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published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

Μελέτη της κυτταροτοξικής και κυτταρογενετικής δράσης της δοξορουβικίνης σε καλλιέργειες ανθρώπινων λεμφοκυττάρων in vitro, καθώς επίσης και της ικανότητας της εν λόγω ένωσης να επάγει την παραγωγή της 8-οξογουανίνης. Επίσης η μελέτη της συμμετοχής του πολυμορφισμού Ser326Cys στη δράση της παραπάνω ένωσης. / Evaluation of the involvment of Ser326Cys polymorphism to the cytotoxic and cytogenetic activity of doxorubicin in human lymphocytes cultured in vitro

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Li-Fraumeni Syndrome (LFS) is a rare cancer predisposition syndrome, typically involving germline mutations in the TP53 gene. Despite the high penetrance of TP53 mutations, LFS patients display striking phenotypic differences, suggesting the presence of secondary risk loci. To date, all genetic modifiers in LFS have been shown to map to either TP53 or its principal negative regulator, Mdm2. Given this strong association, we set out to interrogate the contribution of a recently-described miRNA regulator of the p53-MDM2 loop, called miR-605. We hypothesized that, if functional, the miR-605 gene and its variant (rs2043556) could impact cancer risk in TP53 mutation carriers. Consistent with this proposition, the variant allele of miR-605 was associated with a significant acceleration in tumor onset and caused a decrease in the processing efficiency of its host miRNA. We also demonstrate that miR-605 overexpression activates the MAPK pathway and leads to tumor suppression in TP53 mutant cell lines.

Li-Fraumeni Syndrome (LFS) is a rare cancer predisposition syndrome, typically involving germline mutations in the TP53 gene. Despite the high penetrance of TP53 mutations, LFS patients display striking phenotypic differences, suggesting the presence of secondary risk loci. To date, all genetic modifiers in LFS have been shown to map to either TP53 or its principal negative regulator, Mdm2. Given this strong association, we set out to interrogate the contribution of a recently-described miRNA regulator of the p53-MDM2 loop, called miR-605. We hypothesized that, if functional, the miR-605 gene and its variant (rs2043556) could impact cancer risk in TP53 mutation carriers. Consistent with this proposition, the variant allele of miR-605 was associated with a significant acceleration in tumor onset and caused a decrease in the processing efficiency of its host miRNA. We also demonstrate that miR-605 overexpression activates the MAPK pathway and leads to tumor suppression in TP53 mutant cell lines.

Darbo tikslas - ištirti augimo hormono geno įvairovę kiaulių tarpe ir nustatyti polimorfizmo įtaką kiaulių produktyvumo savybėms. Darbo uždaviniai: 1. Surinkti ir išanalizuoti mokslinę literatūrą apie kiaulių augimo hormoną bei jo genetinį pagrindimą. 2. Įdiegti kiaulių augimo hormono geno tyrimo metodiką LVA K.Janušausko Gyvūnų genetikos laboratorijoje. 3. Ištirti augimo hormono geno (GH) įvairovę kiaulių tarpe, naudojant sumodeliuotus pradmenis pagal geno seką. 4. Suformuoti fenotipinių požymių duomenų bazę. 5. Ištirti augimo hormono geno įvairovės įtaką kiaulių produktyvumo savybėms LVA Gyvūnų genetikos laboratorijoje įdiegta kiaulių augimo hormono geno, ištyrimo metodika. Pirmą kartą ištirtas augimo hormono geno polimorfizmas bei jo variantų įtaka kiaulių produktyvumo savybėms. Įdiegta metodika leidžia ištirti kiaulių genome augimo hormono geną, nustatyti alelių polimorfizmą ir įvertinti jo poveikį kiaulių fenotipinėms savybėms. Siūloma atsižvelgti į kiaulių genome esančio augimo hormono geno polimorfizmą, atrenkant ir parenkant gyvulius, turinčius ekonomiškai naudingus alelius, kad būtų galima pagerinti produktyviąsias savybes. / Object and tasks of work. 1. Analyse and summarize literature about growth hormone and it genetic background. 2. Introduce pig GH and GHR genes research methodology at K. Janušauskas Laboratory of Animal Genetics, LVA. 3. Investigate GH and GHR genes polymorphism and distribution of different alleles at Lithuanian pig population by PCR-RFLP method. 4. Create datebase of pig phenothypical traits 5. Determine correlation between restriction fragment length polymorphism (RFLP) in GH and GHR genes and pig phenothypical traits. Research methodology. 1. DNA extraction from hair roots. 2. PCR to amplify GH and GHR genes. 3. RFLP method. 3. Electrophoresis in agarose gel. 4. Staining with Etidium bromide. 5. Genotyping. 6. Stasitical analysis of data. Results and conclutions. Growth hormone and growth hormone receptor genes have been found to be polymorphic in tested pig population what gives possibility to use them as genetic markers. According to agregated GHRH/GHR1/GHR2 genotype the largest carcass and bacon half length had pigs with genotype ABG1G1G3G3, the lowest fat thickness with genotype BBG1G1G4G4, the largest muscularity with genotype BBG1G1G4G4, the largest makeweight had pigs with genotype ABG1G1G3G3, the smallest feed intake for 1 kg makeweigth had pigs with AAG2G2G3G4 genotype. Unifactorial analysis showed that the largest percent of meat traits variation explains agregated genotype GHRH/GHR1/GHR2 – from 10,8 percent to warm carcass weight to 29,2 percent to fat... [to full text]

In Lithuania, it is a first genetic study that analyses the DNA polymorphism of Scots pine at the level of cell’s nucleus and organelle’s genomes. In Europe, it is one of the first studies of DNR-based population structure covering in detail the eastern range of Scots pine, where the populations originate from Scotland in the west up to the Amur river estuary in the east. Our material represents a great magnitude of adaptive environments including the core populations at the central part of the species range as well as the marginal populations. The analysis was performed using high resolution and repeatability microsatellite DNA markers. / Tai yra pirmas genetinis mokslinis darbas Lietuvoje, nagrinėjantis paprastosios pušies DNR polimorfizmą ląstelės branduolio ir organoidų genomų lygmenyse. Europoje tai vienas iš pirmųjų mokslinių darbų, detaliai analizuojantis DNR polimorfizmą rytinėje paprastosios pušies rūšies arealo dalyje. Darbe lyginamos populiacijos, pradedant Škotija vakaruose, baigiant Amūro upės žiotimis tolimuose rytuose. Taip reprezentuojamas visas adaptacinių aplinkų gradientas: Europa–Uralas–Tolimieji Rytai. Tyrimui naudoti aukštos genetinės rezoliucijos ir patikimo pakartojamumo mikrosatelitinės DNR žymenys.

Phenotypic plasticity in Eurasian perch (Perca fluviatilis) can be driven by a trade-off for ecological specialisation to littoral and pelagic resources. Previous studies on perch have found that this specialisation can have different effects on linkage between the littoral and pelagic food web depending on water transparency. In this study I aimed to answer how foraging efficiency and prey preference of phenotypic divergent perch are affected by high and low water transparency, and the presence of a predator in a series of aquarium experiments. Two different phenotypes of perch were kept in littoral and pelagic environments in the lab. By presenting perch with Daphnia sp. and Ephemeroptera, either separately or combined. I found that in clear water the littoral and pelagic phenotypes were comparatively more efficient on resources that were representative of their habitats (Ephemeroptera and Daphnia, respectively) and that both phenotypes prefer Ephemeroptera over Daphnia. In low visibility the differences in foraging efficiency between phenotypes when feeding on Daphnia disappeared but remained similar to clear water when feeding on Ephemeroptera. When vision was constrained littoral and pelagic perch showed no sign of prey preferences. In the presence of a predator the difference in foraging efficiency between the phenotypes, and also prey preference disappeared. I found that littoral phenotypes interacted more with other group members than did pelagic phenotypes, when foraging on littoral prey. And for perch in general, when foraging for Daphnia the interaction among group members was markedly reduced compared to when foraging for Ephemeroptera. In this study I show that morphological adaptation and prey choice is affected by visibility and predation. I also give suggestions how and argue why this can affect linkage of food webs and the community composition in littoral and pelagic habitats.

In most cases, organic materials exist in the solid phase as polymorphs, solvatomorphs or amorphous forms. Physico-chemical properties in the solid-state are all affected primarily in terms of dissolution, solubility, bioavailability, stability and processability. Therefore investigation into the polymorphic behaviour of APIs has become a mandatory part of drug characterisation studies by pharmaceutical companies (Giron, 2001). The influence polymorphism has on bioavailability and the need for the development of drugs in the amorphous form have instigated regulatory bodies such as the FDA to require solid-state characterisation of pharmaceuticals (Strachan et al., 2005). Subsequently a study was conducted to determine the physico-chemical properties of two poorly watersoluble macrolides; clarithromycin and spiramycin. Characterisation methods included: XRPD, IR, TGA, DSC, SEM, Karl Fischer titration, solubility and stability studies. Recrystallisations of spiramycin from various solvents indicated that this API mainly exists in the amorphous form. The DSC proved to be of little value in the characterisation of this particular macromolecular antibiotic, since wide inter-sample variations were mostly obtained. TGA results showed higher solvent uptake than expected. This was ascribed to the amorphous, sponge-like character of this drug. For the sake of reproducibility and quality of the results, characterisation of spiramycin was more reliant on spectroscopic and crystallographic methods. Samples generated from 2- butanol, chloroform, ethyl acetate, 1.4-dioxane, methanol, n-propanol, iso-propanol and tetrahydrofuran showed characteristic peaks in the range of 2000-2400 cm-1 that were not present in the IR spectrum of the raw material. Conversely, the XRPD patterns were all identical, exhibiting a characteristic “halo” pattern with no detectable Bragg diffraction peaks. A solubility assessment showed no significant differences between the raw material and the recrystallisation products. In fact the raw material seemed to be the form with the highest solubility, albeit it only by a small margin. According to the literature, clarithromycin exists in five forms. Form 0 exists as a solvate, form I is a metastable form, form II is the stable form (Liu & Riley 1998; Deshpande et al., 2006), form III is a solvate of acetonitrile (Liu et al., 2003; Liang & Yao, 2008) and form IV is a hydrate (Avrutov et al., 2003). The stable form II is used in formulations currently on the market. A follow-up study was done relating to a study performed by De Jager (2005). The raw material (form II) was recrystallised from acetonitrile, chloroform and ethyl acetate. Two new crystal forms were prepared from chloroform and acetonitrile. With the necessary driving force, both of these crystals forms are able to convert to the thermodynamically stable form II. In addition, a solvate recrystallised from chloroform together with its corresponding desolvate, showed a 4 and 1.5 fold respective increase in solubility when compared to the raw material. The recrystallisations from ethyl acetate delivered crystals with an XRPD pattern similar to form II. This proved that clarithromycin can be recrystallised directly from this solvent without the need of an additional conversion step, as was the case in the study done by De Jager (2005). / MSc (Pharmaceutics), North-West University, Potchefstroom Campus, 2013