In JoVE (3)

Other Publications (39)

Articles by Claudia Binder in JoVE

Other articles by Claudia Binder on PubMed

Increased Risk for Therapy-associated Hematologic Malignancies in Patients with Carcinoma of the Breast and Combined Homozygous Gene Deletions of Glutathione Transferases M1 and T1

Leukemia Research. Mar, 2002  |  Pubmed ID: 11792413

The most serious long-term complications of anti-tumor therapy are secondary malignancies. Parameters which might allow an estimation of the individual risk to develop a therapy-induced neoplasia are urgently needed. We examined whether the genotypes of the glutathione S-transferases (GST) M1 and T1, which metabolize various cytostatic drugs, as well as reactive oxygen species, influence the risk for secondary neoplasia. In a retrospective study, we analyzed peripheral blood lymphocyte or bone marrow DNA samples from 213 patients with acute myeloid leukemia (AML) and 128 with myelodysplastic syndromes (MDS) 44 of whom suffered from therapy-associated AML/MDS. The control group consisted of 239 healthy individuals with comparable composition as to race and sex. GSTM1 and GSTT1 were analyzed by multiplex PCR. Comparison between patients and control group revealed a significant (P=0.0003) overrepresentation of combined deletions of both GSTM1 and GSTT1 (double null genotype) in the group of patients with AML/MDS secondary to chemo- and/or radiotherapy of a carcinoma of the breast. In this group, 55% of the patients displayed the double null genotype as compared with 8.8% in the control group. We conclude that patients with carcinoma of the breast and inheritance of a combined gene deletion of GSTM1 and GSTT1 might bear an increased risk to develop a secondary therapy-induced hematologic neoplasia. An insufficient detoxification of cytostatic drugs such as cyclophosphamide is suggested to represent the underlying pathomechanism.

Effects of Hexadecylphosphocholine on Phosphatidylcholine and Phosphatidylserine Metabolism in Human Lymphoma Cells

Journal of Experimental Therapeutics & Oncology. Mar-Apr, 2002  |  Pubmed ID: 12415624

Hexadecylphosphocholine (HePC) belongs to a new group of antineoplastic agents, the alkylphosphocholines (APC). HePC shows a broad spectrum of biological effects in various cells in vitro and in vivo. It has pronounced antiproliferative effects on neoplastic cells. The molecular mechanism by which HePC exerts its biological effects is still under investigation. By generating a HePC-resistant cell variant of the lymphoma cell line Raji, we established a model to investigate which molecular mechanism may be responsible for the antiproliferative action of HePC. Here we present data showing that HePC substantially interferes with the metabolism of cellular phosphatidylcholine (PC) and phosphatidylserine (PS) in the human lymphoma cell line Raji. HePC leads to an inhibition of PC synthesis via CDP-choline and as a compensatory mechanism enhances the generation of PC via PS indicating that the reduced PC synthesis seems to significantly disturb cellular homeostasis. In HePC-resistant Raji cells, PC synthesis via CDP-choline is constitutively less active and is not further reduced by HePC. Resistant Raji cells do not seem to use the alternative pathway of PC synthesis via PS nor can this be induced by HePC. The resistance mechanism may therefore be independent of cell membrane metabolism.

Hexadecylphosphocholine Does Not Influence Phospholipase D and Sphingomyelinase Activity in Human Leukemia Cells

Journal of Experimental Therapeutics & Oncology. Jul-Aug, 2002  |  Pubmed ID: 12416025

Hexadecylphosphocholine (HePC) is the first representative of the alkylphosphocholines (APC), a new group of biologically active compounds. HePC has pronounced antiproliferative effects on neoplastic cells in vitro and in vivo. The molecular mechanism by which HePC exerts its biological effects is still under investigation. Recently there has been growing evidence that HePC probably interferes with cellular signalling via phospholipases. It has been shown to inhibit both forms of phospholipase C (PLC), the phosphatidylinositol- and the phosphatidylcholine-specific PLC, and phospholipase A2. Here we present data showing that HePC inhibits the activity of phospholipase D in vitro, whereas the action of this enzyme in leukemic cell lines is not affected. Furthermore HePC does not seem to disturbed the activity of sphingomyelinase, another enzyme of phospholipid metabolism which has been shown to play an important role in cellular signalling as well.

Inhibition of Chemokine Production from Human Airway Smooth Muscle Cells by Fluticasone, Budesonide and Beclomethasone

Pulmonary Pharmacology & Therapeutics. 2004  |  Pubmed ID: 14643170

Human airway smooth muscle cells (HASMC) contribute to the process of airway wall remodelling in asthma by virtue of their secretory functions. This study was performed to investigate the effectiveness of the commonly used steroids beclomethasone, budesonide and fluticasone in downregulating HASMC production of RANTES and IL-8. HASMC (n=5) were cultured from dissected bronchi using collagenase digestion. Confluent HASMC were exposed to TNFalpha and IL-1beta (10 ng/ml) for 24 h. All stimulations were set with and without pre-treatment with beclomethasone, budesonide or fluticasone for 2 h at concentrations of 10(-9)-10(-6)M. IL-8 and RANTES mRNA expression was assessed by RT-PCR and protein secretion was determined by ELISA. Pre-treatment with beclomethasone, budesonide or fluticasone reduced TNFalpha- and IL-1beta-stimulated IL-8 and RANTES release from HASMC in a dose dependent manner. However, beclomethasone was 22-28% less effective than fluticasone and budesonide in inhibiting chemokine production. TNFalpha- and IL-1beta-induced RANTES and IL-8 expression was reduced on the transcriptional level by pre-treatment with fluticasone and budesonide. The results suggest that the topical steroids fluticasone, budesonide and to a lesser extent beclomethasone may have beneficial effects on airway inflammation in asthma by reducing RANTES and IL-8-induced leukocyte infiltration into the airway wall.

Enhanced Invasiveness of Breast Cancer Cell Lines Upon Co-cultivation with Macrophages is Due to TNF-alpha Dependent Up-regulation of Matrix Metalloproteases

Carcinogenesis. Aug, 2004  |  Pubmed ID: 15044327

Apart from the neoplastic cells, malignant tumours consist of the extracellular matrix (ECM) and normal cells, in particular tumour-associated macrophages (TAM). To understand the mechanisms by which TAM can influence tumour cell invasion we co-cultured the human breast cancer cell lines MCF-7, SK-BR-3 and the benign mammary epithelial cell line hTERT-HME1 with macrophages. Co-incubation enhanced invasiveness of the tumour cells, while hTERT-HME1 remained non-invasive. Addition of the broad-spectrum matrix metalloprotease (MMP)-inhibitor FN 439, neutralizing MMP-9 or tumour necrosis factor-alpha (TNF-alpha) antibodies reduced invasiveness to basal levels. As shown by zymography, all cell lines produced low amounts of MMP-2, -3, -7 and -9 under control conditions. Basal MMP production by macrophages was significantly higher. Upon co-incubation, supernatant levels of MMPs -2, -3, -7 and -9 increased significantly, paralleled by an increase of MMP-2 activation. MMP-2 and -9 induction could be blocked by TNF-alpha antibodies. Co-culture of macrophages and hTERT-HME1 did not lead to MMP induction. In the co-cultures, mRNAs for MMPs and TNF-alpha were significantly up-regulated in macrophages, while the mRNA concentrations in the tumour cells remained unchanged. In summary, we have found that co-cultivation of tumour cells with macrophages leads to enhanced invasiveness of the malignant cells due to TNF-alpha dependent MMP induction in the macrophages.

A Role for Endothelin-2 and Its Receptors in Breast Tumor Cell Invasion

Cancer Research. Apr, 2004  |  Pubmed ID: 15059899

We have studied the role of endothelins (ET-1, ET-2 and ET-3) and ET receptors (ET-RA and ET-RB) in the invasive capacity of breast tumor cells, which express ET-1 and ET-2 as well as ET-RA and ET-RB. Of five human breast tumor cell lines tested, all expressed mRNAs for ET-1, ET-2, and ET-RB. ET-RA mRNA was expressed by four of five tumor cell lines. Breast tumor cells migrated toward ET-1 and ET-2 but not toward ET-3. Chemotaxis involved signaling via both receptors, and a pertussis toxin-sensitive p42/p44 mitogen-activated protein kinase (MAPK)-mediated pathway that could be inhibited by MAPK kinase (MEK)1/2 antagonists. Chemotaxis toward ETs did not involve p38 or stress-activated protein kinase (SAPK)/Jun N-terminal kinase (JNK) and was not inhibited by hypoxia. Incubation of tumor cells with ET-2 also increased chemotaxis toward the chemokines CXCL12 and CCL21. As well as inducing chemotaxis of tumor cells, ET-1 and ET-2 increased tumor cell invasion through Matrigel. Furthermore, stimulation of macrophage/tumor cell cocultures with ETs led to increased matrix metalloproteinase (MMP)-2 and -9 production by macrophages and a marked increase in invasion of tumor cells. Antagonism of either ET-RA or ET-RB decreased the invasion seen in ET-stimulated cocultures, as did a broad-spectrum MMP inhibitor. Immunohistochemical staining of human breast tumor sections showed increased ET and ET receptor protein expression by tumor cells in invasive ductal carcinoma compared with normal breast tissue or ductal carcinoma in situ. Furthermore, tumor cell ET and receptor expression was stronger at the invasive margin of invasive ductal carcinomas, in the lymphovascular space, and in lymph node metastases. ET expression often colocalized with ET-RB expression in all neoplastic tissue indicating a possible autocrine action of ETs. We suggest that expression of ETs and their receptors by human breast tumors, particularly in conjunction with a high macrophage infiltrate, may have a role in the progression of breast cancer and the invasion of tumor cells.

Macrophages Induce Invasiveness of Epithelial Cancer Cells Via NF-kappa B and JNK

Journal of Immunology (Baltimore, Md. : 1950). Jul, 2005  |  Pubmed ID: 16002723

Tumor-associated macrophages may influence tumor progression, angiogenesis and invasion. To investigate mechanisms by which macrophages interact with tumor cells, we developed an in vitro coculture model. Previously we reported that coculture enhanced invasiveness of the tumor cells in a TNF-alpha- and matrix metalloprotease-dependent manner. In this report, we studied intracellular signaling pathways and induction of inflammatory genes in malignant cells under the influence of macrophage coculture. We report that coculture of macrophages with ovarian or breast cancer cell lines led to TNF-alpha-dependent activation of JNK and NF-kappaB pathways in tumor cells, but not in benign immortalized epithelial cells. Tumor cells with increased JNK and NF-kappaB activity exhibited enhanced invasiveness. Inhibition of the NF-kappaB pathway by TNF-alpha neutralizing Abs, an NF-kappaB inhibitor, RNAi to RelA, or overexpression of IkappaB inhibited tumor cell invasiveness. Blockade of JNK also significantly reduced invasiveness, but blockade of p38 MAPK or p42 MAPK had no effect. Cocultured tumor cells were screened for the expression of 22 genes associated with inflammation and invasion that also contained an AP-1 and NF-kappaB binding site. EMMPRIN and MIF were up-regulated in cocultured tumor cells in a JNK- and NF-kappaB-dependent manner. Knocking down either MIF or EMMPRIN by RNAi in the tumor cells significantly reduced tumor cell invasiveness and matrix metalloprotease activity in the coculture supernatant. We conclude that TNF-alpha, via NF-kappaB, and JNK induces MIF and EMMPRIN in macrophage to tumor cell cocultures and this leads to increased invasive capacity of the tumor cells.

Expression of Endothelins and Their Receptors Promotes an Invasive Phenotype of Breast Tumor Cells but is Insufficient to Induce Invasion in Benign Cells

DNA and Cell Biology. Nov, 2005  |  Pubmed ID: 16274297

There is increased staining of endothelins (ET-1, -2, and -3) and receptors (ET-RA and -RB) in invasive breast tumors compared to nonneoplastic tissue, and ETs stimulate MCF-7 cell invasion in vitro. We analyzed ETstimulation of benign and transformed mammary epithelial cells, and whether expression of ETs is sufficient to induce invasiveness. In breast cancer patient serum, ET-1 was increased in those patients with lymph node metastases compared to those with no lymph node involvement; ETs, however, had no mitogenic effect on breast tumor cell lines in vitro. The benign mammary epithelial cell line, hTERT-HME1, and the poorly invasive breast tumor cell line MCF-7 secreted low levels of ET-1, while the invasive cell lines SKBR3 and MDAMB231 secreted high levels. Expression of the ETs and receptors by the cell lines broadly correlated with their in vitro invasiveness; overexpression of ETs in MCF-7 cells increased basal invasion. ET-mediated invasion involved both receptors and a calcium influx to induce a pertussis toxin-sensitive MAPK pathway. MMP-14 activity was induced via ET-RA in an autocrine manner. In contrast to transformed cells, ET stimulation or overexpression did not induce an invasive phenotype in benign cells. Benign cells do not respond to ETs, and ET expression is not sufficient to induce invasion; however, the level of ET production by tumor cells correlates with their invasiveness, and increasing expression of the ET axis promotes breast tumor cell invasion via both receptors, while MMP-14 is induced via ET-RA.

Utility of Procalcitonin Concentration in the Evaluation of Patients with Malignant Diseases and Elevated C-reactive Protein Plasma Concentrations

Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. Aug, 2006  |  Pubmed ID: 16838236

Elevated plasma concentrations of the C-reactive protein (CRP) are frequently found in patients with malignant diseases. Discrimination between infection and noninfectious acute-phase reactions is essential for therapeutic decisions.

Safety and Efficacy of Itraconazole Compared to Amphotericin B As Empirical Antifungal Therapy for Neutropenic Fever in Patients with Haematological Malignancy

Onkologie. Apr, 2007  |  Pubmed ID: 17396041

Safety, tolerability and efficacy of itraconazole and amphotericin B (AMB) were compared for empirical antifungal treatment of febrile neutropenic cancer patients.

The Hedgehog Receptor Patched Controls Lymphoid Lineage Commitment

Blood. Sep, 2007  |  Pubmed ID: 17536012

A first step in hematopoiesis is the specification of the lymphoid and myeloid lineages from multipotent progenitor cells in the bone marrow. Using a conditional ablation strategy in adult mice, we show that this differentiation step requires Patched (Ptch), the cell surface-bound receptor for Hedgehog (Hh). In the absence of Ptch, the development of T- and B-lymphoid lineages is blocked at the level of the common lymphoid progenitor in the bone marrow. Consequently, the generation of peripheral T and B cells is abrogated. Cells of the myeloid lineage develop normally in Ptch mutant mice. Finally, adoptive transfer experiments identified the stromal cell compartment as a critical Ptch-dependent inducer of lymphoid versus myeloid lineage commitment. Our data show that Ptch acts as a master switch for proper diversification of hematopoietic stem cells in the adult organism.

The Complex Pathways of Wnt 5a in Cancer Progression

Journal of Molecular Medicine (Berlin, Germany). Mar, 2008  |  Pubmed ID: 17952396

In contrast to the transforming members of the Wnt family, shown to be upregulated in many cancers, the role of Wnt 5a is still controversial. While it has been attributed a tumour suppressor function in some malignancies, there is increasing evidence of promigratory and proinvasive effects in others, mediated predominantly through the planar cell polarity pathway and activation of protein kinase C. Obviously, the outcome of an individual Wnt 5a signal is dependent on a multitude of variables, ranging from availability of receptors, downstream effectors, and inhibitors to external influences coming from the tumour microenvironment and the extracellular matrix.

System Perspectives of Experts and Farmers Regarding the Role of Livelihood Assets in Risk Perception: Results from the Structured Mental Model Approach

Risk Analysis : an Official Publication of the Society for Risk Analysis. Feb, 2009  |  Pubmed ID: 19000068

Pesticide application is increasing and despite extensive educational programs farmers continue to take high health and environmental risks when applying pesticides. The structured mental model approach (SMMA) is a new method for risk perception analysis. It embeds farmers' risk perception into their livelihood system in the elaboration of a mental model (MM). Results from its first application are presented here. The study region is Vereda la Hoya (Colombia), an area characterized by subsistence farming, high use of pesticides, and a high incidence of health problems. Our hypothesis was that subsistence farmers were constrained by economic, environmental, and sociocultural factors, which consequently should influence their mental models. Thirteen experts and 10 farmers were interviewed and their MMs of the extended pesticide system elicited. The interviews were open-ended with the questions structured in three parts: (i) definition and ranking of types of capital with respect to their importance for the sustainability of farmers' livelihood; (ii) understanding the system and its dynamics; and (iii) importance of the agents in the farmers' agent network. Following this structure, each part of the interview was analyzed qualitatively and statistically. Our analyses showed that the mental models of farmers and experts differed significantly from each other. By applying the SMMA, we were also able to identify reasons for the divergence of experts' and farmers' MMs. Of major importance are the following factors: (i) culture and tradition; (ii) trust in the source of information; and (iii) feedback on knowledge.

Spatial Modeling of Personalized Exposure Dynamics: the Case of Pesticide Use in Small-scale Agricultural Production Landscapes of the Developing World

International Journal of Health Geographics. 2009  |  Pubmed ID: 19331690

Pesticide poisoning is a global health issue with the largest impacts in the developing countries where residential and small-scale agricultural areas are often integrated and pesticides sprayed manually. To reduce health risks from pesticide exposure approaches for personalized exposure assessment (PEA) are needed. We present a conceptual framework to develop a spatial individual-based model (IBM) prototype for assessing potential exposure of farm-workers conducting small-scale agricultural production, which accounts for a considerable portion of global food crop production. Our approach accounts for dynamics in the contaminant distributions in the environment, as well as patterns of movement and activities performed on an individual level under different safety scenarios. We demonstrate a first prototype using data from a study area in a rural part of Colombia, South America.

Stromal Endothelin B Receptor-deficiency Inhibits Breast Cancer Growth and Metastasis

Molecular Cancer Therapeutics. Aug, 2009  |  Pubmed ID: 19671740

The endothelin (ET) axis, often deregulated in cancers, is a promising target for anticancer strategies. Whereas previous investigations have focused mostly on ET action in malignant cells, we chose a model allowing separate assessment of the effects of ETs and their receptors ET(A)R and ET(B)R in the tumor cells and the stromal compartment, which is increasingly recognized as a key player in cancer progression. In homozygous spotting lethal rats (sl/sl), a model of constitutive ET(B)R deficiency, we showed significant reduction of growth and metastasis of MAT B III rat mammary adenocarcinoma cells overexpressing ET(A)R and ET-1 but negative for ET(B)R. Lack of stromal ET(B)R expression did not influence angiogenesis. However, it was correlated with diminished infiltration by tumor-associated macrophages and with reduced production of tumor necrosis factor-alpha, both known as powerful promoters of tumor progression. These effects were almost completely abolished in transgenic sl/sl rats, wherein ET(B)R function is restored by expression of an intact ET(B)R transgene. This shows that tumor growth and metastasis are critically dependent on ET(B)R function in cells of the microenvironment and suggests that successful ETR antagonist therapy should also target the stromal component of ET signaling

The Chemically Synthesized Human Relaxin-2 Analog, B-R13/17K H2, is an RXFP1 Antagonist

Amino Acids. Jul, 2010  |  Pubmed ID: 20043231

Relaxin is a pleiotropic hormone which exerts its biological functions through its G-protein coupled receptor, RXFP1. While relaxin is well known for its reproductive and antifibrotic roles, recent studies suggest that it is produced by cancer cells and acts on RXFP1 to induce growth and metastasis. Furthermore, more recently Silvertown et al. demonstrated that lentiviral production of a human gene-2 (H2) relaxin analog reduced the growth of prostate xenograft tumors. The authors proposed that the lentivirally produced peptide was an RXFP1 antagonist; however, the processed form of the peptide produced was not demonstrated. In this study, we have chemically synthesized the H2 relaxin analog, B-R13/17K H2 relaxin, and subjected it to detailed chemical characterization by HPLC, MALDI-TOF mass spectrometry, and amino acid analysis. The biological activity of the synthetic peptide was then tested in three different cell lines. It was found to bind with 500-fold lower affinity than H2 relaxin to RXFP1 receptors over-expressed in HEK-293T cells where it acted as a partial agonist. However, in cells which natively express the RXFP1 receptor, rat renal myofibroblasts and MCF-7 cancer cells, it acted as a full antagonist. Importantly, it was able to significantly inhibit cell invasion induced by H2 relaxin in MCF-7 cells consistent with the results of the lentiviral-driven expression in prostate cancer cells. The relaxin analog, B-R13/17K H2, can now be used as a tool to further understand RXFP1 function, and serve as a template for drug design for a therapeutic to treat prostate and other cancers.

Why Don't Pesticide Applicators Protect Themselves? Exploring the Use of Personal Protective Equipment Among Colombian Smallholders

International Journal of Occupational and Environmental Health. Jan-Mar, 2010  |  Pubmed ID: 20166315

The misuse of personal protective equipment (PPE) during pesticide application was investigated among smallholders in Colombia. The integrative agent-centered (IAC) framework and a logistic regression approach were adopted. The results suggest that the descriptive social norm was significantly influencing PPE use. The following were also important: (1) having experienced pesticide-related health problems; (2) age; (3) the share of pesticide application carried out; and (4) the perception of PPE hindering work. Interestingly, the influence of these factors differed for different pieces of PPE. Since conformity to the social norm is a source of rigidity in the system, behavioral change may take the form of a discontinuous transition. In conclusion, five suggestions for triggering a transition towards more sustainable PPE use are formulated: (1) diversifying targets/tools; (2) addressing structural aspects; (3) sustaining interventions in the long-term; (4) targeting farmers' learning-by-experience; and (5) targeting PPE use on a collective level.

Microglia Promote Colonization of Brain Tissue by Breast Cancer Cells in a Wnt-dependent Way

Glia. Sep, 2010  |  Pubmed ID: 20549749

Although there is increasing evidence that blood-derived macrophages support tumor progression, it is still unclear whether specialized resident macrophages, such as brain microglia, also play a prominent role in metastasis formation. Here, we show that microglia enhance invasion and colonization of brain tissue by breast cancer cells, serving both as active transporters and guiding rails. This is antagonized by inactivation of microglia as well as by the Wnt inhibitor Dickkopf-2. Proinvasive microglia demonstrate altered morphology, but neither upregulation of M2-like cytokines nor differential gene expression. Bacterial lipopolysacharide shifts tumor-educated microglia into a classical M1 phenotype, reduces their proinvasive function, and unmasks inflammatory and Wnt signaling as the most strongly regulated pathways. Histological findings in human brain metastases underline the significance of these results. In conclusion, microglia are critical for the successful colonization of the brain by epithelial cancer cells, suggesting inhibition of proinvasive microglia as a promising antimetastatic strategy.

Pesticide Uptake in Potatoes: Model and Field Experiments

Environmental Science & Technology. Jan, 2011  |  Pubmed ID: 21141816

A dynamic model for uptake of pesticides in potatoes is presented and evaluated with measurements performed within a field trial in the region of Boyacá, Colombia. The model takes into account the time between pesticide applications and harvest, the time between harvest and consumption, the amount of spray deposition on soil surface, mobility and degradation of pesticide in soil, diffusive uptake and persistence due to crop growth and metabolism in plant material, and loss due to food processing. Food processing steps included were cleaning, washing, storing, and cooking. Pesticide concentrations were measured periodically in soil and potato samples from the beginning of tuber formation until harvest. The model was able to predict the magnitude and temporal profile of the experimentally derived pesticide concentrations well, with all measurements falling within the 90% confidence interval. The fraction of chlorpyrifos applied on the field during plant cultivation that eventually is ingested by the consumer is on average 10(-4)-10(-7), depending on the time between pesticide application and ingestion and the processing step considered.

The Weight Method: a New Screening Method for Estimating Pesticide Deposition from Knapsack Sprayers in Developing Countries

Chemosphere. Mar, 2011  |  Pubmed ID: 21183200

Investigations of occupational and environmental risk caused by the use of agrochemicals have received considerable interest over the last decades. And yet, in developing countries, the lack of staff and analytical equipment as well the costs of chemical analyses make it difficult, if not impossible, to monitor pesticide contamination and residues in humans, air, water, and soils. A new and simple method is presented here for estimation of pesticide deposition in humans and soil after application. The estimate is derived on the basis of water mass balance measured in a given number of high absorbent papers under low evaporative conditions and unsaturated atmosphere. The method is presented as a suitable, rapid, low cost screening tool, complementary to toxicological tests, to assess occupational and environmental exposure caused by knapsack sprayers, where there is a lack of analytical instruments. This new method, called the "weight method", was tested to obtain drift deposition on the neighbouring field and the clothes of the applicator after spraying water with a knapsack sprayer in one of the largest areas of potato production in Colombia. The results were confirmed by experimental data using a tracer and the same set up used for the weight method. The weight method was able to explain 86% of the airborne drift and deposition variance.

Nuclear Energy in Europe: Uranium Flow Modeling and Fuel Cycle Scenario Trade-offs from a Sustainability Perspective

Environmental Science & Technology. Mar, 2011  |  Pubmed ID: 21275398

The European nuclear fuel cycle (covering the EU-27, Switzerland and Ukraine) was modeled using material flow analysis (MFA).The analysis was based on publicly available data from nuclear energy agencies and industries, national trade offices, and nongovernmental organizations. Military uranium was not considered due to lack of accessible data. Nuclear fuel cycle scenarios varying spent fuel reprocessing, depleted uranium re-enrichment, enrichment assays, and use of fast neutron reactors, were established. They were then assessed according to environmental, economic and social criteria such as resource depletion, waste production, chemical and radiation emissions, costs, and proliferation risks. The most preferable scenario in the short term is a combination of reduced tails assay and enrichment grade, allowing a 17.9% reduction of uranium demand without significantly increasing environmental, economic, or social risks. In the long term, fast reactors could theoretically achieve a 99.4% decrease in uranium demand and nuclear waste production. However, this involves important costs and proliferation risks. Increasing material efficiency is not systematically correlated with the reduction of other risks. This suggests that an overall optimization of the nuclear fuel cycle is difficult to obtain. Therefore, criteria must be weighted according to stakeholder interests in order to determine the most sustainable solution. This paper models the flows of uranium and associated materials in Europe, and provides a decision support tool for identifying the trade-offs of the alternative nuclear fuel cycles considered.

T Cell Development Critically Depends on Prethymic Stromal Patched Expression

Journal of Immunology (Baltimore, Md. : 1950). Mar, 2011  |  Pubmed ID: 21317383

We recently described that T cell specification in mice deficient in the Hedgehog (Hh) receptor Patched (Ptch) is blocked at the level of the common lymphoid progenitor in the bone marrow (BM). Adoptive transfer of wild-type BM in Ptch-deficient mice provides evidence that T cell development strictly depends on Ptch expression in the nonhematopoietic compartment. Transplantation experiments using BM deficient in the glucocorticoid receptor exclude any involvement of the stress hormone corticosterone in our model. Using cell-type-specific knockout mice, we show that T cell development is independent of T cell-intrinsic Ptch expression. Furthermore, Ptch expression by the thymus stroma is dispensable, as revealed by fetal thymus organ culture and thymus transplantation. In contrast, analysis of the earliest thymic progenitors in Ptch-deficient mice indicated that Ptch is required for the development or supply of thymic homing progenitors that give rise to earliest thymic progenitors. Collectively, our findings identified Ptch as an exclusive T cell-extrinsic factor necessary for proper development of T cells at their prethymic stage. This observation may be important for current considerations using Hh inhibitors upstream of Ptch in diseases accompanied by aberrant Hh signaling.

Dermal Exposure Assessment of Pesticide Use: the Case of Sprayers in Potato Farms in the Colombian Highlands

The Science of the Total Environment. Jul, 2012  |  Pubmed ID: 22652009

Quantifying dermal exposure to pesticides in farming systems in developing countries is of special interest for the estimation of potential health risks, especially when there is a lack of occupational hygiene regulations. In this paper we present the results of a dermal exposure assessment for the potato farming system in the highlands of Colombia, where farmers apply pesticides with hand pressure sprayers without any personal protective equipment. The fractioning of the pesticide, in terms of potential and actual dermal exposure, was determined via the whole-body dosimetry methodology, using the tracer uranine as pesticide surrogate, and luminescence spectrometry as analytical method. We assessed the three activities involved in pesticide management: preparation, application, and cleaning; analyzed three types of nozzles: one with a standard discharge and two modified by farmers to increase the discharge; and derived the protection factor given by work clothing. Our results suggest that to reduce the health risk, three aspects have to be considered: (i) avoiding the modification of nozzles, which affects the droplet size spectrum and increases the level of dermal exposure; (ii) using adequate work clothing made of thick fabrics, especially on the upper body parts; and (iii) cleaning properly the tank sprayer before the application activity.

Inactivation of Patched1 in Mice Leads to Development of Gastrointestinal Stromal-like Tumors That Express Pdgfrα but Not Kit

Gastroenterology. Jan, 2013  |  Pubmed ID: 23041331

A fraction of gastrointestinal stromal tumor (GIST) cells overexpress the platelet-derived growth factor receptor (PDGFR)A, although most overexpress KIT. It is not known if this is because these receptor tyrosine kinases have complementary oncogenic potential, or because of heterogeneity in the cellular origin of GIST. Little also is known about why Hedgehog (HH) signaling is activated in some GIST. HH binds to and inactivates the receptor protein patched homolog (PTCH).

Pesticide Flow Analysis to Assess Human Exposure in Greenhouse Flower Production in Colombia

International Journal of Environmental Research and Public Health. Apr, 2013  |  Pubmed ID: 23528812

Human exposure assessment tools represent a means for understanding human exposure to pesticides in agricultural activities and managing possible health risks. This paper presents a pesticide flow analysis modeling approach developed to assess human exposure to pesticide use in greenhouse flower crops in Colombia, focusing on dermal and inhalation exposure. This approach is based on the material flow analysis methodology. The transfer coefficients were obtained using the whole body dosimetry method for dermal exposure and the button personal inhalable aerosol sampler for inhalation exposure, using the tracer uranine as a pesticide surrogate. The case study was a greenhouse rose farm in the Bogota Plateau in Colombia. The approach was applied to estimate the exposure to pesticides such as mancozeb, carbendazim, propamocarb hydrochloride, fosetyl, carboxin, thiram, dimethomorph and mandipropamide. We found dermal absorption estimations close to the AOEL reference values for the pesticides carbendazim, mancozeb, thiram and mandipropamide during the study period. In addition, high values of dermal exposure were found on the forearms, hands, chest and legs of study participants, indicating weaknesses in the overlapping areas of the personal protective equipment parts. These results show how the material flow analysis methodology can be applied in the field of human exposure for early recognition of the dispersion of pesticides and support the development of measures to improve operational safety during pesticide management. Furthermore, the model makes it possible to identify the status quo of the health risk faced by workers in the study area.

Carcinoma Cells Misuse the Host Tissue Damage Response to Invade the Brain

Glia. Aug, 2013  |  Pubmed ID: 23832647

The metastatic colonization of the brain by carcinoma cells is still barely understood, in particular when considering interactions with the host tissue. The colonization comes with a substantial destruction of the surrounding host tissue. This leads to activation of damage responses by resident innate immune cells to protect, repair, and organize the wound healing, but may distract from tumoricidal actions. We recently demonstrated that microglia, innate immune cells of the CNS, assist carcinoma cell invasion. Here we report that this is a fatal side effect of a physiological damage response of the brain tissue. In a brain slice coculture model, contact with both benign and malignant epithelial cells induced a response by microglia and astrocytes comparable to that seen at the interface of human cerebral metastases. While the glial damage response intended to protect the brain from intrusion of benign epithelial cells by inducing apoptosis, it proved ineffective against various malignant cell types. They did not undergo apoptosis and actually exploited the local tissue reaction to invade instead. Gene expression and functional analyses revealed that the C-X-C chemokine receptor type 4 (CXCR4) and WNT signaling were involved in this process. Furthermore, CXCR4-regulated microglia were recruited to sites of brain injury in a zebrafish model and CXCR4 was expressed in human stroke patients, suggesting a conserved role in damage responses to various types of brain injuries. Together, our findings point to a detrimental misuse of the glial damage response program by carcinoma cells resistant to glia-induced apoptosis.

Relaxins Enhance Growth of Spontaneous Murine Breast Cancers As Well As Metastatic Colonization of the Brain

Clinical & Experimental Metastasis. Aug, 2013  |  Pubmed ID: 23963762

Relaxins are known for their tissue remodeling capacity which is also a hallmark of cancer progression. However, their role in the latter context is still unclear, particularly in breast cancer. In a mouse model with spontaneously arising breast cancer due to erbB2-overexpression we show that exposure to porcine relaxin results in significantly enhanced tumour growth as compared to control animals. This is accompanied by increased serum concentrations of progesterone and estradiol as well as elevated expression of the respective receptors and the relaxin receptor RXFP1 in the tumour tissue. It is also associated with enhanced infiltration by tumour-associated macrophages which are known to promote tumour progression. Additionally, we show in an ex vivo model of metastatic brain colonization that porcine relaxin as well as human brain-specific relaxin-3 promotes invasion into the brain tissue and enhance interaction of breast cancer cells with the resident brain macrophages, the microglia. Relaxin signaling is mediated via RXFP1, since R 3/I5, a specific agonist of the relaxin-3 receptor RXFP3 in the brain, does not significantly enhance invasion. Taken together, these findings strongly support a role of relaxins in the progression of breast cancer where they foster primary tumour growth as well as metastatic colonization by direct and indirect means.

Zoledronic Acid Inhibits Macrophage/microglia-assisted Breast Cancer Cell Invasion

Oncotarget. Aug, 2013  |  Pubmed ID: 24036536

The bisphosphonate zoledronic acid (ZA) significantly reduces complications of bone metastasis by inhibiting resident macrophages, the osteoclasts. Recent clinical trials indicate additional anti-metastatic effects of ZA outside the bone. However, which step of metastasis is influenced and whether thisis due to directtoxicity on cancer cells or inhibition of the tumor promoting microenvironment, is unknown. In particular, tumor-associated and resident macrophages support each step of organ metastasis and could be a crucial target of ZA. Thus, we comparatively investigate the ZA effects on: i) different types of macrophages, ii) on breast cancer cells but also iii) on macrophage-induced invasion. We demonstrate that ZA concentrations reflecting the plasma level affected viability of human macrophages, murine bone marrow-derived macrophages as well as their resident brain equivalents, the microglia, while it did not influence the tested cancer cells. However, the effects on the macrophages subsequently reduced the macrophage/microglia-induced invasiveness of the cancer cells. In line with this, manipulation of microglia by ZA in organotypic brain slice cocultures reduced the tissue invasion by carcinoma cells. The characterization of human macrophages after ZA treatment revealed a phenotype/response shift, in particular after external stimulation. In conclusion, we show that therapeutic concentrations of ZA affect all types of macrophages but not the cancer cells. Thus, anti-metastatic effects of ZA are predominantly caused by modulating the microenvironment. Most importantly, our findings demonstrate that ZA reduced microglia-assisted invasion of cancer cells to the brain tissue, indicating a potential therapeutic role in the prevention of cerebral metastasis.

Induction and Transport of Wnt 5a During Macrophage-induced Malignant Invasion is Mediated by Two Types of Extracellular Vesicles

Oncotarget. Nov, 2013  |  Pubmed ID: 24185202

Recently, we have shown that macrophage (MΦ)-induced invasion of breast cancer cells requires upregulation of Wnt 5a in MΦ leading to activation of β-Catenin-independent Wnt signaling in the tumor cells. However, it remained unclear, how malignant cells induce Wnt 5a in MΦ and how it is transferred back to the cancer cells. Here we identify two types of extracellular particles as essential for this intercellular interaction in both directions. Plasma membrane-derived microvesicles (MV) as well as exosomes from breast cancer cells, although biologically distinct populations, both induce Wnt 5a in MΦ. In contrast, the particle-free supernatant and vesicles from benign cells, such as platelets, have no such effect. Induction is antagonized by the Wnt inhibitor Dickkopf-1. Subsequently, Wnt 5a is shuttled via responding MΦ-MV and exosomes to the tumor cells enhancing their invasion. Wnt 5a export on both vesicle fractions depends at least partially on the cargo protein Evenness interrupted (Evi). Its knockdown leads to Wnt 5a depletion of both particle populations and reduced vesicle-mediated invasion. In conclusion, MV and exosomes are critical for MΦ-induced invasion of cancer cells since they are responsible for upregulation of MΦ-Wnt 5a as well as for its delivery to the recipient cells via a reciprocal loop. Although of different biogenesis, both populations share common features regarding function and Evi-dependent secretion of non-canonical Wnts.

Application of the Analytic Hierarchy Process to the Analysis of Wastewater Nutrient Recycling Options: a Case Based on a Group Study of Residents in the City of Zurich

Water Science and Technology : a Journal of the International Association on Water Pollution Research. 2013  |  Pubmed ID: 24355853

The recycling of anthropogenic nutrients derived from the wastewater management systems is often characterized by a complex and uncertain scenario, due not only to the nature of the process but also to the involvement of different stakeholder groups. Over the past 10 years in Switzerland, policies regarding the use of sewage sludge as fertilizer have gradually shifted to a ban on use in agriculture. As a result, alternative methods for the recycling of anthropogenic nutrients may play a relevant role in the near future. This paper uses the analytic hierarchy process (AHP) to examine more closely the nutrient-recycling dilemma by analysing the preferences of a group of German-speaking residents in the city of Zurich for various management scenarios. Nutrient recycling by the use of urine separation toilets and the BioCon treatment process are presented as possible management alternatives in addition to current practice. The study shows that AHP can incorporate the respondents' preferences and multiple objectives when evaluating alternatives with different attributes.

Integrated MiRNA and MRNA Profiling of Tumor-educated Macrophages Identifies Prognostic Subgroups in Estrogen Receptor-positive Breast Cancer

Molecular Oncology. Jan, 2015  |  Pubmed ID: 25205039

Various studies have identified aberrantly expressed miRNAs in breast cancer and demonstrated an association between distinct miRNAs and malignant progression as well as metastasis. Even though tumor-associated macrophages (TAM) are known mediators of these processes, little is known regarding their miRNA expression upon education by malignant cells in vivo.

Tumor-derived Microvesicles Mediate Human Breast Cancer Invasion Through Differentially Glycosylated EMMPRIN

Journal of Molecular Cell Biology. Apr, 2015  |  Pubmed ID: 25503107

Tumor cells secrete not only a variety of soluble factors, but also extracellular vesicles that are known to support the establishment of a favorable tumor niche by influencing the surrounding stroma cells. Here we show that tumor-derived microvesicles (T-MV) also directly influence the tumor cells by enhancing their invasion in a both autologous and heterologous manner. Neither the respective vesicle-free supernatant nor MV from benign mammary cells mediate invasion. Uptake of T-MV is essential for the proinvasive effect. We further identify the highly glycosylated form of the extracellular matrix metalloproteinase inducer (EMMPRIN) as a marker for proinvasive MV. EMMPRIN is also present at high levels on MV from metastatic breast cancer patients in vivo. Anti-EMMPRIN strategies, such as MV deglycosylation, gene knockdown, and specific blocking peptides, inhibit MV-induced invasion. Interestingly, the effect of EMMPRIN-bearing MV is not mediated by matrix metalloproteinases but by activation of the p38/MAPK signaling pathway in the tumor cells. In conclusion, T-MV stimulate cancer cell invasion via a direct feedback mechanism dependent on highly glycosylated EMMPRIN.

Dermal Exposure Assessment to Pesticides in Farming Systems in Developing Countries: Comparison of Models

International Journal of Environmental Research and Public Health. Apr, 2015  |  Pubmed ID: 25938911

In the field of occupational hygiene, researchers have been working on developing appropriate methods to estimate human exposure to pesticides in order to assess the risk and therefore to take the due decisions to improve the pesticide management process and reduce the health risks. This paper evaluates dermal exposure models to find the most appropriate. Eight models (i.e., COSHH, DERM, DREAM, EASE, PHED, RISKOFDERM, STOFFENMANAGER and PFAM) were evaluated according to a multi-criteria analysis and from these results five models (i.e., DERM, DREAM, PHED, RISKOFDERM and PFAM) were selected for the assessment of dermal exposure in the case study of the potato farming system in the Andean highlands of Vereda La Hoya, Colombia. The results show that the models provide different dermal exposure estimations which are not comparable. However, because of the simplicity of the algorithm and the specificity of the determinants, the DERM, DREAM and PFAM models were found to be the most appropriate although their estimations might be more accurate if specific determinants are included for the case studies in developing countries.

Anti-CSF-1 Treatment is Effective to Prevent Carcinoma Invasion Induced by Monocyte-derived Cells but Scarcely by Microglia

Oncotarget. Jun, 2015  |  Pubmed ID: 26098772

The mononuclear phagocytic system is categorized in three major groups: monocyte-derived cells (MCs), dendritic cells and resident macrophages. During breast cancer progression the colony stimulating factor 1 (CSF-1) can reprogram MCs into tumor-promoting macrophages in the primary tumor. However, the effect of CSF-1 during colonization of the brain parenchyma is largely unknown. Thus, we analyzed the outcome of anti-CSF-1 treatment on the resident macrophage population of the brain, the microglia, in comparison to MCs, alone and in different in vitro co-culture models. Our results underline the addiction of MCs to CSF-1 while surprisingly, microglia were not affected. Furthermore, in contrast to the brain, the bone marrow did not express the alternative ligand, IL-34. Yet treatment with IL-34 and co-culture with carcinoma cells partially rescued the anti-CSF-1 effects on MCs. Further, MC-induced invasion was significantly reduced by anti-CSF-1 treatment while microglia-induced invasion was reduced to a lower extend. Moreover, analysis of lung and breast cancer brain metastasis revealed significant differences of CSF-1 and CSF-1R expression. Taken together, our findings demonstrate not only differences of anti-CSF-1 treatment on MCs and microglia but also in the CSF-1 receptor and ligand expression in brain and bone marrow as well as in brain metastasis.

Oriented Cell Division in the C. Elegans Embryo Is Coordinated by G-Protein Signaling Dependent on the Adhesion GPCR LAT-1

PLoS Genetics. Oct, 2015  |  Pubmed ID: 26505631

Orientation of spindles and cell division planes during development of many species ensures that correct cell-cell contacts are established, which is vital for proper tissue formation. This is a tightly regulated process involving a complex interplay of various signals. The molecular mechanisms underlying several of these pathways are still incompletely understood. Here, we identify the signaling cascade of the C. elegans latrophilin homolog LAT-1, an essential player in the coordination of anterior-posterior spindle orientation during the fourth round of embryonic cell division. We show that the receptor mediates a G protein-signaling pathway revealing that G-protein signaling in oriented cell division is not solely GPCR-independent. Genetic analyses showed that through the interaction with a Gs protein LAT-1 elevates intracellular cyclic AMP (cAMP) levels in the C. elegans embryo. Stimulation of this G-protein cascade in lat-1 null mutant nematodes is sufficient to orient spindles and cell division planes in the embryo in the correct direction. Finally, we demonstrate that LAT-1 is activated by an intramolecular agonist to trigger this cascade. Our data support a model in which a novel, GPCR-dependent G protein-signaling cascade mediated by LAT-1 controls alignment of cell division planes in an anterior-posterior direction via a metabotropic Gs-protein/adenylyl cyclase pathway by regulating intracellular cAMP levels.

Simulating Human and Environmental Exposure from Hand-Held Knapsack Pesticide Application: Be-WetSpa-Pest, an Integrative, Spatially Explicit Modeling Approach

Journal of Agricultural and Food Chemistry. May, 2016  |  Pubmed ID: 26828854

This paper presents an integrative and spatially explicit modeling approach for analyzing human and environmental exposure from pesticide application of smallholders in the potato-producing Andean region in Colombia. The modeling approach fulfills the following criteria: (i) it includes environmental and human compartments; (ii) it contains a behavioral decision-making model for estimating the effect of policies on pesticide flows to humans and the environment; (iii) it is spatially explicit; and (iv) it is modular and easily expandable to include additional modules, crops, or technologies. The model was calibrated and validated for the Vereda La Hoya and was used to explore the effect of different policy measures in the region. The model has moderate data requirements and can be adapted relatively easily to other regions in developing countries with similar conditions.

β-catenin-independent WNT Signaling and Ki67 in Contrast to the Estrogen Receptor Status Are Prognostic and Associated with Poor Prognosis in Breast Cancer Liver Metastases

Clinical & Experimental Metastasis. Apr, 2016  |  Pubmed ID: 26862065

Liver metastasis development in breast cancer patients is common and confers a poor prognosis. So far, the prognostic significance of surgical resection and clinical relevance of biomarker analysis in metastatic tissue have barely been investigated. We previously demonstrated an impact of WNT signaling in breast cancer brain metastasis. This study aimed to investigate the value of established prognostic markers and WNT signaling components in liver metastases. Overall N = 34 breast cancer liver metastases (with matched primaries in 19/34 cases) were included in this retrospective study. Primaries and metastatic samples were analyzed for their expression of the estrogen (ER) and progesterone receptor, HER-2, Ki67, and various WNT signaling-components by immunohistochemistry. Furthermore, β-catenin-dependent and -independent WNT scores were generated and analyzed for their prognostic value. Additionally, the influence of the alternative WNT receptor ROR on signaling and invasiveness was analyzed in vitro. ER positivity (HR 0.09, 95 % CI 0.01-0.56) and high Ki67 (HR 3.68, 95 % CI 1.12-12.06) in the primaries had prognostic impact. However, only Ki67 remained prognostic in the metastatic tissue (HR 2.46, 95 % CI 1.11-5.44). Additionally, the β-catenin-independent WNT score correlated with reduced overall survival only in the metastasized situation (HR 2.19, 95 % CI 1.02-4.69, p = 0.0391). This is in line with the in vitro results of the alternative WNT receptors ROR1 and ROR2, which foster invasion. In breast cancer, the value of prognostic markers established in primary tumors cannot directly be translated to metastases. Our results revealed β-catenin-independent WNT signaling to be associated with poor prognosis in patients with breast cancer liver metastasis.

CCL5 Deficiency Reduces Neointima Formation Following Arterial Injury and Thrombosis in Apolipoprotein E-deficient Mice

Thrombosis Research. Aug, 2016  |  Pubmed ID: 27337700

Activated platelets secrete different chemokines, among others CCL5, thereby triggering inflammatory cell recruitment into the vessel wall. Here, we investigated how CCL5 deficiency influences vascular remodeling processes. Experiments were performed in apolipoprotein E and CCL5 double deficient (ApoE(-/-)×CCL5(-/-)) mice, using ApoE(-/-)×CCL5(+/+) mice as controls. The ferric chloride model was applied to induce thrombosis at the site of carotid artery injury within minutes and the formation of a smooth muscle cell-rich neointima within 3weeks. In both groups, vascular injury resulted in thrombus formation. CCL5 deficiency did not alter thrombus resolution examined at day 7. Analysis at 21days revealed that CCL5 absence was associated with a significant reduction in the neointima area (p<0.05), neointima-to-media ratio (p<0.05) and lumen stenosis (p<0.05) compared to ApoE(-/-)×CCL5(+/+) mice. Immunohistochemical analysis of CCL5 receptors showed decreased CCR5 positive staining in ApoE(-/-)×CCL5(-/-) mice (p<0.01), whereas the amount of CCR1 (p=0.053) and Mac2-positive macrophages (p<0.05) was increased. The amount of SMA-positive smooth muscle cells was lower in ApoE(-/-) mice lacking CCL5 (p<0.05). Positive staining for Krüppel-like factor 4 (KLF4), an atheroprotective transcription factor, was increased in the neointima of ApoE(-/-)×CCL5(-/-) mice (p<0.05) and found to co-localize with smooth muscle cells. In summary, CCL5 deficiency resulted in reduced neointima formation after carotid artery injury and thrombosis. Hemodynamic and histochemical analyses suggested that this was not due to differences in thrombus formation or resolution. Possibly, the atheroprotective effect of CCL5 deficiency is mediated by KLF4 upregulation in smooth muscle cells.

Deciphering and Modulating G Protein Signalling in C. Elegans Using the DREADD Technology

Scientific Reports. Jul, 2016  |  Pubmed ID: 27461895

G-protein signalling is an evolutionary conserved concept highlighting its fundamental impact on developmental and functional processes. Studies on the effects of G protein signals on tissues as well as an entire organism are often conducted in Caenorhabditis elegans. To understand and control dynamics and kinetics of the processes involved, pharmacological modulation of specific G protein pathways would be advantageous, but is difficult due to a lack in accessibility and regulation. To provide this option, we designed G protein-coupled receptor-based designer receptors (DREADDs) for C. elegans. Initially described in mammalian systems, these modified muscarinic acetylcholine receptors are activated by the inert drug clozapine-N-oxide, but not by their endogenous agonists. We report a novel C. elegans-specific DREADD, functionally expressed and specifically activating Gq-protein signalling in vitro and in vivo which we used for modulating mating behaviour. Therefore, this novel designer receptor demonstrates the possibility to pharmacologically control physiological functions in C. elegans.

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