4 research outputs found
mutational status of HER-2, C-MYC, H-RAS and TP53 genes and methylation status of P14 and P16 genes
Uvod: Pleomorfni adenom (PA) je spororastuÄi benigni tumor koji se obiÄno javlja
u petoj deceniji života i mnogo se ÄeÅ”Äe razvija kod žena. NajÄeÅ”Äe pogaÄa velike
pljuvaÄne žlezde, a Äak u preko 70% sluÄajeva lokalizovan je u zauÅ”noj (parotidnoj)
pljuvaÄnoj žlezdi. Uglavnom se uspeÅ”no leÄi hirurÅ”ki, ali je ipak to jedini benigni
tumor pljuvaÄnih žlezda koji pokazuje sklonost ka malignoj transformaciji u
karcinom u pleomorfnom adenomu (CXPA).
U prvim, citogenetiÄkim studijama, analizom kariotipa pokazano je u najveÄem
broju sluÄajeva prisustvo karakteristiÄne hromozomske translokacije koja
ukljuÄuje PLAG1 ili HMGA2 gene. MeÄutim, kod ovih, kao i kod tumora sa
neizmenjenim kariotipom, u nastanak i progresiju tumora su ukljuÄeni i drugi
mehanizmi. NaruŔena mitogena signalna kaskada, koja u normalnim fizioloŔkim
uslovima zapoÄinje na receptorima za faktore rasta (HER-2 npr.), jedan je od
kljuÄnih mehanizama odgovornih za rast tumorske mase. Aberantni mitogeni
signal može takoÄe biti generisan i endogeno kao rezultat mutacione aktivacije
onko-proteina iz familije Ras. Jedan od moguÄih mehanizama prenosa mitogenog
signala realizuje se preko ciklin zavisnih kinaza, Äiji je snažni regulator protein
p16. Mitogeni signal prenosi se dalje u nukleus gde, izmeÄu ostalih c-myc, stimuliÅ”e
transkripciju gena ukljuÄenih u Äelijsku deobu. Ukoliko se u genomu dogode
oÅ”teÄenja, jedan od kljuÄnih tumor supresorskih gena ā TP53, zaustaviÄe Äelijski
ciklus i/ili Äeliju uvesti u apoptozu. Jedan od pozitivnih regulatora p53 funkcije je
p14, koji vezuje Mdm2, Äime onemoguÄava formiranje Mdm2/p53 inhibitornog
kompleksa. Na funkciju i stabilnost ovih proteina mogu da utiÄu razliÄite mutacije,
a na nivo ekspresije razliÄiti epigenetiÄki mehanizmi, u prvom redu metilacija
promotora.
Cilj: Cilj ove doktorske disertacije je ispitivanje povezanosti mutacija u genima
HER-2, c-myc, H-ras i TP53, kao i metilacionog statusa promotora p16 i p14 gena sa
nastankom, progresijom i malignom transformacijom pleomorfnih adenoma
parotidnih pljuvaÄnih žlezda...Introduction: Pleomorphic adenoma (PA) is a slow-growing benign tumor that
usually develops in the fourth or fifth decade of life, more often in women. It is
mostly found in the major salivary glands, and over 70% are localized in the
parotid salivary gland. Surgical removal is usually successful and the patient is
cured. However it is the only benign salivary gland tumor with a tendency toward
malignant transformation into carcinoma ex pleomorphic adenoma (CXPA).
PAs have been extensively studied from a cytogenetic point of view and indeed the
presence of specific chromosomal translocations involving PLAG1 or HMGA2 gene
loci have been reported in many instances. There has been much less studies on
other molecular events potentially involved in tumor development and
progression. Disruption of the mitotic signaling cascade is one of the key
mechanisms responsible for tumor growth. The aberrant signaling does not
necessarily start from growth factors and their receptors. It may be generated
endogenously, for instance from the mutated Ras protein. One possible
transmission of the mitogen signal is through cyclin dependent kinases that are
strongly regulated by the p16 protein. The signal is transmitted to the nucleus
where c-myc, among others, stimulates the transcription of the cell cycle
regulatory genes. Accumulation of DNA damage leads to cell cycle arrest and
programmed cell death under the control of p53. p14 interactions with Mdm2
initiate p53-dependant cell cycle arrest and apoptosis. Lack of p14 results in higher
levels of Mdm2 and p53 inhibition.
Expression, function and stability of these cancer gene products may be
considerably affected by mutations, and epimutations ā primarly gene promoter
methylation.
Aim: The aim of this doctoral dissertation was to assess the frequency and thus the
relevance of mutations in HER-2, c-myc, H-ras and TP53 genes, as well as
methylation status of p16 and p14 gene promoters in the development,
progression and malignant transformation of pleomorphic adenoma of parotid
salivary glands..
Reduced light exposure mitigates streptozotocin-induced vascular changes and gliosis in diabetic retina by an anti-inflammatory effect and increased retinal cholesterol turnover
Diabetic retinopathy is not cured efficiently and changes of lifestyle measures may delay early retinal injury indiabetes. The aim of our study was to investigate the effects of reduced daily light exposure on retinal vascularchanges in streptozotocin (STZ)-induced model of DM with emphasis on inflammation, Aqp4 expression, visualcycle and cholesterol metabolism-related gene expression in rat retina and RPE. Male Wistar rats were dividedinto the following groups: 1. control; 2. diabetic group (DM) treated with streptozotocin (100 mg/kg); 3. groupexposed to light/dark cycle 6/18 h (6/18); 4. diabetic group exposed to light/dark cycle 6/18 h (DM+6/18).Retinal vascular abnormalities were estimated based on lectin staining, while the expression of genes involved inthe visual cycle, cholesterol metabolism, and inflammation was determined by qRT-PCR. Reduced light exposurealleviated vasculopathy, gliosis and the expression of IL-1 and TNF-Ī± in the retina with increased perivascularAqp4 expression. The expression of genes involved in visual cycle and cholesterol metabolism was significantlyup-regulated in RPE in DM+6/18 vs. DM group. In the retina only the expression of APOE was significantlyhigher in DM+6/18 vs. DM group. Reduced light exposure mitigates vascular changes and gliosis in DM via itsanti-inflammatory effect, increased retinal cholesterol turnover and perivascular Aqp4 expression