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1.
Preurejanje genov TMPRSS2 in ERG ter njuna prognostična vloga pri slovenskih bolnikih s karcinomom prostate
Zoran Krstanoski, 2017, doktorsko delo/naloga

Opis: Namen: Rak na prostati (CaP) je najpogostejša rakasta bolezen pri moških in eden glavnih razlogov zbolevnosti in umrljivosti. V zadnjih letih je vse več raziskav o novih tumorskih označevalcih za zgodnjo diagnozo prostatičnega karcinoma. Z dokazanimi napovednimi vrednostmi novih markerjev bi bolje razumeli naravni potek bolezni, omogočili zgodnejše in zanesljivejše odkrivanje karcinoma ter pripomogli k natančnejši napovedi progresa in metastaziranja bolezni pri posamičnem bolniku. Bolniki in metode: Opravili smo retrospektivno raziskavo na vzorcih prostate 202 bolnikov, pri katerih smo zaradi dokazanega karcinoma prostate naredili laparoskopsko radikalno prostatektomijo na urološkem oddelku Splošne bolniš nice Slovenj Gradec. Bolniki so bili operirani v obdobju od januarja 2010 do julija 2011. Morfološke značilnosti in klasične napovedne dejavnike karcinomov smo zbrali iz histopatoloških izvidov in jih potrdili tudi z revizijo preparatov. Za raziskavo smo konstruirali tkivne mreže. Tako pripravljene preparate smo obdelali po metodi fluorescentne hibridizacije in situ. Rezultati: V tumorskem tkivu bolnikov smo odkrili tri glavne oblike preurejanja genov: fuzijo TMPRSS2:ERG smo našli pri 63 (42 %) bolnikih, cepitev TMPRSS2 pri dvanajstih in cepitev ERG pri osmih bolnikih. Fuzijo TMPRSS2:ERG in cepitev TMPRSS2 hkrati smo ugotovili le pri enem bolniku. Pri treh bolnikih smo odkrili istočasno fuzijo TMPRSS2:ERG in cepitev ERG. Ko smo primerjali skupino 63 bolnikov z gensko fuzijo TMPRSS2:ERG in Gleasonov stadij pred operacijo, smo uporabili Freeman-Haltonovo varianto Fisherjevega natančnega testa, pri tem pa med spremenljivkama nismo našli statistične povezave (p = 0,19). Če smo analizirali odnos med gensko fuzijo in stadijem pT v celi kohorti bolnikov, povezave nismo mogli ugotoviti. Ko pa smo razdelili bolnike v dve skupini, eno s stadijem pT2 in drugo s pT3, smo odkrili statistično značilno povezavo med stadijem pT3 in osnovno gensko fuzijo. Med 62 bolniki s stadijem pT3 smo našli gensko fuzijo pri 34 (55 %) bolnikih. Z uporabo Fisherjevega natančnega testa smo odkrili statistično zanesljivost s p = 0,01. Po uporabi Bonferronieve korekcije pa je bila vrednost p še vedno zanesljiva z vrednostjo 0,05. V naslednjem koraku smo preverili še povezavo med gensko fuzijo in stadijem pN. Bolnike z opravljeno elektivno disekcijo bezgavk smo razdelili v dve skupini, in sicer pN0 in pN1. Za ta del odvisnosti smo uporabili Freeman-Haltonovo raširitev Fisherjevega natančnega testa. Med obema spremenljivkama nismo našli statistične povezave (p = 0,66). Za analizo bolnikov z ugotovljenim stadijem N smo izbrali skupino s tumorskim stadijem pT3. Pokazalo se je, da je korelacija z gensko fuzijo statistično značilna (p = 0,02). Ko pa smo uporabili še Bonferronievo korekcijo, vrednost p ni dosegla 0,05. V nadaljnjih statističnih obdelavah smo skupino bolnikov s stadijem pT3 razdelili na dvoje ‒ v skupino z razširjeno limfadenektomijo in skupino brez tega posega. Pri bolnikih, kjer posega nismo opravili, smo gensko fuzijo odkrili v 25 (64 %) primerih. Povezava med gensko fuzijo in to značilnostjo je dosegla statistično vrednost p = 0,039. Zaključek: Na podlagi naših rezultatov pričakujemo, da bi pri bolnikih s fuzijo TMPRSS2:ERG, odkriti že na biopsiji prostate, dokazali stadij T3 po radikalni prostatektomiji v več kot polovici primerov (64 %). Podatek je pomemben predvsem za bolnike s predoperativno nizkimi PSA in GS, kar sicer kaže na rak z nizkim ali zmernim tveganjem, vendar bi tako resno podcenili razširjenost bolezni. Ker bi pri teh bolnikih torej pričakovali lokalno napredovano bolezen oziroma stadij-pT3, bi z radikalnejšim posegom dosegli nižji odstotek pozitivnih robov (ki v zadnjih smernicah še vedno dosegajo 33,5‒66 %). Pri bolnikih s klinič nim stadijem pT3 pričakujemo limfogene metastaze v 7,9‒49 odstotkih.
Ključne besede: rak prostate, prostatektomija, FISH, genske preureditve, klinič no-patološke korelacije, napovedni dejavniki
Objavljeno: 17.10.2017; Ogledov: 906; Prenosov: 44
.pdf Celotno besedilo (4,35 MB)

2.
Specific behavioural phenotype and secondary cognitive decline as a result of an 8.6 Mb deletion of 2q32.2q33.1
Hojka Gregorič Kumperščak, Danijela Krgović, Nadja Kokalj-Vokač, 2016, izvirni znanstveni članek

Opis: Chromosomal abnormalities involving 2q32q33 deletions are very rare and present with a specific phenotype. This case report describes a 37-year-old female patient with 2q32q33 microdeletion syndrome presenting with the characteristic features, but with the addition of secondary cognitive decline. Molecular karyotyping was performed on the patient and her parents. It revealed an 8.6 megabase deletion with the proximal breakpoint in the chromosome band 2q32.2 and the distal breakpoint in 2q33.1. The deletion encompassed 22 known genes, including the GLS, MYO1B, TMEFF2, PGAP1 and SATB2 genes. The observed deletion was confirmed using a paralogue ratio test. This case report provides further evidence that the SATB2 gene, together with GLS, MYO1B, TMEFF2 and possibly PGAP1, is a crucial gene in 2q32q33 microdeletion syndrome. The SATB2 gene seems to be crucial for the behavioural problems noted in our case, but deletion of the GLS, MYO1B and TMEFF2 genes presumably contributed to the more complex behavioural characteristics observed. Our patient is also, to our knowledge, the only patient with 2q32q33 microdeletion syndrome with secondary cognitive decline.
Ključne besede: 2q32q33 microdeletion syndrome, behavioural problems, secondary cognitive decline, developmental delay, SATB2 gene
Objavljeno: 13.07.2017; Ogledov: 564; Prenosov: 287
.pdf Celotno besedilo (411,05 KB)
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3.
Submicroscopic interstitial deletion of chromosome 11q22.3 in a girl with mild mental retardation and facial dysmorphism: Case report
Danijela Krgović, Nataša Marčun-Varda, Andreja Zagorac, Nadja Kokalj-Vokač, 2011, izvirni znanstveni članek

Opis: Background: Except for terminal deletions that lead to Jacobsen syndrome, interstitial deletions involving the long arm of chromosome 11 are not frequently reported. A clinically distinct phenotype is usually observed in these cases, and no clear genotype-phenotype correlation is proposed. Results: Here we present a case study of a 5-year-old girl with de novo submicroscopic deletion of chromosome 11q22.3 with mild mental retardation and facial dysmorphism. A standard cytogenetic analysis did not reveal any structural aberrations. A contrary array-CGH analysis indicated a small deletion of 11q22.3. Discussion: To our knowledge, this is the smallest 11q22.3 deletion reported in literature, containing nine RefSeq genes. Although none of the deleted genes are obvious candidates for the features observed in our patient, genes CUL5 and SLN could play a key role in the features described.
Ključne besede: 11q22.3 deletion, mild mental retardation, facial dysmorphism
Objavljeno: 29.06.2017; Ogledov: 790; Prenosov: 296
.pdf Celotno besedilo (766,41 KB)
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4.
An evaluation of SOX2 and hTERC gene amplifications as screening markers in oral and oropharyngeal squamous cell carcinomas
Nadja Kokalj-Vokač, Bogdan Čizmarevič, Andreja Zagorac, Boris Zagradišnik, Boštjan Lanišnik, izvirni znanstveni članek

Opis: Background: Oral and oropharyngeal squamous cell carcinomas (OSCC) are among the most common cancers. The poor survival rate among oral cancer patients can be attributed to several factors, one of them being lack of early detection. A key approach to this problem would be to detect potentially malignant lesion at their early stage. Using the FISH technique, oral brush cytology slides can be an easy and rapid screening approach for malignant cell detection. The present study was designed to detect hTERC and SOX2 amplifications in OSSC exfoliative tumor cells and evaluate whether those two gene amplifications might serve as a supportive biomarker in early detection and diagnosis of oral and oropharyngeal SCC. Results: Brush biopsies were collected from exophytic and exulcerated oral and oropharyngeal lesions of the oral cavity of 71 patients and 22 healthy controls. FISH techniques using a TERC-specific DNA probe and a SOX2 DNA specific probe both combined with a centromere 3-specific control probe was performed on the cytology slides. A 100 squamous epithelial cell nuclei of the smears per slide were analysed. As abnormal FISH pattern were considered amplified and polyploid patterns. From 71 brush biopsies of oropharynx and other locations in oral cavity analysed by FISH 49 were considered to be abnormal (69%). The over representation of polyploidy and/or TERC/SOX2 amplification in tumour samples was statistically significant when compared to controls (p = 0.01). Conclusion: SOX2 and TERC gene amplifications are common in all squamous cell carcinomas and their detection in early stages could be crucial for early detection and more accurate prognosis. Our study strongly suggests that early detection by FISH on cytobrushed samples could be a possible non-invasive screening method even before a tissue biopsy is performed.
Ključne besede: SOX and hTERC gene amplifications, brush biopsy, Oral, oropharyngeal squamous cell carcinoma
Objavljeno: 29.06.2017; Ogledov: 750; Prenosov: 315
.pdf Celotno besedilo (1,28 MB)
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5.
TMPRSS2:ERG gene aberrations may provide insight into pT stage in prostate cancer
Zoran Krstanoski, Nadja Kokalj-Vokač, Andreja Zagorac, Boris Pospihalj, Miha Munda, Sašo Džeroski, Rastko Golouh, 2016, izvirni znanstveni članek

Opis: Background: TMPRSS2:ERG gene aberration may be a novel marker that improves risk stratification of prostate cancer before definitive cancer therapy, but studies have been inconclusive. Methods: The study cohort consisted of 202 operable prostate cancer Slovenian patients who underwent laparoscopic radical prostatectomy. We retrospectively constructed tissue microarrays of their prostatic specimens for fluorescence in situ hybridization, with appropriate signals obtained in 148 patients for subsequent statistical analyses. Results: The following genetic aberrations were found: TMPRSS2:ERG fusion, TMPRSS2 split (a non-ERG translocation) and ERG split (an ERG translocation without involvement of TMPRSS2). TMPRSS2:ERG gene fusion happened in 63 patients (42 %), TMPRSS2 split in 12 patients and ERG split in 8 patients. Association was tested between TMPRSS2:ERG gene fusion and several clinicopathological variables, i.e., pT stage, extended lymph node dissection status, and Gleason score, correcting for multiple comparisons. Only the association with pT stage was significant at p = 0.05: Of 62 patients with pT3 stage, 34 (55 %) had TMPRSS2:ERG gene fusion. In pT3 stage patients, stronger (but not significant) association between eLND status and TMPRSS2:ERG gene fusion was detected. We detected TMPRSS2:ERG gene fusion in 64 % of the pT3 stage patients where we did not perform an extended lymph node dissection. Conclusions: Our results indicate that it is possible to predict pT3 stage at final histology from TMPRSS2:ERG gene fusion at initial core needle biopsy. FISH determination of TMPRSS2:ERG gene fusion may be particularly useful for patients scheduled to undergo a radical prostatectomy in order to improve oncological and functional results.
Ključne besede: FISH, predicting pT stage, radical prostatectomy, prostate cancer, TMPRSS2:ERG fusion
Objavljeno: 29.06.2017; Ogledov: 963; Prenosov: 335
.pdf Celotno besedilo (1,06 MB)
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6.
A coalescence of two syndromes in a girl with terminal deletion and inverted duplication of chromosome 5
Danijela Krgović, Ana Blatnik, Ante Burmas, Andreja Zagorac, Nadja Kokalj-Vokač, 2014, izvirni znanstveni članek

Opis: Background: Rearrangements involving chromosome 5p often result in two syndromes, Cri-du-chat (CdC) and Trisomy 5p, caused by a deletion and duplication, respectively. The 5p15.2 has been defined as a critical region for CdC syndrome; however, genotype-phenotype studies allowed isolation of particular characteristics such as speech delay, cat-like cry and mental retardation, caused by distinct deletions of 5p. A varied clinical outcome was also observed in patients with Trisomy 5p. Duplications of 5p10-5p13.1 manifest themselves in a more severe phenotype, while trisomy of regions distal to 5p13 mainly causes mild and indistinct features. Combinations of a terminal deletion and inverted duplication of 5p are infrequent in literature. Consequences of these chromosomal rearrangements differ, depending on size of deletion and duplication in particular cases, although authors mainly describe the deletion as the cause of the observed clinical picture. Case presentation: Here we present a 5-month-old Slovenian girl, with de novo terminal deletion and inverted duplication of chromosome 5p. Our patient presents features of both CdC and Trisomy 5. The most prominent features observed in our patient are a cat-like cry and severe malformations of the right ear. Conclusion: The cat-like cry, characteristic of CdC syndrome, is noted in our patient despite the fact that the deletion is not fully consistent with previously defined cat-like cry critical region in this syndrome. Features like dolichocephaly, macrocephaly and ear malformations, associated with duplication of the critical region of Trisomy 5p, are also present, although this region has not been rearranged in our case. Therefore, the true meaning of the described chromosomal rearrangements is discussed.
Ključne besede: deletion with inverted duplication of 5p, trisomy 5, cri-du-chat syndrome, cat-like cry, ear agenesis
Objavljeno: 28.06.2017; Ogledov: 902; Prenosov: 322
.pdf Celotno besedilo (1,07 MB)
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7.
MTHFR C677T and A1298C genotypes and haplotypes in Slovenian couples with unexplained infertility problems and in embryonic tissues from spontaneous abortions
Špela Stangler Herodež, Boris Zagradišnik, Alenka Erjavec Škerget, Andreja Zagorac, Iztok Takač, Veljko Vlaisavljević, Lidija Lokar, Nadja Kokalj-Vokač, 2013, izvirni znanstveni članek

Opis: The objective of this study was to analyze the methylenetetrahydrofolate reductases (MTHFRs) C677T and A1298C genotype distributions in couples with unexplained fertility problems (UFP) and healthy controls, and to analyze the genotype and haplotype distribution in spontaneously aborted embryonic tissues (SAET) using allele specific polymerase chain reaction (PCR) in 200 probands with UFP, 353 samples of SAET and 222 healthy controls. The analysis revealed a significant overall representation of the 677T allele in male probands from couples with UFP (p = 0.036). The combined genotype distribution for both MTHFR polymorphisms was also significantly altered (χ2 21.73, p <0.001) although female probands made no contribution (c2 1.33, p = 0.72). The overall representation of the 677T allele was more pronounced in SAET (0.5 vs. 0.351 in controls, p <0.001) regardless of the karyotype status (aneuploidy vs. normal karyotype). In addition, the frequencies of the CA and CC haplotypes were significantly lower than in the control group (p = 0.021 and p = 0.001, respectively), whereas the frequency of the TC haplotype was significantly higher than in controls (p <0.0001). The presented findings indicate that only male probands contribute to the association of MTHFR mutations with fertility problems in grown adults and demonstrate a high prevalence of mutated MTHFR genotypes in SAET.
Ključne besede: methylenetetrahydrofolate reductase (MTHFR), genotype, haplotype, infertility, miscarriage
Objavljeno: 30.03.2017; Ogledov: 795; Prenosov: 240
.pdf Celotno besedilo (266,46 KB)
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8.
Detection of mutations in the CYP21A2 gene
Špela Stangler Herodež, Lusien Fijavž, Boris Zagradišnik, Nadja Kokalj-Vokač, 2015, izvirni znanstveni članek

Opis: The objective of this study was to compare the CYP 21A2 genetic profiles of couples with unexplained fertility problems (UFP) with genetic profiles of healthy controls (HCs). Furthermore, we analyzed associations between mutations in the CYP21A2 gene and various clinical and laboratory parameters. Allele-specific polymerase chain reaction (PCR) was used in 638 probands with UFP and 200 HCs. Statistic analysis with χ2 was used to study the association of mutations with infertility. The effect of mutations on particular clinical and laboratory parameters was assessed with the analysis of variance (ANOVA) test. With regard to the CYP21A2 gene, 0.6% of probands with UFP and 0.5% of HCs were positive for the c.290-13A/C>G mutation; 0.6% of probands with UFP and 1.5% of HCs were positive for the p.I172N mutation; there were no probands with UFP positive for the p.P30L mutation, whereas 0.5% of HCs were; and 0.2% of probands with UFP and 0.5% of HCs were found to have the p.V281L mutation. We found a significant association between c.290-13A/C>G mutation and the frequency of significant hormone deviations (χ2 = 6.997, p = 0.008). Similar association was also observed between the c.29013A/C>G mutation and the frequency of polycystic ovary syndrome (PCOS) (χ2 = 16.775, p = 0.000). Our findings indicate that no significant difference in the prevalence of CYP 21A2 mutations can be found in probands with UFP when compared with HCs without infertility history. The results also imply the significant association of the c.290-13A/ C>G mutation in the CYP21A2 gene, not only with the frequency of PCOS, but also with the frequency of significant hormone deviations.
Ključne besede: CYP21A2 gene, genetics, infertility, mutations, unexplained infertility problems (UFP), healthy controls (HCs)
Objavljeno: 30.03.2017; Ogledov: 654; Prenosov: 107
.pdf Celotno besedilo (249,68 KB)
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9.
Uporaba PRT začetnih oligonukleotidov za določanje kromosomskih anevploidij
Klavdija Lipnik, 2015, druge monografije in druga zaključena dela

Ključne besede: kromosomske anevploidije, splav, kapilarna elektroforeza, PRT metoda, začetni oligonukleotidi
Objavljeno: 03.08.2016; Ogledov: 966; Prenosov: 91
.pdf Celotno besedilo (622,62 KB)

10.
Vloga polimorfizma v genu GABRG2 in insercije citozina v genu SEZ6 ter kliničnih dejavnikov pri nastanku vročinskih krčev
Peter Gradišnik, 2016, doktorsko delo/naloga

Opis: NAMEN. Vročinski krči so najpogostejša konvulzivna motnja v otroštvu. Na njihov nastanek vplivajo tako genetski kot okoljski dejavniki. Kandidatne gene predstavljajo predvsem geni, ki kodirajo sestavo enot napetostno-odvisnih ionskih kanalčkov, receptorjev v centralnem živčevju ter geni, ki vplivajo na medsebojno prepoznavo živčnih celic in njihovo povezovanje. Naš namen je bil, prispevati drobec informacije k raziskavam tako na kliničnem kot na genetskem področju. Na slednjem smo se posvetili raziskavi vloge genov SEZ6 in GABRG2, ki bi bila lahko, glede na rezultate predhodnih študij, vpletena v nastanek vročinskih krčev, pa tudi kasnejše epilepsije. METODE. V prospektivno študijo smo vključili 179 otrok, obravnavanih na Kliniki za pediatrijo Maribor zaradi prve epizode vročinskih krčev. Iz obstoječe medicinske dokumentacije in kasnejšim dopolnjevanjem anamneze smo pridobili podatke o kliničnih parametrih. EEG posnetke smo opravili pri bolnikih brez povišane temperature 2 do 3 tedne po napadu. Paciente smo klinično sledili 2,1 do 9,2 let, v povprečju 6,6 let. Ob tem nas je zanimalo število ponovitev vročinskih krčev in morebiten prehod v epilepsijo. Iz vzorcev njihove krvi in iz vzorcev krvi 200 zdravih odraslih preiskovancev kontrolne skupine smo izolirali genomsko DNA ter ugotavljali prisotnost polimorfizma rs209354 v genu GABRG2 in polimorfizma rs11450637 (insercije citozina) v genu SEZ6 z metodo polimerazne verižne reakcije, agarozne gelske in kapilarne elektroforeze. Kategorične spremenljivke smo primerjali s testom hi-kvadrat ali Fischerjevim testom. Za normalno razporejene zvezne spremenljivke smo uporabili Studentov test t, Mann-Whitneyev test U pa smo uporabili, kadar razporeditev ni bila normalna. Za primerne spremenljivke smo uporabili tudi model binarne regresije. REZULTATI. Vročinski krči so se vsaj enkrat ponovili pri 58 (32,5 %) otrok. Pri 32 otrocih (17,9 %) je šlo za le eno ponovitev, večkratne ponovitve je imelo 26 (14,5 %) otrok. Epileptiformne spremembe smo našli pri 30 otrocih (16,8 %). Med njimi je polovica imela primarno generalizirane, polovica pa žariščne spremembe. Do razvoja epilepsije je prišlo pri 12 (6,7 %) otrok. Med 27 bolniki, pri katerih je bil prvi napad klinično žariščen, je 5 otrok (18,5 %) kasneje zbolelo za epilepsijo. Ob hkratni vključitvi klinične žariščnosti in žariščnih epileptiformnih sprememb je do razvoja epilepsije prišlo v polovici primerov. Z višjim tveganjem nastanka epilepsije so povezani tudi nizko povišana temperatura ob prvi epizodi vročinskih krčev, število ponovitev vročinskih krčev in pozitivna družinska anamneza epilepsije. Dejavniki tveganja ponovitev vročinskih krčev so pozitivna družinska anamneza vročinskih krčev, nizka starost ob prvi epizodi, ponovitev napada v roku 24 ur, pa tudi žariščne spremembe v EEG. Z višjo verjetnostjo prve ponovitve nista pomembno povezana klinična žariščnost napada in nizka temperatura ob prvi epizodi, vendar obstaja statistično značilna obratno sorazmerna povezava višine telesne temperature in števila ponovitev. Polimorfizem rs209354 v genu GABRG2 in insercija citozina v genu SEZ6 nista povezana ne z višjo verjetnostjo ponovitev vročinskih krčev, ne z višjim tveganjem kasnejše epilepsije. ZAKLJUČKI. Med rezultati izstopa predvsem podatek, da je elektroencefalografska žariščnost napadov statistično pomemben napovedni dejavnik tako glede verjetnosti ponovitev vročinskih krčev kakor tudi kasnejšega prehoda v epilepsijo, glede prehoda v epilepsijo pa je statistično pomembno napovedna tudi klinična žariščnost. Negativen rezultat genetskega dela kaže, da se delež vpliva posameznih genov h genetski nagnjenosti k vročinskim krčem v različnih populacijah najverjetneje razlikuje.
Ključne besede: vročinski krči, epilepsija, otrok, EEG, genetika, SEZ6, GABRG2
Objavljeno: 16.05.2016; Ogledov: 1047; Prenosov: 116
.pdf Celotno besedilo (2,45 MB)

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