Application of Molecular Ultrasound for Imaging Integrin Expression

Stabilized microbubbles with a size between 1-5 µm are used as ultrasound contrast agents in the clinical routine. They have shown convincing results for the vascular characterization of tissues as well as in echocardiography. Due to their size, microbubbles strictly remain intravascular where they can be detected with high sensitivity and specificity. This qualifies them for intravascular molecular imaging. Many studies have been published reporting on the successful use of microbubbles conjugated to specific ligands for target identification in vivo. Among them, there are several promising examples on how to use molecular ultrasound for the imaging of integrin expression. This review provides an overview on the composition of ultrasound contrast agents that can be used for molecular imaging and their detection by ultrasound using destructive and non destructive methods. Furthermore, concrete examples are given on the use of molecular ultrasound to characterize integrin expression on vessels. These cover oncological applications where integrin targeted microbubbles were used to identify and characterize tumor angiogenesis and to assess tumor response to antiangiogenic drugs as well as to radiotherapy. In addition, increased accumulation of integrin targeted microbubbles was found during vascular reformation in ischemic tissues as well as in vulnerable atherosclerotic plaques. In summary, there is clear evidence from preclinical studies that integrin targeted ultrasound imaging is a valuable tool for the characterization of a broad spectrum of diseases. Thus, more efforts should be put into translating this promising technology into the clinics

Sources of Growth in the Turkish Economy: A Non-parametric Approach

Bir ekonomide büyümenin kaynaklarının geleneksel büyüme muhasebesi çerçevesinde tahmini faktör piyasalarının rekabetçi oldukları ve üretim fonksiyonunun belirli bir kalıba uyduğu şeklindeki varsayımların sağlanmasını gerektirmektedir. Bu çalışmada Iwata vd. (2003) çalışmasından hareketle Türkiye ekonomisinde büyümenin kaynakları ve toplam faktör verimliliği (TFV) 1968-2006 dönemi için söz konusu varsayımların sağlanmasını gerektirmeyen parametrik olmayan regresyon analizi ile tahmin edilmiştir. Çıktının sermaye ve işgücü girdisine göre esneklik katsayılarının parametrik olmayan regresyon tahminleri Türkiye ekonomisinde ölçeğe göre azalan getiri olduğunu göstermektedir. Tahmin sonuçlarına göre 1980 öncesi dönemde büyümenin kaynağı sermaye birikimi iken, 1980 sonrası dönemde 1991-95 yılları dışında TFV büyümesidir. İşgücünün büyümeye en önemli katkısını 1991-95 döneminde yaptığı gözlenmiştir.Estimating the sources of economic growth within the framework of the conventional growth accounting approach is based on two assumptions namely the factor markets are competitive and the underlying aggregate production function has a specific form. In this study, following Iwata et al (2003), sources of economic growth and total factor productivity (TFP) growth in the Turkish economy for the period 1968-2006 were estimated with nonparametric regression approach which does not require imposing these restrictive assumptions. Nonparametric estimates of income share of capital and labor indicated there are diminishing returns to scale in the Turkish economy. According to results, capital formation is the main sources of growth before in the pre-1980 period, TFP is the sources of growth with the exception of 1991-95 period and post-1980 period seems to be the sources of growth. It is observed that labor's contribution to economic growth reached the highest level in the 1991-95

Lifetime of magnetic excitations in supported ferromagnetic and antiferromagnetic spin-1/2 Heisenberg chains

The lifetime of magnetic excitations in finite 1D-supported Heisenberg chains of magnetic atoms is studied theoretically for a model system formed of S = 1/2 spins. Both ferromagnetic and antiferromagnetic cases are considered as well as open chains and rings of atoms. Different chain lengths are considered allowing extrapolation to infinite chains. All the excited magnetic states in the finite chains and rings are studied, not only the spin-wave mode. The magnetic excitations decay by electron-hole pair creation in the substrate. As the main result, for all the systems considered, the decay rate appears to vary approximately proportionally to the excitation energy of the state, with a proportionality constant independent of the strength of the Heisenberg exchange term. In certain finite systems, a stable state is evidenced at low energy, associated with a special spin coupling structure. © 2012 American Physical Society.Peer Reviewe

Activation of the Catalytic Activity of Thrombin for Fibrin Formation by Ultrasound

The regulation of enzyme activity is a method to control biological function. We report two systems enabling the ultrasound-induced activation of thrombin, which is vital for secondary hemostasis. First, we designed polyaptamers, which can specifically bind to thrombin, inhibiting its catalytic activity. With ultrasound generating inertial cavitation and therapeutic medical focused ultrasound, the interactions between polyaptamer and enzyme are cleaved, restoring the activity to catalyze the conversion of fibrinogen into fibrin. Second, we used split aptamers conjugated to the surface of gold nanoparticles (AuNPs). In the presence of thrombin, these assemble into an aptamer tertiary structure, induce AuNP aggregation, and deactivate the enzyme. By ultrasonication, the AuNP aggregates reversibly disassemble releasing and activating the enzyme. We envision that this approach will be a blueprint to control the function of other proteins by mechanical stimuli in the sonogenetics field

Activation of the Catalytic Activity of Thrombin for Fibrin Formation by Ultrasound

The regulation of enzyme activity is a method to control biological function. We report two systems enabling the ultrasound-induced activation of thrombin, which is vital for secondary hemostasis. First, we designed polyaptamers, which can specifically bind to thrombin, inhibiting its catalytic activity. With ultrasound generating inertial cavitation and therapeutic medical focused ultrasound, the interactions between polyaptamer and enzyme are cleaved, restoring the activity to catalyze the conversion of fibrinogen into fibrin. Second, we used split aptamers conjugated to the surface of gold nanoparticles (AuNPs). In the presence of thrombin, these assemble into an aptamer tertiary structure, induce AuNP aggregation, and deactivate the enzyme. By ultrasonication, the AuNP aggregates reversibly disassemble releasing and activating the enzyme. We envision that this approach will be a blueprint to control the function of other proteins by mechanical stimuli in the sonogenetics field. © 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH Gmb

Biomedical metal–organic framework materials : perspectives and challenges

The authors gratefully acknowledge financial support from the German Research Foundation (DFG: LA2937/4-1; SH1223/1-1; SFB 1066; GRK/RTG 2735 (project number 331065168)), the German Federal Ministry of Research and Education (BMBF: Gezielter Wirkstofftransport, PP-TNBC, Project No. 16GW0319K) and the European Research Council (ERC: Meta-Targeting (864121)). The financial support from Welch Foundation (AT-1989-20220331) and from the Human Frontier Science Program (HFSP, within the project RGP0047/2022) are also acknowledged. The authors thank the European Union (European Cooperation in Science and Technology) for the COST Action EU4MOFs (CA22147). Figures were created using BioRender.com.Metal–organic framework (MOF) materials are gaining significant interest in biomedical research, owing to their high porosity, crystallinity, and structural and compositional diversity. Their versatile hybrid organic/inorganic chemistry endows MOFs with the capacity to retain organic (drug) molecules, metals, and gases, to effectively channel electrons and photons, to survive harsh physiological conditions such as low pH, and even to protect sensitive biomolecules. Extensive preclinical research has been carried out with MOFs to treat several pathologies and, recently, their integration with other biomedical materials such as stents and implants has demonstrated promising performance in regenerative medicine. However, there remains a significant gap between MOF preclinical research and translation into clinically and societally relevant medicinal products. Here, the intrinsic features of MOFs are outlined and their suitability to specific biomedical applications such as detoxification, drug and gas delivery, or as (combination) therapy platforms is discussed. Furthermore, relevant examples of how MOFs have been engineered and evaluated in different medical indications, including cancer, microbial, and inflammatory diseases is described. Finally, the challenges facing their translation into the clinic are critically examined, with the goal of establishing promising research directions and more realistic approaches that can bridge the translational gap of MOFs and MOF‐containing (nano)materials.Publisher PDFPeer reviewe

A proof-of-concept pipeline to guide evaluation of tumor tissue perfusion by dynamic contrast-agent imaging: Direct simulation and inverse tracer-kinetic procedures

Dynamic contrast-enhanced (DCE) perfusion imaging has shown great potential to non-invasively assess cancer development and its treatment by their characteristic tissue signatures. Different tracer kinetics models are being applied to estimate tissue and tumor perfusion parameters from DCE perfusion imaging. The goal of this work is to provide an in silico model-based pipeline to evaluate how these DCE imaging parameters may relate to the true tissue parameters. As histology data provides detailed microstructural but not functional parameters, this work can also help to better interpret such data. To this aim in silico vasculatures are constructed and the spread of contrast agent in the tissue is simulated. As a proof of principle we show the evaluation procedure of two tracer kinetic models from in silico contrast-agent perfusion data after a bolus injection. Representative microvascular arterial and venous trees are constructed in silico. Blood flow is computed in the different vessels. Contrast-agent input in the feeding artery, intra-vascular transport, intra-extravascular exchange and diffusion within the interstitial space are modeled. From this spatiotemporal model, intensity maps are computed leading to in silico dynamic perfusion images. Various tumor vascularizations (architecture and function) are studied and show spatiotemporal contrast imaging dynamics characteristic of in vivo tumor morphotypes. The Brix II also called 2CXM, and extended Tofts tracer-kinetics models common in DCE imaging are then applied to recover perfusion parameters that are compared with the ground truth parameters of the in silico spatiotemporal models. The results show that tumor features can be well identified for a certain permeability range. The simulation results in this work indicate that taking into account space explicitly to estimate perfusion parameters may lead to significant improvements in the perfusion interpretation of the current tracer-kinetics models