RESUMO
OBJECTIVES: To assess the prevalence, distribution and clinical correlates of myocardial fibrosis, as detected by cardiac magnetic resonance (CMR), in systemic lupus erythematosus (SLE). METHODS: Forty-one subjects (average age 39 ± 12 years and 80% female) with SLE underwent CMR imaging at 1.5T, using late gadolinium enhancement (LGE) to quantify the area of myocardial fibrosis in the left ventricle (LV). Subjects also underwent transthoracic echocardiography (TTE) and exercise testing. RESULTS: LGE was detected in 15/41 subjects, 11 with localized LGE (<15% LV mass) and four with extensive LGE (>15% LV mass). The commonest site of LGE was the interventricular septum, with all but one case demonstrating an intramural or inflammatory pattern. The mean age of the >15% LGE group (55 ± 15 years) was significantly higher than the <15% or absent LGE subgroups. Based on both CMR and TTE measurements, subjects with LGE > 15% demonstrated a reduced E/A ratio of 0.9 ± 0.4 relative to the <15% and absent LGE subgroups. LV end-systolic volume (ESVi), end-diastolic volume (EDVi) and maximum exercise capacity were also reduced in the >15% LGE group. CONCLUSIONS: Mid-wall myocardial fibrosis occurs frequently in SLE and is strongly associated with advancing subject age, but not with SLE duration or severity. Extensive LGE may be associated with diastolic dysfunction and impaired exercise capacity, although this may be an epiphenomenon of age. Cardiac magnetic resonance with quantitative assessment of LGE may provide a basis for cardiac risk stratification in SLE.
Assuntos
Cardiomiopatias/diagnóstico por imagem , Lúpus Eritematoso Sistêmico/complicações , Imageamento por Ressonância Magnética/métodos , Disfunção Ventricular Esquerda/diagnóstico por imagem , Adulto , Fatores Etários , Idoso , Cardiomiopatias/epidemiologia , Cardiomiopatias/etiologia , Meios de Contraste/administração & dosagem , Ecocardiografia , Tolerância ao Exercício , Feminino , Fibrose , Humanos , Masculino , Pessoa de Meia-Idade , Compostos Organometálicos/administração & dosagem , Prevalência , Fatores de Risco , Disfunção Ventricular Esquerda/epidemiologia , Disfunção Ventricular Esquerda/etiologiaRESUMO
Molecular imaging has moved to the forefront of drug development and biomedical research. The identification of appropriate imaging targets has become the touchstone for the accurate diagnosis and prognosis of human cancer. Particularly, cell surface- or membrane-bound proteins are attractive imaging targets for their aberrant expression, easily accessible location, and unique biochemical functions in tumor cells. Previously, we published a literature mining of potential targets for our in-house enzyme-mediated cancer imaging and therapy technology. Here we present a simple and integrated bioinformatics analysis approach that assembles a public cancer microarray database with a pathway knowledge base for ascertaining and prioritizing upregulated genes encoding cell surface- or membrane-bound proteins, which could serve imaging targets. As examples, we obtained lists of potential hits for six common and lethal human tumors in the prostate, breast, lung, colon, ovary, and pancreas. As control tests, a number of well-known cancer imaging targets were detected and confirmed by our study. Further, by consulting gene-disease and protein-disease databases, we suggest a number of significantly upregulated genes as promising imaging targets, including cell surface-associated mucin-1, prostate-specific membrane antigen, hepsin, urokinase plasminogen activator receptor, and folate receptors. By integrating pathway analysis, we are able to organize and map "focused" interaction networks derived from significantly dysregulated entity pairs to reflect important cellular functions in disease processes. We provide herein an example of identifying a tumor cell growth and proliferation subnetwork for prostate cancer. This systematic mining approach can be broadly applied to identify imaging or therapeutic targets for other human diseases.
Assuntos
Acesso à Informação , Biologia Computacional/métodos , Bases de Dados Genéticas , Diagnóstico por Imagem/métodos , Regulação Neoplásica da Expressão Gênica , Genoma Humano/genética , Neoplasias/genética , Proliferação de Células , Perfilação da Expressão Gênica , Redes Reguladoras de Genes/genética , Humanos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias/patologia , Ligação ProteicaRESUMO
This special report aims to inform the medical community about the many challenges involved in managing radiation exposure in a way that maximizes the benefit-risk ratio. The report discusses the state of current knowledge and key questions in regard to sources of medical imaging radiation exposure, radiation risk estimation, dose reduction strategies, and regulatory options.
Assuntos
Diagnóstico por Imagem/efeitos adversos , Lesões por Radiação/prevenção & controle , Fluoroscopia/efeitos adversos , Humanos , Neoplasias Induzidas por Radiação/prevenção & controle , Doses de Radiação , Proteção Radiológica , Radiografia Intervencionista/efeitos adversos , Medição de Risco , Fatores de Risco , Fatores SexuaisRESUMO
The widely used agarose gel electrophoresis method for assessing radiation-induced single-strand-break (SSB) yield in plasmid DNA involves measurement of the fraction of relaxed-circular (C) form that migrates independently from the intact supercoiled (SC) form. We rationalized that this method may underestimate the SSB yield since the position of the relaxed-circular form is not altered when the number of SSB per DNA molecule is >1. To overcome this limitation, we have developed a novel method that directly probes and quantifies SSBs. Supercoiled (3)H-pUC19 plasmid samples were irradiated with γ-rays, alkali-denatured, dephosphorylated, and kinated with γ-[(32)P]ATP, and the DNA-incorporated (32)P activities were used to quantify the SSB yields per DNA molecule, employing a standard curve generated using DNA molecules containing a known number of SSBs. The same irradiated samples were analyzed by agarose gel and SSB yields were determined by conventional methods. Comparison of the data demonstrated that the mean SSB yield per plasmid DNA molecule of [21.2±0.59]×10(-2)Gy(-1) as measured by direct probing is ~10-fold higher than that obtained from conventional gel-based methods. These findings imply that the SSB yields inferred from agarose gels need reevaluation, especially when they were utilized in the determination of radiation risk.
Assuntos
Quebras de DNA de Cadeia Simples , DNA Circular/análise , DNA Circular/efeitos da radiação , DNA Super-Helicoidal/análise , DNA Super-Helicoidal/efeitos da radiação , Eletroforese em Gel de Ágar/métodos , Escherichia coli/química , Escherichia coli/efeitos da radiação , Estudos de Avaliação como Assunto , Raios gama , Vetores Genéticos , Plasmídeos/química , Plasmídeos/genética , Plasmídeos/efeitos da radiação , Radioisótopos/análiseRESUMO
Common variable immunodeficiency (CVID) is a B cell immunodeficiency disorder characterized frequently by failure of memory B cell development and antibody secretion. A unifying cellular pathogenesis for CVID has not been forthcoming, but given the immunoregulatory role of invariant NK (iNK) T cells and their absence in several other immunodeficiencies, we quantified these cells in the blood of 58 CVID patients. There was a marked decrease in the proportion of iNK T cells in CVID patients compared with controls. This was particularly notable in those with low isotype-switched memory B cells, but subset analysis demonstrated no difference when stratified by specific clinical features. We propose that the decreased proportion of iNK T cells in CVID might be linked to the failure of memory B cell generation, which may contribute to reduced antibody production in these patients.
Assuntos
Imunodeficiência de Variável Comum/imunologia , Células T Matadoras Naturais/imunologia , Formação de Anticorpos , Linfócitos B/imunologia , Estudos de Casos e Controles , Criopreservação , Citometria de Fluxo , Humanos , Switching de Imunoglobulina , Memória Imunológica , Ativação Linfocitária , Contagem de Linfócitos , Estatísticas não Paramétricas , Fatores de TempoRESUMO
The immune system normally avoids producing antibodies that react with autologous ("self") antigens by censoring self-reactive T and B cells. Unlike the T cell repertoire, antibody diversity is generated within the B cell repertoire in two phases; the first occurs by gene rearrangement in primary lymphoid organs, and the second phase involves antigen-driven hypermutation in peripheral lymphoid organs. The possibility that distinct cellular mechanisms may impose self tolerance at these two different phases of B cell diversification may explain recent findings in transgenic mouse models, in which self-reactive B cells appear to be silenced both by functional inactivation and by physical elimination.
Assuntos
Linfócitos B/imunologia , Tolerância Imunológica , Animais , Diversidade de Anticorpos/imunologia , Autoanticorpos/biossíntese , Autoanticorpos/imunologia , Autoantígenos/imunologia , Sítios de Ligação de Anticorpos , Sobrevivência Celular , Regulação para Baixo , Rearranjo Gênico do Linfócito B , Antígenos H-2/imunologia , Camundongos , Camundongos Transgênicos , Muramidase/imunologia , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/imunologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologiaRESUMO
Self-tolerance to a transgene-encoded protein, hen egg lysozyme, was examined in the T and B cell repertoires of a series of lines of transgenic mice that expressed different serum concentrations of soluble lysozyme. T cells were tolerant in all lines in which lysozyme was expressed irrespective of the antigen concentration, whereas B cell tolerance did not occur when the serum lysozyme concentration was less than 1.5 nanograms per milliliter (0.1 nM). Induction of elevated transgene expression could restore B cell tolerance. These findings support the hypothesis that autoimmune disease may in some instances arise through a bypass of T cell tolerance.
Assuntos
Linfócitos B/imunologia , Tolerância Imunológica , Muramidase/genética , Linfócitos T/imunologia , Animais , Galinhas , Clara de Ovo , Ensaio de Imunoadsorção Enzimática , Feminino , Fluoresceína-5-Isotiocianato , Fluoresceínas , Corantes Fluorescentes , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Muramidase/sangue , Muramidase/imunologia , TiocianatosRESUMO
Alpha particles are energetic short-range ions whose higher linear energy transfer produces extreme cytotoxicity. An alpha-particle-emitting radioimmunoconjugate consisting of a bismuth-212-labeled monoclonal immunoglobulin M specific for the murine T cell/neuroectodermal surface antigen Thy 1.2 was prepared. Analysis in vitro showed that the radioimmunoconjugate was selectively cytotoxic to a Thy 1.2+ EL-4 murine tumor cell line. Approximately three bismuth-212-labeled immunoconjugates per target cell reduced the uptake of [3H]thymidine by the EL-4 target cells to background levels. Mice inoculated intraperitoneally with EL-4 cells were cured of their ascites after intraperitoneal injection of 150 microcuries of the antigen-specific radioimmunoconjugate, suggesting a possible role for such conjugates in intracavitary cancer therapy.
Assuntos
Partículas alfa , Antígenos de Superfície , Imunoglobulina M , Linfoma/radioterapia , Animais , Bismuto/uso terapêutico , Imunoterapia , Camundongos , Camundongos Endogâmicos C57BL , Radioisótopos/uso terapêutico , Antígenos Thy-1RESUMO
An investigation of the efficacy of astatine-211--tellurium colloid for the treatment of experimental malignant ascites in mice reveals that this alpha-emitting radiocolloid can be curative without causing undue toxicity to normal tissue. By comparison, negatron-emitting phosphorus-32 as colloidal chromic phosphate had no antineoplastic activity. The most compelling explanation for this striking difference is the dense ionization and short range of action associated with alpha-emission. These results have important implications for the development and use of alpha-emitters as radiocolloid therapy for the treatment of human tumors.
Assuntos
Ascite/radioterapia , Astato/uso terapêutico , Compostos de Cromo , Neoplasias Experimentais/radioterapia , Radioisótopos/uso terapêutico , Telúrio/uso terapêutico , Partículas alfa , Animais , Sobrevivência Celular/efeitos da radiação , Cromo/uso terapêutico , Coloides , Feminino , Camundongos , Transplante de Neoplasias , Neoplasias Ovarianas , Fosfatos/uso terapêutico , Radioisótopos de Fósforo/uso terapêutico , Transplante HomólogoRESUMO
We are developing a noninvasive approach for targeting imaging and therapeutic radionuclides to prostate cancer. Our method, Enzyme-Mediated Cancer Imaging and Therapy (EMCIT), aims to use enzyme-dependent, site-specific, in vivo precipitation of a radioactive molecule within the extracellular space of solid tumors. Advanced methods for data mining of the literature, protein databases, and knowledge bases (IT. Omics LSGraph and Ingenuity Systems) identified prostatic acid phosphatase (PAP) as an enzyme overexpressed in prostate cancer and secreted in the extracellular space. Using AutoDock 3.0 software, the prodrug ammonium 2-(2'-phosphoryloxyphenyl)-6-iodo-4-(3H)-quinazolinone (IQ(2-P)) was docked in silico into the X-ray structure of PAP. The data indicate that IQ(2-P) docked into the PAP active site with a calculated inhibition constant (K(i)) more favorable than that of the PAP inhibitor alpha-benzylaminobenzylphosphonic acid. When (125)IQ(2-P), the radioiodinated form of the water-soluble prodrug, was incubated with PAP, rapid hydrolysis of the compound was observed as exemplified by formation of the water-insoluble 2-(2'-hydroxyphenyl)-6-[(125)I]iodo-4-(3H)-quinazolinone ((125)IQ(2-OH)). Similarly, the incubation of IQ(2-P) with human LNCaP, PC-3, and 22Rv1 prostate tumor cells resulted in the formation of large fluorescent IQ(2-OH) crystals. No hydrolysis was seen in the presence of normal human cells. Autoradiography of tumor cells incubated with (125)IQ(2-P) showed accumulation of radioactive grains ((125)IQ(2-OH)) around the cells. We anticipate that the EMCIT approach will enable the active in vivo entrapment of radioimaging and radiotherapeutic compounds within the extracellular spaces of primary prostate tumors and their metastases.
Assuntos
Carcinoma/tratamento farmacológico , Simulação por Computador , Sistemas de Liberação de Medicamentos , Espaço Extracelular/efeitos dos fármacos , Pró-Fármacos/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Proteínas Tirosina Fosfatases/metabolismo , Fosfatase Ácida , Carcinoma/patologia , Humanos , Radioisótopos do Iodo/administração & dosagem , Radioisótopos do Iodo/farmacocinética , Masculino , Modelos Biológicos , Modelos Moleculares , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Compostos de Amônio Quaternário/administração & dosagem , Compostos de Amônio Quaternário/farmacocinética , Quinazolinonas/administração & dosagem , Quinazolinonas/farmacocinética , Células Tumorais CultivadasRESUMO
BACKGROUND: Myotonic dystrophy type 1 is an autosomal dominant disorder characterized by muscle weakness, myotonia, cataracts, and cardiac conduction defects; it is associated with expansions of cytosine-thymine-guanine repeats in the myotonic dystrophy protein kinase. Hypogammaglobulinemia is a lesser known association of myotonic dystrophy type 1 and the underlying pathogenesis of immunoglobulin G depletion remains unclear. CASE PRESENTATION: Here we report a kindred of two members (a 62-year-old white woman and a 30-year-old white man; mother and son) with myotonic dystrophy type 1-associated hypogammaglobulinemia associated with altered intravenous immunoglobulin elimination kinetics and reduced half-life. There was no history of systemic immunosuppression or renal or gastrointestinal protein loss in either patient, and no underlying case for a secondary immunodeficiency could be found. One patient required fortnightly intravenous immunoglobulin to maintain adequate trough immunoglobulin G levels. CONCLUSIONS: Ongoing study of myotonic dystrophy type 1-associated hypogammaglobulinemia using contemporary tools of genomic medicine may help to further delineate the pathogenesis of this entity.
Assuntos
Agamaglobulinemia/diagnóstico , Imunoglobulina G/sangue , Imunoglobulinas Intravenosas/uso terapêutico , Mães , Distrofia Miotônica/diagnóstico , Núcleo Familiar , Adulto , Agamaglobulinemia/imunologia , Agamaglobulinemia/terapia , Feminino , Predisposição Genética para Doença , Humanos , Hospedeiro Imunocomprometido , Masculino , Pessoa de Meia-Idade , Distrofia Miotônica/imunologia , Distrofia Miotônica/terapiaRESUMO
From a structural perspective, the factors controlling and the mechanisms underlying the toxic effects of ionizing radiation remain elusive. We have studied the consequences of superhelical/torsional stress on the magnitude and mechanism of DSBs induced by low-energy, short-range, high-LET Auger electrons emitted by (125)I, targeted to plasmid DNA by m-[(125)I]iodo-p-ethoxyHoechst 33342 ((125)IEH). DSB yields per (125)I decay for torsionally relaxed nicked (relaxed circular) and linear DNA (1.74+/-0.11 and 1.62+/-0.07, respectively) are approximately threefold higher than that for torsionally strained supercoiled DNA (0.52+/-0.02), despite the same affinity of all forms for (125)IEH. In the presence of DMSO, the DSB yield for the supercoiled form remains unchanged, whereas that for nicked and linear forms decreases to 1.05+/-0.07 and 0.76+/-0.03 per (125)I decay, respectively. DSBs in supercoiled DNA therefore result exclusively from direct mechanisms, and those in nicked and linear DNA, additionally, from hydroxyl radical-mediated indirect effects. Iodine-125 decays produce hydroxyl radicals along the tracks of Auger electrons in small isolated pockets around the decay site. We propose that relaxation of superhelical stress after radical attack could move a single-strand break lesion away from these pockets, thereby preventing further breaks in the complementary strand that could lead to DSBs.
Assuntos
Quebras de DNA de Cadeia Dupla/efeitos da radiação , Elétrons , DNA/química , DNA/metabolismo , DNA/efeitos da radiação , Plasmídeos/química , Plasmídeos/metabolismo , Plasmídeos/efeitos da radiação , TitulometriaRESUMO
Preparations of circular plasmid DNA in either supercoiled or nicked circular form often are contaminated with undesired linear DNA fragments arising from shearing/degradation of chromosomal DNA or linearization of plasmid DNA itself. We report a simple enzymatic method, using a combination of lambda exonuclease and RecJ(f), for the selective removal of linear DNA from such mixtures. lambda exonuclease digests one strand of linear duplex DNA in the 5' to 3' direction, whereas RecJ(f), a single-strand-specific exonuclease, digests the remaining complementary single strand into mononucleotides. This combination of exonucleases can remove linear DNA from a mixture of linear and supercoiled DNA, leaving the supercoiled form intact. Furthermore, the inability of lambda exonuclease to initiate digestion at nicks or gaps enables the removal of undesired linear DNA when nicked circular DNA has been enzymatically prepared from supercoiled DNA. This method can be useful in the preparation of homogeneous circular plasmid DNA required for therapeutic applications and biophysical studies.
Assuntos
DNA Super-Helicoidal/isolamento & purificação , Biologia Molecular/métodos , Plasmídeos/isolamento & purificação , DNA Super-Helicoidal/química , Eletroforese em Gel de Ágar , Etídio , Exonucleases/metabolismo , Conformação de Ácido Nucleico , Plasmídeos/químicaRESUMO
PURPOSE: To determine double-strand-break (DSB) yields produced by decay of minor-groove-bound (123)I-labeled Hoechst 33342 ((123)IEH) in supercoiled (SC) and linear (L) forms of pUC19 DNA, to compare strand-break efficiency of (123)IEH with that of (125)IEH, and to examine the role of DNA topology in DSB induction by these Auger electron emitters. MATERIALS AND METHODS: Tritium-labeled SC and L pUC19 DNA were incubated with (123)IEH (0-10.9 MBq) at 4 degrees C. After (123)I had completely decayed (10 days), samples were analyzed on agarose gel, and single-strand-break (SSB) and DSB yields were measured. RESULTS: Each (123)I decay in SC DNA produces a DSB yield of 0.18 +/- 0.01. On the basis of DSB yields for (125)IEH (0.52 +/- 0.02 for SC and 1.62 +/- 0.07 for L, reported previously) and dosimetric expectations, a DSB yield of approximately 0.5 (3 x 0.18) per (123)I decay is expected for L DNA. However, no DSB are observed for the L form, even after approximately 2 x 10(11) decays of (123)I per microg DNA, whereas a similar number of (125)I decays produces DSB in approximately 40% of L DNA. CONCLUSION: (123)IEH-induced DSB yield for SC but not L DNA is consistent with the dosimetric expectations for Auger electron emitters. These studies highlight the role of DNA topology in DSB production by Auger emitters and underscore the failure of current theoretical dosimetric methods per se to predict the magnitude of DSB.
Assuntos
Quebras de DNA de Cadeia Dupla/efeitos da radiação , Quebras de DNA de Cadeia Simples/efeitos da radiação , DNA Super-Helicoidal/efeitos da radiação , Radioisótopos do Iodo/química , Benzimidazóis , Elétrons , Conformação de Ácido Nucleico , Plasmídeos , RadioatividadeRESUMO
PURPOSE: To synthesize N-(3-(3-aminopropylamino)propyl)-2-oxo-2H-chromene-3-carboxamide (7), a novel DNA-binding, coumarin-based, fluorescent hydroxylradical ((*)OH) indicator and to assess its quantum efficiency compared with that of coumarin-3-carboxylic acid (1) and N1,N12-bis[2-oxo-2H-chromene-3-carbonyl]- 1,12-diamine-4,9-diazadodecane (9). MATERIALS AND METHODS: Using computer-generated molecular modeling, 7 and 9 and their respective 7-hydroxylated derivatives 8 and 10 were docked onto DNA dodecamer d(CGCGAATTCGCG)2, the ligand-DNA complexes were energy minimized, and binding free energies and inhibition constants were calculated. Compound 7 was judged an appropriate target molecule and was synthesized. Compounds 1, 7, and 9 were incubated with Na(125)I or irradiated with (137)Cs gamma-rays, and the influence of pH, dose, type of radiation, and the concentration of indicator on fluorescence yield were determined. RESULTS: Non-fluorescent 7 and 9 are converted to fluorescent, 7-hydroxylated derivatives 8 and 10 after interaction with (*)OH in aqueous solution. For 1, 7, and 9, hydroxylation yield increases linearly with both Na(125)I dose (0-700 x 10(6) decays) and (137)Cs dose (0-11.0 Gy). Fluorescence induction is significantly reduced at acidic pH and the fluorescent quantum yield of 8 is approximately 3 times that of 2 or 10 at pH 7.0. With Na(125)I incubation and gamma-ray irradiation, the fluorescence signal of 7 increases linearly with concentration and saturates at approximately 50 microM. CONCLUSION: Compound 7 quantifies lower concentrations of (*)OH than do 1 and 9. This detector is therefore likely to be a good reporter of (*)OH produced within a few nanometers of DNA.
Assuntos
Cumarínicos/síntese química , Corantes Fluorescentes/síntese química , Raios gama , Radical Hidroxila/análise , Sondas Moleculares/síntese química , Oligonucleotídeos/química , Iodeto de Sódio/química , Espermidina/análogos & derivados , Espermina/análogos & derivados , Cumarínicos/química , Corantes Fluorescentes/química , Concentração de Íons de Hidrogênio , Radioisótopos do Iodo , Sondas Moleculares/química , Conformação de Ácido Nucleico , Oligonucleotídeos/efeitos da radiação , Soluções , Espermidina/síntese química , Espermidina/química , Espermina/síntese química , Espermina/química , ÁguaRESUMO
PURPOSE: Neoplastic meningitis is often the final outcome of disseminated cancer and is rapidly lethal. Its limited treatment relies on systemic or intrathecal chemotherapy with methotrexate (MTX) or thiotepa. When 5-iodo-2'-deoxyuridine labeled with (125)I ((125)IUdR) is incorporated into the DNA of mitotic tumor cells, the Auger electrons emitted during iodine decay are highly cytotoxic. The radiotherapeutic efficacy of (125)IUdR administered intrathecally has also been established in animals bearing spinal cord tumors, and MTX is known to potentiate the response. This approach has not been tested in the clinic. METHODS: A 44-year-old woman, with locally advanced pancreatic cancer, was treated for three years with complete systemic remission, but then relapsed with cytologically proven neoplastic meningitis. The patient was given four successive intrathecal injections of MTX (10 mg) every 12 h and, with the fourth dose, 1850 MBq (125)IUdR, followed by four additional MTX doses. The response was monitored by cytology and CA19.9 (carbohydrate antigen 19.9) levels in the cerebrospinal fluid (CSF) as well as by clinical status of the patient. RESULTS: The follow-up of cytology and CA19.9 levels in the CSF showed dramatic improvement within 26 days followed by a biological relapse on Day +36. There was no evidence of local central nervous system toxicity. Three months later, neoplastic meningitis recurred and meningeal tumor infiltration was observed on magnetic resonance imaging. Six months after MTX-(125)IUdR treatment, the patient died. CONCLUSION: (125)IUdR treatment proved to be feasible without acute neurological toxicity and seemed to have produced a biological response. This attempt provides the basis for designing prospective clinical trials.
Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Idoxuridina/uso terapêutico , Neoplasias Meníngeas/tratamento farmacológico , Neoplasias Meníngeas/radioterapia , Metotrexato/uso terapêutico , Compostos Radiofarmacêuticos/uso terapêutico , Adulto , Antibióticos Antineoplásicos/administração & dosagem , Antígenos Glicosídicos Associados a Tumores/líquido cefalorraquidiano , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/secundário , Terapia Combinada , Resistencia a Medicamentos Antineoplásicos , Evolução Fatal , Feminino , Humanos , Idoxuridina/administração & dosagem , Injeções Espinhais , Radioisótopos do Iodo , Neoplasias Meníngeas/secundário , Metotrexato/administração & dosagem , Recidiva Local de Neoplasia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Compostos Radiofarmacêuticos/administração & dosagemRESUMO
Consensus guidelines on anti-beta 2 glycoprotein I (anti-beta2GPI) testing have been developed to help minimise laboratory variation in the performance and reporting of assays for these antibodies. These guidelines include minimum and optional recommendations for the following aspects of anti-beta2GPI testing and reporting: (1) isotype of anti-beta2GPI tested; (2) specimen type; (3) controls and assay precision; (4) calibrators; (5) patient samples; (6) rheumatoid factors and IgM anti-beta2GPI testing; (7) reporting of results; (8) cutoff values; and (9) interpretative comments. Issues related to inter-kit/assay standardisation and the manufacturing process of commercial anti-beta2GPI kits/assays have not been addressed in the current guidelines.
Assuntos
Anticorpos Anti-Idiotípicos/sangue , Síndrome Antifosfolipídica/diagnóstico , beta 2-Glicoproteína I/imunologia , Anticorpos Anti-Idiotípicos/imunologia , Síndrome Antifosfolipídica/sangue , Síndrome Antifosfolipídica/imunologia , Australásia , Cardiolipinas/imunologia , Técnicas de Laboratório Clínico , Humanos , Sensibilidade e EspecificidadeRESUMO
A high-yield radioiodination method for various types of molecules is described. The approach employs DMSO as precursor solvent, a reaction ratio of 2-5 precursor molecules per iodine atom, 5-10 microg oxidant, and a 10-25 microl reaction volume. The solution is vortexed at room temperature for 1-5 min and progress of the reaction is assessed by HPLC. Radioiodinated products are obtained in > or = 95% yield and meet the requirements for radiotracer imaging, biodistribution studies, and molecular and cellular biology research.
Assuntos
Radioisótopos do Iodo/isolamento & purificação , Compostos Radiofarmacêuticos/isolamento & purificação , Animais , Anticorpos Monoclonais/isolamento & purificação , Anticorpos Antineoplásicos/isolamento & purificação , Cromatografia Líquida de Alta Pressão , Dimetil Sulfóxido , Imunoglobulina G/isolamento & purificação , Camundongos , Radioquímica , Compostos Radiofarmacêuticos/síntese química , SolventesRESUMO
Most cancer therapeutics (chemo, radiation, antibody-based, anti-angiogenic) are at best partially and/or temporarily effective. In general, the causes for failure can be summarized as: (i) poor diffusion and/or nonuniform distribution of drug/prodrug molecules in solid tumors; (ii) high drug concentration and retention in normal tissues (leading to side effects); (iii) requirement for plasma-membrane permeability and/or internalization of drug/prodrug molecules; (iv) low uptake of drug by tumor; (v) lack of retention of drug within tumor (most have gradient-driven reversible binding); and (vi) multidrug resistance. We are developing an innovative technology that aims to surmount these problems by actively concentrating and permanently entrapping radioimaging and radiotherapeutic prodrugs specifically within solid tumors. The approach will enable noninvasive sensing (imaging) and effective therapy of solid tumors, allowing tumor detection, diagnosis, and treatment to be closely coupled (personalized medicine).
Assuntos
Sistemas de Liberação de Medicamentos , Neoplasias/diagnóstico por imagem , Pró-Fármacos/administração & dosagem , Radioisótopos/uso terapêutico , Animais , Humanos , Pró-Fármacos/química , Radioisótopos/química , CintilografiaRESUMO
Enzyme-mediated cancer imaging and therapy (EMCIT) is a novel approach in which radioactive water-soluble molecules are precipitated in vivo following their hydrolysis by extracellular enzymes overexpressed by cancer cells. AutoDock 3.0 was used to model the interaction-binding between a series of iodinated quinazolinone derivatives and human placental alkaline phosphatase (PLAP, crystal structure in the Protein Data Bank) and to assess the effects of structural modification of the derivatives. Ammonium 2-(2',4'-diphosphoryloxyphenyl)-6-iodo-4-(3H)-quinazolinone (IQ2-P,4-P), having the most favorable calculated inhibition constant, was synthesized and characterized. Concentration-dependent, PLAP-mediated conversion of IQ2-P,4-P (4)/125IQ2-P,4-P (6) to water-insoluble 2-(2',4'-dihydroxyphenyl)-6-[127I/125I]iodo-4-(3H)-quinazolinone (127IQ2-OH,4-OH (2)/125IQ2-OH,4-OH (7)) was observed in solution. Autoradiography indicated that 6 is hydrolyzed by human cancer cells and the resulting 7 precipitates on exterior cell surfaces. Biodistribution studies in mice demonstrated that 6 is minimally retained by normal tissues. The findings support the validity of the EMCIT approach.