myosin inhibition may have promising potential in stroke therapies as a follow-up treatment of physical or chemical removal of the occluding thrombus.Published versio

Results of a systematic review and meta-analysis of early studies on ivermectin in SARS-CoV-2 infection

Ivermectin, an antiparasitic drug, has been repurposed for COVID-19 treatment during the SARS-CoV-2 pandemic. Although its antiviral efficacy was confirmed early in vitro and in preclinical studies, its clinical efficacy remained ambiguous. Our purpose was to assess the efficacy of ivermectin in terms of time to viral clearance based on the meta-analysis of available clinical trials at the closing date of the data search period, one year after the start of the pandemic. This meta-analysis was reported by following the PRISMA guidelines and by using the PICO format for formulating the question. The study protocol was registered on PROSPERO. Embase, MEDLINE (via PubMed), Cochrane Central Register of Controlled Trials (CENTRAL), bioRvix, and medRvix were searched for human studies of patients receiving ivermectin therapy with control groups. No language or publication status restrictions were applied. The search ended on 1/31/2021 exactly one year after WHO declared the public health emergency on novel coronavirus. The meta-analysis of three trials involving 382 patients revealed that the mean time to viral clearance was 5.74 days shorter in case of ivermectin treatment compared to the control groups [WMD = -5.74, 95% CI (-11.1, -0.39), p = 0.036]. Ivermectin has significantly reduced the time to viral clearance in mild to moderate COVID-19 diseases compared to control groups. However, more eligible studies are needed for analysis to increase the quality of evidence of ivermectin use in COVID-19

Differential Regulatory Role of Pituitary Adenylate Cyclase–Activating Polypeptide in the Serum-Transfer Arthritis Model

OBJECTIVE: Pituitary adenylate cyclase-activating polypeptide (PACAP) expressed in capsaicin-sensitive sensory neurons and immune cells has divergent functions in inflammatory and pain processes. This study was undertaken to investigate the involvement of PACAP in a mouse model of rheumatoid arthritis. METHODS: Arthritis was induced in PACAP(-/-) and wild-type (PACAP(+/+) ) mice by K/BxN serum transfer. General features of the disease were investigated by semiquantitative scoring, plethysmometry, and histopathologic analysis. Mechano- and thermonociceptive thresholds and motor functions were also evaluated. Metabolic activity was assessed by positron emission tomography. Bone morphology was measured by in vivo micro-computed tomography, myeloperoxidase activity and superoxide production by bioluminescence imaging with luminol and lucigenin, respectively, and vascular permeability by fluorescent indocyanine green dye study. RESULTS: PACAP(+/+) mice developed notable joint swelling, reduced grasping ability, and mechanical (but not thermal) hyperalgesia after K/BxN serum transfer. In PACAP(-/-) mice clinical scores and edema were significantly reduced, and mechanical hyperalgesia and motor impairment were absent, throughout the 2-week period of observation. Metabolic activity and superoxide production increased in the tibiotarsal joints of wild-type mice but were significantly lower in PACAP(-/-) animals. Myeloperoxidase activity in the ankle joints of PACAP(-/-) mice was significantly reduced in the early phase of arthritis, but increased in the late phase. Synovial hyperplasia was also significantly increased, and progressive bone spur formation was observed in PACAP-deficient mice only. CONCLUSION: In PACAP-deficient mice with serum-transfer arthritis, joint swelling, vascular leakage, hyperalgesia, and early inflammatory cell accumulation are reduced; in the later phase of the disease, immune cell function and bone neoformation are increased. Elucidation of the underlying pathways of PACAP activity may open promising new avenues for development of therapy in inflammatory arthritis. © 2014 The Authors. Arthritis & Rheumatology is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology

A novel ACE2 decoy for both neutralization of SARS-CoV-2 variants and killing of infected cells

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