Methyl 2-cyano-3,11-dioxo-18b-olean-1,12-dien-30-oate (CDODA-Me) is a synthetic triterpenoid that inhibits growth of Panc1 and Panc28 pancreatic cancer cell lines and activates peroxisome proliferator-activated receptor B (PPARB)-dependent transactivation in these cells. CDODA-Me has also induced p21 and p27 protein expression and downregulated cyclin D1; however, these responses were receptor-independent. CDODA-Me induced apoptosis, which was accompanied by receptor-independent induction of the proapoptotic proteins early growth response-1 (Egr-1), nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1), and activating transcription factor-3 (ATF3). Induction of NAG-1 in Panc28 cells was p38-mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3-K)-dependent, but Egr-1-independent, whereas induction in Panc1 cells was associated with activation of p38-MAPK, PI3-K and p42-MAPK and was only partially Egr-1-dependent. Specificity protein (Sp) transcription factors Sp1, Sp3 & Sp4 are overexpressed in multiple tumor types and negative prognostic factors for survival. Since Sp proteins regulate genes associated with survival (survivin), angiogenesis [vascular endothelial growth factor and its receptors] and growth [cyclin D1, epidermal growth factor receptor], research in this laboratory has focused on development of anticancer drugs that decrease Sp protein expression. Arsenic trioxide, curcumin, 2-cyano-3,12-dioxoleana-1,9-dien-28-oic acid (CDDO), CDDO-Me, and celastrol exhibit antiproliferative, antiangiogenic and proapoptotic activity in many cancer cells and tumors. Treatment of cancer cells derived from urologic and gastrointestinal tumors with arsenic trioxide decreased Sp1, Sp3 and Sp4 transcription factors and cotreatment with the proteosome inhibitor MG132 did not inhibit downregulation of Sp proteins in these cancer cells. Mechanistic studies suggested that compound-dependent downregulation of Sp and Sp-dependent genes was due to decreased mitochondrial membrane potential and induction of reactive oxygen species, and the role of peroxides in mediating these responses was confirmed using hydrogen peroxide, demonstrating that the mitochondriotoxic effects of these compounds are important for their anticancer activities. Moreover, repression of Sp and Sp-dependent genes by CDDO-Me and celastrol was due to downregulation of microRNA-27a and induction of ZBTB10, an Sp repressor, and these responses were also reversed by antioxidants. Thus, the anticancer activity of CDDO-Me and celastrol is due, in part, to activation of ROS which in turn targets the microRNA-27a:ZBTB10?Sp transcription factor axis to decrease growth inhibitory, pro-apoptotic and antiangiogenic genes and responses.

Anthropogenic and geogenic sources of arsenic (As) have been identified in mining-impacted soils from the Giant mine (1948-1999), NT and the North Brookfield mine (1886-1906), NS. Both used roasting to extract gold from the arsenopyrite ore, decomposing it to As-bearing iron oxides (roaster oxides or RO) containing As, and releasing As3+-bearing arsenic trioxide (As2O3). Arsenic trioxide is considered highly soluble with the dissolved As3+ species being more mobile and toxic than other oxidation states. Soil profiles from the Giant mine show elevated As and antimony (Sb) at the surface (As=140-3300ppm) and decreasing concentrations with depth (As=22-600ppm). Surface soils contain anthropogenically-derived As2O3 identified using synchrotron methods (µXRD, µXANES) and environmental SEM. The persistence of As2O3 is attributed to Sb in As2O3 grains, dry climate and high organics in the soils. Anthropogenically-derived RO of maghemite (containing both As3+ and As5+) and natural arsenopyrite were observed. Sequential selective extractions (SSE) from surface soils show between 20% and 75% of As extracted in the crystalline iron-oxide phase is attributed to As2O3 and RO, while at depth As is bound by organics in the weaker leaches. North Brookfield mine soils show lower total As (2ppm to 45ppm) except near the roaster (4300ppm). No As2O3 was identified, probably due to the smaller scale and age of the mine, lower organic content and the lack of Sb. As-bearing phases include RO of hematite (As5+), As-rich rims on titanium-oxides, and As associated with clays and goethite. Adjacent to the roaster, SSE show As was also in the amorphous iron-oxide phase, also shown by As in arsenopyrite weathering rims. There are many differences between the North Brookfield and Giant mine soils including roasting techniques which produced different RO mineralogy, the scale of mining, climate, soil type, and the presence of As2O3. Currently, the Giant property is not publically accessible but may become so in the future while the North Brookfield property is accessible. Understanding the form and distribution of As phases is critical because of the potential risk to human and ecosystem health associated with ingestion of soil particles and their control on the total dissolved As in surface and groundwater. / Thesis (Master, Geological Sciences & Geological Engineering) -- Queen's University, 2008-09-29 17:21:50.73

Orientador: Wilma De Grava Kempinas / Texto em português e inglês / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-24T16:12:27Z (GMT). No. of bitstreams: 1 Silva_RaquelFrenedoso_M.pdf: 3492189 bytes, checksum: 66cf94f64336b7c79f7b1cf8981d8d60 (MD5) Previous issue date: 2014 / Resumo: O trióxido de arsênio (As2O3) tem se mostrado altamente eficaz e muito utilizado no tratamento para diminuir ou eliminar a leucemia promielocítica aguda. Estudos mostram relação entre exposição a este composto e inibição da espermatogênese ou desenvolvimento do espermatozoide, uma vez que exerce efeito inibitório nos testículos. Diante da crescente utilização do As2O3 no tratamento da leucemia e da escassez de resultados sobre os seus efeitos adversos na reprodução masculina, justifica-se a realização do presente estudo, pelo qual se avaliou os efeitos imediatos e tardios do tratamento com As2O3 sobre fisiologia reprodutiva de camundongos Swiss adultos e se a co-administração de N-acetilcisteína (NAC), previne esses efeitos. Em um primeiro experimento, camundongos Swiss adultos foram tratados com veículo, 0,3 ou 3,0 mg/Kg/dia de As2O3, via subcutânea, em 25 aplicações. No final do tratamento, metade dos animais foram eutanasiados para avaliação dos efeitos pós-tratamento e a outra metade foi mantida sem a droga por período de 50 dias, até que se procedeu a eutanasia para avaliação da possível reversibilidade dos efeitos. Foram investigados: peso dos órgãos vitais, reprodutores e glândulas sexuais acessórias, quantidade e qualidade espermáticas, dosagem de testosterona e dosagem de arsênio no sangue. Os animais tratados com 3,0 mg/kg de As2O3 e eutanasiados logo após o fim do tratamento mostraram diminuição no peso da vesícula seminal, número de espermatozoides móveis e produção espermática diária. Após período de suspensão do tratamento, os animais tratados com a mesma dose continuaram apresentando redução nos mesmos parâmetros. Em um segundo experimento, foi avaliada a contratilidade do ducto epididimário isolado tanto frente ao tratamento in vivo dos animais (tratados com o veículo ou com a dose de 3,0 mg/kg/dia de As2O3) quanto ao tratamento in vitro do tecido. Essa análise revelou que a contração máxima do ducto epididimário estava significativamente aumentada nos animais tratados com As2O3 in vivo. E em uma terceira etapa os animais foram divididos em Controle, As2O3 (3,0 mg/Kg/dia), NAC na água de beber (40mM) e As2O3 + NAC, tratados por 5 semanas. Após o final do tratamento, os animais foram avaliados quanto aos parâmetros que se apresentaram prejudicados com o tratamento anterior, descrito na etapa um. Quando a NAC foi oferecida aos animais, houve uma melhora significativa nos parâmetros espermáticos antes prejudicados pela administração da droga, i.e., o peso de vesícula seminal, número de espermatozoides móveis e produção espermática diária do grupo As2O3 + NAC foram similares ao grupo controle. Podemos concluir que o As2O3 exerce efeitos tóxicos sobre o sistema genital de camundongos machos, e que esses efeitos podem ser persistentes mesmo após o término do tratamento. Os resultados mostraram, também, que a administração de um antioxidante pode prevenir os efeitos deletérios dessa droga sobre os parâmetros avaliados / Abstract: Arsenic trioxide (As2O3), a trivalent arsenic form has proven highly effective and widely used in the treatment to reduce or eliminate acute promyelocytic leukemia. Studies show a relationship between exposure to this compound and inhibition of spermatogenesis and sperm development since it exerts an inhibitory effect on the testis. Given the growing use of As2O3 on treatment of leukemia and the lack of results about the side effects on male reproduction, it is justified to carry out this study, which evaluated the immediate and late effects of treatment with As2O3 on the structure and reproductive physiology of adult Swiss mice and whether the co-administration of N-acetylcysteine (NAC) prevents these effects. In a first experiment, adult Swiss mice were treated with vehicle, 0.3 or 3.0 mg/Kg/day of As2O3, subcutaneously in 25 applications. At the end of treatment, half of the animals were euthanized for evaluation of the post- treatment effects and the other half was maintained without the drug for 50 days until the euthanasia to evaluate the potential reversibility of the effects. It was evaluated: the vital, reproductive and accessories organ weights, analyzes of sperm quantity and quality, testosterone and arsenic measurements in blood. Animals treated with 3.0 mg/Kg of As2O3 and euthanized immediately after the end of treatment showed a decrease of seminal vesicle weight, in number of motile spermatozoa and daily sperm production. After suspension of treatment, animals treated with this same dose continued to show reduction in these same parameters. In a second experiment, the contractility of the epididymal duct was evaluated both in vivo treatment of animals (treated with vehicle or a 3.0 mg/Kg/day of As2O3) and in vitro treatment of the tissues. This analysis revealed that the maximum contraction of the epididymal duct was significantly increased in in vivo treated animals. And in a third step animals were divided into Control, As2O3 (3.0 mg/Kg/day) NAC in tap water (40 mM) and As2O3 + NAC, treated for 5 weeks. After the end of treatment, animals were assessed for previously impaired parameters described in step one. When NAC was given to the animals, there was a significant improvement in sperm parameters before harmed by the drug administration, i.e. seminal vesicle weight, number of motile sperm and daily sperm production in As2O3 + NAC group were similar to the control group. We conclude that As2O3 exerts toxic effects on the male mice genital system, and that these effects may be persistent even after the end of treatment. Also, the results showed that administration of an antioxidant can prevent the deleterious effects of this drug on the parameters evaluated / Mestrado / Biologia Celular / Mestra em Biologia Celular e Estrutural

In the last 150 years, the City of Yellowknife has transitioned from an area of traditional subsistence living to the largest city in the Northwest Territories (Canada) due to the economic influence of resource extraction. As resource extraction in the area boomed, large quantities of pollutants from mine tailings and emissions from roaster stacks adjacent to gold mines were deposited on the landscape, leaving a known legacy of elevated surface water, sediment, and soil metal(loid) concentrations. Most of the research to date has focused on arsenic in the region, and my thesis expands the body of knowledge to include other metal(loids) of interest, including antimony, lead, and mercury. My thesis's main objective was to determine the spatial and temporal extent of legacy mining emissions near Yellowknife and assess the associated biological risk from these historic emissions. I analyzed select intervals from 20 lake sediment cores for time constrained metal(loid) contaminants of concern. I used a combination of paleotoxicity and paleoecotoxicology methods to establish a spatial and temporal footprint of biological risk associated with historic gold mining activities in the Yellowknife region. I determined that lakes close to the mine exhibited a low-level hazard to aquatic communities before mining, while the onset of mining increased the hazard posed by sediments deposited to acute levels. I also discovered that lakes within 5 km of Giant Mine exceeded guideline values for sedimentary mercury during active mining. Further, I developed methods in paleoecotoxicology that indicated a concordance between time deposited, estimated risk, and observed mortality of native Daphnia sp exposed to time-constrained sediment archives. My thesis demonstrates that paleotoxicity and paleoecotoxicology are effective methods to separate historic and modern influences of industrial development on aquatic biota. Additionally, my research has application extensions for policymakers, remediation scientists, Indigenous Peoples, and those proposing new industrial ventures.

Submitted by MARCIA ROVADOSCHI (marciar@unifra.br) on 2018-08-16T19:52:36Z No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Dissertacao_MauberEduardoSchultzMoreira.pdf: 14104089 bytes, checksum: cdd198bace6b9a1b1e4ce9262baded58 (MD5) / Made available in DSpace on 2018-08-16T19:52:36Z (GMT). No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Dissertacao_MauberEduardoSchultzMoreira.pdf: 14104089 bytes, checksum: cdd198bace6b9a1b1e4ce9262baded58 (MD5) Previous issue date: 2015-03-23 / Cancer is a public health problem of great impact. Relapses require higher doses of drugs or new approaches to minimizing toxicity. The use of liposome-based carrier systems pharmaceuticals may be an alternative by the use of the enhanced permeability and retention effect present in the tumor area. The aim of this project was to develop and characterize liposomes containing arsenic trioxide (ATO). They were prepared according reverse phase evaporation method using ethyl acetate (EA) as solvent followed by ultrasonication with probe to reduce the size and homogenization. In determining the arsenic, titanium and residual EA we used Atomic Absorption Spectrometry with Graphite Furnace (GF- AAS), Mass Spectrometry Inductively Coupled Plasma (ICP -MS) and Gas Chromatography coupled to mass detector (GC-MS), respectively. We also carried out stability studies with formulations being subjected to room temperature (25° C), cooling (4 to 8° C) and climate chamber (40° C and 60% humidity) for a period of 90 days. Cytotoxicity assays were performed by the method of reduction of 3- (4,5) dimetiltialzoil 2,5 - diphenyltetrazolium bromide (MTT). Data of physical-chemical characterization showed that the best condition was sonication with a power of 750 W, 40% amplitude and cycles of 8 seconds on and 2 seconds off, to avoid overheating. The average particle size was 87.5±1.07 nm and polydispersity index (IPD) 0.28±0.03 for liposomes blank (BL) and 71.17±0.06 nm and 0.29±0.04 for liposomes containing TOA (LAs / LAS). TOA content of LAs was 1.0 mg ml-1 and the encapsulation efficiency (%EE) of 7,43±0.72%. ICP-MS showed the presence of titanium in the formulation and the determination of the residual solvent was below the tolerable limit. The stability study showed that formulations remained stable over a period of 30 days, regardless of storage condition wherein the stored under refrigeration remained stable for 60 days. Cytotoxicity assays with MTT revealed that in 72 hours the LB, AE and the buffer did not exercise death activity. The reverse phase evaporation method followed by ultrasonication appears to be suitable for obtaining liposomal vesicles containing arsenic trioxide . / Câncer é um problema de saúde pública de grande impacto. As recidivas necessitam de doses maiores de fármacos ou de novas abordagens para minimizar a toxicidade. O uso de sistemas carreadores de fármacos baseados em lipossomas pode ser uma alternativa por fazer uso do efeito permeabilidade e retenção aumentada presente na área do tumor. O objetivo desta dissertação foi desenvolver e caracterizar lipossomas contendo trióxido de arsênio (TOA). Foi utilizado o método de evaporação em fase reversa com solvente acetato de etila (AE) seguido de ultrassonicação com sonda para reduzir o tamanho e homogeinização. Na determinação do arsênio, titânio e acetato de etila residual utilizaram-se as técnicas de Espectrometria de Absorção Atômica com Forno de Grafite (GF- AAS), Espectrometria de Massa com Plasma Indutivamente Acoplado (ICP-MS) e Cromatografia a Gás acoplado a detector de massa (GCMS), respectivamente. Foi realizado também estudo de estabilidade com as formulações sendo submetidas a temperatura ambiente (25°C), refrigeração (4 a 8°C) e câmara climática (40°C e umidade de 60%), por um período de 90 dias. Os ensaios de citotoxicidade foram realizados pelo método de redução do 3-(4,5) dimetiltialzoil-2,5 difeniltetrazolium (MTT). Os dados da caracterização físico-química mostraram que a melhor condição de sonicação foi com potência de 750 W, amplitude de 40% e ciclos de 8 segundos ligado e 2 segundos desligado, para evitar o aquecimento. O tamanho médio foi de 87,5 ± 1,07 nm e índice de polidispersão (IPD) 0,28 ± 0,03 para os lipossomas branco (LB) e 71,17 ± 0,06 nm e 0,29 ± 0,04 para os lipossomas contendo TOA (LAs/LAS), respectivamente. O teor de TOA nos LAs foi de 1,0 mg mL-1 e a eficiência de encapsulação (%EE) de 7,43 ± 0,72%. O ICP-MS revelou a presença de titânio nas formulações e a determinação do solvente residual ficou abaixo do limite tolerável. O estudo de estabilidade mostrou que as formulações permaneceram estáveis por um período de 30 dias, independente da condição de armazenamento, sendo que as armazenadas sob refrigeração permaneceram estáveis por 60 dias. Os ensaios de citotoxicidade com MTT revelaram que em 72 horas os LB, AE e a solução tampão não exerceram atividade de morte. O método de evaporação em fase reversa seguido de ultrassonicação parece ser adequado para a obtenção de vesículas lipossomais contendo trióxido de arsênio.

Les Formes réactives de l’oxygène (FRO) ont un rôle bien établi dans l’oncogénèse en augmentant les capacités de prolifération et d’invasion des cellules tumorales. Mais les FRO exercent aussi un effet important sur le microenvironnement tumoral, en particulier en participant à l’échappement des tumeurs au système immunitaire. Une modulation pharmacologique de l’équilibre oxydo-réductif tumoral est donc susceptible d’influencer la progression tumorale. Il a été montré que l’induction pharmacologique d’un stress oxydant dans les cellules tumorales peut induire un effet cytotoxique mais ses effets sur le microenvironnement sont moins bien connus. L’objectif de nos travaux était d’étudier l’effet d’une modulation du stress oxydant sur les cellules immunitaires du microenvironnement tumoral et in fine de préciser les conséquences potentielles sur la progression tumorale. L’arsenic trioxyde (As2O3), inducteur de FRO, présentait à faible dose, dénuée d’effet cytotoxique direct sur les cellules malignes, un effet antitumoral dans un modèle de cancer colique murin. Cet effet était lié à une déplétion sélective en lymphocytes T régulateurs (Tregs) et était médié par la génération d’anions superoxyde (O2°-) et de monoxyde d’azote (NO), eux même responsables de la formation de peroxynitrite. Les Tregs présentaient un niveau basal de FRO plus élevé que les autres populations lymphocytaires, qui pourrait expliquer leur plus grande sensibilité à un surcroît de stress oxydant induit par l’As2O3. Un cytotoxique antitumoral, la vinorelbine, s’est également montré capable d’exercer un effet sur le microenvironnement tumoral. Par co-cultures, nous avons montré que la vinorelbine induisait un effet bystander toxique sur les cellules immunitaires effectrices voisines des cellules tumorales. In vivo, le prétraitement par vinorelbine de cellules malignes implantées à la souris était responsable d’une perte de la réactivité anti-tumorale des cellules mono-nuclées. Cet effet était dépendant de la production d’O2°- et de NO par les cellules malignes. Un modulateur du stress oxydant, le mangafodipir, inhibait cet effet, permettant ainsi de restaurer la réponse immunitaire antitumorale locale. Notre travail a donc permis de mettre en évidence que des modulateurs du stress oxydant peuvent agir sur le microenvironnement, et spécialement sur les cellules immunitaires. Ils pourraient être utilisés en clinique pour restaurer la réponse immunitaire antitumorale. Une meilleure compréhension du rôle du stress oxydant dans la défaillance de l’immunité antitumorale est nécessaire. / Several reports have demonstrated the involvement of reactive oxygen species (ROS) in carcinogenesis, through promotion of cancer cell proliferation and invasion. But ROS could also have consequences on non cancerous cells which are part of the tumor microenvironment, such as immune cells. Therefore, a pharmacological modulation of oxidative stress can induce a cytotoxic effect on tumor cells but its consequences on microenvironment are unknown. The aim of our studies was to evaluate the effects of a pharmacological modulation of oxidative stress on immune cells from the tumor microenvironment. At low dose, Arsenic trioxide (As203), an oxidative stress modulator, was shown to exert antitumor effects in colon tumor-bearing mice. We observed that this effect was related to As203-induced regulatory T cells (Tregs) -selective depletion in vitro and in vivo and was mediated by oxidative and nitrosative bursts. The differential effect of As203 on Tregs versus other CD4 cells was related to difference in the cells’redox status. We also observed that vinorelbine, an anticancer agent, could interfere with the antitumor immune response. We showed that vinorelbine could alter the function of immune cells surrounding tumor cells by a bystander toxic effect against tumor effector cells. In vivo experiment in A549 tumor bearing nude mice showed that adoptive transfer of A549 immune splenocytes was not able to delay tumor growth when vinorelbine-pretreated A549 cells were used for immunization. This effect was mediated by ROS and was inhibited by an oxidative stress modulator, mangafodipir, which restored antitumor immune function. Therefore, our work showed that oxidative stress modulators can influence tumor microenvironment and more specifically, immune cells. They could be used to restore antitumor immune response.

La leucémie aiguë promyélocytaire (APL) est un cancer des globules blancs qui se caractérise par l’accumulation de granulocytes immatures appelés promyélocytes. Dans la majorité des cas, la maladie est causée par la translocation réciproque des gènes RARα et PML, menant à l’expression de la protéine de fusion PML/RARα qui compromet à la fois les fonctions assurées normalement par RARα et par PML. Ainsi, la répression de la transcription des gènes cibles de RARα et la perturbation de la formation des corps nucléaires PML seraient la cause de la non-différenciation et de la survie par inhibition de l’apoptose des promyélocytes. Un des agents thérapeutiques utilisés dans le traitement de la maladie est le trioxyde d’arsenic (ATO) et malgré le fait que son efficacité soit prouvée, les mécanismes moléculaires par lesquels il exerce son action ne sont pas entièrement caractérisés. PML étant SUMOylée en réponse à l’ATO, nous avons émis l’hypothèse que d’autres protéines pourraient être régulées dans leurs modifications post-traductionnelles (PTMs) en réponse à l’agent thérapeutique et pourraient occuper un rôle dans le processus de guérison. Une analyse par protéomique quantitative de cellules HEK293 traitées à l’ATO a permis d’identifier 92 protéines significativement régulées en SUMOylation, incluant certains substrats connus de la caspase-3. Suite à cette observation, nous avons supposé que la SUMOylation pourrait protéger les substrats de la caspase-3 de leur clivage protéolytique. À l’aide d’essais in vitro et d’immunobuvardages, nous avons confirmé que la SUMOylation de PARP1 empêche son clivage par la caspase-3, ce qui pourrait jouer un rôle dans le destin cellulaire. / Acute promyelocytic leukemia (APL) is a cancer of white blood cells characterized by the accumulation of immature granulocytes called promyelocytes. In most cases, the disease is caused by the reciprocal translocation of the RARα and PML genes, leading to the expression of the PML/RARα fusion protein that compromises both the functions normally provided by RARα and by PML. Thus, repression of the transcription of RARα target genes and disruption of the formation of PML nuclear bodies may cause the non-differentiation of promyelocytes and the promotion of their survival by inhibition of apoptosis. One of the therapeutic agents used to treat the disease is arsenic trioxide (ATO) and despite the fact that its effectiveness is proven, the molecular mechanisms through which it exerts its action are not fully characterized. Since PML is SUMOylated in response to ATO, it is likely that other proteins may also exhibit changes in their post-translational modifications (PTMs) and play a role in the response. By using large-scale proteomic workflows on HEK293 cells following ATO treatment, we identified 92 proteins that shown significant changes in SUMOylation, including some known capase-3 substrates. Following this observation, we surmised that SUMOylation may protect these substrates from caspase-3 cleavage. Using in vitro assays and immunoblots, we confirmed that SUMOylation of PARP1 prevents its cleavage by caspase-3, an event that could mediate cell fate.

Myelodysplastic syndrome (MDS) with deletion of the long arm of the chromosome 5 (5q - syndrome, del( 5q)) can be characterized by anemia, macrocytosis, a normal or high platelet count, and hypolobulated megakaryocytes in the bone marrow. 5q - syndrome belongs to low - risk MDS, which means low risk to transform to acute myeloid leukemia. 5q - syndrome is ass ociated with female predominance and older age. Another sign is transfusion burden that is treated by erythropoiesis - stimulating agents (ESA) as erythropoietin (EPO). Moreover, the response of MDS patients is around 30 - 60% with the median of the response b eing ~ 24 months. The second line of treatment is lenalidomide (LEN) which is a derivate of teratogenic analog thalidomide. LEN increases erythropoiesis and inhibits the growth of del(5q) erythroid progenitors in vivo and it does not have a significant effe ct on the growth of normal CD34+ progenitors or cytogenetically normal progenitors in MDS with del(5q) clones. LEN is used as therapy in multiple myeloma, myelodysplastic syndrome, and lymphoma. LEN is an expensive agent and not every MDS patient re sponds to this therapy. This is a reason why is a need to find a biomarker for the determination of successful treatment. Some multiple myeloma studies showed that cereblon can be the biomarker...

In this work, an electrochemical method based on a cyt c biosensor has been developed, for the detection of selected arsenic and cyanide compounds. Boron Doped Diamond (BDD) electrode was used as a transducer, onto which cyt c was immobilised and used for direct determination of Prussian blue, potassium cyanide and arsenic trioxide by inhibition mechanism. The sensitivity as calculated from cyclic voltammetry (CV) and square wave voltammetry (SWV), for each analyte in phosphate buffer (pH= 7) was found to be (1.087- 4.488 ×10-9 M) and the detection limits ranging from 0.0043- 9.1 μM. These values represent a big improvement over the current Environmental Protection Agency (EPA) and World Health Organisation (WHO) guidelines.

In this work, an electrochemical method based on a cyt c biosensor has been developed, for the detection of selected arsenic and cyanide compounds. Boron Doped Diamond (BDD) electrode was used as a transducer, onto which cyt c was immobilised and used for direct determination of Prussian blue, potassium cyanide and arsenic trioxide by inhibition mechanism. The sensitivity as calculated from cyclic voltammetry (CV) and square wave voltammetry (SWV), for each analyte in phosphate buffer (pH= 7) was found to be (1.087- 4.488 ×10-9 M) and the detection limits ranging from 0.0043- 9.1 μM. These values represent a big improvement over the current Environmental Protection Agency (EPA) and World Health Organisation (WHO) guidelines.