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1.
Artículo en Inglés | MEDLINE | ID: mdl-33007476

RESUMEN

OBJECTIVES: Investigation whether in depth characterization of virus variant patterns can be used for epidemiological analysis of the first SARS-CoV-2 infection clusters in Hamburg, Germany. METHODS: Metagenomic RNA- and amplicon-sequencing and subsequent variant calling in 25 respiratory samples from SARS-CoV-2 infected patients involved in the earliest infection clusters in Hamburg. RESULTS: Amplikon sequencing and cluster analyses of these SARS-CoV-2 sequences allowed the identification of the first infection cluster and five non-related infection clusters occurring at the beginning of the viral entry of SARS-CoV-2 in the Hamburg metropolitan region. Viral genomics together with epidemiological analyses revealed that the index patient acquired the infection in Northern Italy and transmitted it to two out of 134 contacts. Single nucleotide polymorphisms clearly distinguished the virus variants of the index and other clusters and allowed to track in which sequences worldwide these mutations were first described. Minor variant analyses identified the transmission of intra-host variants in the index cluster and household clusters. CONCLUSIONS: SARS-CoV-2 variant tracing allows the identification of infection clusters and the follow up of infection chains occurring in the population. Furthermore, the follow up of minor viral variants in infection cluster can provide further resolution on transmission events indistinguishable on consensus sequence level.

2.
PLoS One ; 11(11): e0166963, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27875570

RESUMEN

The long-term outcome of patients with single ventricles improved over time, but remains poor compared to other congenital heart lesions with biventricular circulation. Main cause for this unfavourable outcome is the unphysiological hemodynamic of the Fontan circulation, such as subnormal systemic cardiac output and increased systemic-venous pressure. To overcome this limitation, we are developing the concept of a contractile extracardiac Fontan-tunnel. In this study, we evaluated the survival and structural development of a tissue-engineered conduit under in vivo conditions. Engineered heart tissue was generated from ventricular heart cells of neonatal Wistar rats, fibrinogen and thrombin. Engineered heart tissues started beating around day 8 in vitro and remained contractile in vivo throughout the experiment. After culture for 14 days constructs were implanted around the right superior vena cava of Wistar rats (n = 12). Animals were euthanized after 7, 14, 28 and 56 days postoperatively. Hematoxylin and eosin staining showed cardiomyocytes arranged in thick bundles within the engineered heart tissue-conduit. Immunostaining of sarcomeric actin, alpha-actin and connexin 43 revealed a well -developed cardiac myocyte structure. Magnetic resonance imaging (d14, n = 3) revealed no constriction or stenosis of the superior vena cava by the constructs. Engineered heart tissues survive and contract for extended periods after implantation around the superior vena cava of rats. Generation of larger constructs is warranted to evaluate functional benefits of a contractile Fontan-conduit.


Asunto(s)
Contracción Miocárdica , Miocitos Cardíacos , Ingeniería de Tejidos , Vena Cava Superior , Animales , Células Cultivadas , Ventrículos Cardíacos/citología , Ventrículos Cardíacos/trasplante , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/trasplante , Ratas , Ratas Wistar
3.
PLoS One ; 9(4): e95822, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24752554

RESUMEN

Induced overexpression of the secretory protein YKL-40 promotes tumor growth in xenograft experiments. We investigated if targeting YKL-40 with a monoclonal antibody could inhibit tumor growth. YKL-40 expressing human melanoma cells (LOX) were injected subcutenously in Balb/c scid mice. Animals were treated with intraperitoneal injections of anti-YKL-40, isoptype control or PBS. Non-YKL-40 expressing human pancreatic carcinoma cell line PaCa 5061 served as additional control. MR imaging was used for evaluation of tumor growth. Two days after the first injections of anti-YKL-40, tumor volume had increased significantly compared with controls, whereas no effects were observed for control tumors from PaCa 5061 cells lacking YKL-40 expression. After 18 days, mean tumor size of the mice receiving repeated anti-YKL-40 injections was 1.82 g, >4 times higher than mean tumor size of the controls (0.42 g). The effect of anti-YKL-40 on the increase of tumor volume started within hours after injection and was dose dependent. Intratumoral hemorrhage was observed in the treated animals. The strong effect on tumor size indicates important roles for YKL-40 in melanoma growth and argues for a careful evaluation of antibody therapy directed against YKL-40.


Asunto(s)
Adipoquinas/inmunología , Adipoquinas/metabolismo , Anticuerpos Monoclonales/uso terapéutico , Lectinas/inmunología , Lectinas/metabolismo , Animales , Línea Celular , Línea Celular Tumoral , Proteína 1 Similar a Quitinasa-3 , Modelos Animales de Enfermedad , Citometría de Flujo , Humanos , Inmunohistoquímica , Imagen por Resonancia Magnética , Ratones , Ratones Endogámicos BALB C , Ensayos Antitumor por Modelo de Xenoinjerto
4.
Bone ; 64: 222-7, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24769333

RESUMEN

Tumor-induced osteomalacia (TIO) is a paraneoplastic syndrome characterized by renal phosphate wasting, hypophosphatemia and low calcitriol levels as well as clinical symptoms like diffuse bone and muscle pain, fatigue fractures or increased fracture risk. Conventional imaging methods, however, often fail to detect the small tumors. Lately, tumor localization clearly improved by somatostatin-receptor (SSTR) imaging, such as octreotide scintigraphy or octreotide SPECT/CT. However, recent studies revealed that still a large number of tumors remained undetected by octreotide imaging. Hence, studies focused on different SSTR imaging methods such as 68Ga DOTA-NOC, 68Ga DOTA-TOC and 68Ga DOTA-TATE PET/CT with promising first results. Studies comparing different SSTR imaging methods for tumor localization in TIO are rare and thus little is known about diagnostic alternatives once a particular method failed to detect a tumor in patients with TIO. Here, we report the data of 5 consecutive patients suffering from TIO, who underwent both 111Indium-octreotide scintigraphy (111In-OCT) SPECT/CT as well as 68Ga DOTA-TATE PET/CT for tumor detection. While 111In-OCT SPECT/CT allowed tumor detection in only 1 of 5 patients, 68Ga DOTA-TATE PET/CT was able to localize the tumor in all patients. Afterwards, anatomical imaging of the region of interest was performed with CT and MRI. Thus, successful surgical resection of the tumor was achieved in all patients. Serum phosphate levels returned to normal and all patients reported relief of symptoms within weeks. Moreover, an iliac crest biopsy was obtained from every patient and revealed marked osteomalacia in all cases. Follow-up DXA revealed an increase in BMD of up to 34.5% 1-year postoperative, indicating remineralization. No recurrence was observed. In conclusion our data indicates that 68Ga DOTA-TATE PET/CT is an effective and promising diagnostic tool in the diagnosis of TIO, even in patients in whom 111In-OCT prior failed to detect a tumor.


Asunto(s)
Radioisótopos de Galio , Neoplasias/diagnóstico por imagen , Osteomalacia/etiología , Radiofármacos , Adulto , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Imagen Multimodal , Neoplasias/complicaciones , Tomografía Computarizada de Emisión de Fotón Único , Tomografía Computarizada por Rayos X
5.
Methods Mol Biol ; 1070: 203-11, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24092442

RESUMEN

Magnetic resonance imaging (MRI) has become an important technique for noninvasive cell tracking in preclinical research. Following appropriate cell labeling MRI can be used to detect larger cell cohorts and also single cells in vivo in mice. Cell distribution to different organs such as brain, liver, spleen, and kidneys can be visualized, semi-quantified, and followed over time. Thus, the fate of single tumor cells and their eventual development to solid metastases could be investigated. Mesenchymal stromal cells can be used as a paradigm for metastasizing tumor cells. We have demonstrated a strategy for magnetic and fluorescent co-labeling of mesenchymal stromal cells (MSC), ultrasound-guided intracardial cell injection with efficient systemic cell delivery, and high-resolution MRI for repetitive visualization of disseminated co-labeled MSC on a single-cell level in vivo in mice. Furthermore, the fluorescent labeling of cells enabled effective histopathological validation.


Asunto(s)
Imagen por Resonancia Magnética/métodos , Miocardio/patología , Metástasis de la Neoplasia/diagnóstico por imagen , Metástasis de la Neoplasia/patología , Análisis de la Célula Individual/métodos , Ultrasonido/métodos , Animales , Vías de Administración de Medicamentos , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Coloración y Etiquetado , Ultrasonografía
6.
Methods Mol Biol ; 1070: 213-22, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24092443

RESUMEN

Magnetic resonance imaging (MRI) of small animals has emerged as a valuable tool to noninvasively monitor tumor growth in mouse models of cancer. However, imaging of metastases in mouse models is difficult due to the need for high spatial resolution. We have demonstrated MRI of metastases in the liver, brain, adrenal glands, and lymph nodes in different xenograft mouse models of cancer. MRI of mice was performed with a clinical 3.0 T magnetic resonance scanner and a commercially available small-animal receiver coil. The imaging protocol consisted of T1- and T2-weighted fat-saturated spin echo sequences with a spatial resolution of 200 µm × 200 µm × 500 µm. Total acquisition time was 30 min per mouse. The technique allowed for repetitive examinations of larger animal cohorts to observe the development of metastases.


Asunto(s)
Modelos Animales de Enfermedad , Imagen por Resonancia Magnética/métodos , Metástasis de la Neoplasia/diagnóstico , Ensayos Antitumor por Modelo de Xenoinjerto , Anestesia , Animales , Línea Celular Tumoral , Medios de Contraste/administración & dosificación , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/secundario , Metástasis Linfática/diagnóstico , Ratones , Metástasis de la Neoplasia/patología
7.
Mol Imaging ; 12(2): 100-10, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23415398

RESUMEN

The purpose of this study was to analyze the influence of E- and P-selectins on the migratory pattern of magnetically labeled multipotent mesenchymal stromal cells (MSCs) in mice using magnetic resonance imaging (MRI). Murine MSCs were labeled with fluorescent iron oxide microparticles and carboxyfluorescein succinidyl ester (CFSE). Expression of common MSC markers, CD44, CD90, CD105, and Sca-1, as well as of selectin ligands, CD15s and CD162, was assessed using flow cytometry and immunocytochemistry. Labeled MSCs were injected into E-/P-selectin-deficient and wild-type mice applying doses of 5 × 10(4) cells intracardially, 1 × 10(6) cells intravenously, and 5 × 10(6) cells intraperitoneally. After cell administration, mice underwent MRI repeatedly and histologic evaluation after 7 days. The results demonstrate that magnetically labeled murine MSCs retain their expression of the above-mentioned surface markers and their ability to interact with P-selectin. Furthermore, MRI examinations and histologic analysis revealed that E-/P-selectin deficiency in mice significantly alters the distribution of labeled MSCs after cell injection via different routes.


Asunto(s)
Selectina E/metabolismo , Imagen por Resonancia Magnética/métodos , Células Madre Mesenquimatosas/metabolismo , Selectina-P/metabolismo , Animales , Células Cultivadas , Citometría de Flujo , Inmunohistoquímica , Hierro/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL
8.
Gut ; 62(5): 741-50, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-22490524

RESUMEN

BACKGROUND AND OBJECTIVE: E- and P-selectins expressed on the luminal surface of mesodermally derived endothelial cells play a crucial role in the formation of haematogenous metastases in a number of malignancies. As peritoneal mesothelial cells are also derived form the mesoderm, it was hypothesised that selectins are also of importance in peritoneal tumour spread. METHODS: Immunohistochemistry was used to identify selectin expression on normal human peritoneum and isolated mesothelial cells. E- and P-selectin interactions with human pancreatic adenocarcinoma cells were investigated in dynamic flow assays and flow cytometry; the latter was also used to determine the main selectin ligands on pancreatic adenocarcinoma cell lines PaCa 5061, BxPC-3 and PaCa 5072, and selectin expression on human mesothelial cells. All cell lines were xenografted into the peritoneum of E- and P-selectin-deficient pfp/rag2 mice and selectin wild-type controls. Peritoneal carcinomatosis was quantified using MRI or a scoring system. RESULTS: E- and P-selectin were constitutively expressed on human mesothelial and endothelial cells in the peritoneum. PaCa 5061 and BxPC-3 cells interacted with E- and P-selectins in dynamic flow assays and flow cytometry, with CA19-9 (Sialyl Lewis a) being the main E-selectin ligand. For xenografted PaCa 5061 and BxPC-3 cells, peritoneal metastasis was significantly reduced in E- and P-selectin double knockout mice compared with wild-type pfp/rag2 animals. In contrast, PaCa 5072 cells were almost devoid of selectin binding sites and no intraperitoneal tumour growth was observed. CONCLUSION: Interactions of tumour cells with peritoneal selectins play an important role in the peritoneal spread of pancreatic adenocarcinoma.


Asunto(s)
Adenocarcinoma/metabolismo , Biomarcadores de Tumor/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Peritoneales/metabolismo , Selectinas/metabolismo , Adenocarcinoma/secundario , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Selectina E/metabolismo , Citometría de Flujo , Humanos , Inmunohistoquímica , Ratones , Ratones Endogámicos , Ratones Noqueados , Selectina-P/metabolismo , Neoplasias Pancreáticas/patología , Neoplasias Peritoneales/secundario , Trasplante Heterólogo
9.
Eur Radiol ; 23(2): 570-8, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22843058

RESUMEN

OBJECTIVES: To compare the diagnostic performance of whole-body magnetic resonance imaging (WBMRI) versus (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) for determination of remission status in patients with multiple myeloma (MM) after stem cell transplantation (SCT). METHODS: Thirty-one patients were examined by both WBMRI and PET/CT after SCT. Imaging results and clinical remission status as determined by the clinical gold standard (Uniform Response Criteria) were compared. RESULTS: One hundred four lesions were detected in 21 patients. PET/CT had a sensitivity of 50.0 %, a specificity of 85.7 %, a positive predictive value of 62.5 %, a negative predictive value of 78.3 %, and an overall accuracy of 74.2 % for determination of remission status. MRI had a sensitivity of 80.0 %, a specificity of 38.1 %, a positive predictive value of 38.1 %, a negative predictive value of 80 %, and an overall accuracy of 51.6 %. Concordant results were observed in only 12 (11.5 %) of the 104 lesions. CONCLUSIONS: In the post-treatment setting, both FDG PET/CT and WBMRI provide information about the extent of disease, allowing for a more comprehensive evaluation of persisting or recurrent myeloma. MRI may often be false positive because of persistent non-viable lesions. Therefore, PET/CT might be more suitable than MRI for determination of remission status.


Asunto(s)
Fluorodesoxiglucosa F18 , Imagen por Resonancia Magnética/métodos , Imagen Multimodal/métodos , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/cirugía , Tomografía de Emisión de Positrones , Trasplante de Células Madre/métodos , Tomografía Computarizada por Rayos X , Adulto , Anciano , Estudios de Cohortes , Intervalos de Confianza , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Supervivencia de Injerto , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Cuidados Posoperatorios/métodos , Valor Predictivo de las Pruebas , Trasplante de Células Madre/efectos adversos , Análisis de Supervivencia , Factores de Tiempo , Resultado del Tratamiento
10.
ACS Nano ; 6(4): 3346-55, 2012 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-22463104

RESUMEN

The biofunctionalization of CdSe/CdS/ZnS quantum dots and Fe(3)O(4) nanocrystals using a novel ligand system based on polyisoprene-block-poly(ethylene oxide) ligands is described. The synthesis includes a partial ligand exchange of the hydrophobic nanocrystals with amino-functionalized polyisoprene ligands, followed by seeded micelle formation of the diblock-copolymers in water. The resulting water-soluble quantum dots showed fluorescence quantum efficiencies in the 40 to 50% range and extraordinary fluorescence stability in the biological environment after cross-linking of the polyisoprene moiety of the ligand shell. No toxicity was detected by water-soluble tetrazolium (WST8) and lactate dehydrogenase (LDH) assays, even at very high nanoparticle concentrations, and almost no nonspecific cell adhesion was detected. The ligand shell was further coupled to the antigen-related cell adhesion molecule (CEACAM) specific monoclonal antibody T84.1. The so-conjugated Fe(3)O(4) nanocrystals allowed in vitro and in vivo tumor targeting by magnetic resonance imaging.


Asunto(s)
Neoplasias del Colon/diagnóstico , Medios de Contraste/química , Compuestos Férricos/química , Imagen por Resonancia Magnética/métodos , Puntos Cuánticos , Animales , Moléculas de Adhesión Celular/metabolismo , Transformación Celular Neoplásica , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Óxido de Etileno/análogos & derivados , Óxido de Etileno/química , Femenino , Regulación Neoplásica de la Expresión Génica , Células HT29 , Hemiterpenos/química , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Ratones , Solubilidad , Agua/química
11.
PLoS One ; 6(12): e28030, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-22162753

RESUMEN

Members of the carcinoembryonic antigen cell adhesion molecules (CEACAMs) family are the prototype of tumour markers. Classically they are used as serum markers, however, CEACAMs could serve as targets for molecular imaging as well.In order to test the anti CEACAM monoclonal antibody T84.1 for imaging purposes, CEACAM expression was analysed using this antibody. Twelve human cancer cell lines from different entities were screened for their CEACAM expression using qPCR, Western Blot and FACS analysis. In addition, CEACAM expression was analyzed in primary tumour xenografts of these cells. Nine of 12 tumour cell lines expressed CEACAM mRNA and protein when grown in vitro. Pancreatic and colon cancer cell lines showed the highest expression levels with good correlation of mRNA and protein level. However, when grown in vivo, the CEACAM expression was generally downregulated except for the melanoma cell lines. As the CEACAM expression showed pronounced expression in FemX-1 primary tumours, this model system was used for further experiments. As the accessibility of the antibody after i.v. application is critical for its use in molecular imaging, the binding of the T84.1 monoclonal antibody was assessed after i.v. injection into SCID mice harbouring a FemX-1 primary tumour. When applied i.v., the CEACAM specific T84.1 antibody bound to tumour cells in the vicinity of blood vessels. This binding pattern was particularly pronounced in the periphery of the tumour xenograft, however, some antibody binding was also observed in the central areas of the tumour around blood vessels. Still, a general penetration of the tumour by i.v. application of the anti CEACAM antibody could not be achieved despite homogenous CEACAM expression of all melanoma cells when analysed in tissue sections. This lack of penetration is probably due to the increased interstitial fluid pressure in tumours caused by the absence of functional lymphatic vessels.


Asunto(s)
Antígeno Carcinoembrionario/metabolismo , Moléculas de Adhesión Celular/metabolismo , Albúminas/metabolismo , Animales , Antígenos CD/biosíntesis , Biomarcadores/metabolismo , Células CACO-2 , Antígeno Carcinoembrionario/química , Moléculas de Adhesión Celular/biosíntesis , Moléculas de Adhesión Celular/química , Línea Celular Tumoral , Azul de Evans/farmacología , Femenino , Humanos , Inmunohistoquímica/métodos , Vasos Linfáticos/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Imagen Molecular/métodos , Metástasis de la Neoplasia , Trasplante de Neoplasias , ARN Mensajero/metabolismo
12.
Nat Med ; 17(2): 200-5, 2011 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21258337

RESUMEN

Brown adipose tissue (BAT) burns fatty acids for heat production to defend the body against cold and has recently been shown to be present in humans. Triglyceride-rich lipoproteins (TRLs) transport lipids in the bloodstream, where the fatty acid moieties are liberated by the action of lipoprotein lipase (LPL). Peripheral organs such as muscle and adipose tissue take up the fatty acids, whereas the remaining cholesterol-rich remnant particles are cleared by the liver. Elevated plasma triglyceride concentrations and prolonged circulation of cholesterol-rich remnants, especially in diabetic dyslipidemia, are risk factors for cardiovascular disease. However, the precise biological role of BAT for TRL clearance remains unclear. Here we show that increased BAT activity induced by short-term cold exposure controls TRL metabolism in mice. Cold exposure drastically accelerated plasma clearance of triglycerides as a result of increased uptake into BAT, a process crucially dependent on local LPL activity and transmembrane receptor CD36. In pathophysiological settings, cold exposure corrected hyperlipidemia and improved deleterious effects of insulin resistance. In conclusion, BAT activity controls vascular lipoprotein homeostasis by inducing a metabolic program that boosts TRL turnover and channels lipids into BAT. Activation of BAT might be a therapeutic approach to reduce elevated triglyceride concentrations and combat obesity in humans.


Asunto(s)
Tejido Adiposo Pardo/metabolismo , Triglicéridos/metabolismo , Tejido Adiposo Pardo/fisiología , Animales , Regulación de la Temperatura Corporal/fisiología , Antígenos CD36/metabolismo , Colesterol/metabolismo , Colesterol/fisiología , Frío , Humanos , Hiperlipidemias/metabolismo , Hiperlipidemias/fisiopatología , Resistencia a la Insulina/fisiología , Lipoproteína Lipasa/metabolismo , Lipoproteínas/metabolismo , Lipoproteínas/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/metabolismo , Obesidad/fisiopatología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/fisiología
13.
J Magn Reson Imaging ; 32(2): 459-65, 2010 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-20677278

RESUMEN

PURPOSE: To compare signal-enhancing properties of the high relaxivity Gd chelates P1152 and Gd-BOPTA for contrast-enhanced MR angiography (CE-MRA) in rabbits at 1.5 Tesla (T) and 3.0T. MATERIALS AND METHODS: Three-dimensional CE-MRA of the abdominal vasculature was performed in six rabbits using both contrast agents at a dose of 0.1 mmol/kg. Data acquisition was carried out during first pass and up to 10 min after contrast material administration. CNR was determined in aorta, vena cava, and renal cortex. Image quality (5-point scale, 5 = best) of first pass MR angiograms was rated by two radiologists. RESULTS: During first pass CNR of the aorta was 55.1 +/- 5.8 (P1152) and 40.3 +/- 3.9 (Gd-BOPTA) at 1.5T (P < 0.05), and 114.9 +/- 9.9 (P1152) and 73.5 +/- 8.1 (Gd-BOPTA) at 3.0T (P < 0.05). Both contrast agents showed a comparable decline of CNR within 10 min. Image quality was rated 4.8 +/- 0.40 (P1152) and 4.5 +/- 0.50 (Gd-BOPTA) at 1.5T (P = 0.17), and 4.8 +/- 0.37 (P1152) and 4.7 +/- 0.47 (Gd-BOPTA) at 3.0T (P = 0.61). CONCLUSION: The high relaxivity Gd-chelate P1152 offers potential to improve image contrast for CE-MRA compared with a clinically approved high relaxivity contrast agent.


Asunto(s)
Quelantes/farmacología , Medios de Contraste/farmacología , Complejos de Coordinación/farmacología , Angiografía por Resonancia Magnética/métodos , Meglumina/análogos & derivados , Compuestos Organometálicos/farmacología , Animales , Aorta/patología , Femenino , Procesamiento de Imagen Asistido por Computador , Corteza Renal/patología , Meglumina/farmacología , Conejos , Factores de Tiempo , Vena Cava Inferior/patología
14.
Mol Imaging ; 9(4): 211-22, 2010 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-20643024

RESUMEN

The objective of this study was to quantify enzymatic activity on the surface of T cells by magnetic resonance imaging (MRI) using R2 and R2* relaxometry. Lymphoma cells expressing adenosine diphosphate (ADP)-ribosyltransferase 2 (ART2) were incubated with increasing doses of its substrate etheno-nicotinamide adenine dinucleotide (NAD), resulting in increasing amounts of surface protein ADP-ribosylation. Etheno-ADP-ribosylated proteins were detected with monoclonal antibody 1G4 and superparamagnetic iron oxide conjugated secondary antibodies (Ab-SPIO). Labeling efficiency was determined with R2 and R2* relaxometry on a clinical 3.0 T scanner. Parallel aliquots of cells were analyzed by flow cytometry. Cell-bound SPIO conjugates were detected by immunofluorescence and electron microscopy and quantified by atomic absorption spectroscopy. To mimic an inflammatory site in vivo, Ab-SPIO-labeled cells were injected subcutaneously in mice and analyzed by MRI. Immunofluorescence and electron microscopy confirmed cell-surface localization of Ab-SPIO. MRI of Ab-SPIO-labeled cells showed a corresponding signal reduction. Increases in R2 and R2* determined by magnetic resonance relaxometry correlated linearly with the expression level of ART2 and the concentration of the ART2 substrate etheno-NAD. R2 and R2* increases correlated linearly with the results from flow cytometry and atomic absorption spectroscopy analyses. Quantitative R2 and R2* mapping enable noninvasive determination of enzymatic activity on T cells and holds promise for characterization of inflammatory sites in vivo by MRI.


Asunto(s)
ADP Ribosa Transferasas/metabolismo , Membrana Celular/enzimología , Compuestos Férricos/metabolismo , Imagen por Resonancia Magnética/métodos , Linfocitos T/enzimología , Adenosina Difosfato Ribosa/metabolismo , Animales , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/metabolismo , Línea Celular Tumoral , Compuestos Férricos/química , Citometría de Flujo , Modelos Lineales , Ratones , Ratones Endogámicos BALB C , Microscopía Electrónica de Transmisión , Microscopía Fluorescente , NAD/metabolismo , NAD/farmacología , Reproducibilidad de los Resultados , Imagen de Cuerpo Entero
15.
Mol Cancer Ther ; 9(7): 2037-45, 2010 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-20606043

RESUMEN

This study aimed to determine the targeted efficacy of trastuzumab (Herceptin) on human epidermal growth factor receptor 2 (HER-2)-overexpressing metastatic esophageal cancer in an orthotopic mouse model. HER-2 overexpression and amplification of human esophageal primary and metastatic tumors were shown with HER-2-fluorescence in situ hybridization analysis and HER-2 immunostaining. Following orthotopic implantation with the HER-2-overexpressing OE19 human esophageal cancer cell line, mice were treated with trastuzumab. Sequential magnetic resonance imaging was used to monitor primary tumor and metastasis during treatment. After six weeks, a significant inhibition of primary tumor development was imaged in trastuzumab-treated animals in comparison with the control group. Trastuzumab treatment also led to a reduction of lymphatic metastasis. Thus, HER-2 targeted therapy with trastuzumab resulted in a significant primary tumor growth reduction as well as a decrease of lymph node metastases in the orthotopic model of metastatic esophageal carcinoma. The results of the present study suggest the clinical use of trastuzumab for HER-2-overexpressing esophageal cancer, which is a significant fraction of the patient population. Treatment of this highly treatment-resistant disease with trastuzumab in the adjuvant setting to prevent lymph node metastasis after primary tumor resection is suggested by the data in this report.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Neoplasias Esofágicas/tratamiento farmacológico , Receptor ErbB-2/antagonistas & inhibidores , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Anticuerpos Monoclonales Humanizados , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Regulación Neoplásica de la Expresión Génica , Humanos , Metástasis Linfática/prevención & control , Imagen por Resonancia Magnética , Ratones , Ratones Endogámicos , Ratones Desnudos , Metástasis de la Neoplasia , Receptor ErbB-2/genética , Receptor ErbB-2/inmunología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Trastuzumab , Carga Tumoral/efectos de los fármacos
16.
Magn Reson Imaging ; 28(4): 599-606, 2010 May.
Artículo en Inglés | MEDLINE | ID: mdl-20117898

RESUMEN

PURPOSE: To detect anti-CEACAM5 targeted superparamagnetic iron oxide (SPIO) particles in vitro on the cell surface by quantitative magnetic resonance (MR) imaging and to compare with flow cytometry. MATERIALS AND METHODS: The monoclonal mouse antibody T84.1 and an appropriate IgG isotype antibody were conjugated to dextran-coated SPIO particles. HT29 cells expressing carcinoembryonic antigen (CEACAM5) were treated with antibody-conjugated SPIO particles. Purified cell samples were examined on a 3.0-T MR scanner using a multi-echo spin-echo sequence for MR relaxometry. Aliquots of the cell samples were further treated with a fluorescein isothiocyanate (FITC) anti-dextran antibody and an Alexa Fluor 488 anti-mouse antibody for the corresponding flow cytometry. RESULTS: MR relaxometry revealed a dose-dependent binding of T84.1-conjugated SPIO particles with a positive correlation between R(2) relaxation rate of cell samples and SPIO particle concentration during incubation (r=0.993, P<.01). Positive correlations were also observed between R(2) relaxation rate and flow cytometry (geometric mean) with both fluorescent antibodies (r=0.972 and r=0.953, both P<.01), respectively. CONCLUSION: The study revealed the feasibility of quantitative MR imaging of targeted SPIO particles on the cell surface comparable to flow cytometry.


Asunto(s)
Membrana Celular/patología , Medios de Contraste/farmacología , Óxido Ferrosoférrico/farmacología , Citometría de Flujo/métodos , Imagen por Resonancia Magnética/métodos , Animales , Anticuerpos Monoclonales/metabolismo , Antígeno Carcinoembrionario/química , Línea Celular Tumoral , Membrana Celular/metabolismo , Fluoresceína-5-Isotiocianato/farmacología , Proteínas Ligadas a GPI , Humanos , Hidrazinas/farmacología , Ratones
17.
Int J Cancer ; 126(11): 2671-81, 2010 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-19847813

RESUMEN

We describe the development of an aggressive orthotopic metastatic model of esophageal cancer, which is visualized in real time with combined magnetic resonance imaging (MRI) and fluorescence imaging. The aim of the study was to describe the development of a novel model of metastatic tumor disease of esophageal carcinoma and use this model to evaluate fluorescence and MRI in early detection of local and metastatic disease. The human esophageal adenocarcinoma cell line PT1590 was stably transfected with green fluorescent protein (GFP). Nude mice were orthotopically implanted with PT1590-GFP cells. Orthotopic tumor growth as well as metastatic spread was examined by fluorescence imaging and high-resolution MRI at defined intervals after orthotopic implantation. Highly aggressive novel fluorescent cell lines were isolated from metastatic tissues and put into culture. After implantation of these cells, 100% of the animals developed orthotopic primary tumors. In 83% of animals, metastatic spread to liver, lung and lymph nodes was observed. Primary tumor growth could be visualized with fluorescence imaging and with MRI with high correlation between the 2 methods. Fluorescence imaging allows fast, sensitive, and economical imaging of the primary and metastatic tumor without anesthesia. With MRI, anatomical structures are visualized more precisely and tumors can be more accurately localized to specific organs. This model should prove highly useful to understand esophageal carcinoma and to identify novel therapeutics for this treatment-resistant disease.


Asunto(s)
Neoplasias Esofágicas/patología , Adenocarcinoma/patología , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Neoplasias Esofágicas/mortalidad , Proteínas Fluorescentes Verdes/análisis , Proteínas Fluorescentes Verdes/genética , Humanos , Imagen por Resonancia Magnética , Ratones , Metástasis de la Neoplasia/patología , Espectrometría de Fluorescencia , Análisis de Supervivencia , Transfección
18.
Nat Nanotechnol ; 4(3): 193-201, 2009 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-19265850

RESUMEN

Semiconductor quantum dots and superparamagnetic iron oxide nanocrystals have physical properties that are well suited for biomedical imaging. Previously, we have shown that iron oxide nanocrystals embedded within the lipid core of micelles show optimized characteristics for quantitative imaging. Here, we embed quantum dots and superparamagnetic iron oxide nanocrystals in the core of lipoproteins--micelles that transport lipids and other hydrophobic substances in the blood--and show that it is possible to image and quantify the kinetics of lipoprotein metabolism in vivo using fluorescence and dynamic magnetic resonance imaging. The lipoproteins were taken up by liver cells in wild-type mice and displayed defective clearance in knock-out mice lacking a lipoprotein receptor or its ligand, indicating that the nanocrystals did not influence the specificity of the metabolic process. Using this strategy it is possible to study the clearance of lipoproteins in metabolic disorders and to improve the contrast in clinical imaging.


Asunto(s)
Lipoproteínas/metabolismo , Imagen por Resonancia Magnética , Nanopartículas/química , Animales , Apolipoproteínas E/deficiencia , Dextranos , Óxido Ferrosoférrico , Inyecciones Intravenosas , Hierro/administración & dosificación , Hierro/farmacocinética , Hierro/farmacología , Cinética , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/ultraestructura , Nanopartículas de Magnetita , Ratones , Óxidos/administración & dosificación , Óxidos/farmacocinética , Óxidos/farmacología , Puntos Cuánticos , Receptores de LDL/deficiencia , Factores de Tiempo , Distribución Tisular/efectos de los fármacos
19.
Cancer Lett ; 274(2): 194-200, 2009 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-18922631

RESUMEN

This study aimed to analyse (i) the metastatic behaviour of human melanoma FEMX-1 cells in scid mice after surgical excision of the PT and (ii) to evaluate the feasibility of magnetic resonance imaging (MRI) for the detection of melanoma metastases. Histology proved both high specificity (95%), and high sensitivity of MRI detection of melanoma metastasis. CEACAM1, L1, and HPA-binding site expression, all markers predicting metastasis in clinical studies, were preserved in the metastatic nodules. Thus, our xenograft model closely resembles the clinical situation of post-operative development of distant organ metastasis and demonstrates that MRI is a sensitive and highly qualified technology for intra-vital monitoring of melanoma progression.


Asunto(s)
Melanoma/diagnóstico , Animales , Biomarcadores de Tumor , Modelos Animales de Enfermedad , Humanos , Inmunohistoquímica , Melanoma/patología , Ratones , Ratones SCID , Metástasis de la Neoplasia , Trasplante Heterólogo
20.
Invest Radiol ; 43(12): 837-42, 2008 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19002055

RESUMEN

OBJECTIVES: To evaluate the gadolinium-based contrast agent P846 and compare it with gadoterate meglumine (Gd-DOTA) for contrast-enhanced magnetic resonance angiography (MRA) in rabbits at 1.5 T and 3.0 T, respectively. MATERIALS AND METHODS: Five rabbits underwent contrast-enhanced MRA of the abdominal vasculature applying gadolinium doses of 0.025 mmoL/kg for P846 and 0.1 mmoL/kg for Gd-DOTA, respectively. All animals were examined on a 1.5-T and 3.0-T MR system. Image data were acquired during the first-pass arterial phase and repeatedly over 10 minutes. Contrast-to-noise-ratio (CNR) was determined in the aorta, the inferior vena cava, and the renal cortex. Image quality of arterial phase MR angiograms was consensually judged on a 5-point scale (5 = high). RESULTS: Contrast-enhanced MRA was successful in all cases with both contrast agents. CNR values consistently proved statistically significantly higher for P846 compared with Gd-DOTA. CNR values in the aorta during the arterial phase were 46.0 +/- 3.7 (P846) and 28.0 +/- 3.2 (Gd-DOTA) at 1.5 T (P < 0.05), and correspondingly 89.3 +/- 12.7 (P846) and 64.1 +/- 15.0 (Gd-DOTA) at 3.0 T (P < 0.05). Image quality of arterial phase MR angiograms was rated with scores of 4.8 +/- 0.4 (P846) and 4.0 +/- 0.0 (Gd-DOTA) at 1.5 T (P = 0.06), and 5.0 +/- 0.0 (P846) and 4.8 +/- 0.4 (Gd-DOTA) at 3.0 T (P = 0.42), respectively. CONCLUSIONS: The contrast agent P846 provides high contrast enhancement and image quality for contrast-enhanced MRA in rabbits at 1.5 T and 3.0 T with a 4-fold lower gadolinium dose compared with a standard extracellular contrast agent.


Asunto(s)
Aorta Abdominal/anatomía & histología , Aumento de la Imagen/métodos , Angiografía por Resonancia Magnética/métodos , Meglumina , Compuestos Organometálicos , Animales , Medios de Contraste , Femenino , Ratas , Reproducibilidad de los Resultados , Sensibilidad y Especificidad
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