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    Keywords: tumor targeting ; TARGETS ; STRATEGIES ; CANCER ; PATHWAY ; PATHWAYS ; THERAPY ; DISEASE ; DISEASES
    Abstract: As our understanding of apoptotic pathway expands, we are coming to realize the great potential of utilizing this pathway to treat diseases such as cancer. The book attempts to review, summarize, and speculate on the apoptotic pathways, how are they regulated and how targeted therapies are being used to treat a wide variety of diseases. Special emphasis is placed on cancer since new treatments either being developed or currently in the clinical setting are showing great promise to increase survival rates for cancer patients. Chapters will address the biology behind regulating the apoptotic pathways and what goes wrong in disease states whereas other chapters will concentrate on new therapies targeting apoptotic pathways. The reader by the end of the book should have greater insight into the understanding and utilization of apoptotic pathways to fight diseases such as cancer.
    Type of Publication: Book chapter
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  • 3
    Keywords: BLOOD ; IN-VIVO ; MODEL ; IMAGES ; liver ; TISSUE ; ACCUMULATION ; COMPLEX ; LIGAND ; COMPLEXES ; REPERFUSION ; RAT ; blood flow ; KINETICS ; ISCHEMIA ; myocardium ; BAT ligands ; BMS-181321 ; HYPOXIC TISSUE MARKER ; ischaemia ; nitroimidazole ; RAT-HEART ; TC-99M-MIBI ; technetium ; TECHNETIUM-99M-NITROIMIDAZOLE BMS181321
    Abstract: Myocardial perfusion single-photon emission tomography (SPET) performed with cationic technetium-99m complexes indicates ischaemic areas as cold lesions. By contrast, nitroimidazole derivatives labelled with fluorine-18 or Tc-99m have recently shown promising results for hot spot imaging of ischaemic myocardium. This study evaluates (TcO)-Tc-99m(BAT-NI), a new Tc-99m complex comprising the nitroimidazole ligand, 2,10- dimercapto-2,10-dimethyl-4,8-diaza-6-[4-(2-nitroimidazolyl)- butyl]undecane, in a low-flow in vivo model of myocardial ischaemia in thoracotomised rats. To elucidate the influence of the 2-nitroimidazole group on ischaemia-induced uptake, comparisons with ligand derivatives were performed where (a) the 2-nitro group was deleted [(TcO)-Tc-99m(BAT-I)], (b) the 2- nitroimidazole functionality was replaced by a Br atom [(TcO)- Tc-99m(BAT-Br)] and (c) the (TcO)-Tc-99m(BAT) moiety was replaced by an iodine-125 iodophenoxybutyl ligand ((IP)-I-125- NI). The radiolabelled compounds were i.v. injected 15 min after reducing resting myocardial blood flow by 50-60% and the uptake of radioactivity was assessed 90 min post injection. Autoradiography of left ventricular short-axis slices showed median uptake ratios of ischaemic/non-ischaemic myocardium (I/N) of 3.4, 4.5 and 3.4 for (TcO)-Tc-99m(BAT-NI), 99mTcO(BAT- I) and (TcO)-Tc-99m(BAT-Br), respectively. In contrast, (IP)-I- 125-NI was not preferentially taken up by ischaemic myocardium. Accumulation of (TcO)-Tc-99m(BAT-NI) in ischaemic heart regions was comparable to that in the liver. Biodistribution studies showed a median uptake of 0.65% ID/g of (TcO)-Tc-99m(BAT-NI) in ischaemic tissue and an IN of 3.3. On planar images of the thorax and upper abdomen the ischaemic hearts were visualised faintly; the median heart to lung count ratio for (TcO)-Tc- 99m(BAT-NI) was 1.7, and the median heart to liver count ratio was 1.0. We conclude that uptake of (TcO)-Tc-99m(BAT-NI) in ischaemic myocardium does not depend on the nitroimidazole moiety but is intrinsic to the BAT complex. Clinical use of the (TcO)-Tc-99m(BAT)-labelled tracers seems unlikely owing to their low uptake and their low ischaemic tissue contrast on planar images in vivo
    Type of Publication: Journal article published
    PubMed ID: 12574972
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  • 4
    Keywords: CANCER ; Germany ; PATIENT ; LYMPH-NODES ; SKIN ; treatment ; PROBE ; IDENTIFICATION ; AGE ; MALES ; MELANOMA ; REGION ; SURFACE ; LOCALIZATION ; TECHNETIUM-99M ; MALIGNANT-MELANOMA ; ULTRASONOGRAPHY ; malignant melanoma ; SONOGRAPHY ; BIOPSY ; DISSECTION ; DYE ; LOCATION ; lymphoscintigraphy ; M1 ; sentinel lymph node (SLN)
    Abstract: BACKGROUND. Dissection of the "sentinel lymph node" (SLN) as identified by lymphoscintigraphy is becoming increasingly important in the treatment of patients with malignant melanoma. The purpose of the current study was to determine whether the SLN also could be identified by ultrasound. METHODS. Sixty-seven patients with malignant melanoma (40 females and 27 males, with an average age of 48.8 years) in whom extirpation of the SLN was indicated underwent ultrasonography of the regional lymph nodes prior to preoperative lymphoscintigraphy. The location of the melanoma was the legs in 30 patients, the arms in 14 patients, and the trunk in 23 patients. During regional ultrasonography, the location of the lymph nodes that differed in the cortex/medulla ratio from the surrounding lymph nodes was marked on the skin corresponding to the planes of insonation (M1) when the probe was held vertically to the skin surface. After lymphoscintigraphy using technetium-99m, the position of a gamma probe at which the highest count rate vertical to the skin surface was recorded also was marked (M2). RESULTS. in the inguinal region, the agreement between M1 and M2 was found to be 100% (40 of 40 SLNs) and was 72.5% in the axilla (29 of 40 SLNs). In patients with melanomas located on the leg, the location of M1 and M2 agreed in 97% of cases (36 of 37 lymph nodes in 30 patients); in patients with melanomas located on the arms, the agreement was 76% (13 of 17 lymph nodes in 14 patients) and in patients with melanomas located on the trunk, the agreement was 75% (21 of 28 lymph nodes in 23 patients). The position documented by ultrasound relative to the neighboring structures of the SLN was confirmed intraoperatively in all cases. CONCLUSIONS. The results of the current study indicate that the SLN in patients with melanoma located on the limbs, especially the legs, are characterized by a specific sonomorphologic pattern. Preoperative sonography might constitute an important addition to lymphoscintigraphy in the planning of SLN biopsy. (C) 2003 American Cancer Society
    Type of Publication: Journal article published
    PubMed ID: 12673722
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  • 5
    Keywords: RECEPTOR ; ANGIOGENESIS ; APOPTOSIS ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; proliferation ; tumor ; carcinoma ; CELL ; CELL-PROLIFERATION ; ENDOTHELIAL GROWTH-FACTOR ; FACTOR RECEPTOR ; Germany ; human ; IN-VIVO ; MODEL ; PERFUSION ; imaging ; SYSTEM ; GENE ; GENES ; TUMORS ; gene therapy ; LINES ; gene transfer ; GENE-TRANSFER ; COMPLEX ; COMPLEXES ; DNA ; INDUCTION ; RAT ; ANTIGEN ; CELL-LINES ; signal transduction ; SIGNAL ; immunohistochemistry ; VECTOR ; NUMBER ; STRESS ; SIGNAL-TRANSDUCTION ; CELL-LINE ; LINE ; HEPATOMA ; EXTRACELLULAR-MATRIX ; PET ; RECEPTORS ; OXIDATIVE STRESS ; OVEREXPRESSION ; cell lines ; CELL-MIGRATION ; VASCULARIZATION ; VEGF ; HUMAN COLON-CANCER ; MATRIX ; OXIDATIVE-STRESS ; TUMOR-GROWTH ; INCREASE ; extracellular matrix ; ENHANCED EXPRESSION ; cell proliferation ; TUMOR PERFUSION ; MIGRATION INHIBITORY FACTOR ; CHIP ; functional imaging ; function ; GROWTH-FACTOR-RECEPTOR ; angiopoietin-2 ; TIE2 ; TUNEL ; UP-REGULATES ANGIOPOIETIN-2
    Abstract: Monitoring of angiogenesis-relevant approaches with functional imaging and histomorphometric analyses is desirable to evaluate the biologic effects. In this study we wished to examine the complex effects of angiopoietin-2 (Ang-2) gene transfer in a rat hepatoma model. Methods: Using a bicistronic retroviral vector for Ang-2, Morris hepatoma (MH3924A) cell lines with Ang-2 expression were generated (Ang-2-MH3924A). In human umbilical vein endothelial cells (HUVECs) cocultured with Ang-2MH3924A, the proliferative action with or without growth factors were determined. Furthermore, animal experiments were performed to measure effects on tumor growth and perfusion. Finally, tumors were examined by immunohistochemistry and DNA chip analysis. Results: Ang-2-expressing MH3924A enhanced basic fibroblast growth factor-mediated endothelial cell proliferation. Perfusion, as measured by (H2O)-O-15 PET, was increased in genetically modified tumors. Consistent with the increased perfusion, micro- and macrovascularization were increased. However, tumor growth was similar to wild-type MH3924A (WT-MH3924A). Proliferating cell nuclear antigen and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling) staining revealed an increased number of positive cells, indicating a compensation of increased proliferation by enhanced apoptosis. DNA chip analysis showed an induction of angiogenesis-promoting genes, including crucial vascular growth factor receptors, as well as genes related to extracellular matrix (ECM), apoptosis, signal transduction, and oxidative stress. Conclusion: Our results suggest that Ang-2 expression increases perfusion or vascularization, especially in interaction with the vascular growth factor system, without affecting tumor growth. Simultaneous, enhanced expression of genes for ECM, apoptosis, and signal transduction indicates Ang-2's versatile role in angiogenesis including its destabilizing function on ECM and endothelium
    Type of Publication: Journal article published
    PubMed ID: 16954561
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  • 6
    Keywords: RECEPTOR ; ANGIOGENESIS ; APOPTOSIS ; CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; INHIBITOR ; proliferation ; ANGIOSTATIN ; BLOOD ; CELL ; CELL-PROLIFERATION ; Germany ; human ; IN-VIVO ; PERFUSION ; VIVO ; imaging ; VOLUME ; HEPATOCELLULAR-CARCINOMA ; NEW-YORK ; GENE ; GENE-EXPRESSION ; GENES ; PROTEIN ; METABOLISM ; cell line ; gene therapy ; LINES ; NUCLEAR-MEDICINE ; TRANSDUCTION ; RAT ; RATS ; tumour ; CELL-LINES ; signal transduction ; SIGNAL ; gene expression ; ARRAYS ; STRESS ; SIGNAL-TRANSDUCTION ; CELL-LINE ; chemotherapy ; LINE ; HEPATOMA ; EXCHANGE ; positron emission tomography ; POSITRON-EMISSION-TOMOGRAPHY ; tomography ; SQUAMOUS-CELL CARCINOMA ; RT-PCR ; GLUCOSE ; PET ; cell lines ; nuclear medicine ; TNF-ALPHA ; INCREASED EXPRESSION ; INHIBITORS ; HUMAN BREAST-CANCER ; radiology ; MATRIX ; TUMOR-GROWTH ; ARRAY ; TRANSPORTER ; cell proliferation ; methods ; HIGH-THROUGHPUT ; NUCLEAR ; USA ; uptake ; vascular endothelial growth factor ; FDG-PET ; in vivo ; ENDOTHELIAL-CELL ; FDG ; EMISSION-TOMOGRAPHY ; gene profiling ; gene array ; MEDICINE ; EMISSION ; emission tomography ; positron ; ENDOTHELIAL GROWTH ; HSV THYMIDINE KINASE ; MORRIS HEPATOMA
    Abstract: Purpose Human troponin I (TROP), the soluble receptor for vascular endothelial growth factor (sFLT) and angiostatin (ASTAT) are potent inhibitors of endothelial cell proliferation, angiogenesis and tumour growth in vivo. Transfer of these genes into tumours may induce changes not only in perfusion, but also more general ones such as changes in metabolism. The aim of this study was to assess these reactions using FDG-PET and high-throughput methods such as gene profiling. Methods We established Morris hepatoma (MH3924A) cell lines expressing TROP, sFLT or ASTAT and quantified F-18-fluorodeoxyglucose ((18)FDG) uptake by dynamic positron emission tomography (PET) after tumour inoculation in ACI rats. Furthermore, expression of glucose transporter-1 and -3 (GLUT-1 and GLUT-3) as well as hexokinase-1 and -2 were investigated by RT-PCR and immunohistomorphometry. In addition, gene array analyses were performed. Results (18)FDG uptake, vascular fraction and distribution volume were significantly higher in all genetically modified tumours. Immunohistomorphometry showed an increased percentage of hexokinase-1 and -2 as well as GLUT-1 and -3 immunoreactive (ir) cells. Using gene arrays and comparing all three groups of genetically modified tumours, we found upregulated expression of 36 genes related to apoptosis, signal transduction, stress or metabolism. Conclusion TROP-, sFLT- or ASTAT-expressing MH3924A tumours show enhanced influx of (18)FDG, which seems to be caused by several factors: enhanced exchange of nutrients between blood and tumour, increased amounts of glucose transporters and hexokinases, and increased expression of genes related to apoptosis, matrix and stress, which induce an increased demand for glucose
    Type of Publication: Journal article published
    PubMed ID: 17701172
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  • 7
    Abstract: Abstract: Aim: Evaluate the clinical benefit of external beam radiotherapy (RTx) for locally invasive thyroid carcinoma with follicular cell differentiation (DTC), Patients, methods: The Multicentre Study on Differentiated Thyroid Cancer (MSDS) was planned as a prospective multicenter trial on the benefit of adjuvant RTx in locally invasive DTC (pT4; UICC 1997) with or without lymph node metastases and no known distant metastases. All patients were treated with thyroidectomy, I-131-therapy, and TSH-suppression and were randomized to receive additional RTx or not. In 4/2003 the trial became a prospective cohort study after only 45 of then 311 patients had consented to randomization, 351 of 422 patients met the trial's inclusion criteria. Age was 48 12 years (mean +/- SD). 25% were men. Tumours were papillary in 90% and follicular in 10%. Of 47 patients randomized or allocated to RTx, 26 actually received RTx. Results: Mean follow-up was 930 days. In an actual treatment analysis, 96%(25/26) of the RTx-patients reached complete remission (CR) vs. 86% in the non-RTx patients. Recurrences occurred in 0 vs. 3 % of patients: 6 reoperated for regional lymph node metastases, 1 tracheal invasion treated with tracheoplasty, 1 local invasion necessitating laryngectomy, 2 distant metastases (1 lung, 1 lung + bone). Serious chronic RTx toxicity occurred in 1/26 patients. Conclusion: The MSDS trial showed low mortality and recurrence rates and a weak benefit of RTx in terms of local control that did however not reach statistical significance. Routine RTx in locally invasive DTC can no longer be recommended.
    Type of Publication: Journal article published
    PubMed ID: 19322503
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  • 8
    Keywords: PEPTIDE ; RECEPTOR ; radiotherapy ; Germany ; imaging ; IMPACT ; tumour ; SEQUENCE ; ACID ; FORM ; NUMBER ; SPECTROMETRY ; MASS-SPECTROMETRY ; PEPTIDES ; CARRIERS ; MASSES ; targeting ; CHAIN ; CAPACITY ; DOTA ; ANALOG ; chelating agents ; PHASE SYNTHESIS
    Abstract: The clinical impact of peptides that accumulate in tumours is determined by the number of particle emitting or paramagnetic isotopes attached. Therefore, attempts should be made to increase the cargo capacity of the peptide carriers. A general synthetic route to Conjugates is described that allows insertion Of multiple DOTA (1,4,7,10-tetraazacyclododecane-N',N",N''',N"" tetraacetic acid) moieties at the N-terminal end of the cyclic peptide Tyr(3)-octreotate. The peptide moiety was assembled by Fmoc solid phase synthesis and oxidised to form the cyclic disulfide. Subsequently, the required number of DOTA-tris tert-butyl ester chelating units were attached to the side chains of lysines. The conjugates were Purified and thoroughly studied by RP-HPLC, size exclusion HPLC and mass spectrometry. The labelling of the novel conjugates and of DOTA(0)-Tyr(3)-octreotate (DOTATATE) was exemplified for Y-90 and In-111. The methodology described here allows the versatile introduction of multiple DOTA chelates into a peptide sequence, thus, introducing a new scope to the receptor affine peptides that can be synthesised using solid phase synthesis. (C) 2004 Elsevier Ltd. All rights reserved
    Type of Publication: Journal article published
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  • 9
    Abstract: Due to poor correlation of slice thickness and orientation, verification of radiological methods with histology is difficult. Thus, a procedure for three-dimensional reconstruction, reslicing and parameterization of histological data was developed, enabling a proper correlation with radiological data. Two different subcutaneous tumors were examined by MR microangiography and DCE-MRI, the latter being post-processed using a pharmacokinetic two-compartment model. Subsequently, tumors were serially sectioned and vessels stained with immunofluorescence markers. A ray-tracing algorithm performed three-dimensional visualization of the histological data, allowing virtually reslicing to thicker sections analogous to MRI slice geometry. Thick slices were processed as parameter maps color coding the marker density in the depth of the slice. Histological 3D reconstructions displayed the diffuse angioarchitecture of malignant tumors. Resliced histological images enabled specification of high enhancing areas seen on MR microangiography as large single vessels or vessel assemblies. In orthogonally reconstructed histological slices, single vessels were delineated. ROI analysis showed significant correlation between histological parameter maps of vessel density and MR parameter maps (r=0.83, P=0.05). The 3D approach to histology improves correlation of histological and radiological data due to proper matching of slice geometry. This method can be used with any histological stain, thus enabling a multivariable correlation of non-invasive data and histology.
    Type of Publication: Journal article published
    PubMed ID: 15747142
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  • 10
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