Nyelőcső betegségek etiológiájának és kezelésének néhány új klinikai és kísérletes aspektusa

The esophagus is one of the most inscrutable organs of the gastrointestinal tract, hereby it challenges all physicians who specialize on it, including gastroenterologists, surgeons and also primary care physicians. The complexity of the esophagus manifests itself on the colorful spectrum of complications that develop on the ground of gastroesophageal reflux disease (GERD). It is already unexplainable why chronic acid regurgitation provokes reflux esophagitis in some patients, while in others no endoscopic or histologic sign of inflammation can be detected, yet patients have severe complains. Development of diverse functional and structural esophageal disorders have been described in association with gastroesophageal reflux disease, but to date, it is unclear whether these secondary pathologies are simple consequences of GERD or is it possible that some of them are defensive reactions? Is there an expediency in their development or is it mere coincidence? Do the presumed adaptive esophageal changes influence the therapeutic strategy? Gastroesophageal reflux disease has become an endemic malady worldwide in the past decades. Understanding the longterm impacts of acid regurgitation on the esophagus would be imperative in order to better comprehend the behavior of this organ and to improve our knowledge about the possible complications of GERD

„A világ egy városban”1 Liverpooli EKF tapasztalatok

Az elmúlt időszakban, tekintve, hogy 2010-ben egy magyarországi város, Pécs viselte az Európa Kulturális Fővárosa (EKF) címet, egyre több írás látott napvilágot hazai szakfolyóiratokban is, górcső alá véve a fent nevezett uniós projektet, annak történelmét, nemzeti sajátosságait, társadalmasítását, tényleges népszerűségét. A nagyközönség a pécsi projektet könyv formájában is megismerhette. Jelen tanulmány témáját tekintve ebbe a sorba illeszkedik, hiszen egyet a sikeres EKF programok közül igyekszik bemutatni, jelesül a liverpoolit. A dolgozat keretei nem teszik lehetővé, hogy teljes spektrumát bejárjuk az elemzésnek, hiszen megannyi kérdés vár megválaszolásra az integráció eme lakosság körében is egyre ismertebb kezdeményezésével kapcsolatban. Arra azonban vállalkozni merünk, hogy a többszintű kormányzás hatékony megvalósulását és az EKF program sikerét összevessük az angliai város példáján keresztül. Írásunk célja Liverpool esetén keresztül felhívni a figyelmet a kultúrában rejlő lehetőségekre, amelyek felhasználásával elérhetővé válik egy korábban komoly gazdasági, társadalmi problémákkal küzdő város átalakítása, és az EKF programnak köszönhetően nemzetközi szintű megismertetése. Állításunk, hogy a többszintű kormányzás megvalósulása (mindig a szereplők kívánt arányú beavatkozásával), a döntéshozatali mechanizmusok hierarchia központúságának mellőzése, magában hordozza egy közösségi kezdeményezés sikerét

A gastrooesophagealis refluxbetegség nyelőcsőszövődményei: következmények vagy védekezőreakciók? | Esophageal complications of gastroesophageal reflux disease: consequences or defensive reactions?

Absztrakt: A gastrooesophagealis refluxbetegség a felnőtt lakosság több mint 10%-át érinti. A betegek nagy többsége életmódbeli változtatásokkal és hatásos savcsökkentő szerekkel jól kezelhető. Az érintettek körülbelül 10%-a azonban a kezelés dacára panaszos marad, és náluk súlyos szövődmények fejlődhetnek ki. Különös módon a szövődmények egy része védekező jellegűnek tűnik, amivel a beteg panaszai mérséklődhetnek, illetve mintha az állapot súlyosbodásának és további szövődmények kialakulásának megelőzését céloznák. Az egyértelműen refluxszövődménynek tekinthető Barrett-oesophagusban jelentősen mérséklődhetnek az életminőséget rontó panaszok, mert a Barrett-hám sokkal ellenállóbb a gyomorsav maró hatásával szemben, mint a nyelőcsövet normálisan bélelő laphám. A refluxszövődményként kialakuló motilitászavarok (hipertenzív alsó nyelőcsősphincter, achalasia cardiae és cricopharyngealis achalasia) és strukturális elváltozások (Schatzki-gyűrű, nyelőcsőstrictura, subglotticus tracheastenosis) pedig segítenek megelőzni az aspirációt, amely újabb panaszok megjelenésével járhat, és további súlyos szövődmények kialakulásának a lehetőségét hordozza magában. Orv Hetil. 2017; 158(20): 763–769. | Abstract: Gastroesophageal reflux disease affects more than 10% of the adult population. Most patients can be effectively treated with lifestyle changes and adequate acid-reducing therapy. However, about 10% of the patients remain symptomatic despite treatment and severe complications may develop. Interestingly, some of these complications seem to be a sort of defensive mechanism that may either alleviate the patient’s symptoms or prevent developing further complications. In Barrett’s esophagus, which can be unambigously considered as a complication of gastroesophageal reflux disease, reflux symptoms ruining the quality of life may significantly improve, since the metaplastic Barrett epithelium is much more resistent to gastric acid, than the normal epithelial lining of the esophagus. Furthermore, the motility disorders (hypertensive lower esophageal sphincter, achalasia, cricopharyngeal achalasia) and structural changes (Schatzki’s ring, esophageal stricture, subglottic trachea stenosis), which develop as a complication of reflux may help to prevent aspiration that can cause new complaints and may lead to further complications. Orv Hetil. 2017; 158(20): 763–769

Light Control of Salt-Induced Proline Accumulation is Mediated by Elongated Hypocotyl 5 in Arabidopsis

Plants have to adapt their metabolism to constantly changing environmental conditions, among which the availability of light and water is crucial in determining growth and development. Proline accumulation is one of the sensitive metabolic responses to extreme conditions; it is triggered by salinity or drought and is regulated by light. Here we show that red and blue but not far-red light is essential for salt-induced proline accumulation, upregulation of Delta 1-PYRROLINE-5-CARBOXYLATE SYNTHASE 1 (P5CS1) and downregulation of PROLINE DEHYDROGENASE 1 (PDH1) genes, which control proline biosynthetic and catabolic pathways, respectively. Chromatin immunoprecipitation and electrophoretic mobility shift assays demonstrated that the transcription factor ELONGATED HYPOCOTYL 5 (HY5) binds to G-box and C-box elements of P5CS1 and a C-box motif of PDH1. Salt-induced proline accumulation and P5CS1 expression were reduced in the hy5hyh double mutant, suggesting that HY5 promotes proline biosynthesis through connecting light and stress signals. Our results improve our understanding on interactions between stress and light signals, confirming HY5 as a key regulator in proline metabolism

Light Control of Salt-Induced Proline Accumulation Is Mediated by ELONGATED HYPOCOTYL 5 in Arabidopsis

Plants have to adapt their metabolism to constantly changing environmental conditions, among which the availability of light and water is crucial in determining growth and development. Proline accumulation is one of the sensitive metabolic responses to extreme conditions; it is triggered by salinity or drought and is regulated by light. Here we show that red and blue but not far-red light is essential for salt-induced proline accumulation, upregulation of Delta 1-PYRROLINE-5-CARBOXYLATE SYNTHASE 1 (P5CS1) and downregulation of PROLINE DEHYDROGENASE 1 (PDH1) genes, which control proline biosynthetic and catabolic pathways, respectively. Chromatin immunoprecipitation and electrophoretic mobility shift assays demonstrated that the transcription factor ELONGATED HYPOCOTYL 5 (HY5) binds to G-box and C-box elements of P5CS1 and a C-box motif of PDH1. Salt-induced proline accumulation and P5CS1 expression were reduced in the hy5hyh double mutant, suggesting that HY5 promotes proline biosynthesis through connecting light and stress signals. Our results improve our understanding on interactions between stress and light signals, confirming HY5 as a key regulator in proline metabolism

Prognosis in human glioblastoma based on expression of ligand growth hormone-releasing hormone, pituitary-type growth hormone-releasing hormone receptor, its splicing variant receptors, EGF receptor and PTEN genes

Purpose G lioblastoma (GB) is the most frequent brain tumor. Despite recent improvement in therapeutic strategies, the prognosis of GB remains poor. Growth hormone-releasing hormone (GHRH) may act as a growth factor; antagonists of GHRH have been successfully applied for experimental treatment of different types of tumors. The expression profile of GHRH receptor, its main splice variant SV1 and GHRH have not been investigated in human GB tissue samples. Methods We examined the expression of GHRH, fulllength pituitary-type GHRH receptor (pGHRHR), its functional splice variant SV1 and non-functional SV2 by RTPCR in 23 human GB specimens. Epidermal growth factor receptor (EGFR) and phosphatase and tensin homolog gene (PTEN) expression levels were also evaluated by quantitative RT-PCR. Correlations between clinico-pathological parameters and gene expressions were analyzed. Results E xpression of GHRH was found to be positive in 61.9 % of samples. pGHRH receptor was not expressed in our sample set, while SV1 could be detected in 17.4 % and SV2 in 8.6 % of the GB tissues. In 65.2 and 78.3 % of samples, significant EGFR over-expression or PTEN under-representation could be detected, respectively. In 47.8 % of cases, EGFR up-regulation and PTEN down-regulation occurred together. Survival was significantly poorer in tumors lacking GHRH expression. This worse prognosis in GHRH negative group remained significant even if SV1 was also expressed. Conclusion Our study shows that GHRH and SV1 genes expressed in human GB samples and their expression patterns are associated with poorer prognosis

Synthesis and direct assay of large macrocycle diversities by combinatorial late-stage modification at picomole scale

Macrocycles have excellent potential as therapeutics due to their ability to bind challenging targets. However, generating macrocycles against new targets is hindered by a lack of large macrocycle libraries for high-throughput screening. To overcome this, we herein established a combinatorial approach by tethering a myriad of chemical fragments to peripheral groups of structurally diverse macrocyclic scaffolds in a combinatorial fashion, all at a picomole scale in nanoliter volumes using acoustic droplet ejection technology. In a proof-of-concept, we generate a target-tailored library of 19,968 macrocycles by conjugating 104 carboxylic-acid fragments to 192 macrocyclic scaffolds. The high reaction efficiency and small number of side products of the acylation reactions allowed direct assay without purification and thus a large throughput. In screens, we identify nanomolar inhibitors against thrombin (Ki = 44 ± 1 nM) and the MDM2:p53 protein-protein interaction (Kd MDM2 = 43 ± 18 nM). The increased efficiency of macrocycle synthesis and screening and general applicability of this approach unlocks possibilities for generating leads against any protein target

TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma

Telomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in <5 % of cases and showed no association wit