Construção e estudos de perfomance de um reator fotoquímico tipo CPC ("Compound Parabolic Concentrator")

A CPC (Compound Parabolic Concentrator) reactor was projected and constructed aiming to promote the degradation of the organic matter present in considerable volumes of aqueous effluents, under the action of solar radiation. The essays were done using a model effluent which consists of a mixture of fragments of a sodium salt of lignosulphonic acid possessing a mean molecular weigth of 52,000 Daltons, and a real effluent, from a chip board industry. The volume of effluent in each test was about 50 L. The tests involved heterogeneous (TiO2 P25 Degussa and formulations made from the association of TiO2 with a photosensitiser), and homogeneous (thermal and photochemical Fenton reactions) catalysis of the effluents. The results demonstrate the viability of application of this kind of reactor even when the load of organic pollutants is high.

Mikkelin Pursialan pohjavesialueen haitta-aineet

Mikkelin talousvedestä kahden kolmasosan tullessa Pursialan pohjavesialueelta on alueen suojeleminen tärkeää. Pohjaveden laatua uhkaavat etenkin alueella sattuneet pohjavedenpilaantumistapaukset. Merkittävimmät pohjaveden pilaantumistapaukset ovat VAPO Oy:n sahan aiheuttama pohjaveden pilaantuminen kloorifenoleilla (CP) ja VR:n ratapölkkykyllästämön aiheuttama pohjaveden pilaantuminen kreosoottiöljyllä sekä Rinnekadun Nesteen aiheuttama pohjaveden pilaantuminen MTBE:llä. Alueella on tehty tutkimuksia ja kunnostuksia pilaantumiin liittyen, mutta näiden tuloksia ei ole aikaisemmin koottu yhteen. Tämän työn tavoitteena oli koota tulokset samaan aineistoon. Työssä keskityttiin kloorifenolien leviämisen tarkasteluun sen Pursialan pohjavedenottamolle muodostaman suurimman uhan vuoksi. Kallioperätietojen, maanpintatietojen ja näytetietojen pohjalta laadittiin myös pienoismalli CP-pilaantuman leviämisen kokonaiskuvan hahmottamiseksi. Työn tavoitteena oli lisäksi tehdä riskitarkastelua CP-pilaantumaan liittyen ja etsiä keinoja hallita havaittuja riskejä. Riskinhallintaan liittyen työssä tutkittiin kloorifenoleilla pilaantuneen alueen maaperä- ja kalliotietoja sekä pohjaveden laatutietoja. Pursialan pohjavedessä on runsaasti rautaa ja mangaania sekä aggressiivista hiilihappoa. Pohjaveden pH on alueella noin 6,5, lämpötila noin 7,5 ºC ja happipitoisuus noin 0,7 mg/l. Pursialan kaupunginalueen kallioperässä on havaittavissa VAPO Oy:n sahalta vedenottamolle etenevä kalliopainanne, jota pitkin CP etenee. Alueen kallioperä on kiillegneissiä, jossa on pohjois–etelä-suuntaista rakoilua. Maaperätuloksien perusteella on havaittavissa vettä hyvin johtavien maakerrosten jatkuminen koko vedenottamon ja sahan välisen matkan, mikä tarkoittaa, että CP-pitoisella pohjavedellä voi olla aiemmin oletettua nopeampikin yhteys sahalta vedenottamolle. Suurin CP-pitoisuus noin 100 000 µg/l on mitattu KY-5-altaan kohdalle asennetun M14-pohjavesiputken pohjasta. Talousvesiasetuksen raja-arvo CP:lle on 10 µg/l. Sahan ja vedenottamon puolivälissä on havaittu yli 10 000 µg/l meneviä CP-pitoisuuksia. Suurin vedenottamon kaivoista (kaivo 10) mitattu pitoisuus on 149 µg/l. Jakotukilta raakavedestä otetuissa näytteissä tai talousvedessä ei ole kuitenkaan havaittu talousvesiasetuksen ylittäviä CP-pitoisuuksia. Pienoismallin perusteella CP sijaitsee sahan alueella lähellä kallionpintaa ja hajaantuu koko pohjavesipatjaan vedenottamolle päin mentäessä. CP-mittaustuloksissa on havaittavissa pulssimaisuutta. Tämä johtuu todennäköisesti Saimaan pinnan vaihtelun seurauksena muuttuvasta rantaimeytyneen pohjaveden määrästä. Saimaan pinnan nousu näyttäisi tuloksien perusteella nostavan CP-pitoisuuksia saha-alueella ja laskevan lähellä vedenottamoa. Pohjaveden pintatietojen perusteella tehdyn tarkastelun mukaan pohjavesi voi kulkeutua sahalta vedenottamolle parhaimmillaan noin vuodessa. Työssä arvioitiin KY-5–liuoksen vuosittaiseksi käyttömääräksi noin 648–970 m3. Allassakkaa arvioitiin syntyneen yhteensä noin 10–31 m3. Pohjaveteen arvioitiin joutuneen toiminnan aikana yhteensä noin 3 000–4 000 kg CP:tä. Kloorifenolit esiintyvät pohjavedessä lähes täysin kloorifenolaatteina. Kloorifenolien hajoaminen ja muuntuminen pohjavedessä on epätodennäköistä. Käsitteellisen mallin mukaan kloorifenolipilaantuman suurimmat riskit aiheutuvat kloorifenolien mahdollisuudesta pilata Pursialan vedenottamon talousvesi. Tällä hetkellä riskejä hallitaan kloorifenolien leviämisen tarkkailulla, sahan ja vedenottamon puolivälissä sijaitsevalla koepumppauksella sekä varautumalla aktiivihiilijauheen syöttöön talousvesiprosessiin. Koepumppauksen avulla on saatu ylös tällä hetkellä noin 69 kg kloorifenoleita. Tutkimuksen perusteella suositeltavimmat riskinhallintatoimet tulevaisuudessa ovat sahalla sijaitseva kunnostuspumppaus, sahan ja vedenottamon väliin sijoittuva suojapumppaus- ja vesiverhoyhdistelmä sekä sahan rannan kautta tapahtuvan rantaimeytymisen estäminen.

Cyanobacteria from the Baltic Sea and Finnish lakes as an energy source and modulators of bioenergetic pathways

Cyanobacteria are a diverse group of oxygenic photosynthetic bacteria that inhabit in a wide range of environments. They are versatile and multifaceted organisms with great possibilities for different biotechnological applications. For example, cyanobacteria produce molecular hydrogen (H2), which is one of the most important alternatives for clean and sustainable energy. Apart from being beneficial, cyanobacteria also possess harmful characteristics and may become a source of threat to human health and other living organisms, as they are able to form surface blooms that are producing a variety of toxic or bioactive compounds. The University of Helsinki Culture Collection (UHCC) maintains around 1,000 cyanobacterial strains representing a large number of genera and species isolated from the Baltic Sea and Finnish lakes. The culture collection covers different life forms such as unicellular and filamentous, N2-fixing and non-N2-fixing strains, and planktonic and benthic cyanobacteria. In this thesis, the UHCC has been screened to identify potential strains for sustainable biohydrogen production and also for strains that produce compounds modifying the bioenergetic pathways of other cyanobacteria or terrestrial plants. Among the 400 cyanobacterial strains screened so far, ten were identified as high H2-producing strains. The enzyme systems involved in H2 metabolism of cyanobacteria were analyzed using the Southern hybridization approach. This revealed the presence of the enzyme nitrogenase in all strains tested, while none of them are likely to have contained alternative nitrogenases. All the strains tested, except for two Calothrix strains, XSPORK 36C and XSPORK 11A, were suggested to contain both uptake and bidirectional hydrogenases. Moreover, 55 methanol extracts of various cyanobacterial strains were screened to identify potent bioactive compounds affecting the photosynthetic apparatus of the model cyanobacterium, Synechocystis PCC 6803. The extract from Nostoc XPORK 14A was the only one that modified the photosynthetic machinery and dark respiration. The compound responsible for this effect was identified, purified, and named M22. M22 demonstrated a dual-action mechanism: production of reactive oxygen species (ROS) under illumination and an unknown mechanism that also prevailed in the dark. During summer, the Baltic Sea is occupied by toxic blooms of Nodularia spumigena (hereafter referred to as N. spumigena), which produces a hepatotoxin called nodularin. Long-term exposure of the terrestrial plant spinach to nodularin was studied. Such treatment resulted in inhibition of growth and chlorosis of the leaves. Moreover, the activity and amount of mitochondrial electron transfer complexes increased in the leaves exposed to nodularin-containing extract, indicating upregulation of respiratory reactions, whereas no marked changes were detected in the structure or function of the photosynthetic machinery. Nodularin-exposed plants suffered from oxidative stress, evidenced by oxidative modifications of various proteins. Plants initiated strategies to combat the stress by increasing the levels of alpha-tocopherol, mitochondrial alternative oxidase (AOX), and mitochondrial ascorbate peroxidase (mAPX).

Enhancing absorptive capacity in a non-research and development. An action research approach to converting individual observations into organisational awareness

The ability to recognize potential knowledge and convert it into business opportunities is one of the key factors of renewal in uncertain environments. This thesis examines absorptive capacity in the context of non-research and development innovation, with a primary focus on the social interaction that facilitates the absorption of knowledge. It proposes that everyone is and should be entitled to take part in the social interaction that shapes individual observations into innovations. Both innovation and absorptive capacity have been traditionally related to research and development departments and institutions. These innovations need to be adopted and adapted by others. This so-called waterfall model of innovations is only one aspect of new knowledge generation and innovation. In addition to this Science–Technology–Innovation perspective, more attention has been recently paid to the Doing–Using–Interacting mode of generating new knowledge and innovations. The amount of literature on absorptive capacity is vast, yet the concept is reified. The greater part of the literature links absorptive capacity to research and development departments. Some publications have focused on the nature of absorptive capacity in practice and the role of social interaction in enhancing it. Recent literature on absorptive capacity calls for studies that shed light on the relationship between individual absorptive capacity and organisational absorptive capacity. There has also been a call to examine absorptive capacity in non-research and development environments. Drawing on the literature on employee-driven innovation and social capital, this thesis looks at how individual observations and ideas are converted into something that an organisation can use. The critical phases of absorptive capacity, during which the ideas of individuals are incorporated into a group context, are assimilation and transformation. These two phases are seen as complementary: whereas assimilation is the application of easy-to-accept knowledge, transformation challenges the current way of thinking. The two require distinct kinds of social interaction and practices. The results of this study can been crystallised thus: “Enhancing absorptive capacity in practicebased non-research and development context is to organise the optimal circumstances for social interaction. Every individual is a potential source of signals leading to innovations. The individual, thus, recognises opportunities and acquires signals. Through the social interaction processes of assimilation and transformation, these signals are processed into the organisation’s reality and language. The conditions of creative social capital facilitate the interplay between assimilation and transformation. An organisation that strives for employee-driven innovation gains the benefits of a broader surface for opportunity recognition and faster absorption.” If organisations and managers become more aware of the benefits of enhancing absorptive capacity in practice, they have reason to assign resources to those practices that facilitate the creation of absorptive capacity. By recognising the underlying social mechanisms and structural features that lead either to assimilation or transformation, it is easier to balance between renewal and effective operations.

New perspectives on the melanocortins and their cardiovascular effects: Potential implications for the treatment of cardiovascular diseases with melanocortin analogues

The melanocortin peptides, including melanocyte-stimulating hormones, α-, β- and γ-MSH, are derived from the precursor peptide proopiomelanocortin and mediate their biological actions via five different melanocortin receptors, named from MC1 to MC5. Melanocortins have been implicated in the central regulation of energy balance and cardiovascular functions, but their local effects, via yet unidentified sites of action, in the vasculature, and their therapeutic potential in major vascular pathologies remain unclear. Therefore, the main aim of this thesis was to characterise the role of melanocortins in circulatory regulation, and to investigate whether targeting of the melanocortin system by pharmacological means could translate into therapeutic benefits in the treatment of cardiovascular diseases such as hypertension. In experiments designed to elucidate the local effects of α-MSH on vascular tone, it was found that α-MSH improved blood vessel relaxation via a nitric oxide (NO)-dependent mechanism without directly contracting or relaxing blood vessels. Furthermore, α-MSH was shown to regulate the expression and function of endothelial NO synthase in cultured human endothelial cells via melanocortin 1 receptors. In keeping with the vascular protective role, pharmacological treatment of mice with α-MSH analogues displayed therapeutic efficacy in conditions associated with vascular dysfunction such as obesity. Furthermore, α-MSH analogues elicited marked diuretic and natriuretic responses, which together with their vascular effects, seemed to provide protection against sodium retention and blood pressure elevation in experimental models of hypertension. In conclusion, the present results identify novel effects for melanocortins in the local control of vascular function, pointing to the potential future use of melanocortin analogues in the treatment of cardiovascular pathologies.

Glyphosate as a tool to produce shikimic acid in plants

Oseltamivir phosphate is a potent viral inhibitor produced from shikimic acid extracted from seeds of Ilicium verum, the most important natural source. With the site of action 5-enolpyruvylshikimate-3-phosphate synthase (EPSP), glyphosate is the only compound capable of inhibiting its activity with the consequent accumulation of shikimic acid in plants. Corn and soybean plants were sprayed with reduced rates of glyphosate (0.0 to 230.4 g a.i. ha¹) and shikimic acid content in the dry mass was determined by HPLC 3, 7 and 10 days after application. Results showed shikimic acid accumulation in dry mass with increases of up to 969% in corn and 33,000% on soybeans, with peak concentrations 3 days after treatment (DAT). Industrial feasibility for shikimic acid production, combined with favorable climatic conditions for growing corn and soybean in virtually all over Brazil, favor the use of reduced rates of glyphosate in shikimic acid biosynthesis, with potential for use as an inducer in exploration of alternative sources for production of oseltamivir phosphate with low environmental impact.

Assessing the Potential of the Water Soluble Allelopaths of Marsilea minuta in Rice and Wheat

To investigate the allelopathic effect of Marsilea minuta against the germination and seedling growths of rice (Oryza sativa) and wheat (Triticum aestivum), germination bioassays were conducted in both Petri dish and soil cultures in laboratory conditions. Rice and wheat seeds were allowed to germinate in a 1, 2, 3, 4, and 5% (w/v) aqueous extract of whole plant and 2, 4, 6, and 8% (w/w) plant residue-incorporated soils of M. minuta. In Petri dish experiments, 5% (w/v) an aqueous extract of M. mimuta showed significantly lower germination percentages (18.8% and 56.3%), root lengths (0.9 and 4.5 cm), shoot lengths (3.3 and 12.4 cm), seedling lengths (4.1 and 25.0 cm), root dry weights (1.4 and 5.6 g), shoot dry weights (1.1 and 9.0 g), seedling biomasses (2.5 and 14.6 g), and seedling vigor indices (77.4 and 957.3) in rice and wheat, respectively. In pot experiments, the M. minuta residue infested soil, with 8% concentration, produced significantly lower germination percentages (25.3 and 37.5%), root lengths (2.7 and 6.1 cm), shoot lengths (6.2 and 16.5 cm), seedling lengths (8.9 and 22.6 cm), root dry weights (2.4 and 5.5 g), shoot dry weights (4.0 and 2.8 g), seedling biomasses (6.4 and 8.3 g), and seedling vigor indices (224.1 and 855.3) in rice and wheat, respectively. The highest phytotoxic action of 5% aqueous whole plant extract of M. minuta against test crops seem to be due to the presence of two potent phenolic compounds, namely p-coumaric acid (2.91 mg L-1) and m-coumaric acid (1.59 mg L-1) as determined by HPLC analysis.

Hyperthermia increases the metastatic potential of murine melanoma

Hyperthermia, either alone or combined with radio-, immuno- or chemotherapy, can control tumor growth, but its effect on metastasis is still controversial. In the present study, we investigated the influence of hyperthermia on the metastatic potential of B16-F10 murine melanoma cells. Incubation of melanoma cells at 43ºC for 30 min led to a significant decrease in cell viability. About half of the cells survived the acute exposure to heat. These thermoresistant cells displayed a longer lag phase as compared to control unheated B16-F10 melanoma cells. Other parameters of cell growth such as doubling time and saturation density were equivalent in both control and thermoresistant cells. Both control and treated cells were adherent, but thermoresistant cells failed to spread during the first 48 h after heat exposure. B16-F10 cells colonize the lungs of C57BL/6J mice when injected intravenously; the number of lung colonies is a measure of the metastatic potential of injected cells. Median values of 22, 10.5 and 31 colonies per injected mouse were observed for control cells, cells heated to 43ºC for 30 min and thermoresistant cells, respectively, with statistically significant differences between groups (Mann-Whitney test, P<0.02). Thus, despite its cytotoxic action, heat exposure induced the acquisition of a more metastatic phenotype in a subpopulation of B16-F10 cells

Conventional and novel strategies in the treatment of adrenocortical cancer

Adrenocortical carcinoma is a highly malignant neoplasm with an incidence of two per million people per year. Several treatment strategies have resulted in temporary or partial tumor regression but very few cases have attained long survival. Surgical resection of the primary tumor and metastases is most effective. Several chemotherapeutic protocols have been employed with variable success. Mitotane (o,p'-DDD) is an adrenalytic drug effective in inducing a tumor response in 33% of patients treated. Mitotane requires metabolic transformation for therapeutic action. Tumors may vary in their ability to metabolize mitotane and the ability of tumors to transform mitotane may predict the clinical response to the drug. Preliminary data show a possible correlation between metabolic activity of neoplastic adrenocortical tissue and response to mitotane. We have attempted to develop mitotane analogs with enhanced adrenalytic effect. Compared to mitotane, a di-chloro compound, the bromo-chloro and di-bromo analogs appear to have a greater effect. Future approaches to the treatment of adrenocortical carcinoma are likely to be based on blocking or reversing the biological mechanisms of tumorigenesis. Angiogenic and chemotactic mechanisms may play a role in adrenal tumor growth and inhibition of these mechanisms may result in inhibition of tumor growth. New mitotane analogs with greater adrenalytic potential could be a promising approach to developing more effective and selective therapies for adrenal cancer. Alternative approaches should attempt to suppress tumor growth by means of compounds with anti-angiogenic and anti-chemotactic activity.

Imidazoline receptors in the heart: a novel target and a novel mechanism of action that involves atrial natriuretic peptides

Chronic stimulation of sympathetic nervous activity contributes to the development and maintenance of hypertension, leading to left ventricular hypertrophy (LVH), arrhythmias and cardiac death. Moxonidine, an imidazoline antihypertensive compound that preferentially activates imidazoline receptors in brainstem rostroventrolateral medulla, suppresses sympathetic activation and reverses LVH. We have identified imidazoline receptors in the heart atria and ventricles, and shown that atrial I1-receptors are up-regulated in spontaneously hypertensive rats (SHR), and ventricular I1-receptors are up-regulated in hamster and human heart failure. Furthermore, cardiac I1-receptor binding decreased after chronic in vivo exposure to moxonidine. These studies implied that cardiac I1-receptors are involved in cardiovascular regulation. The presence of I1-receptors in the heart, the primary site of production of natriuretic peptides, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), cardiac hormones implicated in blood pressure control and cardioprotection, led us to propose that ANP may be involved in the actions of moxonidine. In fact, acute iv administration of moxonidine (50 to 150 µg/rat) dose-dependently decreased blood pressure, stimulated diuresis and natriuresis and increased plasma ANP and its second messenger, cGMP. Chronic SHR treatment with moxonidine (0, 60 and 120 µg kg-1 h-1, sc for 4 weeks) dose-dependently decreased blood pressure, resulted in reversal of LVH and decreased ventricular interleukin 1ß concentration after 4 weeks of treatment. These effects were associated with a further increase in already elevated ANP and BNP synthesis and release (after 1 week), and normalization by 4 weeks. In conclusion, cardiac imidazoline receptors and natriuretic peptides may be involved in the acute and chronic effects of moxonidine.

In vitro activity of hypnophilin from Lentinus strigosus: a potential prototype for Chagas disease and leishmaniasis chemotherapy

Hypnophilin and panepoxydone, terpenoids isolated from Lentinus strigosus, have significant inhibitory activity onTrypanosoma cruzi trypanothione reductase (TR). Although they have similar TR inhibitory activity at 10 μg/mL (40.3 μM and 47.6 μM for hypnophilin and panepoxydone, respectively; ~100%), hypnophilin has a slightly greater inhibitory activity (~71%) on T. cruzi amastigote (AMA) growth in vitro as well as on in vitro phytohemagglutinin (PHA)-induced peripheral blood mononuclear (PBMC) proliferation (~70%) compared to panepoxydone (69% AMA inhibition and 91% PBMC inhibition). Hypnophilin and panepoxydone at 1.25 μg/mL had 67% inhibitory activity onLeishmania (Leishmania) amazonensis amastigote-like (AMA-like) growth in vitro. The panepoxydone activity was accompanied by a significant inhibitory effect on PHA-induced PBMC proliferation, suggesting a cytotoxic action. Moreover, incubation of human PBMC with panepoxydone reduced the percentage of CD16+ and CD14+ cells and down-regulated CD19+, CD4+ and CD8+ cells, while hypnophilin did not alter any of the phenotypes analyzed. These data indicate that hypnophilin may be considered to be a prototype for the design of drugs for the chemotherapy of diseases caused by Trypanosomatidae.

Biotechnological richness of the northeastern semi-arid region: antioxidant activity of casein hydrolysates from Moxotó goat milk (Capra hircus Linnaeus, 1758) obtained by papain action

This study aimed to identify antioxidant peptides from caprine casein hydrolysates by papain application using MALDI-TOF mass spectrometer, and a 2² full factorial design, with 4 axial points, in order to evaluate kinetic parameters (time and pH) effects on the degree of hydrolysis as well as the antioxidant activity of Moxotó goat milk casein peptides. Degree of hydrolysis was determined by total and soluble protein ratio in casein. Antioxidant activity was measured by ABTS method with 2, 2-cation-azinobis (3-ethylbenzothiazoline-6-sulfonic acid). TROLOX was used as standard. Peptide pattern and sequence of antioxidant amino acids were obtained using MALDI-TOF/MS. The highest degree of hydrolysis (28.5%) and antioxidant activity (2329.6 mmol.L TROLOX. mg- 1 peptide) were observed in the permeate. NENLL, NPWDQVK and LLYQEPVLGPV peptides, detected in the permeate, were pointed as the responsible for antioxidant activity, suggesting their potential application as food supplement and pharmaceutical products.

Evaluation of antioxidant potential of Brazilian rice cultivars

This study quantified the fatty acids and evaluated the proximate composition, antioxidant activity (using the Quencher procedure), and total phenolic compound concentrations in Brazilian rice cultivars. The cultivars studied showed high amounts of unsaturated fatty acids, such as linoleic and oleic acid. The ratios of polyunsaturated and saturated fatty acids obtained were high. Regarding the antioxidant activity, the best results were found using the ABTS method and the worst in the DPPH assay. The results of the DPPH and FRAP assays showed the highest correlation. The antioxidant capacity results obtained were also much higher than those reported for other varieties worldwide. Therefore, the Quencher procedure is highly suitable for application in cereals such as rice, especially when combined with the ABTS radical capture method.

Hypercalcemia and acute kidney injury caused by abuse of a parenteral veterinary compound containing vitamins A, D, and E

A previously healthy 19 year-old male presented to the hospital with anorexia, nausea, and vomiting. Laboratory studies were significant for hypercalcemia (peak calcium value of 14.8 mg/dL) and acute kidney injury (peak serum creatinine of 2.88 mg/dL). He admitted to using a parenteral formulation of vitamins A, D and E restricted for veterinary use containing 20,000,000 IU of vitamin A; 5,000,000 IU of vitamin D3; and 6,800 IU of vitamin E per 100 mL vial. The patient stated to have used close to 300 mL of the product over the preceding year. Interestingly, the young man was not interested in the massive amounts of vitamins that the product contained; he was only after the local effects of the oily vehicle. The swelling produced by the injection resulted in a silicone-like effect, which gave the impression of bigger muscles. Nevertheless, the product was absorbed and caused hypervitaminosis. The serum level of 25(OH) vitamin D was clearly elevated at 150 ng/mL (reference range from 30 to 60 ng/mL), but in most published cases of vitamin D toxicity, serum levels have been well above 200 ng/mL. His PTH level was undetectable and other potential causes of hypercalcemia were excluded. Therefore, we posit that the severity of the hypercalcemia observed in this case was the result of a synergistic effect of vitamins A and D. The patient was treated with normal saline, furosemide and zolendronic acid, with rapid normalization of calcium levels and renal function.

Action anti-leucémique des inhibiteurs de la méthylation de l’ADN et de la déacétylation des histones

Les gènes suppresseurs de tumeurs (TSGs) contrôlent la prolifération cellulaire et leur inactivation joue un rôle important dans la leucémogénèse. Deux mécanismes épigénétiques majeurs sont impliqués dans la répression des TSGs: 1- la méthylation de l’ADN et 2- la déacétylation des histones des chromosomes. On les dit épigénétiques car ils n’affectent pas la séquence de l’ADN. Ces phénomènes sont réversibles, faisant donc d’eux des cibles thérapeutiques de choix. Dans le cadre de cette thèse, nous avons évalué le potentiel chimiothérapeutique de différents agents qui visent ces mécanismes épigénétiques et nous les avons administrés seuls et en combinaison dans le but d’améliorer leur efficacité. La 5-aza-2’-désoxycytidine (5-Aza-CdR) est un inhibiteur de la méthylation de l’ADN qui permet la ré-expression des TSGs. Cet agent s’est avéré efficace contre certaines maladies hématologiques et est d’ailleurs approuvé aux États-Unis dans le traitement du syndrome myélodysplasique depuis 2006. Cependant, le protocole d’administration optimal de cet agent, en termes de doses et de durée, n’est toujours pas établi. Nos recherches suggèrent que le celui-ci devrait être plus intensif que ce que rapporte la littérature. Les inhibiteurs des déacétylases des histones (HDACi) ont également montré une activité antinéoplasique intéressante. De récentes recherches ont montré que la combinaison d’agents ciblant à la fois la méthylation de l’ADN et la déacétylation des histones produit une réactivation synergique des TSGs, ce à quoi nous nous sommes intéressé. Nous avons observé que la co-administration d’un HDACi avec la 5-Aza-CdR potentialise son action anti-leucémique. Il est aussi possible d’augmenter l’activité de la 5-Aza-CdR en inhibant sa dégradation par l’enzyme cytidine (CR) désaminase. Nous avons observé que la co-administration du zebularine, un inhibiteur de la CR désaminase, avec la 5-Aza-CdR accroît son efficacité. Le zebularine est aussi un inhibiteur de la méthylation de l’ADN, ce qui pourrait contribuer à la potentialisation de la réponse anti-leucémique observée lors de la co-administration de ces deux agents. En résumé, il est possible d’augmenter l’efficacité anti-leucémique de la 5-Aza-CdR en : 1- intensifiant son protocole d’administration, en termes de doses et de durée, 2- la combinant avec un HDACi, et 3- diminuant sa dégradation par la CR désaminase. L’utilisation de ces résultats précliniques dans l’élaboration de protocoles cliniques pourrait être bénéfique à beaucoup de patients.