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Messenger RNA levels of oncogenic tyrosine kinases were determined in canine mammary tumours using real-time RT-PCR. The following tyrosine kinases and vascular endothelial growth factors (VEGF) were examined in malignant and healthy mammary tissues of 13 dogs: VEGFR1, VEGFR2, EGFR, ErbB2, PDGFR1, c-KIT and c-MET. Expression levels of all these factors were significantly higher in tumour samples than in normal mammary tissues taken from the same animal. Higher grading was associated with higher VEGFR1 levels. Grade III tumours showed significantly higher VEGF, c-MET and c-KIT mRNA expression, while Grade I tumours with lower malignancy showed significantly higher PDGFR1 and EGFR expression than tumours classified as Grade II or III. The increased presence of VEGF, VEGFR1, c-KIT and c-MET is a negative prognostic factor as these signal transduction molecules contribute to increased tumour malignancy. The presented data provide evidence, for the first time, for the existence of a complex overexpression and dysregulation of VEGF and several oncogenic tyrosine kinases such as VEGR1, PDGFR1, c-KIT and c-MET in canine mammary tumours. Therefore, canine mammary tumours may be potential targets for tyrosine kinase inhibitor therapy.

Open access

Abstract

Pitfalls of peroxynitrite (ONOO) formation in diabetic rat aorta on luminol-induced chemiluminescence (LCL) are investigated based on a detailed reaction mechanism in a case where 1.0 × 10−7 M s−1 superoxide formation rate and nitric oxide (NO) formation were measured by electron paramagnetic resonance, while ONOO formation by LCL. Modeling ONOO formation at equimolar reactant ratio at pH 7.4 and 37 °C predicts 2.0 nM ONOO and 2.1 × 10−6 M steady-state NO concentrations, which are both biologically relevant. Comparison of steady-state concentrations to those obtained by modeling the LCL intensity at pH 10 shows that ONOO concentration increases with 10% while peroxynitrous acid (ONOOH) concentration decreases complying with the pH shift. Evaluation of steady-state reaction rates reveals that the contribution of CO3•− radicals to the formation of luminol radicals is 76%, that of NO2 is 24%, considerable, but that of OH radicals negligible. The contribution of additional superoxide formation by autoxidation of luminol is 13%, not negligible, but that of ONOOH homolysis is negligible. The NO2 is predominantly formed from the decomposition of the ONOO–carbon dioxide adduct and only 0.5% directly from NO oxidized by molecular oxygen. But the contribution of the latter pathway depends strongly on the NO and superoxide formation rate ratio, at a ratio of 2:1, it would increase to 14%. The measured time interval of the initial increase of LCL intensity complies with the time needed luminol aorta outside and inside concentrations in the sample to be equalized by diffusion, the 7 × 10−3 s−1 rate constant obtained by modeling enabled to estimate 5 × 10−7 cm2 s−1 as the diffusion coefficient of luminol in the diabetic rat aorta.

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Kezdeti tapasztalataink spinalis muscularis atrophiában szenvedő gyermekek intravénás génterápiájával

Our initial experiences with intravenous gene therapy for spinal muscular atrophy in children

Orvosi Hetilap
Authors: Borbála Mikos, Anita Gergely, Réka Balázsfi, Edina Bányász, Beáta Gyömörei, Mónika Hantos, Judit Czelecz, Rita Jakus, Hajnalka Kárász, Mónika Zilahy, Eszter Molnár, Éva Paraicz, Ágnes Csohány, Fanni Szénási, Lejla Vendégh, András Fogarasi, and György Velkey

Összefoglaló. A veleszületett gerincvelői izomsorvadás ritka, progresszív neurodegeneratív betegség, a gyermekkori halál egyik legjelentősebb genetikai oka. Az orvostudomány lehetőségei a XXI. század előtt a progresszió megfékezésére, a szövődmények késleltetésére és ellátására korlátozódtak. A legsúlyosabb génhibában szenvedő gyermekeket általában kétéves kor előtt elveszítettük. A genetikai diagnosztika fejlődése lehetővé teszi a korai diagnózist, a súlyosság és a progresszió előrejelzését. A 2018-ban hazánkban engedélyezett intrathecalis nuszinerszennel a nagy betegszámon alapuló klinikai eredmények meggyőzőek. A 2019-től elérhető új, intravénás génpótló terápiával (onaszemnogén abeparvovek) kapcsolatos tapasztalatok még kisebb betegszámon alapulnak. Hazánkban öt betegnél került sor az alkalmazására a Bethesda Gyermekkórházban, szigorú szakmai kritériumok és előkészületek alapján. Közülük annak a három gyermeknek a kezeléséről számolunk be dolgozatunkban, akiknél már rendelkezünk utánkövetési tapasztalatokkal. Vizsgálatunk szerint a készítmény elősegíti a mozgásteljesítmény javulását. A mellékhatások elsősorban reverzibilis májenzim-emelkedésben, thrombocytopeniában, granulocytopeniában és a szívizom-nekroenzim emelkedésében nyilvánultak meg. Ezért fontosnak tartjuk a betegek szoros és tartós követését, a mellékhatások korai észlelése és elhárítása érdekében. Orv Hetil. 2020; 161(42): 1806–1816.

Summary. Congenital spinal muscular atrophy is a rare, progressive neurodegenerative disease, one of the major genetic causes of childhood death. The possibilities of medicine to curb its progression and to delay and treat the disease’s complications were limited before the 21st century. Therefore, children with the most severe genetic defects were usually lost before their second birthday. Advances in genetic diagnostics allow for early diagnosis, prediction of severity and expected progression. Using intrathecal nusinersen (available in Hungary since 2018), clinical results based on a large number of patients are convincing. Experience with the new intravenous gene therapy (onasemnogene abeparvovec) available from 2019 is still based on a less number of patients. It was used in Hungary in Bethesda Hospital in five children based on strict professional criteria and preparations. Our paper summarizes the most important efficacy and safety data of the first three consecutive patients. According to our experiences, the product helps to improve movement performance. Side effects are mainly reversible elevations of liver enzymes and serum troponin-I levels, thrombocytopenia and granulocytopenia. Therefore, we found that it is important to monitor patients closely on a long-term basis in order to detect and eliminate side effects early. Orv Hetil. 2020; 161(42): 1806–1816.

Open access