RESUMO
Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukemia (Ph+ BCPALL) is a high-risk acute lymphoblastic leukemia subtype characterized by the presence of BCR::ABL1 fusion gene. Tyrosine kinase inhibitors (TKIs) combined with chemotherapy are established as the first-line treatment. Additionally, rituximab (RTX), an anti-CD20 monoclonal antibody (mAb) is administered in adult BCP-ALL patients with ≥20% of CD20+ blasts. In this study, we observed a marked prevalence of CD20 expression in patients diagnosed with Ph+ BCP-ALL, indicating a potential widespread clinical application of RTX in combination with TKIs. Consequently, we examined the influence of TKIs on the antitumor effectiveness of anti-CD20 mAbs by evaluating CD20 surface levels and conducting in vitro functional assays. All tested TKIs were found to uniformly downregulate CD20 on leukemic cells, diminishing the efficacy of RTX-mediated complement-dependent cytotoxicity. Interestingly, these TKIs displayed varied effects on NK cell-mediated antibody-dependent cytotoxicity and macrophage phagocytic function. While asciminib demonstrated no inhibition of effector cell functions, dasatinib notably suppressed the anti-CD20-mAb-mediated NK cell cytotoxicity and macrophage phagocytosis of BCP-ALL cells. Dasatinib and ponatinib also decreased NK cell degranulation in vitro. Importantly, oral administration of dasatinib, but not asciminib, compromised NK cell activity within patients' blood, determined by ex vivo degranulation assay. Our results indicate that asciminib might be preferred over other TKIs for combination therapy with anti-CD20 mAbs.
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B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with chromosome translocations like KMT2A gene rearrangement (KMT2A-r) and BCR-ABL1 fusion gene have been recognized as crucial drivers in both BCP-ALL leukemogenesis and treatment management. Standard diagnostic protocols for proliferative diseases of the hematopoietic system, like KMT2A-r-ALL, are genetically based and strongly molecularly oriented. Therefore, an efficient diagnostic procedure requires not only experienced and multidisciplinary laboratory staff but also considerable instrumentation and material costs. In recent years, a Raman spectroscopy method has been increasingly used to detect subtle chemical changes in individual cells resulting from stress or disease. Therefore, the objective of this study was to identify Raman signatures for the molecular subtypes and to develop a classification method based on the unique spectroscopic profile of in vitro models that represent specific aberrations aimed at KMT2A-r (RS4;11, and SEM) and the BCR-ABL1 fusion gene (SUP-B15, BV-173, and SD-1). Data analysis was based on chemometric methods, i.e. principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and support vector machine (SVM). The PCA-based multivariate model was used for pattern recognition of each investigated group of cells while PLS-DA and SVM were used to build models for the discrimination of spectra from the studied BCP-ALL molecular subtypes. The results showed that the studied molecular subtypes of ALL have characteristic spectroscopic profiles reflecting their peculiar biochemical state. The content of lipids (1600 cm-1), nucleic acids (789 cm-1), and haemoproteins (754, 1130, and 1315 cm-1), which are crucial in cell metabolism, was indicated as the main source of differentiation between subtypes. Identification of spectroscopic markers of cells with BCR-ABL1 or KMT2A-r may be useful in pharmacological studies to monitor the effectiveness of chemotherapy and further to understand differences in molecular responses between leukemia primary cells and cell lines.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Análise Espectral Raman/métodosRESUMO
The aim of this study was to evaluate the effect of everolimus, a mammalian target of rapamycin (mTOR) inhibitor, on red blood cell parameters in the context of iron homeostasis in patients with tuberous sclerosis complex (TSC) and evaluate its effect on cell size in vitro. Everolimus has a significant impact on red blood cell parameters in patients with TSC. The most common alteration was microcytosis. The mean MCV value decreased by 9.2%, 12%, and 11.8% after 3, 6, and 12 months of everolimus treatment. The iron level declined during the first 3 months, and human soluble transferrin receptor concentration increased during 6 months of therapy. The size of K562 cells decreased when cultured in the presence of 5 µM everolimus by approximately 8%. The addition of hemin to the cell culture with 5 µM everolimus did not prevent any decrease in cell size. The stage of erythroid maturation did not affect the response to everolimus. Our results showed that the mTOR inhibitor everolimus caused red blood cell microcytosis in vivo and in vitro. This effect is not clearly related to a deficit of iron and erythroid maturation. This observation confirms that mTOR signaling plays a complex role in the control of cell size.
Assuntos
Tamanho Celular/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Eritrócitos/patologia , Inibidores de Proteínas Quinases/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Adolescente , Biomarcadores , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Criança , Pré-Escolar , Índices de Eritrócitos , Eritrócitos/metabolismo , Everolimo/administração & dosagem , Everolimo/efeitos adversos , Everolimo/farmacologia , Citometria de Fluxo , Humanos , Ferro/metabolismo , Células K562 , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversosAssuntos
Anemia Aplástica , Hemoglobinúria Paroxística , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Criança , Humanos , Anemia Aplástica/patologia , Anemia Aplástica/complicações , Hemoglobinúria Paroxística/complicações , Hemoglobinúria Paroxística/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/complicaçõesRESUMO
Melanomas are highly heterogeneous tumors and there is no treatment effective at achieving long-term remission for metastatic melanoma patients. Thus, an appropriate model system for studying melanoma biology and response to drugs is necessary. It has been shown that composition of the medium is a critical factor in preserving the complexity of the tumor in in vitro settings, and melanospheres maintained in stem cell medium are a good model in this respect. In the present study, we observed that not all nodular melanoma patient-derived cell populations grown in stem cell medium were capable of forming melanospheres, and cell aggregates and anchorage-independent single-cell cultures emerged instead. Self-renewing capacity and unlimited growth potential indicated the presence of cells with stem-like properties in all patient-derived populations but immunophenotype and MITF expression exhibited variability. Enhanced MITF expression and activity was observed in melanospheres in comparison with cell aggregates and single-cell culture, and hypoxic-like conditions that increased the ability of single-cell population to form melanospheres enhanced MITF expression and cell pigmentation as well. Thus, MITF seems to be a critical transcription factor for formation of both patient-derived and hypoxia-induced melanospheres. After 2 years of continuous culturing, melanospheres progressively underwent transition into cell aggregates that was accompanied by changes in expression of several MITF-dependent genes associated with melanogenesis and survival and alterations in the composition of subpopulations but not in the frequency of ABCB5-positive cells. Several biological properties of parent tumor are well preserved in patient-derived melanospheres, but during prolonged culturing the heterogeneity is substantially lost when the melanospheres are substituted by cell aggregates. This should be considered when cell aggregates instead of melanospheres are used in the study of melanoma biology and cell response to drugs.
Assuntos
Melanoma/química , Melanoma/metabolismo , Células-Tronco Neoplásicas/citologia , Esferoides Celulares/citologia , Antígeno AC133 , Antígenos CD/química , Antígenos CD/metabolismo , Técnicas de Cultura de Células , Hipóxia Celular , Meios de Cultura , Glicoproteínas/química , Glicoproteínas/metabolismo , Humanos , Fator de Transcrição Associado à Microftalmia/química , Fator de Transcrição Associado à Microftalmia/metabolismo , Monofenol Mono-Oxigenase/química , Monofenol Mono-Oxigenase/metabolismo , Células-Tronco Neoplásicas/química , Células-Tronco Neoplásicas/metabolismo , Peptídeos/química , Peptídeos/metabolismo , Esferoides Celulares/química , Esferoides Celulares/metabolismo , Células Tumorais CultivadasRESUMO
Acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) are the two most common hematologic malignancies, challenging to treat and associated with high recurrence and mortality rates. This work aims to identify specific Raman biomarkers of ALL cells with the KMT2A gene rearrangement (KMT2A-r), representing a highly aggressive subtype of childhood leukemia with a poor prognosis. The proposed approach combines the sensitivity and specificity of Raman spectroscopy with machine learning and allows us to distinguish not only myelo- and lymphoblasts but also discriminate B-cell precursor (BCP) ALL with KMT2A-r from other blasts of BCP-ALL. We have found that KMT2A-r ALL cells fixed with 0.5% glutaraldehyde exhibit a unique spectroscopic profile that enables us to identify this subtype from other leukemias and normal cells. Therefore, a rapid and label-free method was developed to identify ALL blasts with KMT2A-r based on the ratio of the two Raman bands assigned to phenylalanine - 1040 and 1008 cm-1. This is the first time that a particular group of leukemic cells has been identified in a label-free way. The identified biomarker can be used as a screening method in diagnostic laboratories or non-reference medical centers.
Assuntos
Leucemia Mieloide Aguda , Proteína de Leucina Linfoide-Mieloide , Humanos , Proteína de Leucina Linfoide-Mieloide/genética , Análise Espectral Raman , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Biomarcadores , Células-Tronco HematopoéticasRESUMO
Leukemias are a remarkably diverse group of malignancies originating from abnormal progenitor cells in the bone marrow. Leukemia subtypes are classified according to the cell type that has undergone neoplastic transformation using demanding and time-consuming methods. Alternative is Raman imaging that can be used both for living and fixed cells. However, considering the diversity of leukemic cell types and normal leukocytes, and the availability of different sample preparation protocols, the main objective of this work was to verify them for leukemia and normal blood cell samples for Raman imaging. The effect of glutaraldehyde (GA) fixation in a concentration gradient (0.1 %, 0.5 %, and 2.5 % GA) on the molecular structure of T-cell acute lymphoblastic leukemia (T-ALL) and peripheral blood mononuclear cells (PBMCs) was verified. Changes in the secondary structure of proteins within cells were indicated as the main effect of fixation, as shown by an increase in band intensity at 1041 cm-1, characteristic for in-plane δ(CH) deformation in phenylalanine (Phe). Different sensitivity of mononuclear and leukemic cells to fixation was observed. While the 0.1 % concentration of GA was too low to preserve the cell structure for an extended period of time, a GA concentration of 0.5 % seemed optimal for both normal and malignant cells. Chemical changes in PBMCs samples stored for 11 days were also investigated, which manifested in numerous modifications in the secondary structure of proteins and the content of nucleic acids. The impact of cell preculturing for 72 h after unbanking was verified, and there was no significant effect on the molecular structure of cells fixed with 0.5 % GA. In summary, the developed protocol for the preparation of samples for Raman imaging allows for the effective differentiation of fixed normal leukocytes from malignant T lymphoblasts.
Assuntos
Leucemia , Leucócitos Mononucleares , Humanos , Leucócitos , Leucemia/metabolismo , Diferenciação CelularRESUMO
We analyzed the pattern of whole-genome copy number alterations (CNAs) and their association with the kinetics of blast clearance during the induction treatment among 195 pediatric patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) who displayed intermediate or high levels of minimal residual disease (MRD). Using unsupervised hierarchical clustering of CNAs > 5 Mbp, we dissected three clusters of leukemic samples with distinct kinetics of blast clearance [A - early slow responders (n=105), B - patients with persistent leukemia (n=24), C - fast responders with the low but detectable disease at the end of induction (n=66)] that corresponded with the patients' clinical features, the microdeletion profile,the presence of gene fusions and patients survival. Low incidence of large CNAs and chromosomal numerical aberrations occurred in cluster A which included ALL samples showing recurrent microdeletions within the genes encoding transcription factors (i.e., IKZF1, PAX5, ETV6, and ERG), DNA repair genes (XRCC3 and TOX), or harboring chromothriptic pattern of CNAs. Low hyperdiploid karyotype with trisomy 8 or hypodiploidy was predominantly observed in cluster B. Whereas cluster C included almost exclusively high-hyperdiploid ALL samples with concomitant mutations in RAS pathway genes. The pattern of CNAs influences the kinetics of leukemic cell clearance and selected aberrations affecting DNA repair genes may contribute to BCP-ALL chemoresistance.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Humanos , Variações do Número de Cópias de DNA , Cinética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Neoplasia Residual , Aberrações Cromossômicas , Fatores de Transcrição/genéticaRESUMO
INTRODUCTION: Human peripheral blood mononuclear cells (PBMCs) are a heterogeneous population of cells that includes T and B lymphocytes. The total number of lymphocytes and their percentage in the blood can be a marker for the diagnosis of several human diseases. Currently, cytometric methods are widely used to distinguish subtypes of leukocytes and quantify their number. These techniques use cell immunophenotyping, which is limited by the number of fluorochrome-labeled antibodies that can be applied simultaneously. OBJECTIVE: B and T lymphocytes were isolated from peripheral blood obtained from healthy human donors. METHODS: The immunomagnetic negative selection was used for the enrichment of B and T cells fractions, and their purity was assessed by flow cytometry. Isolated cells were fixed with 0.5% glutaraldehyde and measured using confocal Raman imaging. K-means cluster analysis, principal component analysis and partial least squares discriminant methods were applied for the identification of spectroscopic markers to distinguish B and T cells. HPLC was the reference method for identifying carotene in T cells. RESULTS: Reliable discrimination between T and B lymphocytes based on their spectral profile has been demonstrated using label-free Raman imaging and chemometric analysis. The presence of carotene in T lymphocytes (in addition to the previously reported in plasma) was confirmed and for the first time unequivocally identified as ß-carotene. In addition, the molecular features of the lymphocytes nuclei were found to support the discriminant analysis. It has been shown that although the presence of carotenoids in T cells depends on individual donor variability, the reliable differentiation between lymphocytes is possible based on Raman spectra collected from individual cells. CONCLUSIONS: This proves the potential of Raman spectroscopy in clinical diagnostics to automatically differentiate between cells that are an important component of our immune system.
Assuntos
Leucócitos Mononucleares , Linfócitos , Humanos , Análise Discriminante , Análise dos Mínimos Quadrados , CarotenoidesRESUMO
Acute lymphoblastic leukemia (ALL) is the most common type of malignant neoplasms in the pediatric population. B-cell precursor ALLs (BCP-ALLs) are derived from the progenitors of B lymphocytes. Traditionally, risk factors stratifying therapy in ALL patients included age at diagnosis, initial leukocytosis, and the response to chemotherapy. Currently, treatment intensity is modified according to the presence of specific gene alterations in the leukemic genome. Raman imaging is a promising diagnostic tool, which enables the molecular characterization of cells and differentiation of subtypes of leukemia in clinical samples. This study aimed to characterize and distinguish cells isolated from the bone marrow of patients suffering from three subtypes of BCP-ALL, defined by gene rearrangements, i.e., BCR-ABL1 (Philadelphia-positive, t(9;22)), TEL-AML1 (t(12;21)) and TCF3-PBX1 (t(1;19)), using single-cell Raman imaging combined with multivariate statistical analysis. Spectra collected from clinical samples were compared with single-cell spectra of B-cells collected from healthy donors, constituting the control group. We demonstrated that Raman spectra of normal B cells strongly differ from spectra of their malignant counterparts, especially in the intensity of bands, which can be assigned to nucleic acids. We also showed that the identification of leukemia subtypes could be automated with the use of chemometric methods. Results prove the clinical suitability of Raman imaging for the identification of spectroscopic markers characterizing leukemia cells.
RESUMO
Resistance to L-asparaginase (L-asp) is a major contributor to poor treatment outcomes of several subtypes of childhood B cell precursor acute lymphoblastic leukemia (BCP-ALL). Asparagine synthetase (ASNS), legumain (LGMN) and cathepsin B (CTSB) serve a key role in L-asp resistance. The association between genetic subtypes of BCP-ALL and the expression of ASNS, LGMN and CTSB may elucidate the mechanisms of treatment failure. Bone marrow samples of 52 children newly diagnosed with BCP-ALL were screened for major genetic abnormalities and ASNS, LGMN and CTSB gene expression levels. The cohort was further divided into groups corresponding to the key genetic aberrations occurring in BCP-ALL: Breakpoint cluster region and Abelson murine leukemia viral oncogene homolog 1 fusion; hyperdiploidy, hypodiploidy, ETS variant 6 and runt-related transcription factor 1 fusion and other BCP-ALL with no primary genetic aberration identified. A subgroup analysis based on the differences in copy number variations demonstrated a significant increase of ASNS, LGMN and CTSB median expression in other BCP-ALL cases with paired box 5 (PAX5) deletion (P=0.0117; P=0.0036; P<0.0001, respectively) compared with those with wild-type PAX5. Patients with high ASNS expression exhibited longer relapse-free survival (RFS) compared with those with low ASNS levels (P=0.0315; HR, 0.19; 95% CI, 0.04-0.86); the 5-year RFS for patients in the high ASNS expression group was 90.15% (95% CI, 87.90-92.40%). Despite the impact on ASNS, LGMN and CTSB expression, PAX5 deletion did not influence RFS in the other BCP-ALL group (P=0.6839). Therefore, the results of the present study revealed high levels of ASNS, LGMN and CTSB expression in the other BCP-ALL group with concomitant PAX5 deletion and no subsequent deterioration in 5-year RFS. High ASNS expression level, as a single factor, was strongly associated with an improved outcome.
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Differentiation therapy is considered as a supplementary approach to the currently applied treatments for leukemia. We have previously shown that a morpholine derivative of doxorubicin (DOXM) appeared to be a more efficient inducer of erythroid differentiation of K562 cells than the parent drug [Czyz, M., Szulawska, A., Bednarek, A.K., Duchler, M., 2005. Effects of anthracycline derivatives on human leukemia K562 cell growth and differentiation. Biochem. Pharmacol. 70, 1431-1442.; Szulawska, A., Arkusinska, J., Czyz, M., 2007. Accumulation of gamma-globin mRNA and induction of irreversible erythroid differentiation after treatment of CML cell line K562 with new doxorubicin derivatives. Biochem. Pharmacol. 73, 175-184.]. In the current study we used this compound in combination with STI571, a front-line drug in therapy of chronic myelogenous leukemia (CML), to evaluate possible benefits of the combined treatment on the cellular level. Using K562 cells, we analyzed the response of CML cells to low concentrations of DOXM when Bcr-Abl activity was reduced to various levels by its specific inhibitor, STI571. Differentiation was significantly enhanced with the combination of 150 nM STI571 and 100 nM DOXM as compared to the levels obtained with either drug alone. A higher concentration of STI571 was required to diminish Bcr-Abl activity to the level which was sufficient to stimulate apoptotic cell death pathway in K562. Apoptosis induced by 250 nM STI571 was markedly enhanced by DOXM in the combined treatment. Mitochondrial transmembrane potential dissipation and translocation of phosphatydylserine to the outer plasma membrane were increased by 50%. Our results clearly indicate that differentiation and apoptosis, both reducing cellular proliferation, could be substantially enhanced by the combined treatment. We provide experimental evidence implicating that the diversification of cellular effects obtained in the combined treatment employing non-toxic approaches to enhance efficacy of STI571 might be considered as an alternative therapeutic strategy against CML, especially for apoptosis-reluctant cells.
Assuntos
Antineoplásicos/farmacologia , Apoptose , Doxorrubicina/análogos & derivados , Doxorrubicina/farmacologia , Mitocôndrias/fisiologia , Morfolinas/farmacologia , Piperazinas/farmacologia , Pirimidinas/farmacologia , Benzamidas , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Interações Medicamentosas , Células Precursoras Eritroides/efeitos dos fármacos , Humanos , Mesilato de Imatinib , Células K562 , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Proteína Supressora de Tumor p53/biossínteseRESUMO
STI571 (imatinib mesylate; Gleevec) is an inhibitor that targets the tyrosine kinase activity of Bcr-Abl present in chronic myelogenous leukemia (CML) cells. Some preclinical studies have demonstrated that the combination of STI571 with chemotherapeutic drugs results in enhanced toxicity in Bcr-Abl-positive leukemias. We investigated the potential benefit of using STI571 to down-regulate Bcr-Abl activity for the enhancement of doxorubicin anti-proliferative action in K562 cell line derived from blast crisis of CML. At low concentrations of both drugs (40 nM doxorubicin combined with STI571 in the range of 100-150 nM), the antiproliferative effects were mainly due to cellular differentiation as assessed by benzidine staining for hemoglobin synthesis level and real-time PCR for gamma-globin expression. Higher concentrations of STI571 used in combinations with doxorubicin caused mainly apoptosis as shown by DNA degradation and nuclear fragmentation visualized by fluorescence microscopy after DAPI staining, changes in cell morphology observed after Giemza-May Grünwald staining and cellular membrane organization estimated by flow cytometry after Annexin V staining. As compared with either drug alone, cotreatment with STI571 and DOX induced stronger cellular responses. A low concentration of STI571 in combination with a low concentration of DOX might be tested as an alternative approach to increasing the efficacy of chemotherapy against CML.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Piperazinas/farmacologia , Pirimidinas/farmacologia , Sequência de Bases , Benzamidas , Primers do DNA , Humanos , Mesilato de Imatinib , Células K562 , Reação em Cadeia da PolimeraseRESUMO
The aim of this study was analysis of content of barium in pharyngeal tonsils from children living on Southern Poland in during exposure on ETS. Barium contents in pharyngeal tonsils were higher for no exposure ETS children (0.099 microg/g) in comparison to exposure by ETS (0.033 microg/g), p=0.0042. The interaction between Ba and Ca, Fe, K or higher arithmetic and geometric mean, statistical range of changes contributed the role ETS in relation to children.
Assuntos
Tonsila Faríngea/química , Bário/análise , Poluição por Fumaça de Tabaco/efeitos adversos , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Polônia , Poluição por Fumaça de Tabaco/análiseRESUMO
The present and future air contamination by mercury is and will continue to be a serious risk for human health. This publication presents a review of the literature dealing with the issues related to air contamination by mercury and its transformations as well as its natural and anthropogenic emissions. The assessment of mercury emissions into the air poses serious methodological problems. It is particularly difficult to distinguish between natural and anthropogenic emissions and re-emissions from lands and oceans, including past emissions. At present, the largest emission sources include fuel combustion, mainly that of coal, and "artisanal and small-scale gold mining" (ASGM). The distinctly highest emissions can be found in South and South-East Asia, accounting for 45% of the global emissions. The emissions of natural origin and re-emissions are estimated at 45-66% of the global emissions, with the largest part of emissions originating in the oceans. Forecasts on the future emission levels are not unambiguous; however, most forecasts do not provide for reductions in emissions. Ninety-five percent of mercury occurring in the air is Hg0-GEM, and its residence time in the air is estimated at 6 to 18 months. The residence times of its HgII-GOM and that in Hgp-TPM are estimated at hours and days. The highest mercury concentrations in the air can be found in the areas of mercury mines and those of ASGM. Since 1980 when it reached its maximum, the global background mercury concentration in the air has remained at a relatively constant level.
RESUMO
STI571 (imatinib; Gleevec) was developed as the first molecularly targeted therapy. It was the result of an extensive search for molecules to block the aberrant activity of Abl kinase in the fusion protein Bcr-Abl. In addition, it can specifically inhibit the activity of c-Kit and PDGF receptors. This orally bioavailable drug has a low toxicity profile. It is approved to treat the patients with chronic myelogenous leukemia (CML) or gastrointestinal stromal tumor (GIST). It produces hematological, cytogenetic, and molecular remission with significant efficacy, particularly in patients with chronic-phase CML. However, there is well-documented proof of primary and secondary resistance to STI571 with progression of leukemia. More evidence indicates that this single drug may not be sufficient to completely eradicate BCR-ABL-positive stem cells. A variety of strategies has already been developed to improve the effectiveness of CML treatment, including targeting the expression or stability of the Bcr-Abl kinase itself, targeting signaling pathways activated by this kinase, as well as designing novel Abl inhibitors. In this review the molecular mechanisms of STI571 action, its effectivenes against CML, GIST, and melanoma, as well as new approaches to improve its efficacy, mainly by overcoming STI571 resistance, are discussed.
Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Animais , Antineoplásicos/química , Benzamidas , Quimioterapia Combinada , Tolerância a Medicamentos , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Fusão bcr-abl/efeitos dos fármacos , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/metabolismo , Humanos , Mesilato de Imatinib , Concentração Inibidora 50 , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Camundongos , Estrutura Molecular , Mutação , Proteínas Proto-Oncogênicas c-kit/efeitos dos fármacos , Transdução de SinaisRESUMO
STI571 (imatinib; Gleevec) was developed to specifically target the tyrosine kinase activity of the Bcr-Abl protein in Philadelphia chromosome-positive chronic myeloid leukemia (CML). It also inhibits the activity of c-Kit and PDGFR. It is the first-line drug for newly diagnosed CML, with remarkable efficacy to patients in the chronic phase of this cancer. However, CML patients in the accelerated phase or blast crisis often relapse due to drug resistance. STI571 fails to eradicate leukemic stem cells, and BCR-ABL(+). cells remain detectable in the majority of patients. The necessity for alternative or additional treatment for STI571-resistant leukemia resulted in the development of a second generation of drugs for targeted therapies. In this review a literature overview of the alternative inhibitors which were designed to override STI571 resistance and decrease the aberrant kinase activity of Bcr-Abl protein with higher efficiency is presented.
Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Mutação , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Trifosfato de Adenosina/análogos & derivados , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Benzamidas , Dasatinibe , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Fusão bcr-abl/efeitos dos fármacos , Humanos , Ácidos Hidroxâmicos , Mesilato de Imatinib , Indóis , Concentração Inibidora 50 , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Camundongos , Estrutura Molecular , Panobinostat , Piperazinas , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas , Piridonas , Pirimidinas , TiazóisRESUMO
The objective of this study was qualification of content chromium in femur head in aspect of smoking cigarette. Investigated of femur head from habitants of Upper Silesian Region. The content of chromium was marked at non-smoking persons, smoking in past and smoking at present. Determination of contents chromium realized by ASA method (Pye Unicam SP-9) in flame acetylene-oxygen. Higher contents of chromium were observed for smoking people. The most of the correlations described by large values of the correlation factors were concerned Cr with Ni, Cu, Zn, Na.
Assuntos
Compostos de Cromo/análise , Cabeça do Fêmur/química , Fumar/metabolismo , Poluição por Fumaça de Tabaco/análise , Idoso , Artroplastia de Quadril , Estudos de Casos e Controles , Cromo/análise , Monitoramento Ambiental , Monitoramento Epidemiológico , Feminino , Humanos , Masculino , Polônia/epidemiologia , Fumar/epidemiologia , Espectrofotometria AtômicaRESUMO
The problem of statistical characteristics of occurrence barium and strontium content in gallstones from smoking and non-smoking women living in southern Poland is presented in the work. The subjects of the research were gallstones, gained intraoperatively from 146 women (49 smoking, 97 non-smoking). The content of barium and strontium was determined using atomic emission spectroscopy with inductive coupled plasma (ICP-AES). The statistical characteristic of barium and strontium content in gallstones shows that smoking does not decide about content level of these elements in gallstones. Content of barium (2.32 microgBa/g) as well as strontium (3.23 microgSr/g) in gallstones from non smoking women are higher in comparison to content of these elements in gallstones from smoking women (1.91 microgBa/g and 2.76 microgSr/g).
Assuntos
Bário/análise , Cálculos Biliares/química , Cálculos Biliares/epidemiologia , Fumar/epidemiologia , Estrôncio/análise , Poluição por Fumaça de Tabaco/análise , Estudos de Casos e Controles , Comorbidade , Feminino , Humanos , Polônia/epidemiologia , Espectrofotometria AtômicaRESUMO
Mercury contamination in water has been an issue to the environment and human health. In this article, mercury in marine and oceanic waters has been reviewed. In the aquatic environment, mercury occurs in many forms, which depend on the oxidation-reduction conditions. These forms have been briefly described in this article. Mercury concentrations in marine waters in the different parts of the world have been presented. In the relevant literature, two models describing the fate and behavior of mercury in saltwater reservoirs have been presented, a conceptual model which treats all the oceans as one ocean and the "ocean margin" model, providing that the ocean margins manifested themselves as the convergence of continents and oceans, covering such geological features, such as estuaries, inland seas, and the continental shelf. These two conceptual models have been summarized in the text. The mercury content in benthic sediments usually reflects is level in the water reservoir, particularly in reservoirs situated in contaminated areas (mines, metallurgical plants, chemically protected crops). The concentrations of mercury and its compounds determined in the sediments in surface waters in the different parts of the world have been presented. Due to the fact that the pollution caused by mercury is a serious threat for the marine environment, the short paragraph about mercury bioaccumulation in aquatic organisms has been included. The cited data demonstrated a large scatter of mercury contents both between the fish species and the water areas. Mathematical models, valuable tools which provide information about the possible responses of ecosystems, developed to simulate mercury emissions, both at a small scale, for local water reservoirs, and at a global scale, as well as to model mercury bioaccumulation in the chain web of aquatic systems have been described.