RESUMO
Adaptor chimeric antigen receptor (CAR) T-cell therapy offers solutions for improved safety and antigen escape, which represent main obstacles for the clinical translation of CAR T-cell therapy in myeloid malignancies. The adaptor CAR T-cell platform 'UniCAR' is currently under early clinical investigation. Recently, the first proof of concept of a well-tolerated, rapidly switchable, CD123-directed UniCAR T-cell product treating patients with acute myeloid leukaemia (AML) was reported. Relapsed and refractory AML is prone to high plasticity under therapy pressure targeting one single tumour antigen. Thus, targeting of multiple tumour antigens seems to be required to achieve durable anti-tumour responses, underlining the need to further design alternative AML-specific target modules (TM) for the UniCAR platform. We here present the preclinical development of a novel FMS-like tyrosine kinase 3 (FLT3)-directed UniCAR T-cell therapy, which is highly effective for in vitro killing of both AML cell lines and primary AML samples. Furthermore, we show in vivo functionality in a murine xenograft model. PET analyses further demonstrate a short serum half-life of FLT3 TMs, which will enable a rapid on/off switch of UniCAR T cells. Overall, the presented preclinical data encourage the further development and clinical translation of FLT3-specific UniCAR T cells for the therapy of AML.
Assuntos
Leucemia Mieloide Aguda , Tirosina Quinase 3 Semelhante a fms , Humanos , Animais , Camundongos , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/metabolismo , Imunoterapia Adotiva , Linfócitos T , Antígenos de Neoplasias , Leucemia Mieloide Aguda/tratamento farmacológicoAssuntos
Antígenos Glicosídicos Associados a Tumores/imunologia , Imunoterapia Adotiva , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/imunologia , Animais , Biomarcadores Tumorais , Citotoxicidade Imunológica , Modelos Animais de Doenças , Humanos , Imunoterapia Adotiva/métodos , Camundongos , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genética , Linfócitos T/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Bisphosphonates have a high adsorption on calcified tissues and are commonly used in the treatment of bone disorder diseases. Conjugates of bisphosphonates with macrocyclic chelators open new possibilities in bone targeted radionuclide imaging and therapy. Subsequent to positron emission tomography (PET) examinations utilizing 68Ga-labelled analogues, endoradiotheraphy with 177Lu-labelled macrocyclic bisphosphonates may have a great potential in the treatment of painful skeletal metastases. METHODS: Based on the established pharmaceuticals pamidronate and zoledronate two new DOTA-α-OH-bisphosphonates, DOTAPAM and DOTAZOL(MM1.MZ) were successfully synthesized. The ligands were labelled with the positron emitting nuclide 68Ga and the ß- emitting nuclide 177Lu and compared in in vitro studies and in ex vivo biodistribution studies together with small animal PET and single photon emission computed tomography (SPECT) studies against [18F]NaF and a known DOTA-α-H-bisphosphonate conjugate (BPAPD) in healthy Wistar rats. RESULTS: The new DOTA-bisphosphonates can be labelled in high yield of 80 to 95 % in 15 min with post-processed 68Ga and >98 % with 177Lu. The tracers showed very low uptake in soft tissue, a fast renal clearance and a high accumulation on bone. The best compound was [68Ga]DOTAZOL (SUV Femur = 5.4 ± 0.6) followed by [18F]NaF (SUV Femur = 4.8 ± 0.2), [68Ga]DOTAPAM (SUV Femur = 4.5 ± 0.2) and [68Ga]BPAPD (SUV Femur = 3.2 ± 0.3). [177Lu]DOTAZOL showed a similar distribution as the diagnostic 68Ga complex. CONCLUSION: The 68Ga labelled compounds showed a promising pharmacokinetics, with similar uptake profile and distribution kinetics. Bone accumulation was highest for [68Ga]DOTAZOL, which makes this compound probably an interesting bone targeting agent for a therapeutic approach with 177Lu. The therapeutic compound [177Lu]DOTAZOL showed a high target-to-background ratio. SPECT experiments showed concordance to the PET scans in healthy rats. [68Ga/177Lu]DOTAZOL appears to be a potential theranostic combination in the management of disseminated bone metastases.
RESUMO
The bifunctional chelating agent 2-[4,7-bis(2-pyridylmethyl)-1,4,7-triazacyclononan-1-yl]acetic acid, DMPTACN-COOH, has been found to bind strongly to copper(II), resulting in a radiocopper(II)-ligand complex that exhibits high in vivo stability. The pendant carboxylic acid group enables this derivative to be conjugated to the N-terminal amino acid residues of peptides. Exploiting this, two stabilized bombesin (BBN) derivatives, ßAla-ßAla-[Cha(13),Nle(14)]BBN(7-14) and ßhomo-Glu-ßAla-ßAla-[Cha(13),Nle(14)]BBN(7-14) have been coupled to DMPTACN-COOH and radiolabeled with the positron emitter copper-64 ((64)Cu-1 and (64)Cu-3). The in vitro binding characteristics of the [(64)Cu]Cu-labeled bombesin conjugates in gastrin-releasing peptide receptor (GRPR) over-expressing prostate cancer (PC-3) cells have been evaluated. Biodistribution studies performed in Wistar rats indicate a specific uptake in the GRPR-rich pancreas and rapid renal elimination for both (64)Cu-1 and (64)Cu-3. Small animal PET imaging studies performed in NMRI nu/nu mice bearing the human prostate tumor PC-3 demonstrated a very high degree of tumor accumulation for (64)Cu-1 and (64)Cu-3. Incorporation of a single additional glutamic acid residue within the spacer between bombesin and the radiolabeled complex ((64)Cu-3) leads to a higher tumor-to-muscle uptake ratio (amounting to >30 at 100 min post injection) compared to (64)Cu-1.
Assuntos
Bombesina , Quelantes , Radioisótopos de Cobre , Neoplasias da Próstata/química , Compostos Radiofarmacêuticos , Animais , Bombesina/química , Bombesina/farmacocinética , Linhagem Celular Tumoral , Quelantes/química , Quelantes/farmacocinética , Radioisótopos de Cobre/química , Radioisótopos de Cobre/farmacocinética , Humanos , Masculino , Camundongos , Camundongos Nus , Estrutura Molecular , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/metabolismo , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Ratos Wistar , Receptores da Bombesina/biossíntese , Distribuição TecidualRESUMO
Pheochromocytoma is a rare but potentially lethal chromaffin cell tumor with currently no effective treatment. Peptide hormone receptors are frequently overexpressed on endocrine tumor cells and can be specifically targeted by various anti-tumor peptide analogs. The present study carried out on mouse pheochromocytoma cells (MPCs) and a more aggressive mouse tumor tissue-derived (MTT) cell line revealed that these cells are characterized by pronounced expression of the somatostatin receptor 2 (sst2), growth hormone-releasing hormone (GHRH) receptor and the luteinizing hormone-releasing hormone (LHRH) receptor. We further demonstrated significant anti-tumor effects mediated by cytotoxic somatostatin analogs, AN-162 and AN-238, by LHRH antagonist, Cetrorelix, by the cytotoxic LHRH analog, AN-152, and by recently developed GHRH antagonist, MIA-602, on MPC and for AN-152 and MIA-602 on MTT cells. Studies of novel anti-tumor compounds on these mouse cell lines serve as an important basis for mouse models of metastatic pheochromocytoma, which we are currently establishing.
Assuntos
Neoplasias das Glândulas Suprarrenais/tratamento farmacológico , Feocromocitoma/tratamento farmacológico , Receptores de Neuropeptídeos/efeitos dos fármacos , 2-Hidroxifenetilamina/análogos & derivados , 2-Hidroxifenetilamina/farmacologia , Compostos de Anilina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/análogos & derivados , Doxorrubicina/farmacologia , Hormônio Liberador de Gonadotropina/análogos & derivados , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Hormônio Liberador de Gonadotropina/farmacologia , Hormônio Liberador de Hormônio do Crescimento/antagonistas & inibidores , Camundongos , Pirróis/farmacologia , Receptores LHRH/biossíntese , Receptores LHRH/efeitos dos fármacos , Receptores LHRH/metabolismo , Receptores de Neuropeptídeos/biossíntese , Receptores de Neuropeptídeos/metabolismo , Receptores de Hormônios Reguladores de Hormônio Hipofisário/biossíntese , Receptores de Hormônios Reguladores de Hormônio Hipofisário/efeitos dos fármacos , Receptores de Hormônios Reguladores de Hormônio Hipofisário/metabolismo , Receptores de Somatostatina/biossíntese , Receptores de Somatostatina/efeitos dos fármacos , Receptores de Somatostatina/metabolismo , Sermorelina/análogos & derivados , Sermorelina/farmacologia , Somatostatina/análogos & derivadosRESUMO
UNLABELLED: Knowledge of the risks of smoking during pregnancy induces only part of the pregnant women to give up smoking. How many pregnant women in Germany smoke from the beginning to delivery, and what characterises these smokers, is the topic of this article. METHODS: Results from the German Mikrozensus, several national surveys, perinatal statistics and Euro-scip III are presented, compared, and assessed. Findings of our own studies conducted between 1999 and 2002 at the obstetric department and gynacological practices in Berlin allow an insight into the magnitude of "underreporting". RESULTS: In the ages 15-45 years 36-45 % of German women smoke, prevalence rates that probably are valid even for the beginning of pregnancy. While smoking prevalence in men has decreased during the last 20 years, there is an increasing trend in women. The prevalence is higher in pregnant women of low social status, living with smoking partners and those of German nationality. At most, half of the women give up smoking during pregnancy. Assuming an "underreporting" in pregnant women of at least one third, the prevalence of smoking up to delivery is 24 %. Although 76 % of the practicing gynacologists in Berlin feel responsible for smoking counselling, only 12 % are convinced that it is successful. CONCLUSIONS: A quarter of the pregnant women in Germany smoke through to delivery, which means that 150 000 newborns per year have been exposed to passive smoking in utero, and its long-term health effects, which is a national disaster.
Assuntos
Gravidez/estatística & dados numéricos , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Fumar/epidemiologia , Adolescente , Adulto , Estudos Transversais , Feminino , Previsões , Alemanha , Inquéritos Epidemiológicos , Humanos , Pessoa de Meia-Idade , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Abandono do Hábito de Fumar , Fatores Socioeconômicos , Poluição por Fumaça de Tabaco/prevenção & controle , Poluição por Fumaça de Tabaco/estatística & dados numéricosRESUMO
The interest in using small peptides for therapeutic and diagnostic in vivo applications is based on several advantageous features such as good penetration into tissues and rapid clearance from the body. Because of their size, they can easily be synthesized chemically. The recently discovered cell-penetrating peptides (CPP) and among them CPP derived from the native peptide hormone human calcitonin (hCT) could meet these requirements. Therefore, they are nowadays widely used as delivery vectors for a variety of bioactive molecules. However, the knowledge about the distribution and metabolism of CPP in vivo is very limited. Hence, evaluation of the pharmacological features of any promising peptide is a crucial challenge in its development process. Herein, we studied the in vivo radiopharmacology of (68)Ga radiolabeled DOTA-modified, hCT-derived CPP in rats using small animal PET. Furthermore, the arterial blood at different time points and urine were analyzed for radio-metabolites. It was shown that d-amino acid modifications of the sequence hCT(9-32) resulted in an increased in vivo stability and lower retention in the kidney cortex of this peptide.
Assuntos
Calcitonina/metabolismo , Calcitonina/farmacocinética , Peptídeos/metabolismo , Peptídeos/farmacocinética , Sequência de Aminoácidos , Animais , Calcitonina/química , Permeabilidade da Membrana Celular , Quelantes/metabolismo , Radioisótopos de Gálio , Compostos Heterocíclicos com 1 Anel/metabolismo , Humanos , Masculino , Dados de Sequência Molecular , Peptídeos/síntese química , Peptídeos/química , Fenilalanina , Tomografia por Emissão de Pósitrons , Ratos , Ratos Wistar , Distribuição TecidualRESUMO
KIGGS is a health survey on 17,641 children and adolescents in 167 communities representative for Germany, conducted between May 2003 and May 2006. Of the perinatal indicators, only a small proportion of data important for long-term outcomes was available for statistical analysis, and is presented here. In the past 20 years the mean weight gain during pregnancy has increased significantly by 2 kg, the mean birth weight has increased significantly by an average of 50 g, there has been no significant time trend for smoking and alcohol consumption in pregnancy. Birth weight and pregnancy weight gain of the mother correlate significantly. Pregnancy weight gain explains 5% of the birth weight in first-born infants. 17-18% of the mothers smoked during pregnancy, 4 times as many in the lower than the upper social class. 14% of the mothers consumed alcohol in pregnancy, but only 1% regularly. Only 5% of the migrants, but 3 times as many of the non-migrants consumed alcohol in pregnancy, and 2 1/2 times as many of the upper class compared to the lower class. With respect to smoking and alcohol consumption during pregnancy there seems to be an urgent need for political action.
Assuntos
Doenças do Prematuro/epidemiologia , Complicações na Gravidez/epidemiologia , Efeitos Tardios da Exposição Pré-Natal , Adolescente , Consumo de Bebidas Alcoólicas/epidemiologia , Peso ao Nascer , Criança , Pré-Escolar , Emigração e Imigração , Feminino , Alemanha , Inquéritos Epidemiológicos , Humanos , Lactente , Recém-Nascido , Masculino , Gravidez , Fatores de Risco , Fumar/epidemiologia , Fatores Socioeconômicos , Estatística como Assunto , Aumento de PesoRESUMO
BACKGROUND: Peptide receptors seem to be good markers for receptor targeting because of their overexpression in human cancer. Understanding the role of receptors and their cognate ligands, they are currently used for both diagnosis and therapy. Candidates playing a key role in tumor biology are the neurotensin receptors (NTR). The expression of NTR in HT-29 cells (human colon adenocarcinoma cell line), FaDu cells (human squamous cell carcinoma cell line) and in corresponding tumor xenografts on nude mice, was investigated. MATERIALS AND METHODS: Quantitative RT-PCR of the three receptor subtypes was carried out to study mRNA expression. Receptor protein expression was analyzed by immunohistochemistry with specific antibodies for the three known neurotensin receptors NTR1, NTR2 and NTR3. RESULTS: Analysis of receptor mRNA revealed a strong expression of NTR3 and a weak expression of NTR1 and NTR2 in cultured cells and xenografts. Examining the protein levels, a strong signal for NTR1 was detected in tumor cells and xenografts and only a weak signal was detected for NTR3. CONCLUSION: Since the receptor protein is targeted in vivo, the enhanced protein expression of NTR1 in xenografts could be a useful tool for molecular targeting with radioligands and for further characterization of the carcinogenic process.
Assuntos
Adenocarcinoma/metabolismo , Carcinoma de Células Escamosas/metabolismo , Receptores de Neurotensina/metabolismo , Adenocarcinoma/genética , Animais , Butiratos/farmacologia , Carcinoma de Células Escamosas/genética , Diferenciação Celular , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Feminino , Células HT29 , Humanos , Neoplasias Hipofaríngeas/genética , Neoplasias Hipofaríngeas/metabolismo , Masculino , Camundongos , Camundongos Nus , Receptores de Neurotensina/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais CultivadasRESUMO
Resveratrol (3,4',5-trihydroxy-trans-stilbene) is a naturally occurring phytoalexin and polyphenol existing in grapes and various other plants, and one of the best known 'nutriceuticals'. It shows a multiplicity of beneficial biological effects, particularly, by attenuating atherogenic, inflammatory, and carcinogenic processes. However, despite convincing evidence from experimental and clinical studies, data concerning the role of resveratrol and other members of the large polyphenols family for human health is still a matter of debate. One reason for this is the lack of suitable sensitive and specific methods, which would allow direct assessment of biodistribution, biokinetics, and the metabolic fate of these compounds in vivo. The unique features of positron emission tomography (PET) as a non-invasive in vivo imaging methodology in combination with suitable PET radiotracers have great promise to assess quantitative information on physiological effects of polyphenols in vivo. Herein we describe the radiosynthesis of an (18)F-labelled resveratrol derivative, 3,5-dihydroxy-4'-[(18)F]fluoro-trans-stilbene ([(18)F]-1), using the Horner-Wadsworth-Emmons reaction as a novel radiolabelling technique in PET radiochemistry for subsequent functional imaging of polyphenol metabolism in vivo. In a typical "three-step/one-pot" reaction, (18)F-labelled resveratrol derivative [(18)F]-1 could be synthesized within 120-130 min including HPLC separation at a specific radioactivity of about 90 GBq/mumol. The radiochemical yield was about 9% (decay-corrected) related to [(18)F]fluoride and the radiochemical purity exceeded 97%. First radiopharmacological evaluation included measurement of biodistribution ex vivo and positron emission tomography (PET) studies in vivo after intravenous application of [(18)F]-1 in male Wistar rats using a dedicated small animal PET camera with very high spatial resolution. Concordantly with data on bioavailability and metabolism of native resveratrol from the literature, these investigations revealed an extensive uptake and metabolism in the liver and kidney, respectively, of [(18)F]-1. This study represents the first investigation of polyphenols in vivo by means of PET.
Assuntos
Modelos Animais , Tomografia por Emissão de Pósitrons/métodos , Estilbenos/síntese química , Estilbenos/farmacocinética , Animais , Linhagem Celular Tumoral , Radioisótopos de Flúor , Humanos , Masculino , Estrutura Molecular , Ratos , Ratos Wistar , Resveratrol , Sensibilidade e Especificidade , Estereoisomerismo , Estilbenos/química , Células Tumorais CultivadasRESUMO
An alteration of low density lipoprotein (LDL) apolipoprotein (apo) B-100 structure by direct oxidative modification is an important mechanism involved in atherogenesis. There is difficulty in quantifying this type of modification because a lack of specific assays. The use of N(O,S)-ethoxycarbonyl trifluoroethyl amino acid esters for a rapid and sensitive determination of 6-hydroxy-2-aminocaproic acid (HACA), a highly specific marker of metal catalyzed protein oxidation, by using standard gas chromatography/electron impact mass spectrometry, is discussed. The derivatives are formed by the unlabored reaction of amino acids with ethylchloroformate plus trifluoroethanol plus pyridine. Femtomole levels of HACA can be reproducible measured in different LDL preparations subjected to oxidative damage in the presence of iron or copper. HACA determination compares well with the measurement of carbonyl groups that are generally accepted as a nonspecific index of protein oxidation. Thus, the method could prove to be a sensitive assay for studying specific apoB-100 modification.
Assuntos
Aminocaproatos/química , Apolipoproteínas B/química , Carbamatos/química , Lipoproteínas LDL/química , Norleucina/análogos & derivados , Norleucina/química , Aminocaproatos/análise , Apolipoproteína B-100 , Apolipoproteínas B/isolamento & purificação , Apolipoproteínas B/metabolismo , Arteriosclerose/metabolismo , Biomarcadores , Ésteres/análise , Ésteres/química , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Lipoproteínas LDL/isolamento & purificação , Lipoproteínas LDL/metabolismo , Masculino , OxirreduçãoRESUMO
3-O-Methyl-6-[(18)F]fluoro-L-DOPA (OMFD) is a major metabolite of 6-[(18)F]fluoro-L-DOPA. Although synthesis of OFMD was primarily established to study the dopaminergic system, as it is an amino acid analogue, uptake in experimental tumours has been found. The aim of this study was to evaluate the applicability of OMFD for brain tumour imaging and to obtain initial estimates of whole-body biodistribution and radiation dosimetry in humans. Nineteen patients with suspected or confirmed brain tumours were investigated with OMFD and dynamic brain PET, complemented by whole-body PET in seven patients. Tracer kinetics were compared for normal brain and intracerebral lesions. Tissue accumulation was quantified with standardised uptake values (SUVs). Whole-body distribution in combination with tracer kinetics from animal experiments was used for the calculation of radiation dosimetry data. On the basis of OMFD PET, viable brain tumour was suspected in 16 patients with SUVs of 3.0+/-0.8 and a tumour to non-tumour ratio of 1.9+/-0.5. Highest tumour and normal brain uptake occurred between 15 and 30 min, with a subsequent slow decrease. Late whole-body tracer distribution was uniform without specific organ accumulation. Elimination occurred via urine. The mean radiation dose to the whole body was estimated at 0.016 mSv/MBq, with the kidneys as dose-critical organ (0.033 mGy/MBq). In conclusion, OMFD enables the visualisation of brain tumours with SUVs similar to other fluorinated amino acids. The whole-body radiation exposure from OMFD is comparable to that from FDG imaging.
Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/metabolismo , Di-Hidroxifenilalanina/análogos & derivados , Di-Hidroxifenilalanina/farmacocinética , Radiometria/métodos , Adulto , Idoso , Carga Corporal (Radioterapia) , Feminino , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Especificidade de Órgãos , Doses de Radiação , Compostos Radiofarmacêuticos/farmacocinética , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Distribuição Tecidual , Tomografia Computadorizada de Emissão/métodosRESUMO
BACKGROUND: The prevalence of adiposity in childhood is increasing. Is breast-feeding protective as suggested by cross-sectional studies? OBJECTIVE: In a longitudinal birth cohort study, we tested whether breast-feeding for more than 2 months has preventive effects against overweight and adiposity at 6 y. DESIGN: Of 1314 children representing the catchment areas of six delivery units, 918 could be followed up to the age of 6 y. Height, weight, and skin-fold thickness were measured at regular visits. As the criteria of overweight, obesity, and adiposity in the children, the 90th and the 97th percentiles of BMI and skin-fold values were used. Parents with a BMI at or above the 90th percentile, which was 27 kg/m(2) or more, were considered overweight. Infants bottle-fed from birth or breast-fed for less than 3 months were classified as 'bottle-fed' (BO), and those breast-fed for 3 months and more as 'breast-fed' (BR). Univariate comparisons and logistic regression analysis were performed applying SAS 6.12. The final logistic model consisted of the 480 cases for whom complete data for all variables were available. The potential effect of loss to follow-up was analysed by the Cochran-Mantel-Haenzel test: the outcomes were not significantly influenced by loss to follow-up. RESULTS: At birth BMIs were nearly identical in both groups. By 3 months, BO had significantly higher BMIs and thicker skin folds than BR. From 6 months on, compared to BR, a consistently higher proportion of BO children exceeded the 90th and the 97th percentile of BMI and skin-fold thickness reference values. From the age of 4 y to 5 and 6 y, in BO the prevalence of obesity nearly doubled and tripled, respectively. With only minor changes of obesity prevalence in BR, the difference of BMI and skin-fold thickness between groups became statistically significant. Logistic regression analysis revealed that overweight of the mother, maternal smoking during pregnancy, bottle feeding, and low social status remained important risk factors for overweight and adiposity at 6 y of age. CONCLUSION: A maternal BMI of > or =27, bottle-feeding, maternal smoking during pregnancy, and low social status are risk factors for overweight and adiposity at 6 y of age. Early bottle-feeding brings forward the obesity rebound, predictive of obesity in later life.
Assuntos
Aleitamento Materno , Obesidade/prevenção & controle , Índice de Massa Corporal , Alimentação com Mamadeira/efeitos adversos , Criança , Feminino , Humanos , Recém-Nascido , Modelos Logísticos , Estudos Longitudinais , Masculino , Obesidade/etiologia , Gravidez , Fatores de Risco , Fumar/efeitos adversos , Classe SocialRESUMO
Based on a high affinity to the enzyme estrone sulfatase (ES), 16alpha-[18F]fluoroestradiol-3,17beta-disulfamate ([18F]FESDS) has been suggested as a potential PET radiotracer for imaging steroid-dependent breast tumours. The distribution of [18F]FESDS was studied in rats, tumour-bearing nude mice and piglets. In all species evidence for binding to a second target, the enzyme carbonic anhydrase (CA), was obtained. ES and CA inhibitors significantly reduced the radiotracer uptake in various organs but not in tumours. It is concluded that [18F]FESDS binds to ES and CA in vivo but this binding is not strong enough to allow tumour imaging with positron emission tomography (PET).
Assuntos
Estradiol/análogos & derivados , Radioisótopos de Flúor , Neoplasias Experimentais/diagnóstico por imagem , Compostos Radiofarmacêuticos , Animais , Neoplasias da Mama/diagnóstico por imagem , Estradiol/síntese química , Estradiol/farmacocinética , Feminino , Radioisótopos de Flúor/farmacocinética , Humanos , Camundongos , Camundongos Nus , Transplante de Neoplasias , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Ratos Wistar , Suínos , Distribuição Tecidual , Tomografia Computadorizada de Emissão , Transplante Heterólogo , Células Tumorais CultivadasRESUMO
16Alpha-fluoroestradiol-3,17beta-disulfamate (FESDS) strongly inhibits estrone sulfatase (ES), an enzyme which is also present in the brain. The enzyme is probably involved in important regulatory functions of neurosteroids which may be disturbed in certain brain diseases. In the present study, [18F]FESDS was used to measure the amount of ES in various rat brain regions using quantitative in vitro autoradiography. The obtained values vary between 0.29 pmol (mg protein)(-1) (pons) and 11.5 pmol (mg protein)(-1) (striatum). They are positively correlated with the enzyme activity measured in homogenates of the corresponding regions. Because this radiotracer binds also to carbonic anhydrase in the brain it is only of limited use for in vivo imaging studies.
Assuntos
Encéfalo/enzimologia , Estradiol/farmacocinética , Radioisótopos de Flúor , Sulfatases/metabolismo , Adenocarcinoma , Animais , Autorradiografia/métodos , Neoplasias da Mama , Estradiol/análogos & derivados , Feminino , Humanos , Cinética , Especificidade de Órgãos , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sulfatases/genética , Transcrição Gênica , Células Tumorais CultivadasRESUMO
BACKGROUND: Only few studies have tested different ergonomic aspects of the working posture assumed by laparoscopic surgeons. Although no experimental data are available for a laparoscopic setting, a working posture with a horizontal forearm or an elbow angle 90 degrees to 120 degrees has been recommended for performing minimally invasive surgery (MIS). The comparison of electromyogram (EMG) activities in different muscles provides information about the force developed by each muscle and allows assessment of its contribution to a functional movement. The current study aimed to investigate whether certain handles do not support this posture. METHODS: For this study, 12 volunteers were postured in two different standardized arm positions, defined by elbow angles of 90 degrees and 120 degrees. They were manipulating a 0.1-N and a 2.5-N microswitch with four different types of instrument handle design: axial handle, ring handle, shank handle, Hirschberg handle. During the test, the EMG activities of five forearm muscles were recorded and normalized with respect to the maximum voluntary activity of the respective muscle. RESULTS: Virtually no significant difference in EMG activity was found between the two elbow angles in any of five forearm muscles for a simple grasping maneuver. Thus, the muscle activity required to manipulate different types of MIS handles is similar for the elbow angles of 120 degrees and 90 degrees. CONCLUSIONS: The current study did not show relevant differences between the two elbow angles for any of the four handles during a simple grasping maneuver with respect to the force required in the main forearm muscles.
Assuntos
Cotovelo/fisiologia , Eletromiografia/métodos , Ergonomia/instrumentação , Laparoscópios , Amplitude de Movimento Articular/fisiologia , Antebraço/fisiologia , Cirurgia Geral/educação , Humanos , Músculo Esquelético/fisiologiaRESUMO
Total deposition of environmental tobacco smoke (ETS) particles was measured in a group of 15 nonsmokers who inhaled ETS of count median diameter of 0.2 microm and geometric standard deviation of 1.6. A total deposition of 56.0 +/- 15.9% was observed for nasal breathing and 48.7 +/- 11.5% for oral breathing. In contrast, our stochastic deposition model predicted a total deposition of only 17.9% (male) and 15.7% (female) for nose breathing, and 13.4% (male) and 10.7% (female) for mouth breathing, if based on standard breathing conditions. Consideration of individual lung volumes and breathing parameters for each volunteer resulted in total deposition values of 16.9 +/- 2.2% for nose breathing and 12.1 +/- 2.1% for mouth breathing. The apparent discrepancy between experiment and modeling suggests that either single ETS particles increase substantially in size upon inhalation (up to an order of magnitude) and/or additional physical mechanisms must be invoked that are acting specifically upon ETS particles: (1) hygroscopic growth of ETS particles does not exceed 20-30%; (2) number concentrations in the ETS experiments (3.8 x 10(4), to 1.3 x 10(5) cm(-3)) are too low to increase particle size by coagulation; (3) cast experiments indicate that electrical charge (image forces) may play an important role, but theory predicts only an increase of 20-60%; and (4) cloud settling is unlikely to be a significant factor at such low number concentrations. In conclusion, estimates of the magnitudes of these potential effects demonstrate that none of these mechanisms alone can be responsible for the significantly higher total ETS deposition observed in the experiments. This suggests that a combination of all these mechanisms may be necessary to reconcile experimental and theoretical ETS deposition data, the most likely candidates being image forces and hygroscopic growth.
Assuntos
Poluição por Fumaça de Tabaco , Fenômenos Biofísicos , Biofísica , Feminino , Humanos , Masculino , Tamanho da Partícula , Processos EstocásticosRESUMO
After synthesis of fluorine-18 labelled analogues by [18F]fluorobenzoylation at the alpha-amino group, biodistribution and elimination of individual advanced glycation endproducts, namely N epsilon-carboxymethyllysine and N epsilon-carboxyethyllysine, were studied in comparison to lysine in rats after intravenous injection using positron emission tomography (PET). The [18F]radiofluorinated amino acids were fast distributed via the blood, followed by a rapid excretion through the kidneys. Elimination kinetics were similar for both AGEs and lysine. For CML and CEL, but not for lysine, a temporary liver accumulation could be observed, which was not connected with any metabolisation or enterohepatic circulation. No further accumulation in any tissues was observable, indicating that increased tissue levels of CML or CEL, which have been described for certain disorders, are exclusively derived from endogenous origin and should not depend on a dietary intake. However, under uremic conditions, an impaired kidney function might result in a significant increase of the AGE-load of blood and tissues. PET based on 18F-labelled AGEs proved to be a promising tool to elucidate the physiological fate of post-translationally modified amino acids and to clarify the role of AGEs as possible "glycotoxins".
Assuntos
Radioisótopos de Flúor , Produtos Finais de Glicação Avançada/farmacocinética , Rim/metabolismo , Fígado/metabolismo , Tomografia Computadorizada de Emissão/métodos , Animais , Produtos Finais de Glicação Avançada/fisiologia , Meia-Vida , Masculino , Ratos , Ratos Wistar , Distribuição TecidualRESUMO
BACKGROUND: Allergic diseases are more prevalent in affluent countries, which has been attributed to life-style factors. Life-style habits may also differ between socioeconomic (SES) classes. The objective of this paper therefore was to evaluate if SES had an impact on the development of atopic disorders. METHODS: A total of 1314 German children were followed-up in an observational birth cohort study to 6 years of age. Parents filled in questionnaires, and had multi-allergen screening tests for sensitization. Indoor allergen concentrations were determined by ELISA. Children were examined regularly up to 6 years, specific serum IgE values were determined by CAP-Rast-Feia. RESULTS: The risk of aeroallergen sensitization (odds ratio 1.76; 95% CI 1.30-2.37), and the lifetime prevalence of hay fever (2.36; 1.76-3.17), and asthma (1.74; 1.08-2.80), but not of atopic dermatitis (AD: 0.90; 0. 54-1.51) was elevated in parents of high compared to low SES. With high SES the risk of smoking in pregnancy (0.35; 0.23-0.51), in the home (0.31; 0.21-0.46), pet ownership (0.37; 0.26-0.55), high mite (0.42; 0.25-0.74), and high cat (0.38; 0.18-0.82) allergen concentration in house dust was reduced, but elevated for breastfeeding over more than 6 months (4.67; 2.9-7.48). In children, even after controlling for other risk factors, only the risk of AD from 3 to 6 years (2.42; 1.42-4.14) was elevated in families with high SES, but not of AD in infancy or of any other atopic disorder. CONCLUSIONS: While parents of high SES have a higher prevalence of inhalative allergies, their favourable life-style prevents the development of atopic disorders in their children, except for AD beyond infancy.
Assuntos
Hipersensibilidade/epidemiologia , Adulto , Animais , Animais Domésticos , Asma/epidemiologia , Gatos , Criança , Pré-Escolar , Estudos de Coortes , Dermatite Alérgica de Contato/epidemiologia , Feminino , Humanos , Lactente , Ácaros , Razão de Chances , Gravidez , Prevalência , Rinite Alérgica Sazonal/epidemiologia , Fatores de Risco , Fumar , Fatores Socioeconômicos , Inquéritos e QuestionáriosRESUMO
Quality of life and achievements are impaired by unrecognised iron deficiency. The iron requirement of women during their child-bearing age is high and increases in pregnancy. The aim of this study was to determine the prevalence and risk factors for iron deficiency in young mothers under contemporary German life conditions. Between September 1997 and August 1998 the iron status of 507 mothers of one-year old children was assessed. The data was derived from venous blood and questionnaires. Besides conventional methods, the concentration of soluble transferrin receptor was used as leading indicator of iron status. 9.5% had cellular iron deficiency and 2.2% of all mothers had iron deficiency anemia. In addition to absence of school education non-German nationality, a high number of children and vegetarian food are risk factors for iron deficiency. In contrast, high alcohol intake and cigarette smoking are associated with a better iron status. Children of mothers with insufficient iron supply are also at higher risk of iron deficiency.