In Search of Theory and Criteria for the Practice of Distance-Supervision

The growing ease and efficiency of using electronic media for adacemic education promises to bring significant benefits to the field o clinical education. It appears that now is the time for us to ask what professional standards may need to be changed to assure the strong formation of future pastoral caregivers and minimize any possibility of eroding quality in supervision

Die Blockade des CXCR2/CXCL2 Signalweges als therapeutischer Ansatz im Glioblastoma multiforme

EINLEITUNG Das Glioblastoma multiforme (GBM) ist ein extrem wandlungsfähiger und aggressiver Tumor und stellt Forscher immer wieder vor Herausforderungen. Es existieren bereits zahlreiche Ansätze zur Therapie dieses Hirntumors. Die derzeit etablierte Standardtherapie verlängert das mittlere Überleben der PatientInnen bisher aber nur um wenige Monate. Neue experimentelle Ansätze rücken deshalb immunologische und anti-angiogene Therapien in den Vordergrund. Die über Chemokine vermittelte Chemotaxis ist unter anderem Teil des Immunsystems, Chemokine können aber auch angiogene Wirkung entfalten. Die Signalachse über CXCR2/CXCL2 stellt einen alternativen Angiogenesesignalweg im Glioblastom dar. Ziel dieser Arbeit ist die Erforschung eines neuen therapeutischen Ansatzes zur Verlangsamung des Tumorwachstums durch die Blockade des CXCR2-Signalwegs über den small-molecule Inhibitor SB225002. METHODEN GL261 Glioblastomzellen wurden intrakraniell in ein syngenes Mausmodell implantiert. Der Antagonist wurde mittels osmotischer Minipumpen direkt in den Ventrikel appliziert. Der 14- bzw. 7-tägige Behandlungszeitraum wurde am Tag der Tumorzellimplantation bzw. nach 14-tägiger Tumorwachstumsphase begonnen. Die Tumorvolumina wurden mittels MRT vor Therapiestart und am Ende des Behandlungszeitraumes gemessen. Anschließend wurden die Gewebeproben immunhistochemisch gefärbt und Moleküle des Signalweges, Gefäße, Zellen der perivaskulären Nische und Proliferations- und Apoptosemarker ausgewertet und verglichen. GL261 wurden außerdem in vitro mit SB225002 inkubiert und anschließend in Proliferationsassays analysiert. Die Expression der Gene des Signalweges wurden nach Antagonisttherapie mittels real time-PCR ausgewertet. ERGEBNISSE Die Therapie mit SB225002 führte zu signifikant reduzierten Tumorvolumina um 51% nach Tumorzellimplantation mit simultanem Therapiebeginn. Nach CXCR2-Blockade der etablierten Tumore im zweiten Versuchsaufbau waren die Tumorvolumina um 47% reduziert. Die Anzahl der Mikroglia und Gefäße war nach CXCR2-Blockade durch den Antagonisten signifikant reduziert wohingegen CXCR2, CXCL2, Proliferations- und Apoptose-Marker keine Veränderungen zeigten. Die Proliferation von Tumor- und Endothelzellen war in vitro nach Behandlung mit dem CXCR2-Antagonisten signifikant reduziert, bei den Glioblastomzellen war der beobachtete Effekt größer. Die Behandlung der Tumorzellen mit dem small-molecule Inhibitor veränderte außerdem die Expression der Gene des CXCR2-Signalweges in Tumor- und Endothelzellen. SCHLUSSFOLGERUNG Die Blockade des CXCR2/CXCL2 Signalweges im GBM-Mausmodell resultiert in einer reduzierten Tumorgröße, sowohl im Anfangsstadium als auch in der exponentiellen Tumorwachstumsphase. Der small-molecule Antagonist SB225002 repräsentiert somit einen erfolgsversprechenden neuen Therapieansatz. Tiefergehende Untersuchungen des Signalweges und Studien zu Kombinationstherapien sind nötig, um die Etablierung einer lebenszeitverlängernden Therapie des Glioblastoma multiforme voranzutreiben.INTRODUCTION Glioblastoma multiforme (GBM) is one of the most aggressive and heterogeneous tumor entities and is still a challenge for clinicians and scientists in the development of new therapy strategies. Under current standard therapies, patients’ overall survival improves only for a few months. New approaches in GBM therapy relate to immunological and anti-angiogenic strategies. The chemokine system and its receptors are part of the immune system but can also act as an alternative angiogenic mediator. Specifically, CXCL2 and its receptor CXCR2 could be identified as an alternative signaling pathway regulating angiogenesis in GBM. This study investigated the blockage of the CXCR2/CXCL2 signaling axis using the small-molecule inhibitor SB225002 as a new therapeutic approach in GBM. METHODS GL261 glioma cells were implanted intracranially into a syngeneic mouse model. Small-molecule antagonist SB225002 was applied to the ventricle system via osmotic mini pumps. Treatment started either on the day of tumor cell implantation and was administered for 14 days or after two weeks of tumor growth with a shorter treatment period of 7 days. MRI measurements of the tumor volumes were carried out before and after treatment period. Immunofluorescence analysis were conducted focusing on therapy induced changes of the signaling pathway, the tumor vasculature and its perivascular niche with accumulation of tumor associated microglia and macrophages (TAMs) as well as the proliferation and apoptosis behavior. In vitro, MTT-proliferation assay as well as gene expression studies were carried out using GL261 glioma cells and endothelial cells. RESULTS Tumor volumes were reduced by 51% when CXCR2 antagonist were administered in the initial growth phase and by 47% starting administration after two weeks of tumor growth. The tumor vasculature was impaired by significantly reduced vessel counts accompanied by reduced accumulation of TAMs, whereas CXCL2/CXCR2 as well as proliferation and apoptosis were unaffected in vivo. CXCR2 antagonization in vitro showed reduced proliferation in MTT-assay of GL261 tumor cells and endothelial cells. Altered gene expression of CXCR1, CXCR2 and CXCL2 could be detected as well. CONCLUSION The blocking of chemokine receptor CXCR2 resulted in significantly reduced tumor volume in vivo among with diminished vasculature. SB225002, a small-molecule CXCR2 inhibitor, may represent a new and promising treatment strategy in fighting glioblastoma multiforme. Now, further studies and combination strategies are needed to establish effective and life prolonging therapy in GBM

Expanding the Circle: Essays in Honor of Joan E. Hemenway

Reviewed by Sandee Yarlott

Utilizing the sensitization effect for direct laser writing in a novel photoresist based on the chitin monomer N-acetyl-D-glucosamine

The great flexibility of direct laser writing arises from the possibility to fabricate precise three-dimensional structures on very small scales as well as the broad range of applicable materials. However, there is still a vast number of promising materials which are currently inaccessible requiring the continuous development of novel photoresists. Here, a new bio-sourced resist is reported which relies on the monomeric unit of chitin, N-acetyl-D-glucosamine, expanding the existing plant-based biopolymer resists by a bio-based monomer from the animal kingdom. In addition it is shown that combined use of two photoinitiators is advantageous over the use of a single one. In our approach, the first photoinitator is a good two-photon absorber at the applied wavelength, while the second photoinitiator exhibits poor two-photon absorbtion abilities, but is better suited for crosslinking of the monomer. The first photoinitiator absorbs the light acting as a sensitizer and transfers the energy to the second initiator, which subsequently forms a radical and initializes the polymerization. This sensitization effect enables a new route to utilize reactive photointiators with a small two-photon absorption cross-section for direct laser writing without changing their chemical structure

Initiator-free photo-crosslinkable cellulose-based resists for fabricating submicron patterns via direct laser writing

Novel bifunctional cellulose diacetate derivatives were synthesized in order to achieve bio-based photoresists, which can be structured by two-photon absorption via direct laser writing (DLW) without the need to use a photoinitiator. Therefore, cellulose diacetate is functionalized with thiol moieties and olefinic or methacrylic side groups enabling thiol-conjugated crosslinking. These cellulose derivatives are also photo-crosslinkable via UV irradiation ($\lambda$ = 254 nm and 365 nm) without using an initiator

Impact of solar radiation on chemical structure and micromechanical properties of cellulose-based humidity-sensing material Cottonid

Renewable and environmentally responsive materials are an energy- and resource-efficient approach in terms of civil engineering applications, e.g. as so-called smart building skins. To evaluate the influence of different environmental stimuli, like humidity or solar radiation, on the long-term actuation behavior and mechanical robustness of these materials, it is necessary to precisely characterize the magnitude and range of stimuli that trigger reactions and the resulting kinetics of a material, respectively, with suitable testing equipment and techniques. The overall aim is to correlate actuation potential and mechanical properties with process- or application-oriented parameters in terms of demand-oriented stimuli-responsive element production. In this study, the impact of solar radiation as environmental trigger on the cellulose-based humidity-sensing material Cottonid, which is a promising candidate for adaptive and autonomously moving elements, was investigated. For simulating solar radiation in the lab, specimens were exposed to short-wavelength blue light as well as a standardized artificial solar irradiation (CIE Solar ID65) in long-term aging experiments. Photodegradation behavior was analyzed by Fourier-transform infrared as well as electron paramagnetic resonance spectroscopy measurements to assess changes in Cottonid’s chemical composition. Subsequently, changes in micromechanical properties on the respective specimens’surface were investigated with roughness measurements and ultra-micro-hardness tests to characterize variations in stiffness distribution in comparison to the initial condition. Also, thermal effects during long-term aging were considered and contrasted to pure radiative effects. In addition, to investigate the influence of process-related parameters on Cottonid’s humidity-driven deformation behavior, actuation tests were performed in an alternating climate chamber using a customized specimen holder, instrumented with digital image correlation (DIC). DIC was used for precise actuation strain measurements to comparatively evaluate different influences on the material’s sorption behavior. The infrared absorbance spectra of different aging states of irradiated Cottonid indicate oxidative stress on the surface compared to unaged samples. These findings differ under pure thermal loads. EPR spectra could corroborate these findings as radicals were detected, which were attributed to oxidation processes. Instrumented actuation experiments revealed the influence of processing-related parameters on the sorption behavior of the tested and structurally optimized Cottonid variant. Experimental data supports the definition of an optimal process window for stimuli-responsive element production. Based on these results, tailor-made functional materials shall be generated in the future where stimuli-responsiveness can be adjusted through the manufacturing process

Silica replication of the hierarchical structure of wood with nanometer precision

The structural features of wood were replicated in silica on all levels of hierarchy from the macroscopic to the nanoscopic level of the cellulose elementary fibrils. This was achieved by a series of processing steps on spruce wood templates. Sodium chlorite was used to partially remove the lignin matrix from the wood cell walls, exposing the cellulose fibrils. These were optionally functionalized with maleic acid anhydride to stabilize the fibrillar structure and reduce the shrinkage of the template. Repeated infiltration with tetraethyl orthosilicate in ethanol deposited silica on the fibrils. Calcination at 500 °C removed the rest of the organic template by oxidation and resulted in the fusion of the deposited material into a positive silica replica. Small-angle x-ray scattering evidenced fibrillar structures parallel to the original cellulose fibrils at length scales in the order of 10 nm, suggesting the successful nanoscopic replication of the cellulose fibrils and their orientation

LOOKING INTO THE ENERGY LANDSCAPE OF MYOGLOBIN

Using the haem group of myoglobin as a probe in optical experiments makes it possible to study its conformational fluctuations in real time. Results of these experiments can be directly interpreted in terms of the structure of the potential energy surface of the protein. The current view is that proteins have rough energy landscapes comprising a large number of minima which represent conformational substates, and that these substates are hierarchically organized. Here, we show that the energy landscape is characterized by a number of discrete distributions of;barrier heights each representing a tier within a hierarchy of conformational substates. Furthermore, we provide evidence that the energy surface is self-similar and offer suggestions for a characterization of the protein fluctuations

Biomimetics and its tools

Biomimetics, as the transfer of strategies from biology to technology, is an emerging research area and has led to significant concepts over the past decades. The development of such concepts is described by the process of biomimetics, encompassing several steps. In Practice, beneficiaries of the process face challenges. Therefore, to overcome challenges and to facilitate the steps, tools have been developed in various areas, such as engineering, computing and design. However, these tools are not widely used yet. This paper presents an overview and a classification study of more than 40 tools with qualitative criteria. The criteria included, for example, the year of development, the accessibility of tools, the facilitated steps of the process or their contribution to sustainability. The classification shows that certain steps of the process and their challenges are well addressed by the tools, while other steps are not. The presented results contribute to the proposal of an improvement of the state of the art, and they build the foundation for future theoretical and practical analyses. These findings could contribute to increasing the implementation of biomimetics in various disciplines in the long term

Tumor-Associated Microglia/Macrophages as a Predictor for Survival in Glioblastoma and Temozolomide-Induced Changes in CXCR2 Signaling with New Resistance Overcoming Strategy by Combination Therapy

Tumor recurrence is the main challenge in glioblastoma (GBM) treatment. Gold standard therapy temozolomide (TMZ) is known to induce upregulation of IL8/CXCL2/CXCR2 signaling that promotes tumor progression and angiogenesis. Our aim was to verify the alterations on this signaling pathway in human GBM recurrence and to investigate the impact of TMZ in particular. Furthermore, a combi-therapy of TMZ and CXCR2 antagonization was established to assess the efficacy and tolerability. First, we analyzed 76 matched primary and recurrent GBM samples with regard to various histological aspects with a focus on the role of TMZ treatment and the assessment of predictors of overall survival (OS). Second, the combi-therapy with TMZ and CXCR2-antagonization was evaluated in a syngeneic mouse tumor model with in-depth immunohistological investigations and subsequent gene expression analyses. We observed a significantly decreased infiltration of tumor-associated microglia/macrophages (TAM) in recurrent tumors, while a high TAM infiltration in primary tumors was associated with a reduced OS. Additionally, more patients expressed IL8 in recurrent tumors and TMZ therapy maintained CXCL2 expression. In mice, enhanced anti-tumoral effects were observed after combi-therapy. In conclusion, high TAM infiltration predicts a survival disadvantage, supporting findings of the tumor-promoting phenotype of TAMs. Furthermore, the combination therapy seemed to be promising to overcome CXCR2-mediated resistance