For life science infrastructures, sensitive data generate an additional layer of complexity. Cros... more For life science infrastructures, sensitive data generate an additional layer of complexity. Cross-domain categorisation and discovery of digital resources related to sensitive data presents major interoperability challenges. To support this FAIRification process, a toolbox demonstrator aiming at support for discovery of digital objects related to sensitive data (e.g., regulations, guidelines, best practice, tools) has been developed. The toolbox is based upon a categorisation system developed and harmonised across a cluster of 6 life science research infrastructures. Three different versions were built, tested by subsequent pilot studies, finally leading to a system with 7 main categories (sensitive data type, resource type, research field, data type, stage in data sharing life cycle, geographical scope, specific topics). 109 resources attached with the tags in pilot study 3 were used as the initial content for the toolbox demonstrator, a software tool allowing searching of digital...
Optoacoustic imaging emerged in early 1990s as a new biomedical imaging technology that generates... more Optoacoustic imaging emerged in early 1990s as a new biomedical imaging technology that generates images by illuminating tissues with short laser pulses and detecting resulting ultrasound waves. This technique takes advantage of the spectroscopic approach to molecular imaging, and delivers high-resolution images in the depth of tissue. Resolution of the optoacoustic imaging is scalable, so that biomedical systems from cellular organelles to large organs can be visualized and, more importantly, characterized based on their optical absorption coefficient, which is proportional to the concentration of absorbing chromophores. Optoacoustic imaging was shown to be useful in both preclinical research using small animal models and in clinical applications. Applications in the field of molecular imaging offer abundant opportunities for the development of highly specific and effective contrast agents for quantitative optoacoustic imaging. Recent efforts are being made in the direction of nontoxic biodegradable contrast agents (such as nanoparticles made of melanin) that are potentially applicable in clinical optoacoustic imaging. In order to increase the efficiency and specificity of contrast agents and probes, they need to be made smart and capable of controlled accumulation in the target cells. This review was written in recognition of the potential breakthroughs in medical optoacoustic imaging that can be enabled by efficient and nontoxic melanin-based optoacoustic contrast agents.
The Horizon 2020 project EOSC-Life brings together the 13 Life Science 'ESFRI' research i... more The Horizon 2020 project EOSC-Life brings together the 13 Life Science 'ESFRI' research infrastructures to create an open, digital and collaborative space for biological and medical research. Sharing sensitive data is a specific challenge within EOSC-Life. For that reason, a toolbox is developed, providing information to researchers who wish to share sensitive data or to use sensitive data. The toolbox enables researchers to find existing resources that are relevant for sharing sensitive data across life-science research infrastructures (F in FAIR). The toolbox is based upon a tagging (categorisation) system, allowing consistent labelling and categorisation of resources dealing with sensitive data. A first version of the tagging system was provided and tested in a pilot study, where 110 resources were tagged by 12 experts from 6 research infrastructures. Based on the feedback from this study, version 2 was developed and a re-tagging of the 110 resources was performed. The fe...
The Horizon 2020 project EOSC-Life brings together the 13 Life Science 'ESFRI' research i... more The Horizon 2020 project EOSC-Life brings together the 13 Life Science 'ESFRI' research infrastructures to create an open, digital and collaborative space for biological and medical research. Sharing sensitive data is a specific challenge within EOSC-Life. For that purpose, a toolbox is developed, providing information to researchers who wish to share or use sensitive data. The authors developed a categorisation system designed to support consistent labelling and categorisation of the resources stored in the toolbox in terms most relevant to data sharing tasks and activities, so that they are available to users (e.g., as on screen filters) when searching the system. The poster describes the methods and main results of a pilot study set to evaluate the proposed categorisation system for the toolbox resources with respect to applicability, reliability, sustainability and consistency. The primary objective of the pilot study was to identify the main improvements that are necess...
Sharing sensitive data is a specific challenge for research infrastructures in the field of life ... more Sharing sensitive data is a specific challenge for research infrastructures in the field of life sciences. For that reason a toolbox has been developed, providing resources for researchers who wish to share and use sensitive data, to support the workflows for handling these kinds of digital objects. Common and community approved annotations are required to be compliant with FAIR principles (Findability, Accessibility, Interoperability, Reusability). The toolbox makes use of a tagging (categorisation) system, allowing consistent labelling and categorisation of digital objects, in terms relevant to data sharing tasks and activities. A pilot study was performed within the Horizon 2020 project EOSC-Life, in which 2 experts from 6 life sciences research infrastructures were recruited to independently assign tags to the same set of 10 to 25 resources related to sensitive data management and data sharing (in total 110). Summary statistics of agreement and observer variation per research in...
X-ray iodinated contrast media have been shown to generate contrast in MR images when used with t... more X-ray iodinated contrast media have been shown to generate contrast in MR images when used with the chemical exchange saturation transfer (CEST) approach. The aim of this study is to compare contrast enhancement (CE) capabilities and perfusion estimates between radiographic molecules and a Gd-based contrast agent in two tumour murine models with different vascularization patterns. MRI-CEST and MRI-CE T1w images were acquired in murine TS/A and 4 T1 breast tumours upon sequential i.v. injection of iodinated contrast media (iodixanol, iohexol, and iopamidol) and of gadoteridol. The signal enhancements observed in the two acquisition modalities were evaluated using Pearson's correlation, and the correspondence in the spatial distribution was assessed by a voxelwise comparison. A significant, positive correlation was observed between iodinated contrast media and gadoteridol for tumour contrast enhancement and perfusion values for both tumour models (r = 0.51-0.62). High spatial corr...
Although anaplastic large-cell lymphomas (ALCL) carrying anaplastic lymphoma kinase (ALK) have a ... more Although anaplastic large-cell lymphomas (ALCL) carrying anaplastic lymphoma kinase (ALK) have a relatively good prognosis, aggressive forms exist. We have identified a novel translocation, causing the fusion of the TRAF1 and ALK genes, in one patient who presented with a leukemic ALK+ ALCL (ALCL-11). To uncover the mechanisms leading to high-grade ALCL, we developed a human patient-derived tumorgraft (hPDT) line. Molecular characterization of primary and PDT cells demonstrated the activation of ALK and nuclear factor kB (NFkB) pathways. Genomic studies of ALCL-11 showed the TP53 loss and the in vivo subclonal expansion of lymphoma cells, lacking PRDM1/Blimp1 and carrying c-MYC gene amplification. The treatment with proteasome inhibitors of TRAF1-ALK cells led to the downregulation of p50/p52 and lymphoma growth inhibition. Moreover, a NFkB gene set classifier stratified ALCL in distinct subsets with different clinical outcome. Although a selective ALK inhibitor (CEP28122) resulted ...
The tumor microenvironment acidification confers treatment resistance; therefore, the interferenc... more The tumor microenvironment acidification confers treatment resistance; therefore, the interference with pH regulating systems is considered a new therapeutic strategy. In this study, two human prostate cancer cell lines, PC3 and LNCaP, have been treated in vitro with proton pump inhibitors (PPIs), namely Lansoprazole, Esomeprazole (V-ATPases-inhibitors), Cariporide, and Amiloride (NHE1-inhibitors). The cell viability and pH were assessed at several drug concentrations either at normoxic or hypoxic conditions. Since Esomeprazole showed the highest toxicity towards the PC3 cancer cells compared to LNCaP ones, athymic nude mice bearing subcutaneous or orthotopic PC3 tumors were treated with Esomeprazole (dose: 2.5 mg/kg body weight) for a period of three weeks—and tumor growth was monitored. MRI-CEST tumor pH imaging with Iopamidol was performed upon treatment at 3 h, 1 week (in combination with FDG-PET), and after 2 weeks for evaluating acute, early, and late responses. Although acute...
Purpose D-Glucose and 3-O-Methyl-D-glucose (3OMG) have been shown to provide contrast in MRI-CEST... more Purpose D-Glucose and 3-O-Methyl-D-glucose (3OMG) have been shown to provide contrast in MRI-CEST images. However, a systematic comparison between these two molecules has not yet been performed. This study dealt with the assessment of the effect of pH, saturation power level (B1) and magnetic field strength (B0) on the MRI-CEST contrast with the aim of comparing the in vivo CEST contrast detectability of these two agents in the glucoCEST procedure. Methods Phosphate buffered solutions of D-Glucose or 3OMG (20 mM) were prepared at different pH values and Z-spectra acquired at several B1 levels and at 37°C. In vivo glucoCEST images were obtained at 3 T and 7 T over a period of 30 min after injection of D-Glucose or 3OMG (at the doses of 1.5 and 3 g/kg) in a murine melanoma tumour model. Results A markedly different pH dependence of CEST response was observed in vitro for D-Glucose and 3OMG. The glucoCEST contrast enhancement in the tumour region following the intravenous administratio...
Lymph nodes are an essential component of the adaptive immune response where antigen-presenting c... more Lymph nodes are an essential component of the adaptive immune response where antigen-presenting cells are closely housed with their cognate effector cells. Protection of lymph node resident cells from activated immune cells in such close quarters would need to be robust and reversible. Effector functions of T-cells are profoundly and reversibly inhibited by an acidic microenvironment. The underlying mechanisms of this inhibition are unknown, but may relate to glycolysis, which is obligatory for expression of effector functions. Here, we demonstrate that acidification rapidly and potently inhibits monocarboxylate transporter-dependent lactic acid efflux, which dually inhibits glycolysis by end-product accumulation and by reducing cytoplasmic pH. Based on the robustness of these responses, we propose that acid-evoked T-cell inhibition is physiologically important, and that lymph nodes are a natural site for such modulation. Using multiple imaging techniques, we show that paracortical ...
The objective of this study was to compare a clustering approach to conventional analysis methods... more The objective of this study was to compare a clustering approach to conventional analysis methods for assessing changes in pharmacokinetic parameters obtained from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) during antiangiogenic treatment in a breast cancer model. BALB/c mice bearing established transplantable her2+ tumors were treated with a DNA-based antiangiogenic vaccine or with an empty plasmid (untreated group). DCE-MRI was carried out by administering a dose of 0.05 mmol/kg of Gadocoletic acid trisodium salt, a Gd-based blood pool contrast agent (CA) at 1T. Changes in pharmacokinetic estimates (K(trans) and vp) in a nine-day interval were compared between treated and untreated groups on a voxel-by-voxel analysis. The tumor response to therapy was assessed by a clustering approach and compared with conventional summary statistics, with sub-regions analysis and with histogram analysis. Both the K(trans) and vp estimates, following blood-pool CA injection, sh...
MRI contrast agents are routinely used in clinical settings. Important advances in their design h... more MRI contrast agents are routinely used in clinical settings. Important advances in their design have been attained in the past few years to overcome sensitivity issues and to make possible molecular imaging applications by means of this modality. Besides the sensitivity enhancement of paramagnetic relaxation probes, outstanding results have been obtained in the development of novel classes of frequency-encoding agents such as chemical exchange saturation transfer and hyperpolarized (13)C-enriched molecules.:
Beside its role against infections, complement is an important component of the tumor microenviro... more Beside its role against infections, complement is an important component of the tumor microenvironment. However, its role as a regulator of tumor growth is still debated. To assess the role of complement in the progression of autochthonous mammary carcinogenesis we have crossed C3 deficient BALB/c mice (C3KO) with BALB/c females transgenic for the activated rat Her2/neu oncogene (neuT), which develop autochthonous mammary cancer with 100% penetrance. A significantly earlier onset of the first palpable tumor, higher tumor multiplicity and a dramatic increase in the tumor growth rate were found in neuT-C3KO as compared to neuT females. The accelerated tumor onset observed in neuT-C3KO mice was paralleled by the earlier onset of spontaneous lung metastases and by an increase in Her2/neu expression on tumor cells. The percentage of tumor infiltrating immune cells in neuT-C3KO mice was similar to that found in neuT females, except for a significant increase in the frequency of T regulatory cells in neuT-C3KO tumors. Interestingly, the enhanced immunosuppression determined by C3 deficiency influenced the immunogenic phenotype of autochthonous mammary tumors, since tumor cells from neuT-C3KO displayed significantly delayed and reduced incidence as compared to those from neuT mice, when transplanted into syngeneic immunocompetent hosts. Finally, increased vessel permeability was evident in neuT-C3KO tumors, even if a similar number of tumor vessels was found in neuT and neuT-C3KO tumors. All together, these data point to the existence of a crucial role for the complement in the immunosurveillance and editing of Her2/neu autochthonous mammary tumors.
Iopamidol (Isovue®-Bracco Diagnostic Inc.) is a clinically approved X-Ray contrast agent used in ... more Iopamidol (Isovue®-Bracco Diagnostic Inc.) is a clinically approved X-Ray contrast agent used in the last 30 years for a wide variety of diagnostic applications with a very good clinical acceptance. Iopamidol contains two types of amide functionalities that can be exploited for the generation of chemical exchange saturation transfer effect. The exchange rate of the two amide proton pools is markedly pH-dependent. Thus, a ratiometric method for pH assessment has been set-up based on the comparison of the saturation transfer effects induced by selective irradiation of the two resonances. This ratiometric approach allows to rule out the concentration effect of the contrast agent and provides accurate pH measurements in the 5.5-7.4 range. Upon injection of Iopamidol into healthy mice, it has been possible to acquire pH maps of kidney regions. Furthermore, it has been also shown that the proposed method is able to report about pH-changes induced in control mice fed with acidified or basified water for a period of a week before image acquisition.
JBIC Journal of Biological Inorganic Chemistry, 2004
The high binding affinity between avidin and biotin has been exploited to develop a procedure for... more The high binding affinity between avidin and biotin has been exploited to develop a procedure for magnetic resonance imaging (MRI) visualization of target cells. SHIN3 and PANC1 tumor cell lines have been used as target cells because they possess on their membranes galactosyl receptors able to bind avidin molecules. Avidin-Gd chelate adducts have been built by using two Gd complexes containing one (Gd-I) and two (Gd-II) biotin residues, respectively. The relaxivities of such supramolecular adducts are significantly higher than those shown by free Gd-I and Gd-II. There is evidence of the occurrence of multilayered adducts in which the bis-biotinylated Gd 3+ complex acts as a bridge between adjacent avidin molecules. MRI differentiation of labeled versus unlabeled cells has been attained when approximately 6•10 8 Gd units were internalized in each cell. Furthermore, there is a marked decrease in the measured intracellular T 1 relaxivity as the number of internalized Gd complexes increases, probably owing to too short relaxation times of endosomic water protons with respect to their diffusion lifetime.
For life science infrastructures, sensitive data generate an additional layer of complexity. Cros... more For life science infrastructures, sensitive data generate an additional layer of complexity. Cross-domain categorisation and discovery of digital resources related to sensitive data presents major interoperability challenges. To support this FAIRification process, a toolbox demonstrator aiming at support for discovery of digital objects related to sensitive data (e.g., regulations, guidelines, best practice, tools) has been developed. The toolbox is based upon a categorisation system developed and harmonised across a cluster of 6 life science research infrastructures. Three different versions were built, tested by subsequent pilot studies, finally leading to a system with 7 main categories (sensitive data type, resource type, research field, data type, stage in data sharing life cycle, geographical scope, specific topics). 109 resources attached with the tags in pilot study 3 were used as the initial content for the toolbox demonstrator, a software tool allowing searching of digital...
Optoacoustic imaging emerged in early 1990s as a new biomedical imaging technology that generates... more Optoacoustic imaging emerged in early 1990s as a new biomedical imaging technology that generates images by illuminating tissues with short laser pulses and detecting resulting ultrasound waves. This technique takes advantage of the spectroscopic approach to molecular imaging, and delivers high-resolution images in the depth of tissue. Resolution of the optoacoustic imaging is scalable, so that biomedical systems from cellular organelles to large organs can be visualized and, more importantly, characterized based on their optical absorption coefficient, which is proportional to the concentration of absorbing chromophores. Optoacoustic imaging was shown to be useful in both preclinical research using small animal models and in clinical applications. Applications in the field of molecular imaging offer abundant opportunities for the development of highly specific and effective contrast agents for quantitative optoacoustic imaging. Recent efforts are being made in the direction of nontoxic biodegradable contrast agents (such as nanoparticles made of melanin) that are potentially applicable in clinical optoacoustic imaging. In order to increase the efficiency and specificity of contrast agents and probes, they need to be made smart and capable of controlled accumulation in the target cells. This review was written in recognition of the potential breakthroughs in medical optoacoustic imaging that can be enabled by efficient and nontoxic melanin-based optoacoustic contrast agents.
The Horizon 2020 project EOSC-Life brings together the 13 Life Science 'ESFRI' research i... more The Horizon 2020 project EOSC-Life brings together the 13 Life Science 'ESFRI' research infrastructures to create an open, digital and collaborative space for biological and medical research. Sharing sensitive data is a specific challenge within EOSC-Life. For that reason, a toolbox is developed, providing information to researchers who wish to share sensitive data or to use sensitive data. The toolbox enables researchers to find existing resources that are relevant for sharing sensitive data across life-science research infrastructures (F in FAIR). The toolbox is based upon a tagging (categorisation) system, allowing consistent labelling and categorisation of resources dealing with sensitive data. A first version of the tagging system was provided and tested in a pilot study, where 110 resources were tagged by 12 experts from 6 research infrastructures. Based on the feedback from this study, version 2 was developed and a re-tagging of the 110 resources was performed. The fe...
The Horizon 2020 project EOSC-Life brings together the 13 Life Science 'ESFRI' research i... more The Horizon 2020 project EOSC-Life brings together the 13 Life Science 'ESFRI' research infrastructures to create an open, digital and collaborative space for biological and medical research. Sharing sensitive data is a specific challenge within EOSC-Life. For that purpose, a toolbox is developed, providing information to researchers who wish to share or use sensitive data. The authors developed a categorisation system designed to support consistent labelling and categorisation of the resources stored in the toolbox in terms most relevant to data sharing tasks and activities, so that they are available to users (e.g., as on screen filters) when searching the system. The poster describes the methods and main results of a pilot study set to evaluate the proposed categorisation system for the toolbox resources with respect to applicability, reliability, sustainability and consistency. The primary objective of the pilot study was to identify the main improvements that are necess...
Sharing sensitive data is a specific challenge for research infrastructures in the field of life ... more Sharing sensitive data is a specific challenge for research infrastructures in the field of life sciences. For that reason a toolbox has been developed, providing resources for researchers who wish to share and use sensitive data, to support the workflows for handling these kinds of digital objects. Common and community approved annotations are required to be compliant with FAIR principles (Findability, Accessibility, Interoperability, Reusability). The toolbox makes use of a tagging (categorisation) system, allowing consistent labelling and categorisation of digital objects, in terms relevant to data sharing tasks and activities. A pilot study was performed within the Horizon 2020 project EOSC-Life, in which 2 experts from 6 life sciences research infrastructures were recruited to independently assign tags to the same set of 10 to 25 resources related to sensitive data management and data sharing (in total 110). Summary statistics of agreement and observer variation per research in...
X-ray iodinated contrast media have been shown to generate contrast in MR images when used with t... more X-ray iodinated contrast media have been shown to generate contrast in MR images when used with the chemical exchange saturation transfer (CEST) approach. The aim of this study is to compare contrast enhancement (CE) capabilities and perfusion estimates between radiographic molecules and a Gd-based contrast agent in two tumour murine models with different vascularization patterns. MRI-CEST and MRI-CE T1w images were acquired in murine TS/A and 4 T1 breast tumours upon sequential i.v. injection of iodinated contrast media (iodixanol, iohexol, and iopamidol) and of gadoteridol. The signal enhancements observed in the two acquisition modalities were evaluated using Pearson's correlation, and the correspondence in the spatial distribution was assessed by a voxelwise comparison. A significant, positive correlation was observed between iodinated contrast media and gadoteridol for tumour contrast enhancement and perfusion values for both tumour models (r = 0.51-0.62). High spatial corr...
Although anaplastic large-cell lymphomas (ALCL) carrying anaplastic lymphoma kinase (ALK) have a ... more Although anaplastic large-cell lymphomas (ALCL) carrying anaplastic lymphoma kinase (ALK) have a relatively good prognosis, aggressive forms exist. We have identified a novel translocation, causing the fusion of the TRAF1 and ALK genes, in one patient who presented with a leukemic ALK+ ALCL (ALCL-11). To uncover the mechanisms leading to high-grade ALCL, we developed a human patient-derived tumorgraft (hPDT) line. Molecular characterization of primary and PDT cells demonstrated the activation of ALK and nuclear factor kB (NFkB) pathways. Genomic studies of ALCL-11 showed the TP53 loss and the in vivo subclonal expansion of lymphoma cells, lacking PRDM1/Blimp1 and carrying c-MYC gene amplification. The treatment with proteasome inhibitors of TRAF1-ALK cells led to the downregulation of p50/p52 and lymphoma growth inhibition. Moreover, a NFkB gene set classifier stratified ALCL in distinct subsets with different clinical outcome. Although a selective ALK inhibitor (CEP28122) resulted ...
The tumor microenvironment acidification confers treatment resistance; therefore, the interferenc... more The tumor microenvironment acidification confers treatment resistance; therefore, the interference with pH regulating systems is considered a new therapeutic strategy. In this study, two human prostate cancer cell lines, PC3 and LNCaP, have been treated in vitro with proton pump inhibitors (PPIs), namely Lansoprazole, Esomeprazole (V-ATPases-inhibitors), Cariporide, and Amiloride (NHE1-inhibitors). The cell viability and pH were assessed at several drug concentrations either at normoxic or hypoxic conditions. Since Esomeprazole showed the highest toxicity towards the PC3 cancer cells compared to LNCaP ones, athymic nude mice bearing subcutaneous or orthotopic PC3 tumors were treated with Esomeprazole (dose: 2.5 mg/kg body weight) for a period of three weeks—and tumor growth was monitored. MRI-CEST tumor pH imaging with Iopamidol was performed upon treatment at 3 h, 1 week (in combination with FDG-PET), and after 2 weeks for evaluating acute, early, and late responses. Although acute...
Purpose D-Glucose and 3-O-Methyl-D-glucose (3OMG) have been shown to provide contrast in MRI-CEST... more Purpose D-Glucose and 3-O-Methyl-D-glucose (3OMG) have been shown to provide contrast in MRI-CEST images. However, a systematic comparison between these two molecules has not yet been performed. This study dealt with the assessment of the effect of pH, saturation power level (B1) and magnetic field strength (B0) on the MRI-CEST contrast with the aim of comparing the in vivo CEST contrast detectability of these two agents in the glucoCEST procedure. Methods Phosphate buffered solutions of D-Glucose or 3OMG (20 mM) were prepared at different pH values and Z-spectra acquired at several B1 levels and at 37°C. In vivo glucoCEST images were obtained at 3 T and 7 T over a period of 30 min after injection of D-Glucose or 3OMG (at the doses of 1.5 and 3 g/kg) in a murine melanoma tumour model. Results A markedly different pH dependence of CEST response was observed in vitro for D-Glucose and 3OMG. The glucoCEST contrast enhancement in the tumour region following the intravenous administratio...
Lymph nodes are an essential component of the adaptive immune response where antigen-presenting c... more Lymph nodes are an essential component of the adaptive immune response where antigen-presenting cells are closely housed with their cognate effector cells. Protection of lymph node resident cells from activated immune cells in such close quarters would need to be robust and reversible. Effector functions of T-cells are profoundly and reversibly inhibited by an acidic microenvironment. The underlying mechanisms of this inhibition are unknown, but may relate to glycolysis, which is obligatory for expression of effector functions. Here, we demonstrate that acidification rapidly and potently inhibits monocarboxylate transporter-dependent lactic acid efflux, which dually inhibits glycolysis by end-product accumulation and by reducing cytoplasmic pH. Based on the robustness of these responses, we propose that acid-evoked T-cell inhibition is physiologically important, and that lymph nodes are a natural site for such modulation. Using multiple imaging techniques, we show that paracortical ...
The objective of this study was to compare a clustering approach to conventional analysis methods... more The objective of this study was to compare a clustering approach to conventional analysis methods for assessing changes in pharmacokinetic parameters obtained from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) during antiangiogenic treatment in a breast cancer model. BALB/c mice bearing established transplantable her2+ tumors were treated with a DNA-based antiangiogenic vaccine or with an empty plasmid (untreated group). DCE-MRI was carried out by administering a dose of 0.05 mmol/kg of Gadocoletic acid trisodium salt, a Gd-based blood pool contrast agent (CA) at 1T. Changes in pharmacokinetic estimates (K(trans) and vp) in a nine-day interval were compared between treated and untreated groups on a voxel-by-voxel analysis. The tumor response to therapy was assessed by a clustering approach and compared with conventional summary statistics, with sub-regions analysis and with histogram analysis. Both the K(trans) and vp estimates, following blood-pool CA injection, sh...
MRI contrast agents are routinely used in clinical settings. Important advances in their design h... more MRI contrast agents are routinely used in clinical settings. Important advances in their design have been attained in the past few years to overcome sensitivity issues and to make possible molecular imaging applications by means of this modality. Besides the sensitivity enhancement of paramagnetic relaxation probes, outstanding results have been obtained in the development of novel classes of frequency-encoding agents such as chemical exchange saturation transfer and hyperpolarized (13)C-enriched molecules.:
Beside its role against infections, complement is an important component of the tumor microenviro... more Beside its role against infections, complement is an important component of the tumor microenvironment. However, its role as a regulator of tumor growth is still debated. To assess the role of complement in the progression of autochthonous mammary carcinogenesis we have crossed C3 deficient BALB/c mice (C3KO) with BALB/c females transgenic for the activated rat Her2/neu oncogene (neuT), which develop autochthonous mammary cancer with 100% penetrance. A significantly earlier onset of the first palpable tumor, higher tumor multiplicity and a dramatic increase in the tumor growth rate were found in neuT-C3KO as compared to neuT females. The accelerated tumor onset observed in neuT-C3KO mice was paralleled by the earlier onset of spontaneous lung metastases and by an increase in Her2/neu expression on tumor cells. The percentage of tumor infiltrating immune cells in neuT-C3KO mice was similar to that found in neuT females, except for a significant increase in the frequency of T regulatory cells in neuT-C3KO tumors. Interestingly, the enhanced immunosuppression determined by C3 deficiency influenced the immunogenic phenotype of autochthonous mammary tumors, since tumor cells from neuT-C3KO displayed significantly delayed and reduced incidence as compared to those from neuT mice, when transplanted into syngeneic immunocompetent hosts. Finally, increased vessel permeability was evident in neuT-C3KO tumors, even if a similar number of tumor vessels was found in neuT and neuT-C3KO tumors. All together, these data point to the existence of a crucial role for the complement in the immunosurveillance and editing of Her2/neu autochthonous mammary tumors.
Iopamidol (Isovue®-Bracco Diagnostic Inc.) is a clinically approved X-Ray contrast agent used in ... more Iopamidol (Isovue®-Bracco Diagnostic Inc.) is a clinically approved X-Ray contrast agent used in the last 30 years for a wide variety of diagnostic applications with a very good clinical acceptance. Iopamidol contains two types of amide functionalities that can be exploited for the generation of chemical exchange saturation transfer effect. The exchange rate of the two amide proton pools is markedly pH-dependent. Thus, a ratiometric method for pH assessment has been set-up based on the comparison of the saturation transfer effects induced by selective irradiation of the two resonances. This ratiometric approach allows to rule out the concentration effect of the contrast agent and provides accurate pH measurements in the 5.5-7.4 range. Upon injection of Iopamidol into healthy mice, it has been possible to acquire pH maps of kidney regions. Furthermore, it has been also shown that the proposed method is able to report about pH-changes induced in control mice fed with acidified or basified water for a period of a week before image acquisition.
JBIC Journal of Biological Inorganic Chemistry, 2004
The high binding affinity between avidin and biotin has been exploited to develop a procedure for... more The high binding affinity between avidin and biotin has been exploited to develop a procedure for magnetic resonance imaging (MRI) visualization of target cells. SHIN3 and PANC1 tumor cell lines have been used as target cells because they possess on their membranes galactosyl receptors able to bind avidin molecules. Avidin-Gd chelate adducts have been built by using two Gd complexes containing one (Gd-I) and two (Gd-II) biotin residues, respectively. The relaxivities of such supramolecular adducts are significantly higher than those shown by free Gd-I and Gd-II. There is evidence of the occurrence of multilayered adducts in which the bis-biotinylated Gd 3+ complex acts as a bridge between adjacent avidin molecules. MRI differentiation of labeled versus unlabeled cells has been attained when approximately 6•10 8 Gd units were internalized in each cell. Furthermore, there is a marked decrease in the measured intracellular T 1 relaxivity as the number of internalized Gd complexes increases, probably owing to too short relaxation times of endosomic water protons with respect to their diffusion lifetime.
Uploads
Papers by Dario Longo