Size-advantage of monovalent nanobodies against the macrophage mannose receptor for deep tumor penetration and tumor-associated macrophage targeting

Rationale: Nanobodies (Nbs) have emerged as an elegant alternative to the use of conventional monoclonal antibodies in cancer therapy, but a detailed microscopic insight into the in vivo pharmacokinetics of different Nb formats in tumor-bearers is lacking. This is especially relevant for the recognition and targeting of pro-tumoral tumor-associated macrophages (TAMs), which may be located in less penetrable tumor regions.Methods: We employed anti-Macrophage Mannose Receptor (MMR) Nbs, in a monovalent (m) or bivalent (biv) format, to assess in vivo TAM targeting. Intravital and confocal microscopy were used to analyse the blood clearance rate and targeting kinetics of anti-MMR Nbs in tumor tissue, healthy muscle tissue and liver. Fluorescence Molecular Tomography was applied to confirm anti-MMR Nb accumulation in the primary tumor and in metastatic lesions.Results: Intravital microscopy demonstrated significant differences in the blood clearance rate and macrophage targeting kinetics of (m) and (biv)anti-MMR Nbs, both in tumoral and extra-tumoral tissue. Importantly, (m)anti-MMR Nbs are superior in reaching tissue macrophages, an advantage that is especially prominent in tumor tissue. The administration of a molar excess of unlabelled (biv)anti-MMR Nbs increased the (m)anti-MMR Nb bioavailability and impacted on its macrophage targeting kinetics, preventing their accumulation in extra-tumoral tissue (especially in the liver) but only partially influencing their interaction with TAMs. Finally, anti-MMR Nb administration not only allowed the visualization of TAMs in primary tumors, but also at a distant metastatic site.Conclusions: These data describe, for the first time, a microscopic analysis of (m) and (biv)anti-MMR Nb pharmacokinetics in tumor and healthy tissues. The concepts proposed in this study provide important knowledge for the future use of Nbs as diagnostic and therapeutic agents, especially for the targeting of tumor-infiltrating immune cells.Radiolog

What scans we will read: imaging instrumentation trends in clinical oncology

Oncological diseases account for a significant portion of the burden on public healthcare systems with associated costs driven primarily by complex and long-lasting therapies. Through the visualization of patient-specific morphology and functional-molecular pathways, cancerous tissue can be detected and characterized non- invasively, so as to provide referring oncologists with essential information to support therapy management decisions. Following the onset of stand-alone anatomical and functional imaging, we witness a push towards integrating molecular image information through various methods, including anato-metabolic imaging (e.g., PET/ CT), advanced MRI, optical or ultrasound imaging. This perspective paper highlights a number of key technological and methodological advances in imaging instrumentation related to anatomical, functional, molecular medicine and hybrid imaging, that is understood as the hardware-based combination of complementary anatomical and molecular imaging. These include novel detector technologies for ionizing radiation used in CT and nuclear medicine imaging, and novel system developments in MRI and optical as well as opto-acoustic imaging. We will also highlight new data processing methods for improved non-invasive tissue characterization. Following a general introduction to the role of imaging in oncology patient management we introduce imaging methods with well-defined clinical applications and potential for clinical translation. For each modality, we report first on the status quo and point to perceived technological and methodological advances in a subsequent status go section. Considering the breadth and dynamics of these developments, this perspective ends with a critical reflection on where the authors, with the majority of them being imaging experts with a background in physics and engineering, believe imaging methods will be in a few years from now. Overall, methodological and technological medical imaging advances are geared towards increased image contrast, the derivation of reproducible quantitative parameters, an increase in volume sensitivity and a reduction in overall examination time. To ensure full translation to the clinic, this progress in technologies and instrumentation is complemented by progress in relevant acquisition and image-processing protocols and improved data analysis. To this end, we should accept diagnostic images as “data”, and – through the wider adoption of advanced analysis, including machine learning approaches and a “big data” concept – move to the next stage of non-invasive tumor phenotyping. The scans we will be reading in 10 years from now will likely be composed of highly diverse multi- dimensional data from multiple sources, which mandate the use of advanced and interactive visualization and analysis platforms powered by Artificial Intelligence (AI) for real-time data handling by cross-specialty clinical experts with a domain knowledge that will need to go beyond that of plain imaging

Reproducible and highly sensitive detection of the broad spectrum epithelial marker keratin 19 in routine cancer diagnosis

Contains fulltext : 24806___.PDF (publisher's version ) (Open Access

CULTURAL HERITAGE DOCUMENTATION AND INTEGRATED GEOMATICS TECHNIQUES IN AN EDUCATIONAL CONTEXT: CASE BOIS-DU-LUC (BELGIUM)

The Walloon Region in Belgium played a leading role in the world economy and in the industrial sciences and engineering since the 19th century. Several relicts, such as important industrial buildings or sites, are spread over a large area and are still dominating the current landscape. Some of these remnants are preserved as monuments, representing the industrial, cultural and ecological transition of the region during the last two centuries. Since 2012, UNESCO recognized the importance of four of the best preserved 19th and 20th century coal mining sites and classified them as World Heritage ("Major Mining Sites of Wallonia", Le Grand-Hornu, Bois-du- Luc, Le Bois du Cazier and Blegny Mine). The four recognised mining sites together form a strip of about 170 km long, containing important examples of the so-called 'neo classical architecture’ from the early periods of the industrial era in continental Europe. Motivated by this recognition and by the huge touristic and educational potential of the sites, a partnership between the Walloon government and Ghent University was organized. In this first stage, the collaboration focuses on the site of Bois-du-Luc in the municipality of La Louvière, containing a large series of dwellings, several equipments built between 1853 and 1923 by the Société des Charbonnages du Bois-du-Luc, workshops and heaps. Consisting of numerous buildings dating back to the period between 1838 and 1923, this site is one of Europe’s oldest collieries. The collaboration between the Walloon government and Ghent University – Department of Geography fits in the hands-on training which students in land surveying and geomatics receive during their Bachelor studies. For the students it is very interesting that their practical exercises are not limited to the university campus, but that they are involved in a real measurement campaign. The project consists of a series of intensive land surveying campaigns, resulting in highly detailed and accurate maps of the site, including the inside domain of the buildings. Already available aerial photographs are processed to obtain a 3D model of the site and the wider region. In March 2013, the first campaign took place. During this first campaign, a topographical network was set out and a series of detail points were measured for the detailed topographic mapping. The topographical network was well-planned and covers almost the whole site, forming a set of permanently materialized reference points for later measurements. Besides, a large number of ground control points (GCPs) were taken for the 3D reconstruction of the area, based on high resolution airborne imagery. This enables the students to familiarize themselves with photogrammetric principles in a practical exercise. Both the topographic maps and the 3D model fit within the large scale geographic reference map of the Walloon Region. In this contribution, the results of this intensive trans-regional collaboration on the preservation of the sites are presented. This paper will discuss the first deliverables from the project and the advantages for the responsible government, the cultural heritage organisations (Ecomusée du Bois-du-Luc) and the students. The main focus here is on the educational context of the project. Furthermore, future projects on the same site will be discussed

Microstructure and High-Frequency Price Discovery in the Soybean Complex

We develop a theoretical framework and propose a relevant empirical analysis of the soybean complex prices cointegration relationship in a highfrequency setting. We allow for heterogeneous expectations among traders on the multi-asset price dynamics and characterize the resulting market behavior. We demonstrate that the asset prices autoregressive matrix rank and the speed of reversion towards the long-term equilibrium are related to the market realized and potential liquidity, unlike the cointegrating vector. Our empirical application to the soybean complex, where we control for volatility, supports our theoretical results when the price idleness of the different assets is properly accounted for. Our analysis further suggests that the presence of cointegration among assets is related to the time of day and the contract maturities traded at a given time

Effect of cisapride on gastric emptying in dyspeptic patients.

The effect of the new gastrokinetic agent cisapride on gastric emptying was evaluated in 17 dyspeptic patients using the dual radionuclide technique. Eight patients with idiopathic dyspepsia and nine postsurgical dyspeptic patients were studied and compared to a control group. Gastric emptying of solids and liquids was determined after ingestion of a standardized meal using 99mTc-sulfur colloid scrambled eggs as the solid phase and [111In]DTPA-labeled water as the liquid phase. Following a basal study and on a separate occasion, each patient received an intravenous bolus of 10 mg of cisapride after ingestion of the test meal; 10 of the patients were restudied after a two-week period of chronic oral administration of the drug (10 mg four times a day). Baseline gastric emptying of solids was significantly delayed in idiopathic and postsurgical patients; liquid emptying was only delayed in the postsurgical group. Intravenous and oral administration of cisapride significantly shortened gastric emptying in both groups. In all but one patient, the clinical improvement was confirmed by the test. Cisapride appears to be a good alternative to metoclopramide and domperiodone in the treatment of dyspeptic patients. The dual radionuclide technique appears to be a useful physiologic tool for evaluating and predicting the efficacy of a gastric prokinetic therapy in man

Residential and wealth-related disparities of high fertility preferences in Ethiopia: A decomposition analysis.

BackgroundFertility preference significantly influences contraceptive uptake and impacts population growth, especially in low and middle-income countries. In the previous pieces of literature, variations in fertility preference across residence and wealth categories and its contributors were not assessed in Ethiopia. Therefore, we decomposed high fertility preferences among reproductive-aged women by residence and wealth status in Ethiopia.MethodsWe extracted individual women's record (IR) data from the publicly available 2016 Ethiopian Demographic Health Survey (EDHS) dataset. A total of 13799 women were included in the study. Multivariate decomposition analysis was conducted to identify the factors that contributed to the differences in the percentage of fertility preferences between rural and urban dwellers. Furthermore, we used an Erreygers normalized concentration index and curve to identify the concentration of high fertility preferences across wealth categories. The concentration index was further decomposed to identify the contributing factors for the wealth-related disparities in high fertility preference. Finally, the elasticity of wealth-related disparity for a change in the socioeconomic variable was estimated.ResultsThe weighted percentage of women with high fertility preference among rural and urban residents was 42.7% and 19%, respectively, reflecting a 23.7 percentage point difference. The variations in fertility preference due to the differences in respondents' characteristics accounted for 40.9%. Being unmarried (8.4%), secondary (14.1%) and higher education (21.9%), having more than four children (18.4%), having media exposure (6.9%), middle (0.4%), richer (0.2%) and richest (0.1%) wealth were the positive and city administration (-30.2%), primary education (-1.3%) were the negative contributing factors for the variations in high fertility preferences due to population composition. Likewise, about 59% of the variations in fertility preference were due to variations in coefficients. City administration (22.4%), primary (7.8%) and secondary (7.4%) education, poorer wealth (0.86%) were the positive and having media exposure (-6.32%) and being unmarried (-5.89%), having more than four children (-2.1%) were the negative factors contributing to the difference in high fertility preferences due to the change in coefficients across residents. On the other hand, there was a pro-poor distribution for high fertility preferences across wealth categories with Erreygers normalized concentration index of ECI = -0.14, SE = 0.012. Having media exposure (17.5%), primary (7.3%), secondary (5.4%), higher (2.4%) education, being unmarried (8%), having more than four children (7.4%), rural residence (3%) and emerging (2.2%) were the positive and city administration (-0.55) was the negative significant contributor to the pro-poor disparity in high fertility preference.ConclusionThe variations in high fertility preferences between rural and urban women were mainly attributed to changes in women's behavior. In addition, substantial variations in fertility preference across women's residences were explained by the change in women's population composition. In addition, a pro-poor distribution of high fertility preference was observed among respondents. As such, the pro-poor high fertility preference was elastic for a percent change in socioeconomic variables. The pro-poor high fertility preference was elastic (changeable) for a percent change in each socioeconomic variables. Therefore, women's empowerment through education and access to media will be important in limiting women's desire for more children in Ethiopia. Therefore, policymakers should focus on improving the contributing factors for the residential and wealth-related disparities in high fertility preferences