Az emésztőrendszeri peptikus fekély kialakulása = Development of gastrointestinal peptic ulcer

A H. pylori fertőzés nem befolyásolja a szérum CgA- és gasztrinszintet, míg a hosszú távú PPI-kezelés mindkét paraméter növekedéséhez vezet. A veseátültetés után a gyomorfekélyek gyakorisága nagyobb az általános populációban jellemzőnél. A legkritikusabb időszak az átültetést követő első 3 hónap. Az NKX2-3 és az IRGM gyulladásos bélbetegségre (IBD) való hajlamot jelző lókuszok a kelet-európai populációban. A femorális csontsűrűség-értékek IBD-ben szignifikánsan kisebbek, mint IBS-ben. A csökkent csontsűrűség a mikroszkópos colitisben is jellemző. A proliferáció/apoptózis arány (PAR) nő a colorectális adenoma-carcinoma szekvencia során, amellyel az oszteopontin (OPN) szint pozitívan korrelál. A PAR és OPN szint segíthet a rákképződés fázisainak azonosításában. Az MMP9 szint magasabb colitis ulcerosában (UC) a nem-IBD colitis és a kontroll csoporthoz képest. Az MMP9 fokozott kifejeződése összefügg a gyulladás súlyosságával UC-ben és szerepet játszhat a hámkárosodásban. Az IBD perifériás vér alapú elkülönítése a nem-IBD colitis-től lehetséges teljes genom expressziós profilozással. A nyiroksejt aggregátumok körüli kripták hámjában emelkedett CD45-, csontvelői eredetű sejtszám arra utal, hogy ezek a sejtek részt vesznek a hámregenerációban, a nyiroksejt aggregátum vándorlásuk köztes állomása lehet. 3g mesalazine hatékonyabb, mint 9mg budesonide aktív UC remissziójának elérésében. A 9mg budesonide terápia hatékonyabb, mint a 4,5g mesalamine kezelés enyhe-mérsékelt CD-ben. | H. pylori infection do no affect serum CgA and gastrin levels, while both parameters increase under long-term PPI treatment. The frequency of gastric ulcers is higher after kidney transplantation than in the general population. The most vulnerable period is the first 3 months. NKX2-3 and IRGM are susceptibility loci for inflammatory bowel disease (IBD) in Eastern European patients. Femoral bone density values are significantly lower in IBD than in IBS. Decreased bone density is also typical in microscopic colitis. The proliferation/apoptosis ratio (PAR) gradually increases in the colorectal adenoma-carcinoma sequence, osteopontin (OPN) level positively correlates with it. PAR and OPN level can help to identify the stages of carcinogenesis. MMP9 level increases in ulcerative colitis (UC) compared to non-IBD colitis and controls. Elevated MMP9 expression is associated with severity of infammation in UC and may play a role in epithelial damage. Peripheral blood based discrimination of IBD from non-IBD colitis can be done by whole genomic expression profiling. Elevated number of intraepithelial CD45- bone marrow-derived cells at lymphoid aggregates suggests that these cells play a role in epithelial regeneration and lymphoid aggregates serve as their migration route. 3g mesalazine granules are superior to 9mg budesonide for achieving remission in active UC. Budesonide 9 mg is at least as effective as mesalamine 4.5 g in patients with mildly to moderately active CD

Effects of RAL signal transduction in KRAS- and BRAF-mutated cells and prognostic potential of the RAL signature in colorectal cancer

Our understanding of oncogenic signaling pathways has strongly fostered current concepts for targeted therapies in metastatic colorectal cancer. The RALA pathway is novel candidate due to its independent role in controlling expression of genes downstream of RAS. We compared RALA GTPase activities in three colorectal cancer cell lines by GTPase pull-down assay and analyzed the transcriptional and phenotypic effects of transient RALA silencing. Knocking-down RALA expression strongly diminished the active GTP-bound form of the protein. Proliferation of KRAS mutated cell lines was significantly reduced, while BRAF mutated cells were mostly unaffected. By microarray analysis we identified common genes showing altered expression upon RALA silencing in all cell lines. None of these genes were affected when the RAF/MAPK or PI3K pathways were blocked. To investigate the potential clinical relevance of the RALA pathway and its associated transcriptome, we performed a meta-analysis interrogating progression-free survival of colorectal cancer patients of five independent data sets using Cox regression. In each dataset, the RALA-responsive signature correlated with worse outcome. In summary, we uncovered the impact of the RAL signal transduction on genetic program and growth control in KRAS- and BRAF-mutated colorectal cells and demonstrated prognostic potential of the pathway-responsive gene signature in cancer patients

Citokin-gén polimorfizmusok kapcsolata koraszülöttek perinatális szövődményeivel = The association of cytokine genetic polymorphisms with perinatal complications of premature infants

Vizsgálatsorozatunk kapcsán több mint 300 kis súlyú koraszülött bevonásával 32 különböző genetikai polimorfizmus (SNP) hordozás kapcsolatát elemeztük a perinatális szövődményekkel. Több olyan elemre sikerült rámutatni, amelynek jelentősége lehet egy adott szövődmény kialakulásában. Ilyen az ösztrogén-receptorral szembeni érzékenységet befolyásoló SNP, illetve a renin-angiotenzin rendszer polimorfizmusok összefüggése a perinatalis adaptációs zavarokkal, a VEGF SNP-k perinatalis szövődményekkel való kapcsolata, a TNF-alfa és az IFN-gamma, valamint az IL-12 SNP-k lélegeztetés iránti igénnyel való kapcsolata. Vizsgálataink a gyógyszerfejlesztés, valamint a terápia optimálása szempontjából végzett klinikai vizsgálatok számára kiindulási alapot jelenthetnek. Az eredmények másik hasznosítási területe a szövődmény-predikció lehet. Azt, hogy a genotípus-mintázat ismerete a megszületéskor mennyire segíti ezt a célt, egy új statisztikai eljárással (random forest technikával) elemeztük. Ezzel a módszerrel meghatároztuk, hogy az egyes SNP-k milyen mértékben segítik önmagukban a predikciót, illetve olyan SNP-mintázatokat állítottunk össze, amelyekkel megszületéskor a szövődmény-predikció pontossága fokozható. | During our studies we enrolled more than 300 preterm infants and determined the association between carrier status of 32 different genetic polymorphisms with the risk of perinatal complications. Several SNPs with a possible involvement in the investigated complications were identified. These include the association of perinatal adaptational disturaűbances with an SNP with an impact on estrogen sensitivity and with genetic polymorphisms of renin-angiotensin system; the association between VEGF SNPs and some perinatal complications; the link between TNF-alpha, IFN-gamma and IL-12 SNPs and need for ventilatory support. These results may for a basis for studies aiming drug developemnt and optimization of therapy. Another psosible field for the use of these results is complication prediction. We applied a new statistical approach (random forest technique) to determine, whether the information about genotype patterns at birth may improve complication prediction. For this purpose we established the importance score values of individual SNPs and created optimized SNP patterns with the highest predictive value

The Effect of Sleep Deprivation and Subsequent Recovery Period on the Synaptic Proteome of Rat Cerebral Cortex

Sleep deprivation (SD) is commonplace in the modern way of life and has a substantial social, medical, and human cost. Sleep deprivation induces cognitive impairment such as loss of executive attention, working memory decline, poor emotion regulation, increased reaction times, and higher cognitive functions are particularly vulnerable to sleep loss. Furthermore, SD is associated with obesity, diabetes, cardiovascular diseases, cancer, and a vast majority of psychiatric and neurodegenerative disorders are accompanied by sleep disturbances. Despite the widespread scientific interest in the effect of sleep loss on synaptic function, there is a lack of investigation focusing on synaptic transmission on the proteome level. In the present study, we report the effects of SD and recovery period (RP) on the cortical synaptic proteome in rats. Synaptosomes were isolated after 8 h of SD performed by gentle handling and after 16 h of RP. The purity of synaptosome fraction was validated with western blot and electron microscopy, and the protein abundance alterations were analyzed by mass spectrometry. We observed that SD and RP have a wide impact on neurotransmitter-related proteins at both the presynaptic and postsynaptic membranes. The abundance of synaptic proteins has changed to a greater extent in consequence of SD than during RP: we identified 78 proteins with altered abundance after SD and 39 proteins after the course of RP. Levels of most of the altered proteins were upregulated during SD, while RP showed the opposite tendency, and three proteins (Gabbr1, Anks1b, and Decr1) showed abundance changes with opposite direction after SD and RP. The functional cluster analysis revealed that a majority of the altered proteins is related to signal transduction and regulation, synaptic transmission and synaptic assembly, protein and ion transport, and lipid and fatty acid metabolism, while the interaction network analysis revealed several connections between the significantly altered proteins and the molecular processes of synaptic plasticity or sleep. Our proteomic data implies suppression of SNARE-mediated synaptic vesicle exocytosis and impaired endocytic processes after sleep deprivation. Both SD and RP altered GABA neurotransmission and affected protein synthesis, several regulatory processes and signaling pathways, energy homeostatic processes, and metabolic pathways. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12035-021-02699-x

Brain protein expression changes in WAG/Rij rats, a genetic rat model of absence epilepsy after peripheral lipopolysaccharide treatment

Peripheral injection of bacterial lipopolysaccharide (LPS) facilitates 8-10Hz spike-wave discharges (SWD) characterizing absence epilepsy in WAG/Rij rats. It is unknown however, whether peripherally administered LPS is able to alter the generator areas of epileptic activity at the molecular level. We injected 1mg/kg dose of LPS intraperitoneally into WAG/Rij rats, recorded the body temperature and EEG, and examined the protein expression changes of the proteome 12h after injection in the fronto-parietal cortex and thalamus. We used fluorescent two-dimensional differential gel electrophoresis to investigate the expression profile. We found 16 differentially expressed proteins in the fronto-parietal cortex and 35 proteins in the thalamus. It is known that SWD genesis correlates with the transitional state of sleep-wake cycle thus we performed meta-analysis of the altered proteins in relation to inflammation, epilepsy as well as sleep. The analysis revealed that all categories are highly represented by the altered proteins and these protein-sets have considerable overlap. Protein network modeling suggested that the alterations in the proteome were largely induced by the immune response, which invokes the NFkB signaling pathway. The proteomics and computational analysis verified the known functional interplay between inflammation, epilepsy and sleep and highlighted proteins that are involved in their common synaptic mechanisms. Our physiological findings support the phenomenon that high dose of peripheral LPS injection increases SWD-number, modifies its duration as well as the sleep-wake stages and decreases body temperature

Examination of Hardy-Weinberg equilibrium in papers of Kidney International: An underused tool

Background. Population-genetic studies investigating genetic polymorphisms of Mendelian inheritance should always test whether the measured genotype frequencies deviate from the expected one. For this purpose Hardy-Weinberg (HW) criteria are generally used. If genotype distribution of control population misses HW equilibrium, the results should be treated cautiously because the observed genotype distribution in control population does not represent genotype distribution in the overall population. If HW criteria are not fulfilled in the investigated population, this may be further evidence for the correlation between genotype and investigated condition. Methods. Between September, 1998, and September, 2003, we tested papers published in Kidney International if HW criteria were ordinarily and correctly checked in studies investigating genetic polymorphisms. Seventy-five genotype distributions of the selected 39 articles were reanalyzed. Results. HW calculation was reportedly performed in 25 papers (64%). The observed genotype distribution deviated significantly from the expected one in three control, and in 16 patient populations and in three populations of association studies of 15 papers overall; however, this fact was not mentioned in 12 papers. Conclusion. Although the deviation of genotype distribution from the expected one is important information, HW calculations are not performed routinely for each investigated subject groups in these papers investigating genetic polymorphisms