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1.
Psychopharmacology (Berl) ; 236(9): 2653-2666, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30982127

RESUMO

BACKGROUND: 5-methoxy-N,N-dimethyltryptamine (hereinafter referred to as 5-MeO-DMT) is a psychedelic substance found in the secretion from the parotoid glands of the Bufo alvarius toad. Inhalation of vapor from toad secretion containing 5-MeO-DMT has become popular in naturalistic settings as a treatment of mental health problems or as a means for spiritual exploration. However, knowledge of the effects of 5-MeO-DMT in humans is limited. AIMS: The first objective of this study was to assess sub-acute and long-term effects of inhaling vapor from dried toad secretion containing 5-MeO-DMT on affect and cognition. The second objective was to assess whether any changes were associated with the psychedelic experience. METHODS: Assessments at baseline, within 24 h and 4 weeks following intake, were made in 42 individuals who inhaled vapor from dried toad secretion at several European locations. RESULTS: Relative to baseline, ratings of satisfaction with life and convergent thinking significantly increased right after intake and were maintained at follow-up 4 weeks later. Ratings of mindfulness also increased over time and reached statistical significance at 4 weeks. Ratings of depression, anxiety, and stress decreased after the session, and reached significance at 4 weeks. Participants that experienced high levels of ego dissolution or oceanic boundlessness during the session displayed higher ratings of satisfaction with life and lower ratings of depression and stress. CONCLUSION: A single inhalation of vapor from dried toad secretion containing 5-MeO-DMT produces sub-acute and long-term changes in affect and cognition in volunteers. These results warrant exploratory research into therapeutic applications of 5-MeO-DMT.


Assuntos
Alucinógenos/administração & dosagem , Transtornos Mentais/psicologia , Metoxidimetiltriptaminas/administração & dosagem , Atenção Plena/métodos , Satisfação Pessoal , Vaping/psicologia , Administração por Inalação , Adulto , Animais , Bufonidae , Cognição/efeitos dos fármacos , Cognição/fisiologia , Feminino , Seguimentos , Humanos , Masculino , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/epidemiologia
2.
J Chem Phys ; 149(16): 164307, 2018 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-30384761

RESUMO

5-trifluoromethanesulfonyl-uracil (OTfU), a recently proposed radiosensitizer, is decomposed in the gas-phase by attachment of low-energy electrons. OTfU is a derivative of uracil with a triflate (OTf) group at the C5-position, which substantially increases its ability to undergo effective electron-induced dissociation. We report a rich assortment of fragments formed upon dissociative electron attachment (DEA), mostly by simple bond cleavages (e.g., dehydrogenation or formation of OTf-). The most favorable DEA channel corresponds to the formation of the triflate anion alongside with the reactive uracil-5-yl radical through the cleavage of the O-C5 bond, particularly at about 0 eV. Unlike for halouracils, the parent anion was not detected in our experiments. The experimental findings are accounted by a comprehensive theoretical study carried out at the M06-2X/aug-cc-pVTZ level. The latter comprises the thermodynamic thresholds for the formation of the observed anions calculated under the experimental conditions (383.15 K and 3 × 10-11 atm). The energy-resolved ion yield of the dehydrogenated parent anion, (OTfU-H)-, is discussed in terms of vibrational Feshbach resonances arising from the coupling between the dipole bound state and vibrational levels of the transient negative ion. We also report the mass spectrum of the cations obtained through ionization of OTfU by electrons with a kinetic energy of 70 eV. The current study endorses OTfU as a potential radiosensitizer agent with possible applications in radio-chemotherapy.


Assuntos
Elétrons , Radiossensibilizantes/química , Uracila/química , Estrutura Molecular , Termodinâmica , Uracila/metabolismo
3.
J Thromb Haemost ; 16(9): 1800-1813, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29971917

RESUMO

Essentials Tumor-bearing mice were employed to follow oncogenic HRAS sequences in plasma, and blood cells. Cancer DNA accumulated in leukocytes above levels detected in exosomes, platelets and plasma. Extracellular vesicles and nucleosomes are required for uptake of tumor DNA by leukocytes. Uptake of tumor-derived extracellular vesicles by leukocytes triggers coagulant phenotype. SUMMARY: Background Tumor-derived extracellular vesicles (EVs) and free nucleosomes (NSs) carry into the circulation a wealth of cancer-specific, bioactive and poorly understood molecular cargoes, including genomic DNA (gDNA). Objective Here we investigated the distribution of extracellular oncogenic gDNA sequences (HRAS and HER2) in the circulation of tumor-bearing mice. Methods and Results Surprisingly, circulating leukocytes (WBCs), especially neutrophils, contained the highest levels of mutant gDNA, which exceeded the amount of this material recovered from soluble fractions of plasma, circulating EVs, platelets, red blood cells (RBCs) and peripheral organs, as quantified by digital droplet PCR (ddPCR). Tumor excision resulted in disappearance of the WBC-associated gDNA signal within 2-9 days, which is in line with the expected half-life of these cells. EVs and nucleosomes were essential for the uptake of tumor-derived extracellular DNA by neutrophil-like cells and impacted their phenotype. Indeed, the exposure of granulocytic HL-60 cells to EVs from HRAS-driven cancer cells resulted in a selective increase in tissue factor (TF) procoagulant activity and interleukin 8 (IL-8) production. The levels of circulating thrombin-antithrombin complexes (TAT) were markedly elevated in mice harboring HRAS-driven xenografts. Conclusions Myeloid cells may represent a hitherto unrecognized reservoir of cancer-derived, EV/NS-associated oncogenic gDNA in the circulation, and a possible novel platform for liquid biopsy in cancer. In addition, uptake of this material alters the phenotype of myeloid cells, induces procoagulant and proinflammatory activity and may contribute to systemic effects associated with cancer.


Assuntos
DNA de Neoplasias/sangue , Vesículas Extracelulares/química , Genes erbB-2 , Genes ras , Células Mieloides/química , Neutrófilos/química , Animais , Antitrombina III , Plaquetas/química , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular , Transformação Celular Neoplásica , DNA de Neoplasias/farmacocinética , Exossomos/química , Feminino , Células HL-60 , Xenoenxertos , Humanos , Interleucina-8/biossíntese , Camundongos , Camundongos SCID , Células Mieloides/metabolismo , Transplante de Neoplasias , Neutrófilos/metabolismo , Nucleossomos/química , Peptídeo Hidrolases/sangue , Plasma/química , Ratos , Células THP-1 , Tromboplastina/biossíntese , Carga Tumoral
4.
J Extracell Vesicles ; 7(1): 1490144, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30034643

RESUMO

We have previously uncovered the impact of oncogenic and differentiation processes on extracellular vesicles (EVs) in cancer. This is of interested in the context of glioma stem cells (GSC) that are responsible for recurrent nature of glioblastoma multiforme (GBM), while retaining the potential to undergo differentiation and self renewal.  GSCs reside in vascular niches where they interact with endothelial cells through a number of mediators including bioactive cargo of EVs. GSCs can be classified as proneural (PN) or mesenchymal (MES) subtypes on the basis of their gene expression profiles and distinct biological characteristics. In the present study we investigated how GSC diversity and differentiation programmes influence their EV-mediated communication potentials. Indeed, molecular subtypes of GBMs and GSCs differ with respect to their expression of EV-related genes (vesiculome) and GSCs with PN or MES phenotypes produce EVs with markedly different characteristics, marker profiles, proteomes and endothelial stimulating activities. For example, while EVs of PN GSC are largely devoid of exosomal markers their counterparts from MES GSCs express ample CD9, CD63 and CD81 tetraspanins. In both GSC subtypes serum-induced differentiation results in profound, but distinct changes of cellular phenotypes including the enhanced EV production, reconfiguration of their proteomes and the related functional pathways. Notably, the EV uptake was a function of both subtype and differentiation state of donor cells. Thus, while, EVs produced by differentiated MES GSCs were internalized less efficiently than those from undifferentiated cells they exhibited an increased stimulatory potential for human brain endothelial cells. Such stimulating activity was also observed for EVs derived from differentiated PN GSCs, despite their even weaker uptake by endothelial cells. These findings suggest that the role of EVs as biological mediators and biomarkers in GBM may depend on the molecular subtype and functional state of donor cancer cells, including cancer stem cells. Abbreviations: CryoTEM: cryo-transmission electron microscopy; DIFF: differentiated GSCs; EGF: epidermal growth factor; DUC: differential ultracentrifugation; EV: extracellular vesicle; FGF: fibroblast growth factor; GBM: glioblastoma multiforme; GFAP: glial fibrillary acidic protein; GO: gene ontology; GSC: glioma stem cells; HBEC-5i: human brain endothelial cells; MES: mesenchymal cells; MTS - [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt; PMT1: proneural-to-mesenchyman transition cell line 1; PN: proneural cells; TEM: transmission electron microscopy; WB: western blotting.

5.
Org Biomol Chem ; 13(41): 10362-9, 2015 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-26314288

RESUMO

The TYT and TXT trimeric oligonucleotides, where X stands for a native nucleobase, T (thymine), C (cytosine), A (adenine), or G (guanine), and Y indicates a brominated analogue of the former, were irradiated with ionizing radiation generated by a (60)Co source in aqueous solutions containing Tris as a hydroxyl radical scavenger. In the past, these oligomers were bombarded with low energy electrons under an ultra-high vacuum and significant damage to TXT trimers was observed. However, in aqueous solution, hydrated electrons do not produce serious damage to TXT trimers although the employed radiation dose exceeded many times the doses used in radiotherapy. Thus, our studies demonstrate unequivocally that hydrated electrons, which are the major form of electrons generated during radiotherapy, are a negligible factor in damage to native DNA. It was also demonstrated that all the studied brominated nucleobases have a potential to sensitize DNA under hypoxic conditions. Strand breaks, abasic sites and the products of hydroxyl radical attachment to nucleobases have been identified by HPLC and LC-MS methods. Although all the bromonucleobases lead to DNA damage under the experimental conditions of the present work, bromopyrimidines seem to be the radiosensitizers of choice since they lead to more strand breaks than bromopurines.


Assuntos
Dano ao DNA , DNA/química , Elétrons , Água/química , Conformação de Ácido Nucleico , Solubilidade , Soluções
6.
Neoplasma ; 62(3): 372-83, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25866218

RESUMO

The critical role of the vasculature in cancer progression is predominantly studied at the capillary level, and often equated with angiogenesis. However, the mechanisms that ensure the supply of increasing blood volume to the expanding tumor microcirculation remain presently unclear. Here we used established mouse tumor models to document the enlargement (arteriogenesis), of macroscopic feeding vessels at considerable distances upstream from the malignant lesion, but not contralaterally. These changes are not affected by the procoagulant host tissue factor (TF), but are modulated by vascular ageing and atherosclerosis in ApoE-/- mice. Moreover, arteriogenic growth involves infiltration of bone marrow derived (YFP-labeled) cells and changes the gene expression profiles in the vessel wall. Thus, our observations suggest that in addition to local angiogenesis tumors influence distant remodeling of regional macroscopic blood vessels in a manner that is modulated by certain vascular comorbidities.

7.
Environ Sci Pollut Res Int ; 22(10): 7582-9, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25561252

RESUMO

This study explores the inorganic composition of amniotic fluid in healthy human fetuses and fetuses with congenital malformation with a special attention to presence of metal-based solid particles. Amniotic fluid originates from maternal blood and provides fetus mechanical protection and nutrients. In spite of this crucial role, the environmental impact on the composition of amniotic fluid remains poorly studied. The samples of human amniotic fluids were obtained by amniocentesis, including both healthy pregnancies and those with congenital malformations. The samples were analysed using several techniques, including Raman microspectroscopy, scanning electron microscopy with energy-dispersed spectrometry (SEM-EDS), Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD) analysis. Several metal-based particles containing barium, titanium, iron, and other elements were detected by SEM-EDS and Raman microspectroscopy. XRD analysis detected only sodium chloride as the main component of all amniotic fluid samples. Infrared spectroscopy detected protein-like organic components. Majority of particles were in form of agglomerates up to tens of micrometres in size, consisting of mainly submicron particles. By statistical analysis (multiple correspondence analysis), it was observed that groups of healthy and diagnosed fetuses form two separate groups and therefore, qualitative differences in chemical composition may have distinct biological impact. Overall, our results suggest that metal-based nanosized pollutants penetrate into the amniotic fluid and may affect human fetuses.


Assuntos
Líquido Amniótico/química , Anormalidades Congênitas/etiologia , Feto , Metais/toxicidade , Amniocentese , Estudos de Casos e Controles , Feminino , Humanos , Cariótipo , Microscopia Eletrônica de Varredura , Projetos Piloto , Gravidez , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X
8.
J Thromb Haemost ; 12(11): 1838-49, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25163932

RESUMO

BACKGROUND: The coagulation system becomes activated during progression and therapy of high-grade brain tumors. Triggering tissue factor (F3/TF) and thrombin receptors (F2R/PAR-1) may influence the vascular tumor microenvironment and angiogenesis irrespective of clinically apparent thrombosis. These processes are poorly understood in medulloblastoma (MB), in which diverse oncogenic pathways define at least four molecular disease subtypes (WNT, SHH, Group 3 and Group 4). We asked whether there is a link between molecular subtype and the network of vascular regulators expressed in MB. METHODS: Using R2 microarray analysis and visualization platform, we mined MB datasets for differential expression of vascular (coagulation and angiogenesis)-related genes, and explored their link to known oncogenic drivers. We evaluated the functional significance of this link in DAOY cells in vitro following growth factor and thrombin stimulation. RESULTS: The coagulome and angiome differ across MB subtypes. F3/TF and F2R/PAR-1 mRNA expression are upregulated in SHH tumors and correlate with higher levels of hepatocyte growth factor receptor (MET). Cultured DAOY (MB) cells exhibit an up-regulation of F3/TF and F2R/PAR-1 following combined SHH and MET ligand (HGF) treatment. These factors cooperate with thrombin, impacting the profile of vascular regulators, including interleukin 1ß (IL1B) and chondromodulin 1 (LECT1). CONCLUSIONS: Coagulation pathway sensors (F3/TF, F2R/PAR-1) are expressed in MB in a subtype-specific manner, and may be functionally linked to SHH and MET circuitry. Thus coagulation system perturbations may elicit subtype/context-specific changes in vascular and cellular responses in MB.


Assuntos
Proteínas Angiogênicas/genética , Coagulação Sanguínea/genética , Neoplasias Cerebelares/irrigação sanguínea , Neoplasias Cerebelares/genética , Perfilação da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Meduloblastoma/irrigação sanguínea , Meduloblastoma/genética , Neovascularização Patológica , Trombina/metabolismo , Proteínas Angiogênicas/metabolismo , Linhagem Celular Tumoral , Neoplasias Cerebelares/sangue , Neoplasias Cerebelares/patologia , Mineração de Dados , Bases de Dados Genéticas , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Proteínas Hedgehog/metabolismo , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Meduloblastoma/sangue , Meduloblastoma/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , RNA Mensageiro/metabolismo , Receptor PAR-1/genética , Receptor PAR-1/metabolismo , Transdução de Sinais , Tromboplastina/genética , Tromboplastina/metabolismo
10.
J Phys Condens Matter ; 25(19): 195701, 2013 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-23604265

RESUMO

The electronic structure of superconducting Fe1.03Te0.94S0.06 has been studied by angle-resolved photoemission spectroscopy (ARPES). Experimental band topography is compared to the calculations using the methods of Korringa-Kohn-Rostoker (KKR) with the coherent potential approximation (CPA) and the linearized augmented plane wave with local orbitals (LAPW+LO) method. The region of the Γ point exhibits two hole pockets and a quasiparticle peak close to the chemical potential (µ) with undetectable dispersion. This flat band with mainly d(z)(2) orbital character is most likely formed by the top of the outer hole pocket or is evidence of a third hole band. It may cover up to 3% of the Brillouin zone volume and should give rise to a Van Hove singularity. Studies performed for various photon energies indicate that at least one of the hole pockets has a two-dimensional character. The apparently nondispersing peak at µ is clearly visible for 40 eV and higher photon energies, due to an effect of the photoionization cross-section rather than band dimensionality. Orbital characters calculated by LAPW+LO for stoichiometric FeTe do not reveal the flat dz(2) band but are in agreement with the experiment for the other dispersions around Γ in Fe1.03Te0.94S0.06.


Assuntos
Ferro/química , Modelos Químicos , Modelos Moleculares , Espectroscopia Fotoeletrônica/métodos , Selênio/química , Telúrio/química , Simulação por Computador , Condutividade Elétrica , Transporte de Elétrons , Teste de Materiais
12.
Anal Methods ; 3(2): 374-379, 2011 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32938039

RESUMO

We developed a highly sensitive biosensor for quantifying acetylcholine (ACh) using flow injection analysis system with 1,1'-oxalyldiimidazole chemiluminescence (ODI-CL) detection designed based on the principle of liquid core waveguide. ACh in Tris-HCl (pH 8.5) was incubated with the mixture of 1.0 U/ml acetylcholinesterase, 0.5 U/ml choline oxidase, 0.04 U/ml horseradish peroxidase, and 1.0 µM Amplex Red in PBS (pH 7.4) for 15 min at room temperature. The concentration of resorufin formed from the consecutive enzyme reactions was proportional to the concentration of ACh in analytical sample. The dynamic range of linear calibration curve (y = 12444x + 11617, R2 = 0.998) for the quantification of ACh using the biosensor with ODI CL detection was 0.7∼11.3 µM. The limit of detection (LOD = background noise + 3σ) of the biosensor was as low as 0.14 µM. Based on the results of recovery test and linearity study, finally, we confirmed that FIA system with ODI CL detection is accurate, precise, and reproducible.

13.
Arthritis Rheum ; 60(1): 73-80, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19117368

RESUMO

OBJECTIVE: Rheumatoid arthritis (RA) is an autoimmune disease that affects mostly women and is associated with HLA-DRB1 genes having in common a shared epitope sequence. In parallel, cells and/or DNA originating from pregnancy (microchimerism) persist for decades and could contribute to autoimmunity. The aim of this study was to examine whether microchimerism may be a source of the shared epitope among women with RA. METHODS: Women with RA and healthy women who lacked RA-associated genes such as HLA-DRB1*01 (n=33 and n=46, respectively) and/or HLA-DRB1*04 (n=48 and n=64, respectively), were tested for DRB1*01 or DRB1*04 microchimerism by HLA-specific quantitative polymerase chain reaction assays. As controls, alleles not associated with RA (DQB1*02 and DRB1*15/16) were also analyzed. RESULTS: Compared with healthy women, women (42% with RA had a higher frequency and higher levels of DRB1*04 microchimerism versus 8%; P=0.00002) as well as DRB1*01 microchimerism (30% versus 4%; P=0.0015). Moreover, no difference in microchimerism was observed for alleles not associated with RA. CONCLUSION: Women with RA had microchimerism with RA-associated HLA alleles, but not with non-RA-associated HLA alleles, more often and at higher levels compared with healthy women. These observations are the first to indicate that microchimerism can contribute to the risk of an autoimmune disease by providing HLA susceptibility alleles.


Assuntos
Artrite Reumatoide/genética , Quimerismo , Epitopos/genética , Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Troca Materno-Fetal/genética , Artrite Reumatoide/epidemiologia , Feminino , Genótipo , Cadeias beta de HLA-DQ , Cadeias HLA-DRB1 , Humanos , Mães , Gravidez , Fatores de Risco
14.
Ann Rheum Dis ; 68(4): 591-4, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18957483

RESUMO

OBJECTIVE: To identify new IgG autoantibodies in sera from patients with rheumatoid arthritis (RA). METHODS: We tested serum samples from 19 patients with RA with given human leukocyte antigen (HLA)-DR genotypes, from 7 patients with spondylarthropathy, 2 patients with lupus, 4 patients with systemic sclerosis and 10 healthy individuals on 8268 human protein arrays. RESULTS: We identified four antigens (peptidyl arginine deiminase 4 (PAD4), protein kinase Cbeta1 (PKCbeta1), phosphatylinositol 4 phosphate 5 kinase type II gamma (PIP4K2C) and v raf murine sarcoma viral oncogene homologue B1 catalytic domain (BRAF)) that were recognised almost uniquely by sera from patients with RA on protein arrays. Using purified proteins, we confirmed that PAD4 and BRAF are recognised almost uniquely by patients with RA. CONCLUSION: We identified PAD4 and BRAF as RA specific autoantigens.


Assuntos
Artrite Reumatoide/imunologia , Autoanticorpos/sangue , Autoantígenos/imunologia , Imunoglobulina G/imunologia , Análise Serial de Proteínas , Autoanticorpos/imunologia , Western Blotting/métodos , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática/métodos , Humanos , Hidrolases/sangue , Hidrolases/imunologia , Proteína Quinase C/sangue , Proteína Quinase C/imunologia , Proteína Quinase C beta , Proteína-Arginina Desiminase do Tipo 4 , Desiminases de Arginina em Proteínas , Proteínas Proto-Oncogênicas B-raf/sangue , Proteínas Proto-Oncogênicas B-raf/imunologia
15.
Clin Exp Rheumatol ; 26(4): 627-31, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18799094

RESUMO

OBJECTIVE: To test whether the presence of RA associated HLA-DRB1*0101, HLA-DRB1*0401 and HLA-DRB1*0404 alleles individually influences anti-cyclic citrullinated peptide antibodies (anti-CCP) production. METHODS: The frequency of anti-CCP antibodies was calculated in the sera of 260 RA patients expressing either two (double dose genotypes SE+/SE+), one (single dose genotypes SE+/SE-) or no RA associated HLA-DR alleles (SE-/SE-). Anti-CCP antibodies titers were also determined. RESULTS: RA associated HLA-DR alleles are not mandatory for production of anti-CCP. We found that 68% of SE-/SE- patients were anti-CCP positive. There was no significant difference in anti-CCP between SE negative patient (SE-/SE-) and patients expressing at least one SE (SE+/SE+ and SE+/SE-) (p=0.140). We observed no statistical difference in anti-CCP between RA patients expressing one or two SE (82% vs. 77%, p=0.577). Among SE+/SE-patients, HLA-DRB1*0404 was associated with anti-CCP with a statistically significant difference compared with SE negative patients (90% anti-CCP positive, p=0.02). HLA-DRB1*0404 was also associated with high titers of anti CCP with a statistically significant difference compared with HLA-DRB1*0401 and HLA-DRB1*0101 patients (p=0.025). CONCLUSIONS: The RA-associated HLA-DRB1*0404 allele was the most strongly associated with the presence of anti-CCP in RA sera. Moreover, HLA-DRB1*0404 patients had higher titers of anti CCP than patients with other RA associated HLA-DR alleles.


Assuntos
Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Autoanticorpos/sangue , Antígenos HLA-DR/genética , Peptídeos Cíclicos/imunologia , Artrite Reumatoide/sangue , Autoanticorpos/genética , Autoanticorpos/imunologia , Estudos de Casos e Controles , Feminino , Antígenos HLA-DR/imunologia , Cadeias HLA-DRB1 , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/imunologia
16.
Oncogene ; 27(26): 3729-38, 2008 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-18223682

RESUMO

Antiangiogenic therapies are promising approaches to cancer control, but the details of their effects on subsequent tumor progression are not fully understood. Such therapies have the potential to eventually generate extensive amounts of tumor ischemia, and we previously demonstrated that ischemic conditions induce K-ras mutations in cells with deficient mismatch repair (MMR) mechanisms. This suggested that similar effects on oncogene mutagenesis may accompany antiangiogenic therapy. To test this, MMR-deficient colorectal cancer cells (Dks-8) were xenografted into immune-deficient mice and treated with the antiangiogenic regimen of low-dose/metronomic cyclophosphamide for 2 weeks followed by a 2-week recovery period without therapy. This treatment resulted in transient tumor growth inhibition, increased hypoxia, and decreased microvessel density, and cancer cells from treated tumors acquired activating mutations of the K-ras oncogene (K-ras(G13D)). In vitro exposure of Dks-8 cells to the active metabolite of cyclophosphamide (4-hydroxycyclophosphamide) had no effect on the K-ras status, indicating that there was no direct action of this alkylating agent on K-ras mutagenesis. In addition, cells sorted from hypoxic regions of Dks-8 tumors were enriched in K-ras(G13D) mutants. Collectively, our studies suggest that increases in tumor hypoxia induced by antiangiogenic treatment may lead to K-ras mutation and consequently tumor progression, especially in susceptible individuals.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Hipóxia Celular , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Ciclofosfamida/uso terapêutico , Genes ras , Mutação , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/irrigação sanguínea , Neoplasias Colorretais/metabolismo , Ciclofosfamida/análogos & derivados , Humanos , Camundongos , Transplante de Neoplasias , Transplante Heterólogo
18.
Phys Rev Lett ; 96(15): 152301, 2006 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-16712151

RESUMO

We report on results of a measurement of meson production in central Pb-Au collisions at E(lab) = 158A GeV. For the first time in the history of high energy heavy-ion collisions, phi mesons were reconstructed both in the K+K- and the dilepton decay channels in the same experiment. This measurement yields rapidity densities near midrapidity, from the two decay channels, of 2.05 +/- 0.14(stat) +/- 0.25(syst) and 2.04 +/- 0.49(stat) +/- 0.32(syst), respectively. The shape of the measured transverse momentum spectrum is also in close agreement in both decay channels. The data rule out a possible enhancement of the phi yield in the leptonic over the hadronic decay channel of a factor 1.6 or larger at the 95% C.L. This rules out the discrepancy reported in the literature between measurements of the hadronic and dimuon decay channels by two different experiments.

19.
Neoplasma ; 53(2): 111-8, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16575466

RESUMO

The possible role of statins in cancer is controversial. Indeed, among the multiplicity of biological effects ascribed to these widely used cholesterol lowering agents some could, at least in theory, inhibit tumor growth (e.g. by inhibiting Ras oncoproteins), while other actions are inert, or may even stimulate cancer aggressiveness (e.g. through promoting neovascularization). In order to address some of these controversies, we set out to compare the effects of statins on growth of cancer and endothelial cells in vitro, to the impact of these drugs on angiogenesis-dependent expansion of the corresponding tumors in vivo. Water-soluble fluvastatin was used at concentrations (0-800 ng/ml) against human umbilical vein endothelial cells (HUVEC), and several well-characterized cancer cell lines in culture, including: carcinoma (LLC), melanoma (B16F1) and fibrosarcoma driven by mutant H-ras (528ras1). Endpoints were based on 3H-thymidine incorporation assay, cell morphology and tumorigenicity in mice. The growth inhibitory effects of fluvastatin varied among cancer cell lines (LLC>B16F1>528ras1), irrespectively of their mutant H-ras status. Fluvastatin also blocked the action of angiogenic factors on cultured endothelial cells, but was relatively ineffective against highly angiogenic and aggressive tumors both in young mice (6-8 weeks), and in less aggressively growing tumors in aged (80-90 weeks) mice. Thus, antitumor and antiangiogenic activity of fluvastatin in vitro is not recapitulated in vivo. Tumors may display a form of resistance to statins through a mechanism operative only in vivo.


Assuntos
Células Endoteliais/efeitos dos fármacos , Ácidos Graxos Monoinsaturados/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Indóis/farmacologia , Neoplasias Experimentais/tratamento farmacológico , Neovascularização Patológica , Animais , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Fluvastatina , Humanos , Técnicas In Vitro , Camundongos , Camundongos Endogâmicos C57BL
20.
Vnitr Lek ; 52 Suppl 1: 119-22, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16637459

RESUMO

Medical needs associated with diverse thromboembolic conditions are not fully met by currently available anticoagulants. Of those, unfractionated heparin (UFH) is gradually replaced by low molecular weight heparin (LMWH) for prevention and treatment of venous thromboembolism and acute coronary syndromes, along with supportive treatment with oral anticoagulants, such as warfarin derivatives. While generally effective these agents have several shortcomings involving compliance, delivery, efficacy and safety considerations in various disease settings, and for these reasons new anticoagulants are sought, to target more specifically the critical effectors and steps in the blood coagulation process, namely: (i) initiation, (ii) propagation and (iii) the phase of thrombin activity. The emerging agents that block tissue factor/factor VIIa-dependent initiation phase of the coagulation cascade, include: recombinant tissue factor pathway inhibitor (rTFPI), nematode anticoagulant peptide (NAPc2), active site-blocked factor VIIa (FVIIai) and TF targeting antibodies. Some of them are currently evaluated in clinical trials with promising results. Propagation phase of thrombus formation (e.g. the activity of factors IXa, Xa, VIIIa or Va) is targeted mainly by various indirect, direct and bimodal inhibitors, such as fondaparinux, indraparinux, tick anticoagulant peptide (TAP), antistatin (ANT) and antithrombin-heparin covalent complex (ATH), all endowed mostly with an anti-Xa activity. Although promising, some of these agents (TAP, ANT and ATH) have not progressed beyond animal testing while others (fondaparinux) was already assessed for prevention and treatment of venous thromboembolism and for treatment of arterial thrombosis. Lastly, inhibitors of thrombin activity are composed of either indirect (UFH, LMWH), or direct thrombin (FIIa) inhibitors including: hirudin, argatroban, melagatran, ximelagatran, dabigatran, and bivalirudin. These agents are either in advanced development or already approved for clinical use. Bimodal FIIa inhibitory activity of ATH was demonstrated in animal models of venous and arterial thrombosis, but is in need of further development. In conclusion, while some of these emerging anticoagulants, such as fondaparinux, idraparinux, ximelagatran and ATH appear to possess superior efficacy-safety profile, as compared to their conventional predecessors (UFH, LMWH and warfarin), their cost-effectiveness, side effects and antidote availability have to be considered. More importantly, coagulation factors that are targets of these inhibitory activities also affect coagulation independent processes, such as wound healing, inflammation, angiogenesis, mitogenesis and cell survival. Thus the consequences of both coagulation-dependent and -independent effects of new agents should be carefully considered before proper clinical indications are established.


Assuntos
Anticoagulantes , Anticoagulantes/farmacologia , Anticoagulantes/uso terapêutico , Antitrombinas/farmacologia , Antitrombinas/uso terapêutico , Coagulação Sanguínea/efeitos dos fármacos , Hemostasia/efeitos dos fármacos , Humanos , Tromboembolia/prevenção & controle
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