RESUMO
S-metolachlor is a widely used herbicide that may contaminate groundwater when applied to irrigated crops, especially when the soil has a low organic carbon (OC) content. The objective here was to assess the capacity of two organic wastes, namely, green compost (GC) and pelletised organo-mineral manure fertilizer (PM), applied to two soils (S) with different textures at a rate of 10% dry weight to modify the fate of S-metolachlor. The herbicide's Freundlich adsorption coefficient (Kf) increased within a range of 3.2-8.2 times in S + GC and 3.8-6.8 times in S + PM. A positive correlation between adsorption and OC and the coefficient of variation of the OC normalised adsorption coefficients (Kfoc) higher than 20% indicated the evident influence on this process of soil OC content and its nature. The increase in adsorption did not prevent the dissipation of S-metolachlor in the amended soils, although the degradation rate decreased up to ~2 times or was not significantly modified across the different soil types. The S-metolachlor metabolites, metolachlor ethane sulfonic acid and metolachlor oxanilic acid, were detected in the herbicide's dissipation in the unamended soils, but they were not detected in the amended soils. The mobility experiments indicated leached amounts of S-metolachlor higher than 50% in unamended soil. The amounts decreased 1.1-1.7 times and 1.7-1.8 times in the S + GC and S + PM when a saturated flow was applied. Moreover, breakthrough curves indicated a slow leaching kinetics of herbicide in amended soils, with low concentrations continuously detected in the leachates together with a decrease in the maximum peak concentration. The results show the effect of the application of organic wastes especially in sandy soils to promote the immobilisation and/or degradation of S-metolachlor, avoiding its transfer to other environmental compartments.
Assuntos
Herbicidas , Poluentes do Solo , Acetamidas , Adsorção , Herbicidas/análise , Solo , Poluentes do Solo/análiseRESUMO
The addition of organic residues to soil to increase its organic matter content is considered as a viable option for sustainable food production in soils sensitive to degradation and erosion. However, the recycling of these organic residues in agricultural soils needs to be previously appraised because they can modify the behaviour of pesticides when they are simultaneously applied in agricultural practices. This study evaluated the changes in the mobility and persistence of two herbicides, triasulfuron and prosulfocarb, after two repeated applications in field experimental plots in an unamended soil and one amended with green compost (GC) for seven months. Different factors were studied: i) soil without amendment (S), ii) soil amended with two doses of GC (â¼12â¯tâ¯C ha-1, S + GC1 and 40 t C ha-1, S + GC2), and iii) soils unamended and amended with different irrigation conditions: non-irrigated and with additional irrigation (2.8 mm per week). After the first application of herbicides, the results initially indicated no significant effects of soil treatments or irrigation conditions for triasulfuron mobility in agreement with the residual concentrations in the soil profile. The effect of irrigation was noted after one month of herbicide application and the effect of the soil treatment was significant after two months because the persistence of triasulfuron in S + GC2 was maintained until 50% of the applied amount. For prosulfocarb, the influence of soil amendment was significant for the initial persistence of the herbicide in S + GC2, higher than in S or S + GC1, in agreement with its adsorption constants for this soil. However, dissipation or leaching of the herbicide over time was not inhibited in this soil. After the repeated application of herbicides, the influence of the treatment of soils and/or irrigation was significant for the leaching and dissipation of both herbicides. The initial dissipation/degradation or leaching of herbicides was higher than after the first application, although persistence was maintained after five months of application in amended soils for triasulfuron and in unamended and amended soils for prosulfocarb. The results confirm that high doses of GC increased the persistence of both herbicides. This practice may offer the possibility of applying a tailored dose of GC to soil for striking a balance between residual concentrations and the soil agronomic effect.
Assuntos
Herbicidas , Reciclagem , Solo , Agricultura , Poluentes do SoloRESUMO
Herbicides are essential in agricultural systems for maintaining crop yields, as weeds compromise grain production. Furthermore, the application of organic amendments to soil is an increasingly frequent agricultural practice for avoiding irreversible soil degradation. However, this practice could modify the behaviour of the herbicides applied, with implications for their absorption by weeds. This study evaluated the dissipation, persistence and mobility of the herbicides triasulfuron and prosulfocarb in a sandy clay loam soil unamended and amended with green compost (GC) in a field experiment using single or combined commercial formulations of both herbicides. The study was carried out in experimental plots (eight treatments × three replicates) corresponding to unamended soil and soil amended with GC, untreated and treated with the herbicide formulations Logran®, Auros® and Auros Plus® over 100 days. The half-life (DT50) of triasulfuron applied individually was 19.4 days, and increased in the GC-amended soil (46.7 days) due to its higher adsorption by this soil, although non-significant differences between DT50 values were found when it was applied in combination with prosulfocarb. Prosulfocarb dissipated faster than triasulfuron under all the conditions assayed, but non-significant differences were observed for the different treatments. The analysis of the herbicides at different soil depths (0-50 cm) after their application confirmed the leaching of both herbicides to deeper soil layers under all conditions, although larger amounts of residues were found in the 0-10 and 10-20 cm layers. The application of GC to the soil increased the persistence of both herbicides, and prevented the rapid leaching of triasulfuron in the soil, but the leaching of prosulfocarb was not inhibited. The influence of single or combined formulations was observed for triasulfuron, but not for prosulfocarb. The results obtained highlight the interest of obtaining field data to design rational joint applications of GC and herbicides to prevent the possible decrease in their effectiveness for weeds or the risk of water contamination.
Assuntos
Carbamatos , Compostagem , Poluentes do Solo , Compostos de Sulfonilureia , Herbicidas , SoloRESUMO
Lignocellulosic wastes and by-products containing lignin are now available in large amounts from forestry and industrial activities, and could be promising organic materials for the biosorption of pesticides by soils in order to reduce point-source pollution. Adding these materials to soil requires understanding the process of pesticide sorption-desorption by wood-soils, as sorption capacity could increase, with changes in pesticide bioavailability and final fate. The objective of this work was to study the effect that pine and oak wood added to soils had on the sorption/desorption of the pesticides linuron, alachlor, and metalaxyl. Experiments were conducted with two sandy loam and sandy clay soils each amended with two wood doses (5% and 50%) after different incubation times (0, 5 and 12 months). A low wood dose (5%) had no significant impact on the sorption (Kf) of alachlor, but Kf increased for linuron (up to 5.4-1.7 times) and metalaxyl (up to 4.4 and 8.6 times) in all wood-soil systems. The results were not significantly different after different incubation times. The desorption results indicated that wood decreases the sorption irreversibility of alachlor, and increases that of linuron and metalaxyl, with a varying effect of the wood-soil incubation time. The addition of a high wood dose to soil (50%) was more significant for increasing the sorption of all the pesticides, and the sorbed amounts remaining after desorption (>49% for linuron, >33% for alachlor and >6% for metalaxyl), although there was no apparent discrimination between the two types of woods. The role of the nature of the organic carbón (Koc values) for sorption was evidenced for alachlor and metalaxyl, but not for linuron. These outcomes are of interest for extending wood application to soil as a barrier for avoiding environmental risk by point-source pollution due to the use and management of pesticides in farming systems.
Assuntos
Praguicidas/análise , Poluentes do Solo/análise , Solo , Madeira , Acetamidas/análise , Adsorção , Alanina/análogos & derivados , Alanina/análise , Linurona/análiseRESUMO
This study reports the effect that adding spent mushroom substrate (SMS) to a representative vineyard soil from La Rioja region (Spain) has on the behaviour of azoxystrobin in two different environmental scenarios. Field dissipation experiments were conducted on experimental plots amended at rates of 50 and 150 t ha(-1), and similar dissipation experiments were simultaneously conducted in the laboratory to identify differences under controlled conditions. Azoxystrobin dissipation followed biphasic kinetics in both scenarios, although the initial dissipation phase was much faster in the field than in the laboratory experiments, and the half-life (DT50) values obtained in the two experiments were 0.34-46.3 days and 89.2-148 days, respectively. Fungicide residues in the soil profile increased in the SMS amended soil and they were much higher in the top two layers (0-20 cm) than in deeper layers. The persistence of fungicide in the soil profile is consistent with changes in azoxystrobin adsorption by unamended and amended soils over time. Changes in the dehydrogenase activity (DHA) of soils under different treatments assayed in the field and in the laboratory indicated that SMS and the fungicide had a stimulatory effect on soil DHA. The results reveal that the laboratory studies usually reported in the literature to explain the fate of pesticides in amended soils are insufficient to explain azoxystrobin behaviour under real conditions. Field studies are necessary to set up efficient applications of SMS and fungicide, with a view to preventing the possible risk of water contamination.
Assuntos
Metacrilatos , Pirimidinas , Poluentes do Solo , Adsorção , Agaricales/química , Fungicidas Industriais/química , Fungicidas Industriais/farmacocinética , Meia-Vida , Cinética , Laboratórios , Metacrilatos/farmacocinética , Oxirredutases/metabolismo , Pirimidinas/farmacocinética , Solo/química , Poluentes do Solo/química , Poluentes do Solo/farmacocinética , Espanha , EstrobilurinasRESUMO
Deregulation of ErbB/HER receptor tyrosine kinases has been linked to several types of cancer. The mechanism of activation of these receptors includes establishment of receptor dimers. Here, we have analyzed the action of different small molecule HER tyrosine kinase inhibitors (TKIs) on HER receptor dimerization. Breast cancer cell lines were treated with distinct TKIs and the formation of HER2-HER3 dimers was analyzed by coimmunoprecipitation and western blot or by Förster resonance energy transfer assays. Antibody-dependent cellular cytotoxicity was analyzed by measuring the release of lactate dehydrogenase and cell viability. Lapatinib and neratinib interfered with ligand-induced dimerization of HER receptors; while pelitinib, gefitinib, canertinib or erlotinib did not. Moreover, lapatinib and neratinib were able to disrupt previously formed receptor dimers. Structural analyses allowed the elucidation of the mechanism by which some TKIs prevent the formation of HER receptor dimers, while others do not. Experiments aimed at defining the functional importance of dimerization indicated that TKIs that impeded dimerization prevented down-regulation of HER2 receptors, and favored the action of trastuzumab. We postulate that TKIs that prevent dimerization and down-regulation of HER2 may augment the antitumoral action of trastuzumab, and this mechanism of action should be considered in the treatment of HER2 positive tumors which combine TKIs with antireceptor antibodies.
Assuntos
Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Multimerização Proteica/efeitos dos fármacos , Receptor ErbB-2/antagonistas & inibidores , Aminoquinolinas/farmacologia , Compostos de Anilina/farmacologia , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Neoplasias da Mama , Linhagem Celular Tumoral , Proliferação de Células , Receptores ErbB/química , Receptores ErbB/metabolismo , Cloridrato de Erlotinib , Feminino , Gefitinibe , Humanos , Lapatinib , Morfolinas/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/farmacologia , Quinolinas/farmacologia , Receptor ErbB-2/química , Receptor ErbB-2/imunologia , Receptor ErbB-2/metabolismo , TrastuzumabRESUMO
The effect of the addition of spent mushroom substrate (SMS) to the soil as an amendment on the distribution and/or fate of copper from a copper-based fungicide applied to a vineyard soil in La Rioja (N. Spain) was studied. The study was carried out on experimental plots amended or not with SMS at rates of 40 and 100 t ha(-1). The variation in total Cu content in the topsoil (0-10 cm) and in the soil profile (0-50 cm), and the distribution of Cu in different fractions of the topsoil were studied as a function of the dose of Cu added (5 and 10 kg ha(-1)) and of the time elapsed since application (0-12 months). In addition, the changes in the chemical properties (solid organic carbon (OC), dissolved organic carbon (DOC) and pH) of the soils were studied. A greater capacity for Cu retention by the amended soils than by the unamended one was observed only when the fungicide was applied at the high dose. No effect of the amendment rate was noted on this retention capacity. The metal content in the topsoil decreased over time in step with the disappearance of the OC in the amended soil due to its oxidation, mineralization and/or leaching. This decrease in total Cu content was possibly due to the formation of soluble Cu complexes with the DOC, which facilitated its transport through the soil. A re-distribution of Cu in the different soil fractions was also observed over time, mainly from the organic to the residual fraction. The results obtained indicate that the increase in OC due to the application of SMS at the rates used does not lead to any significant increase in the persistence of Cu in the soil over time. Of greater interest would be the assessment of the risk for groundwater quality, owing to possible leaching of the fungicide enhanced by the SMS when SMS and Cu-based fungicides are jointly applied to vineyard soils.
Assuntos
Agricultura/métodos , Cobre/química , Resíduos de Praguicidas/química , Solo/análise , Vitis , Adsorção , Agaricales , Análise de Variância , Carbono/análise , Fracionamento Químico , Concentração de Íons de Hidrogênio , EspanhaRESUMO
The sorption-desorption and interaction mechanisms of three non-ionic (linuron, alachlor, and metalaxyl) and two ionic (paraquat and dicamba) pesticides by three commercial lignins (hydrophobic macromolecule) and cellulose (hydrophilic macromolecule) as wood components were studied. Wood is a low-cost and environmentally friendly material proposed in recent years to immobilize pesticides in soils. The influence of sorbent and pesticide properties and the identification of the functional groups of the organic molecules involved in sorption were evaluated by a statistical approach and by Fourier transform infrared spectroscopy. The sorption isotherms of non-ionic pesticides by the lignins and cellulose fit the Freundlich model, and those of the ionic pesticides also fit the Langmuir model. The sorption constants of pesticides by cellulose were 62-, 9-, 24-, 119-, and 3-fold lower than those for the sorption by lignins. A predictive model of pesticide sorption indicated that 88.5% of the variability in the sorption coefficient normalized to the organic carbon content could be explained in terms of the variability of the polarity index and the octanol-water partition coefficient of sorbent and sorbate. The greater irreversibility observed for ionic pesticides was attributed to the involvement of simultaneous interaction mechanisms. The results obtained contribute the knowledge of sorption capacity of pesticides by lignin/cellulose, the main components of woods and ubiquitous materials in the environment.
Assuntos
Celulose/química , Lignina/química , Praguicidas/química , Acetamidas/química , Adsorção , Alanina/análogos & derivados , Alanina/química , Dicamba/química , Substâncias Húmicas , Linurona/química , Paraquat/química , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
Pharmacological inactivation of cancer genes or products is being used as a strategy for therapy in oncology. To investigate the potential role of BCR-ABLp190 cessation in leukaemia development, we generated mice carrying a tetracycline-repressible BCR-ABLp190 transgene. These mice were morphologically normal at birth, and developed leukaemias. Disease was characterized by the presence of B-cell blasts co-expressing myeloid markers, reminiscent of the human counterpart. BCR-ABLp190 activation can initiate leukaemia in both young and adult mice. Transitory expression of BCR-ABLp190 is enough to develop leukaemia. Suppression of the BCR-ABLp190 transgene in leukaemic CombitTA-p190 mice did not rescue the malignant phenotype, indicating that BCR-ABLp190 is not required to maintain the disease in mice. Similar results were obtained by inactivation of BCR-ABLp190 with STI571 (Gleevec; Novartis, East Hanover, NJ, USA) in leukaemic CombitTA-p190 mice. However, gradual suppression of BCR-ABLp190 in leukaemic CombitTA-p190 mice identified a minimum level of BCR-ABLp190 expression necessary to revert the specific block in B-cell differentiation in the leukaemic cells. Overall, the findings indicate that BCR-ABLp190 appears to cause epigenetic and/or genetic changes in tumour-maintaining cells that render them insensitive to BCR-ABLp190 inactivation.
Assuntos
Proteínas de Fusão bcr-abl/genética , Inativação Gênica , Leucemia Experimental/genética , Animais , Sequência de Bases , Linhagem Celular , Primers do DNA , Camundongos , Camundongos Transgênicos , FenótipoRESUMO
Sorption-desorption of two different hydrophobic fungicides, penconazole and metalaxyl, by a series of clay minerals layered and non-layered (montmorillonite, illite, kaolinite, muscovite, sepiolite and palygorskite) modified with the two-chain cationic surfactant, dihexadecyldimetylammonium (DHDDMA) was studied by first time in this work. DHDDMA-clays showed a good capacity to sorb both fungicides from water. Freundlich sorption constants (K(f)) increased 22-268-fold for penconazole and 4-112-fold for metalaxyl in relation to natural clays. High sorption irreversibility was observed for penconazole for all modified clays, while for metalaxyl this occurred only for some of the modified clays. Additionally, a comparative study of the sorption of the fungicides by clay minerals modified with organic cations of different structure was carried out by a statistical approach. Non-layered and layered clay minerals modified with the two-chain alkylammonium organic cation DHDDMA, and with single-chain organic cations octadecyltrimethylammonium (ODTMA) and hexadecylpyridinium (HDPY) were used as sorbents. The study indicated a significant linear regression between the distribution coefficients K(d) of fungicides and the organic carbon (OC) content of the organo clays (r(2)>or=0.80, p<0.001). According to this sorption of fungicides by partition between the aqueous solution and the organic medium created by the alkyl chains of the exchanged ammonium cations regardless of the type and structure of these cations is suggested. However, linear relationships between K(d) values of each pesticide by the different organo clays and their relative OC contents revealed higher increase in sorption for HDPY-clays (penconazole) and for ODTMA-clays (metalaxyl) pointing out different effectiveness of the OC provided by each organic cation. These effects were also supported by the values of K(d) relative to OC, K(d)(oc). The results evidenced the different relative weight of alkyl cations to make organo clays effective barriers to prevent the mobility of pesticides from a point source of pollution.
Assuntos
Alanina/análogos & derivados , Silicatos de Alumínio/química , Fungicidas Industriais/química , Triazóis/química , Alanina/química , Alanina/isolamento & purificação , Silicatos de Alumínio/análise , Carbono/análise , Argila , Fungicidas Industriais/isolamento & purificação , Cinética , Compostos de Amônio Quaternário/química , Tensoativos , Termodinâmica , Triazóis/isolamento & purificaçãoRESUMO
Adsorption of three surfactants of different nature, Triton X-100 (TX100) (non-ionic), sodium dodecylsulphate (SDS) (anionic) and octadecyltrimethylammonium bromide (ODTMA) (cationic) by four layered (montmorillonite, illite, muscovite and kaolinite) and two non-layered (sepiolite and palygorskite) clay minerals was studied. The objective was to improve the understanding of surfactant behaviour in soils for the possible use of these compounds in remediation technologies of contaminated soils by toxic organic compounds. Adsorption isotherms were obtained using surfactant concentrations higher and lower than the critical micelle concentration (cmc). These isotherms showed different adsorption stages of the surfactants by the clay minerals, and were classified in different subgroups of the L-, S- or H-types. An increase in the adsorption of SDS and ODTMA by all clay minerals is observed up to the cmc of the surfactant in the equilibrium solution is reached. However, there was further TX100 adsorption when the equilibrium concentration was well above the cmc. Adsorption constants from Langmuir and Freundlich equations (TX100 and ODTMA) or Freundlich equation (SDS) were used to compare adsorption of different surfactants by clay minerals studied. These constants indicated the surfactant adsorption by clay minerals followed this order ODTMA>TX100>>SDS. The adsorption of TX100 and ODTMA was higher by montmorillonite and illite, and the adsorption of SDS was found to be higher by kaolinite and sepiolite. Results obtained show the influence of clay mineral structure and surfactant nature on the adsorption capacity of surfactants by clays, and they indicate the interest to consider the soil mineralogical composition when one surfactant have to be selected in order to establish more efficient strategies for the remediation of soils and water contaminated by toxic organic pollutants.
Assuntos
Silicatos de Alumínio/química , Poluentes do Solo/química , Tensoativos/química , Adsorção , Alcanos/química , Bentonita/química , Argila , Caulim/química , Compostos de Magnésio/química , Silicatos de Magnésio/química , Minerais/química , Octoxinol/química , Compostos de Amônio Quaternário/química , Compostos de Silício/química , Dodecilsulfato de Sódio/química , Poluentes do Solo/análise , Análise EspectralRESUMO
Sewage sludges obtained from seven wastewater treatment plants from the province of Salamanca, Spain, were periodically sampled to determine seasonal and time variation of their elemental composition over 2000 to 2002. The aim of this paper was to provide additional insight to evaluate the potential environmental impact following soil incorporation of these materials as amendments. Aqua regia extractable metals (pseudo total content) of Cd, Cr, Cu, Ni, Pb and Zn were determined and furthermore, the main chemical forms of metals within the sludge were evaluated using a five-step fractionation procedure. All the studied sludges displayed high fertility properties due to their richness of OC, P and K. Total mean concentrations of Cd, Cr, Cu, Ni, Pb and Zn in the sludges were within the regulation of the Spanish legislation. Using an multifactor analysis of variance, significant differences between Cr, Cu, Ni, Pb and Zn pseudo total contents (p<0.01) of sludges at different sites were found while the Cd content was statistically similar. Also significant differences were found between these pseudo total contents of heavy metals in samples collected along the time after three years (0.001
Assuntos
Poluentes Ambientais/análise , Metais Pesados/análise , Estações do Ano , Esgotos/química , Purificação da Água , Monitoramento Ambiental , Poluentes Ambientais/química , Metais Pesados/química , EspanhaRESUMO
In this work, the efficiency of reactive clay barriers in the immobilisation of organic pesticides in a sandy soil was studied. Reactive barriers were prepared by modification of montmorillonite, kaolinite and palygorskite clay minerals, and of a clayey soil with the cationic surfactant octadecyltrimethylammonium bromide (ODTMA). Percolation curves of the pesticides linuron, atrazine and metalaxyl of different hydrophobic character, were obtained in columns packed with a natural sandy soil with these barriers intercalated under saturated flow conditions. The cumulative curves in the unmodified soil indicated a leaching of pesticides greater than 85% of the total amount of compound added. After barrier intercalation, the breakthrough curves (BTC) indicated a dramatic decrease in the amounts of linuron leached in all columns and a significant modification of the leaching kinetics of atrazine and metalaxyl. Retardation factors, R, of the pesticides in the columns were significantly correlated with the organic matter content (OM) derived from the ODTMA of the organo clay/soil barriers (r2>or=0.78). Significant correlations were also found between these R factors and the pore volume values corresponding to the maximum peaks of the BTCs (r2=0.83; p<0.01) or the total volumes leached (r2=0.44; p<0.05) for the pesticides atrazine and metalaxyl. The results obtained point to the interest in the use of reactive clay barriers for almost complete immobilisation of hydrophobic pesticides or for decreasing the leaching of moderately hydrophobic pesticides coming from point-like sources of pollution. These barriers would avoid the generation of elevated concentrations of these compounds in the soils due to their rapid washing.
Assuntos
Silicatos de Alumínio/química , Poluição Ambiental/prevenção & controle , Praguicidas/química , Compostos de Amônio Quaternário/química , Solo , Tensoativos/química , Poluição Química da Água/prevenção & controle , Bentonita/química , Argila , Caulim/química , Compostos de Magnésio/química , Praguicidas/análise , Compostos de Silício/químicaRESUMO
INTRODUCTION: Nocturnal sleep-related eating disorder is a non-REM sleep parasomnia that is associated to other sleep disorders, especially sleepwalking. It becomes chronic, is not remitting and consists in episodes of compulsive eating during the night, which are then partially or completely forgotten by the patient. This condition must be differentiated from night-eating syndrome, which is far more common and is linked to endocrinological and psychiatric disorders, as well as to other disorders involving eating behaviour during sleeping hours. CASE REPORT: A 28-year-old male who had suffered from the clinical picture every day for 10 years; this condition consisted in nocturnal episodes of binge eating in a state of semi-sleepiness, with no remembrance of what had happened the next morning. The patient had no history of psychiatric pathologies or any other eating disorder, but he did not rest adequately at night, was overweight and had a family and personal history of other sleep disorders. Since he did not respond to other treatments, we decided to try therapy with topiramate; as a result, the episodes disappeared, tolerance was excellent and effectiveness was maintained throughout the two years' follow-up. CONCLUSIONS: In this paper we review eating disorders that occur during sleep, nocturnal sleep-related eating disorder and its therapeutic possibilities, while highlighting the usefulness of topiramate to treat this condition.
Assuntos
Anticonvulsivantes/uso terapêutico , Transtornos da Alimentação e da Ingestão de Alimentos/tratamento farmacológico , Frutose/análogos & derivados , Transtornos do Sono-Vigília/tratamento farmacológico , Adulto , Comportamento Alimentar/fisiologia , Transtornos da Alimentação e da Ingestão de Alimentos/fisiopatologia , Frutose/uso terapêutico , Humanos , Masculino , Transtornos do Sono-Vigília/fisiopatologia , Sonambulismo/tratamento farmacológico , TopiramatoRESUMO
Genomic studies have identified recurrent somatic mutations in acute leukemias. However, current murine models do not sufficiently encompass the genomic complexity of human leukemias. To develop preclinical models, we transplanted 160 samples from patients with acute leukemia (acute myeloid leukemia, mixed lineage leukemia, B-cell acute lymphoblastic leukemia, T-cell ALL) into immunodeficient mice. Of these, 119 engrafted with expected immunophenotype. Targeted sequencing of 374 genes and 265 frequently rearranged RNAs detected recurrent and novel genetic lesions in 48 paired primary tumor (PT) and patient-derived xenotransplant (PDX) samples. Overall, the frequencies of 274 somatic variant alleles correlated between PT and PDX samples, although the data were highly variable for variant alleles present at 0-10%. Seventeen percent of variant alleles were detected in either PT or PDX samples only. Based on variant allele frequency changes, 24 PT-PDX pairs were classified as concordant while the other 24 pairs showed various degree of clonal discordance. There was no correlation of clonal concordance with clinical parameters of diseases. Significantly more bone marrow samples than peripheral blood samples engrafted discordantly. These data demonstrate the utility of developing PDX banks for modeling human leukemia, and emphasize the importance of genomic profiling of PDX and patient samples to ensure concordance before performing mechanistic or therapeutic studies.
Assuntos
Xenoenxertos/patologia , Leucemia/genética , Doença Aguda , Adolescente , Adulto , Animais , Células Sanguíneas/transplante , Transplante de Medula Óssea , Bovinos , Criança , Perfilação da Expressão Gênica , Humanos , Imunofenotipagem , Leucemia/patologia , Camundongos , Pessoa de Meia-Idade , Adulto JovemRESUMO
The Snail-related zinc-finger transcription factor, SLUG (SNAI2), is critical for the normal development of neural crest-derived cells and loss-of-function SLUG mutations have been proven to cause piebaldism and Waardenburg syndrome type 2 in a dose-dependent fashion. However, little is known about the consequences of SLUG overexpression in embryonic development. We report SLUG duplication in a child with a unique de novo 8q11.2-->q13.3 duplication associated with tetralogy of Fallot, submucous cleft palate, renal anomalies, hypotonia and developmental delay. To investigate the effects of Slug overexpression on development, we analyzed mice carrying a Slug transgene. These mice were morphologically normal at birth, inferring that Slug overexpression is not sufficient to cause overt morphogenetic defects. In the adult mice, there was a 20% incidence of sudden death, cardiomegaly and cardiac failure associated with incipient mesenchymal tumorigenesis. These findings, while not directly implicating Slug in congenital and acquired heart disease, raise the possibility that Slug overexpression may contribute to specific cardiac phenotypes and cancer development.
Assuntos
Cromossomos Humanos Par 8 , Desenvolvimento Embrionário/genética , Fatores de Transcrição/genética , Trissomia , Anormalidades Múltiplas/genética , Animais , Southern Blotting , Mapeamento Cromossômico , Duplicação Gênica , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Hibridização in Situ Fluorescente , Lactente , Cariotipagem , Camundongos , Camundongos Transgênicos , Hibridização de Ácido Nucleico , Fatores de Transcrição da Família Snail , Tetralogia de Fallot/genéticaRESUMO
The most common chromosomal translocation in liposarcomas, t(12;16)(q13;p11), creates the FUS/TLS-CHOP fusion gene. We previously developed a mouse model of liposarcoma by expressing FUS-CHOP in murine mesenchymal stem cells. In order to understand how FUS-CHOP can initiate liposarcoma, we have now generated transgenic mice expressing altered forms of the FUS-CHOP protein. Transgenic mice expressing high levels of CHOP, which lacks the FUS domain, do not develop any tumor despite its tumorigenicity in vitro and widespread activity of the EF1alpha promoter. These animals consistently show the accumulation of a glycoprotein material within the terminally differentiated adipocytes, a characteristic figure of liposarcomas associated with FUS-CHOP. On the contrary, transgenic mice expressing the altered form of FUS-CHOP created by the in frame fusion of the FUS domain to the carboxy end of CHOP (CHOP-FUS) developed liposarcomas. No tumors of other tissues were found in these transgenic mice despite widespread activity of the EF1alpha promoter. The characteristics of the liposarcomas arising in the CHOP-FUS mice were very similar to those previously observed in our FUS-CHOP transgenic mice indicating that the FUS domain is required not only for transformation but also influences the phenotype of the tumor cells. These results provide evidence that the FUS domain of FUS-CHOP plays a specific and critical role in the pathogenesis of liposarcoma.
Assuntos
Proteínas Estimuladoras de Ligação a CCAAT/química , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Lipossarcoma/patologia , Proteínas de Fusão Oncogênica/química , Proteínas de Fusão Oncogênica/metabolismo , Ribonucleoproteínas/química , Ribonucleoproteínas/metabolismo , Fatores de Transcrição/metabolismo , Adipócitos/citologia , Adipócitos/metabolismo , Adipócitos/patologia , Tecido Adiposo/anormalidades , Tecido Adiposo/citologia , Tecido Adiposo/patologia , Animais , Proteínas Estimuladoras de Ligação a CCAAT/genética , Diferenciação Celular , Células Cultivadas , Fibroblastos/citologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Ribonucleoproteínas Nucleares Heterogêneas , Incidência , Lipossarcoma/genética , Lipossarcoma/metabolismo , Camundongos , Camundongos Nus , Camundongos Transgênicos , Mutação/genética , Transplante de Neoplasias , Proteínas de Fusão Oncogênica/genética , Estrutura Terciária de Proteína , Proteína FUS de Ligação a RNA , Ribonucleoproteínas/genética , Fator de Transcrição CHOP , Fatores de Transcrição/química , Fatores de Transcrição/genética , Transgenes/genéticaRESUMO
A key problem in the effective treatment of patients with cancer (both leukemia and solid tumors) is to distinguish between tumor and normal cells. This problem is the main reason why current treatments for cancer are often ineffective. There have been remarkable advances in our understanding of the molecular biology of cancer that provides new selective tumor destruction mechanisms. The molecular characterization of the tumor-specific chromosomal abnormalities has revealed that fusion proteins are the consequence in the majority of cancers. These fusion proteins result from chimeric genes created by the translocations, which form chimeric mRNA species that contain exons from the genes involved in the translocation. Obviously, these chimeric molecules are attractive therapeutic targets since they are unique to the disease (they only exist in the tumor cells but not in the normal cells of the patient), allowing the design of specific anti-tumor drugs. Inhibition of chimeric gene expression by anti-tumor agents specifically kills leukemic cells without affecting normal cells. As therapeutic agents targeting chimeric genes, zinc-finger proteins, antisense RNAs or hammerhead-based ribozymes have been used. All of these agents have some limitations, indicating that new therapeutic tools are required as gene inactivating agents that should be able to inhibit any chimeric fusion gene product. Recently, we have used the catalytic RNA subunit of RNase P from Escherichia coli, which can be specifically directed to cut any mRNA sequence, to specifically destroy tumor-specific fusion genes created as a result of chromosomal translocations. In this chapter, we will review the advances made to selectively destroy tumor cells through specific inhibition of products resulting from chromosomal translocations.