A mikroszkópos colitis rejtekútjai = Concealments of Microscopic Colitis

Microscopic colitis (MC) has come to the highlight in the last decade, which is explained by the more frequent recognition of the disease and a number of new available data related to the pathogenesis. The incidence of MC has reached the level of inflammatory bowel disease in some populations. A number of factors have been implicated in its development: immunological origin, genetic predisposition, hormonal background, the role of microbiome and drugs has also become significant. However, many questions about MC remain unanswered. Thus, its relationship to traditional inflammatory bowel diseases and the reason and significance of the subtypes transformation to each other also needs to be explained. Topical steroids are of primary importance in therapy, but there are also uncontrollable cases that may require immunomodulatory or biological treatment. A mikroszkópos colitis (MC) az utóbbi évtizedben a figyelem előterébe került, amelyet a kórkép gyakoribb felismerése és a kóreredettel kapcsolatos számos új adat magyaráz. Az MC incidenciája egyes népességben elérte a gyulladásos bélbetegségek szintjét. Kialakulásával kapcsolatban számos tényező szerepe vetődött fel: az immunológiai eredet, genetikai hajlam, hormonális háttér és jelentőssé vált a mikrobiom és gyógyszerek szerepe is. Az MC-ről azonban számos kérdés még megválaszolatlan. Így a hagyományos gyulladásos bélbetegségekhez való viszonya, és magyarázatot igényel az egyes kórformák egymásba való átfordulásának oka és jelentősége is. A gyógyításban a helyi szteroid elsődleges jelentőségű, előfordulnak azonban nem befolyásolható esetek is, amelyek immunmodulátor vagy biológiai kezelést is szükségessé tehetnek

A halálreceptor szignálutak működésének változásai a malignus transzformáció során. = Changes in death receptor signaling during malignant transformation

Kutató munkánk során a terveknek megfelelően vizsgáltuk a daganatsejtek aktív sejthalálát szabályozó jelátviteli utak működését. Vastagbélrák sejtekben kimutattuk, hogy a TRAIL halálligand által kiváltott apoptózis szabályozásában elsősorban az IAP (Inhibitor of Apoptózis) fehérjék, elsősorban a XIAP játszik szerepet. A XIAP gátlása közvetlenül siRNA-vel, vagy a SMAC/DIABLO mitokondriumból történő felszabadulását indukáló hatóanyagokkal illetve SMAC/DIABLO oligopeptidekkel fokozhatja a vastagbélráksejtek TRAIL érzékenységét. A rhabdomyoszarkómák esetében kimutattuk, hogy proteasoma gátlók a DR5 halálreceptor expressziójának és aggregációjának növelésével és a Bcl-2 expressziójának gátlásával fokozzák a TRAIL hatékonyságát. Tüdőrákokban kimutattuk, hogy az EGFR (Epidermális Növekedési Faktor Receptor) gátlókra rezisztens tüdődaganatok esetében a TRAIL kezelés hatékony lehet a jövőben. A mellékpajzsmirigy daganatok esetében a kutatási terv eredeti hipotézisével összhangban azt találtuk, hogy a transzformáció során a pro-apoptotikus gének (pl. TRAIL) expressziója emelkedik, azonban ezt az antiapoptotikus (pl. IAP) gének expressziója kompenzálhatja. Nemzetközi kollaborációban kimutattuk, hogy a FAS halálreceptor expressziójának szabályozásában szerepe lehet egy specifikus CpG sziget hypermetilációjának hólyagrákokban. Kutatásaink tehát számos lehetséges terápiás célpontot azonosítottak a halálreceptorok jelátviteli mechanizmusában. | During our research project we have studied several aspects of the signal transduction pathways regulating the active cell death in tumor cells. In colon cancer, we identified the IAP family of proteins (Inhibitor of Apoptosis Proteins), in particular XIAP as the main regulator of TRAIL sensitivity. Silencing of XIAP expression or indirect inhibition by the drug induced release of the SMAC/DIABLO peptide from the mitochondria or by SMAC/DIABLO mimetic oligopeptide restored TRAIL sensitivity. In rhabdomyosarcomas, we found the upregulation and increased aggregation of DR5 death receptor and downregulation of Bcl-2 as the main mechanism of synergism between TRAIL and proteasome inhibitors. In lung cancer cells we found that cells resistant to EGFR (Epidermal Growth Factor Receptor) inhibitors are often sensitive to TRAIL. In the malignancies of the parathyroid gland we found an upregulation of proapoptotic proteins (E.g. TRAIL) which is compensated by the upregulation of anti-apoptotic proteins (e.g. IAP). In international cooperation we found a single CpG site of which hypermethylation can regulate the expression of FAS death receptor in bladder cancer. This research project has identified several potential anti-cancer therapeutic targets in the signal transduction pathways of death receptors

Characteristic mTOR activity in Hodgkin-lymphomas offers a potential therapeutic target in high risk disease – a combined tissue microarray, in vitro and in vivo study

BACKGROUND: Targeting signaling pathways is an attractive approach in many malignancies. The PI3K/Akt/mTOR pathway is activated in a number of human neoplasms, accompanied by lower overall and/or disease free survival. mTOR kinase inhibitors have been introduced in the therapy of renal cell carcinoma and mantle cell lymphoma, and several trials are currently underway. However, the pathological characterization of mTOR activity in lymphomas is still incomplete. METHODS: mTOR activity and the elements of mTOR complexes were investigated by immunohistochemistry on tissue microarrays representing different human non-Hodgkin-lymphomas (81 cases) and Hodgkin-lymphomas (87 cases). The expression of phospho-mTOR, phospho-4EBP1, phospho-p70S6K, phospho-S6, Rictor, Raptor and Bcl-2, Bcl-xL, Survivin and NF-kappaB-p50 were evaluated, and mTOR activity was statistically analyzed along with 5-year survival data. The in vitro and in vivo effect of the mTOR inhibitor rapamycin was also examined in human Hodgkin-lymphoma cell lines. RESULTS: The majority (>50%) of mantle cell lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma, anaplastic large-cell lymphoma and Hodgkin-lymphoma cases showed higher mTOR activity compared to normal lymphoid tissues. Hodgkin-lymphoma was characterized by high mTOR activity in 93% of the cases, and Bcl-xL and NF-kappaB expression correlated with this mTOR activity. High mTOR activity was observed in the case of both favorable and unfavorable clinical response. Low mTOR activity was accompanied by complete remission and at least 5-year disease free survival in Hodgkin-lymphoma patients. However, statistical analysis did not identify correlation beetween mTOR activity and different clinical data of HL patients, such as survival. We also found that Rictor (mTORC2) was not overexpressed in Hodgkin-lymphoma biopsies and cell lines. Rapamycin inhibited proliferation and induced apoptosis in Hodgkin-lymphoma cells both in vitro and in vivo, moreover, it increased the apoptotic effect of chemotherapeutic agents. CONCLUSIONS: Targeting mTOR activity may be a potential therapeutic tool in lymphomas. The presence of mTOR activity probably indicates that the inclusion of mTOR inhibition in the therapy of Hodgkin-lymphomas may be feasible and beneficial, especially when standard protocols are ineffective, and it may also allow dose reduction in order to decrease late treatment toxicity. Most likely, the combination of mTOR inhibitors with other agents will offer the highest efficiency for achieving the best clinical response

The clinical diagnosis and therapy of acute rejection

Next-Generation-Sequencing (NGS) has brought on a revolution in sequence analysis with its broad spectrum of applications ranging from genome resequencing to transcriptomics or metage- nomics, and from fundamental research to diagnostics. The tremendous amounts of data necessi- tate highly ecient computational analysis tools for the wide variety of NGS applications. This thesis addresses a broad range of key computational aspects of resequencing applications, where a reference genome sequence is known and heavily used for interpretation of the newly sequenced sample. It presents tools for read mapping and benchmarking, for partial read mapping of small RNA reads and for structural variant/indel detection, and nally tools for detecting and genotyping SNVs and short indels. Our tools eciently scale to large NGS data sets and are well- suited for advances in sequencing technology, since their generic algorithm design allows handling of arbitrary read lengths and variable error rates. Furthermore, they are implemented within the robust C++ library SeqAn, making them open-source, easily available, and potentially adaptable for the bioinformatics community. Among other applications, our tools have been integrated into a large-scale analysis pipeline and have been applied to large datasets, leading to interesting discoveries of human retrocopy variants and insights into the genetic causes of X-linked intellectual disabilities