Virális antigének, növekedési faktorok és adhéziós molekulák szerepe a krónikus hepatitis progressziójában = The role of viral antigens, growth factors and adhesion molecules in the progression of chronic hepatitis

A munka célja egyes hepatotrop vírusok, kiemelten a hepatitis C vírus (HCV) májkárosodást okozó pathomechanizmusának és a vírus szerepének tanulmányozása volt. Igazoltuk, hogy a Magyarországon legnagyobb arányban előforduló HCV1b genotípus a fertőzöttek 70%-ában steatosissal jár. A máj steatosisa kockázati tényező a krónikus hepatitis C (CH-C) progressziójában. A steatosis fokozatának beépítése a hisztológiai aktivitási indexbe prognosztikailag fontos és korrelál az ALT szint emelkedéssel. Több munkánkban rámutattunk a hepatitis B és C vírus indukált hepatocarcinogenesis különbözőségére, és ebben a virális és gazdasejt faktorok szerepére. A sejtkapcsoló molekulák közül kiemelten a claudinokat vizsgálva igazoltuk, hogy az emelkedett claudin-4 expresszió elkülöníti a cholangiocellularis és hepatocellularis carcinomákat, ugyanis az utóbbiakban nem expresszálódik. A claudin-1 és -2 a fetális és embrionális komponenseket elkülöníti hepatoblastomában, mely differenciál diagnosztikus értékű. Igazoltuk, hogy a hepatikus őssejtek matrilin-2-t, ezen fontos matrix proteint termelik, mely részt vesz a májkárosodást követő szerkezet reorganizációjában, és a máj fibrotikus folyamataiban lényeges tényező. | The aim of the study was to investigate the pathomechanism and role of certain hepatotropic viruses causing liver damage, with special emphasis on the hepatitis C virus (HCV). We proved that the HCV1b genotype - the most frequent in Hungary - is associated with steatosis in 70% of those infected and is a risk factor in the progression of chronic hepatitis C (CH-C). From the viewpoint of prognosis, it is important to include the degree of steatosis in the histological activity index since it was found to correlate with the elevation of the ALT level. In our studies we have emphasized the differences between heptitis B and C virus induced hepatocarcinogenesis and have also thrown light on the role of viral and host cell factors. From the cell junction molecules, our studies have prominently focused on the claudins, finding that high claudin-4 expression differentiates cholangiocellular from hepatocellular carcinomas, since it is not expressed in the latter. Further, we have found claudin-1 and -2 to differentiate between the fetal and embryonal components in hepatoblastomas, which bears differential diagnostic significance. Based on our studies it has gained proof that hepatic stem cells produce the important matrix protein: matrilin-2, which has been noted to take part in the structural reorganization following liver damage and is an essential factor in the fibrotic processes of the liver

A hepatocellularis carcinoma - a makroszkópiától a molekuláris patológiáig

A hepatocellularis carcinoma (HCC) igen rossz prognózisú daganat, azonban diagnosztikája és kezelése területén az utóbbi években jelentős előrehaladás történt. Mindehhez hozzájárult a HCC molekuláris patogenezisének mélyebb megismerése. A cirrhosis talaján kialakult HCC praemalignus elváltozásai a nagy regeneratív nodulus, az alacsony („low”) és magas („high”) fokozatú diszplasztikus nodulus. Mikroszkóposan a WHO trabecularis (micro-, macrotrabecularis), acinaris (pseudoglandularis,), scirrhosus és szolid formát különít el, speciális altípusként a világos sejtes, fibrolamellaris és kevert cholangiohepatocellularis szöveti forma ismert. Ezen szövettani típusok prognosztikai jelentősége vitatott. A fibrolamellaris, fiatalokban előforduló, nem cirrhoticus HCC-t jobb prognózisúnak tartják, bár valószínű, hogy ez annak a következménye, hogy ezen típust cirrhosis nem kíséri. A diagnózist segíthetik egyes, a szérumban és a daganatban is kimutatható tumormarkerek, így a jól ismert alfa-fetoprotein (AFP) mellett a glipikán-3 és a survivin, az újabban leírt agrin és claudinok, valamint a májsejteredetet bizonyító hepatocytaspecifikus antigén (HSA). Újabban az úgynevezett mikro-RNS-ek diagnosztikus jelentősége, elsősorban a májsejtspecifikus mir-122-é is felmerült. A HCC molekuláris osztályozása, a kezelés irányait is megszabó barcelonai beosztás (BCLC) mellett, kulcsfontosságú molekuláris eltérések alapján csoportosítja a HCC-t. Számos olyan molekuláris alteráció észlelhető, amely minden HCC-ben megfigyelhető, míg egyes eltérések csak bizonyos tumorokban detektálhatók. | Hepatocellular carcinoma (HCC) is a tumor with rather bad prognosis. Recent years, however, have seen considerable progress in the diagnostics and treatment of this disease, contributing to better understanding of its molecular pathogenesis. Large regenerative nodules, low and high grade dysplastic nodules are premalignant alterations of HCC developing on the grounds of cirrhosis. Microscopically the WHO distinguishes trabecular, acinar (pseudoglandular), scirrhous and solid forms. Special histological subtypes are the clear cell, fibrolamellar and mixed hepato-cholangiocellular variants. The prognostic significance of these histological types is argued. The fibrolamellar, non-cirrhotic form of HCC occurring in young age is considered to be of better prognosis, but this is probably due to the fact that this type is not accompanied by cirrhosis. Certain tumor markers may help the diagnosis, such as alpha-fetoprotein (AFP), glypican-3, survivin, the recently described agrin and claudins, furthermore, the hepatocyte specific antigen (HSA), which confirms the hepatocytic origin of the tumor. Recently, the diagnostic significance of microRNAs, primarily of the hepatocyte-specific mir122 has also emerged. In addition to the Barcelona Clinic Liver Cancer (BCLC) staging classification which determines the course of therapy, the molecular classification of HCC is based on key molecular alterations, many of which are observable in all HCC cases, whereas some alterations are only detectable in certain tumors

Az ALK-pozitív tüdőrák korszerű diagnosztikája

ALK translocation is the 3rd most frequent genetic aberration in lung adenocarcinoma, and several inhibitors are now clinically available in first and second line settings. Accordingly, molecular diagnostics of ALK-positive lung cancer is very important and can be done with the rational combination of several methods. All international recommendations suggest that, except for cytological samples, screening technology for ALK-positive tumors is immunohistochemistry using a validated test. It is highly recommended that in case of ALK protein positive samples gene translocation must be confirmed by fluorescent in situ hybridization (FISH). In case of cytological samples FISH technique must be used as ALK diagnostics. In equivocal cases the genetic alteration of ALK can be confirmed by alternative molecular techniques such as next generation sequencing or RNAbased PCR methods. Upon administration of ALK inhibitors, acquired resistance is frequent which is mostly due to ALK amplification and/or mutation. It is evident that the diagnostics of these secondary ALK gene alterations must be done from recurrent tumors or circulating nucleic acids

Localization of apoptosis proteins and lymphocyte subsets in chronic rejection of human liver allograft

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Postconditioning in major vascular surgery: prevention of renal failure

This study investigates teachers in the Swedish ten-year compulsory school who use ICT(Information and communication technology) in their classroom practice. It poses andgives answers to questions about what is contributing most to explain why they choose touse computers and information technology in their work with students/pupils and usesmultiple regression analysis in order to investigate the best pattern of predictive variables.A significant model emerged suggesting that teachers using ICT with students wereinterested in changing their classroom practice. They also felt self-efficacious in usingcomputers in education and they have positive attitudes toward using ICT in education.The present investigation differs from other studies in that it examines teachers whoalready are using technology in their classroom practice and it could be seen as a buildingblock in the development of knowledge about how teachers can become more competentand confident in using ICT in their pedagogical work in classroom practice

Klinikopatológiai szemléletű emlőrákkutatások

In the second half of the 20th century research focusing to breast carcinomas at the Semmelweis University had been mostly linked to the 2nd Department of Pathology. Nowadays, following the rapidly improving treatment modalities in breast cancer there is an increasing need for defining new predictive and prognostic markers. The modern molecular pathological approach helps tremendously in mapping the biological behavior of individual cases of breast cancers and meanwhile, it is one of the prerequisites of a more efficient treatment both in neoadjuvant and adjuvant settings, as well as in metastatic disease. We provide a brief review of the relevant results we have obtained in breast cancer research between 2000 and 2015

Isoform-Dependent Changes in Cytochrome P450-Mediated Drug Metabolism after Portal Vein Ligation in Rat

Surgical removal of complicated liver tumors may be realized in two stages via selective portal vein ligation, inducing the atrophy of portally ligated lobes and the compensatory hypertrophy of nonligated liver lobes. Unlike morphological changes, functional aspects such as hepatic cytochrome P450 (CYP)-mediated drug metabolism remain vaguely understood, despite its critical role in both drug biotransformation and hepatic functional analysis. Our goal was the multilevel characterization of hepatic CYP-mediated drug metabolism after portal vein ligation in the rat.Male Wistar rats (n = 24, 210-230 g) were analyzed either untreated (controls; n = 4) or 24/48/72/168/336 h (n = 4 each) following portal vein ligation affecting approximately 80% of the liver parenchyma. Besides the weights of ligated and nonligated lobes, pentobarbital (30 mg/kg)-induced sleeping time, CYP1A(2), CYP 2B(1/2), CYP2C(6/11/13), CYP3A(1) enzyme activities, and corresponding isoform mRNA expressions, as well as CYP3A1 protein expression were determined by in vivo sleeping test, CYP isoform-selective assays, polymerase chain reaction, and immunohistochemistry, respectively.Portal vein ligation triggered atrophy in ligated lobes and hypertrophy nonligated lobes. Sleeping time was transiently elevated (p = 0.0451). After an initial rise, CYP1A, CYP2B, and CYP3A enzyme activities dropped until 72 h, followed by a potent increase only in the nonligated lobes, paralleled by an early (24-48 h) transcriptional activation only in nonligated lobes. CYP2C enzyme activities and mRNA levels were bilaterally rapidly decreased, showing a late reconvergence only in nonligated lobes. CYP3A1 immunohistochemistry indicated substantial differences in positivity in the early period.Beyond the atrophy-hypertrophy complex, portal vein ligation generated a transient suppression of global and regional drug metabolism, re-established by an adaptive, CYP isoform-dependent transcriptional response of the nonligated lobes

Sejtadhéziós molekulák szerepe a daganatok, kiemelten a májrákok patogenezisében = The role of cell adhesion molecules in the pathogenesis of tumors, with emphasis on liver cancers

A sejtkapcsolatok a daganatokban megváltoznak, különösen a tight junction (TJ) gerincét alkotó claudin (CLDN) fehérje család komponensei, melynek 24 típusa ismert emberben. Több daganatban elsőként vizsgálatuk a CLDN expresszió eltéréseit protein és mRNS szinten. Megállapítottuk, hogy az egyes CLDN-ok expressziója jelentősen nő a nyelőcső rákban, a Barrett oesophagusban és adenocarcinomában (ACC). A CLDN mintázat elkülöníti a hepatoblastoma és endometrialis carcinoma formáit, a pancreas endocrin tumorait és a ductalis ACC-t, valamint a tüdőtumorokat, a primer és metasztatikus májdaganatokat. Egyes extracellularis matrix (ECM) komponensek, így az agrin, valamint a matrilin2 expressziója és lokalizációja megváltozik a cirrhosisban és májrákokban. Fenti vizsgálatok jelentősége, hogy számos daganatban feltárta a sejtkapcsolatok és ECM változásait és igazolta, hogy az eltérések jellemzők az egyes tumorokra, követik a kiindulási szövet sejtkapcsoló struktúráinak fehérje összetételét, bár expressziójuk mértéke változik. A vizsgált daganatok CLDN mintázata diagnosztikus értékű. A vizsgálatok igazolták, hogy a TJ dinamikusan változó protein összetétele a carcinogenesis során bonyolult funkcionális változást takar és az egyes összetevők aránya és egymással való kapcsolata a döntő az intakt sejtkapcsolat kialakulásában. | Cell junctions change in tumors, especially the components of the claudin (CLDN) protein family (24 types of which are known in humans) forming the backbone of tight junctions (TJ). We were first to study CLDN expression alterations in several tumors at protein and mRNA levels. Our studies confirmed that expression of certain CLDNs shows significant increase in oesophageal squamous cell carcinoma, Barrett?s oesophagus and adenocarcinoma (ACC). The CLDN pattern differentiates components of hepatoblastomas and 2 types of endometrial carcinomas, endocrine tumors of the pancreas, ductal ACCs, lung tumors, primary and metastatic liver tumors. Certain extracellular matrix (ECM) components, as agrin, matrilin-2 exhibited altered expression and location in cirrhosis and liver cancers. Our observations revealed TJ and ECM changes in several tumor types, confirming that the changes are characteristic to the tumor. The CLDN pattern of the studied tumors are of diagnostic significance. Our studies confirmed that the dynamically changing protein composition of TJs covers complex functional changes during carcinogenesis, and the proportion and interrelationship of various components are decisive in the development of intact TJs