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Zusammenfassung Ziel der Studie Vor dem Hintergrund des Versorgungsengpasses im allgemeinmedizinischen Sektor stellt sich die Frage, ob im zahnärztlichen Sektor eine ähnliche Entwicklung zu erwarten ist. Die vorliegende Studie untersucht präferierte Tätigkeitsorte von jungen Zahnärztinnen und -ärzten in Deutschland und ihre zukünftige Verteilung auf Stadt und Land. Methodik Die Online-Befragung wurde im Frühjahr 2017 als zweite Befragungswelle der longitudinalen deutschlandweiten Studie „Y-Dent: Berufsbild angehender und junger Zahnärzte“ durchgeführt. Studienendpunkt waren (1) die Abbildung der gewünschten dauerhaften Tätigkeitsregion, (2) die Präferenz der Ortsklassengröße junger Zahnärzte und Zahnärztinnen für ihre zukünftige Tätigkeit und (3) der Zusammenhang zwischen der Heimatregion und der gewünschten Tätigkeitsregion. Die erhobenen Daten wurden einer deskriptiven univariaten Analyse unterzogen. Ergebnisse 625 (51,2% aller angeschriebenen) Zahnärztinnen und -ärzte beteiligten sich an der Studie. Beliebte Kammer-/KZV-Bereiche für eine dauerhafte Tätigkeit lagen vor allem im Süden und im Westen Deutschlands. Ostdeutsche sowie kleinflächigere Bereiche wurden seltener als mögliche Beschäftigungsregion genannt (unter 10%). Etwa die Hälfte der Teilnehmenden konnte sich vorstellen, im mittelstädtischen Raum zu arbeiten, doch auch der ländliche Raum kam für einen Teil der Befragten in Betracht. Je nach Bundesland konnten sich 57–95% vorstellen, in der Heimatregion tätig zu werden. Schlussfolgerung Ein Versorgungsengpass, der dem im ärztlichen Bereich gleichkommt, ist nach den Bekundungen des zahnärztlichen Nachwuchses zunächst nicht zu befürchten: Grundsätzlich ist ein Teil der jungen Zahnärztinnen und -ärzte gewillt, auch in weniger stark bevölkerten Regionen und Ortsgrößen tätig zu werden.

In the context of a shortfall in medical care, the question arises whether a similar trend in dental care may be anticipated. This study analyses preferred working regions and future town-country distribution of young dentists in Germany.This online-survey was conducted in spring 2017. It is the second wave of the longitudinal nationwide study "Y-dent: Professional identity of future and young dentists". Study end points were (1) favoured permanent working region of young dentists, (2) favoured future working city size, and (3) correlation between the region of origin and the favoured working region.625 (51.2% of contacted) young dentists participated in this study. Dental chambers and associations of health insurance dentists in southern and western Germany were the most favoured future working regions. Regions in eastern Germany as well as smaller regions were chosen less often (10%). For approximately half of the participants, medium-sized cities were an option, and some young dentists were ready to work in smaller cities. Depending on the federal state, 57-95% of young dentists entertained the idea of working in their region of origin.Based on young dentists' statements on their favoured future working region, it can be concluded that there is no risk of a shortfall in dental care comparable to the shortfall in medical care. A proportion of young dentists is willing to work in thinly populated or rural areas.Vor dem Hintergrund des Versorgungsengpasses im allgemeinmedizinischen Sektor stellt sich die Frage, ob im zahnärztlichen Sektor eine ähnliche Entwicklung zu erwarten ist. Die vorliegende Studie untersucht präferierte Tätigkeitsorte von jungen Zahnärztinnen und -ärzten in Deutschland und ihre zukünftige Verteilung auf Stadt und Land.Die Online-Befragung wurde im Frühjahr 2017 als zweite Befragungswelle der longitudinalen deutschlandweiten Studie „Y-Dent: Berufsbild angehender und junger Zahnärzte“ durchgeführt. Studienendpunkt waren (1) die Abbildung der gewünschten dauerhaften Tätigkeitsregion, (2) die Präferenz der Ortsklassengröße junger Zahnärzte und Zahnärztinnen für ihre zukünftige Tätigkeit und (3) der Zusammenhang zwischen der Heimatregion und der gewünschten Tätigkeitsregion. Die erhobenen Daten wurden einer deskriptiven univariaten Analyse unterzogen.625 (51,2% aller angeschriebenen) Zahnärztinnen und -ärzte beteiligten sich an der Studie. Beliebte Kammer-/KZV-Bereiche für eine dauerhafte Tätigkeit lagen vor allem im Süden und im Westen Deutschlands. Ostdeutsche sowie kleinflächigere Bereiche wurden seltener als mögliche Beschäftigungsregion genannt (unter 10%). Etwa die Hälfte der Teilnehmenden konnte sich vorstellen, im mittelstädtischen Raum zu arbeiten, doch auch der ländliche Raum kam für einen Teil der Befragten in Betracht. Je nach Bundesland konnten sich 57–95% vorstellen, in der Heimatregion tätig zu werden.Ein Versorgungsengpass, der dem im ärztlichen Bereich gleichkommt, ist nach den Bekundungen des zahnärztlichen Nachwuchses zunächst nicht zu befürchten: Grundsätzlich ist ein Teil der jungen Zahnärztinnen und -ärzte gewillt, auch in weniger stark bevölkerten Regionen und Ortsgrößen tätig zu werden.

Background: The aim of this study was to collect information on oral health-related quality of life (OHRQoL) in people with rare diseases. Methods: A questionnaire comprising free text questions and the German version of the standardized Oral Health Impact Profile-14 (OHIP-14) questionnaire on OHRQoL was developed. All participants who indicated oral symptoms in the questionnaire were included in a cluster analysis. Different cluster analyses were performed (Ward&rsquo, s, k-Means) to find symptom profile groups in the data. Results: A total of 484 questionnaires with 96 rare diseases were included in the study. The most reported symptoms were anomalies of the tooth formation, dysgnathia, changes in number of the teeth, and malocclusions. The OHIP mean values of the five resulting symptom clusters ranged from 15.1 to 19.9, which is very high compared to the general population in Germany, which has a mean value of 4.09. Discussion: All investigated symptoms show a negative association with OHRQoL, but the strongest were for symptoms of the oral mucosa and periodontal diseases. All the symptoms described in this cluster analysis can lead to considerably higher mean values of the OHIP total score among people with rare disease and thus to worse OHRQoL than reported in the general population.

Nanomedicine is a rapidly growing field in nanotechnology, which has great potential in the development of new therapies for numerous diseases. For example iron oxide nanoparticles are in clinical use already in the thermotherapy of brain cancer. Although it has been shown, that tumor cells take up these particles in vitro, little is known about the internalization routes. Understanding of the underlying uptake mechanisms would be very useful for faster and precise development of nanoparticles for clinical applications. This study aims at the identification of key proteins, which are crucial for the active uptake of iron oxide nanoparticles by HeLa cells (human cervical cancer) as a model cell line. Cells were transfected with specific siRNAs against Caveolin-1, Dynamin 2, Flotillin-1, Clathrin, PIP5Kα and CDC42. Knockdown of Caveolin-1 reduces endocytosis of superparamagnetic iron oxide nanoparticles (SPIONs) and silica-coated iron oxide nanoparticles (SCIONs) between 23 and 41%, depending on the surface characteristics of the nanoparticles and the experimental design. Knockdown of CDC42 showed a 46% decrease of the internalization of PEGylated SPIONs within 24 h incubation time. Knockdown of Dynamin 2, Flotillin-1, Clathrin and PIP5Kα caused no or only minor effects. Hence endocytosis in HeLa cells of iron oxide nanoparticles, used in this study, is mainly mediated by Caveolin-1 and CDC42. It is shown here for the first time, which proteins of the endocytotic pathway mediate the endocytosis of silica-coated iron oxide nanoparticles in HeLa cells in vitro. In future studies more experiments should be carried out with different cell lines and other well-defined nanoparticle species to elucidate possible general principles.

Therapy options at the time of recurrence of glioblastoma multiforme are often limited. We investigated whether treatment with a new intratumoral thermotherapy procedure using magnetic nanoparticles improves survival outcome. In a single-arm study in two centers, 66 patients (59 with recurrent glioblastoma) received neuronavigationally controlled intratumoral instillation of an aqueous dispersion of iron-oxide (magnetite) nanoparticles and subsequent heating of the particles in an alternating magnetic field. Treatment was combined with fractionated stereotactic radiotherapy. A median dose of 30 Gy using a fractionation of 5 × 2 Gy/week was applied. The primary study endpoint was overall survival following diagnosis of first tumor recurrence (OS-2), while the secondary endpoint was overall survival after primary tumor diagnosis (OS-1). Survival times were calculated using the Kaplan–Meier method. Analyses were by intention to treat. The median overall survival from diagnosis of the first tumor recurrence among the 59 patients with recurrent glioblastoma was 13.4 months (95% CI: 10.6–16.2 months). Median OS-1 was 23.2 months while the median time interval between primary diagnosis and first tumor recurrence was 8.0 months. Only tumor volume at study entry was significantly correlated with ensuing survival (P

Magnetic nanoparticles are increasingly used for clinical applications such as drug delivery, magnetic resonance imaging and magnetic fluid hyperthermia. A novel method of interstitial heating of tumours following direct injection of magnetic nanoparticles has been evaluated in humans in recent clinical trials. In prostate cancer this approach has been investigated in two separate phase I studies, employing magnetic nanoparticle thermotherapy alone and in combination with permanent seed brachytherapy. The feasibility and good tolerability was shown in both trials, using the first prototype of an alternating magnetic field applicator. As with any other heating technique, this novel approach requires specific tools for planning, quality control and thermal monitoring, based on appropriate imaging and modelling techniques. In these first clinical trials a newly developed method for planning and non-invasive calculations of the 3-dimensional temperature distribution based on computed tomography was validated. Limiting factors of the new approach at present are patient discomfort at high magnetic field strengths and irregular intratumoural heat distribution. Until these limitations are overcome and thermoablation can safely be applied as a monotherapy, this treatment modality is being evaluated in combination with irradiation in patients with localised prostate cancer.

In order to increase the specific power absorption (SAR) in deep seated tumors, the idea was born to use AC magnetic fields in combination with magnetic particles instead of conventional E-field dominant systems. It was found, that nanoscaled particles were superior to micron-sized, multi-domain particles in terms of SAR due to different mechanisms how the field energy is converted into heat. Crucial parameters were identified for the human application of the method, such as the AC magnetic field amplitude and frequency, the nanoparticle composition and size distribution. Based on these physical and chemical relationships, a new thermotherapy method has been developed to heat up deep regional tumors using aqueous dispersions of iron oxide nanoparticles (magnetic fluids). Several clinical studies were initiated using this new heating technology. The results of the most advanced efficacy study for recurrent glioblastoma multiforme patients in combination with conventional radiation therapy are expected at the end of this year, 16 years after publication of this fundamental paper.

The potential of colloidal subdomain ferrite particle suspensions (SDP) ('magnetic fluids'), exposed to an alternating magnetic field, is evaluated for hyperthermia. Power absorption measurements of different magnetic fluids are presented in comparison to multidomain ferrite particles (MDP). Variations with frequency as well as magnetic field strength have been investigated. The experimental results clearly indicate a definite superiority of even non-optimized magnetic fluids over MDP ferrites regarding their specific absorption rate (SAR). Based on the work of Shliomis et al. (1990) and Hanson (1991), a solid-state physical model is applied to explain the specific properties of magnetic fluids with respect to a possible use in hyperthermia. The experimentally determined SAR data on magnetic fluids are used to estimate the heating capabilities of a magnetic induction heating technique assuming typical human dimensions and tissue parameters. It is considered that for a moderate concentration of 5 mg ferrite per gram tumour (i.e. 0.5% w/w) and clinically acceptable magnetic fields, intratumoral power absorption is comparable to RF heating with local applicators and superior to regional RF heating (by comparison with clinical SAR measurements from regional and local hyperthermia treatments). Owing to the high particle density per volume, inductive heating by magnetic fluids can improve temperature distributions in critical regions. Furthermore, localized application of magnetic fluids in a tumour might be easier and less traumatic than interstitial implantation techniques.

Magnetic fluids are increasingly used for clinical applications such as drug delivery, magnetic resonance imaging and magnetic fluid hyperthermia. The latter technique that has been developed as a cancer treatment for several decades comprises the injection of magnetic nanoparticles into tumors and their subsequent heating in an alternating magnetic field. Depending on the applied temperature and the duration of heating this treatment either results in direct tumor cell killing or makes the cells more susceptible to concomitant radio- or chemotherapy. Numerous groups are working in this field worldwide, but only one approach has been tested in clinical trials so far. Here, we summarize the clinical data gained in these studies on magnetic fluid induced hyperthermia.

En recientes ensayos clínicos, se ha evaluado en tumores malignos humanos, un nuevo método de dispensación de calor en pequeños espacios (intersticios) utilizando nanopartículas magnéticas y una técnica de inyección directa. En el cáncer de próstata, este procedimiento se ha investigado en dos estudios fase I separados empleando en uno solamente termoterapia de nanopartículas magnéticas y en otro en combinación con braquiterapia (implantes permanentes). En ambos estudios se demostró viabilidad y buena tolerancia, usando el primer prototipo de un aplicador de campo magnético. Como con cualquier otra técnica por calor, este nuevo procedimiento requiere herramientas específicas para su planificación, control de calidad y monitorización térmica, basado en una imagen apropiada y en técnicas de planificación. En estos primeros estudios, se evalúa un nuevo método que permite una planificación y distribución tridimensional no invasiva de la temperatura basado en la tomografía computerizada (TC). En la actualidad, los factores limitantes de este procedimiento son el malestar del paciente a altas intensidades de campos magnéticos y la distribución intratumoral subóptima de las nanopartículas. Hasta que estas limitaciones sean superadas y la termoablación pueda ser aplicada con seguridad como monoterapia, esta modalidad de tratamiento está siendo evaluada en combinación con la irradiación en pacientes con cáncer de próstata localizado.

Thermotherapy using magnetic nanoparticles (nano cancer therapy) is a new concept of local tumour therapy, which is based on controlled heating of intra-tumoural injected magnetic nanoparticles. The aim of this study was to evaluate the usefulness of PET with a recently introduced amino acid tracer O-(2-[18F]fluoroethyl)-]L-tyrosine (FET) for targeting the nanoparticles implantation.Eleven patients with glioblastoma recurrences underwent MR and FET-PET imaging for planning of the nano cancer therapy. Thereafter, the gross tumour volumes (GTV) were defined, taking into consideration the results of both imaging tools.The MRI-based mean GTV was 24.3 cm3 (range 2.5-59.7) and the PET-based mean GTV 31.9 cm3 (range 5.2-77.9). On the average the MRI identified an additional 8.9 +/- 4.7 cm3 and the FET-PET scan-an additional 16.5 +/- 15.2 cm3 outside of the common GTV (15.4 +/- 11.0 cm3). The mean final GTV accounted to 33.8 cm3 (range, 5.2-77.9). The additional information of FET-PET led to an increase in GTV by 22-286% in eight patients and to a decrease of 23% and 26%, respectively, in two patients. In one patient, the final GTV was defined on the basis of MRI data only.FET-PET adds important information on the actual tumour volume in recurrent glioblastomas and is highly valuable for defining the target volume for the nano cancer therapy.

The concept of magnetic fluid hyperthermia is clinically evaluated after development of the whole body magnetic field applicator MFH 300F and the magnetofluid MFL 082AS. This new system for localized thermotherapy is suitable either for hyperthermia or thermoablation. The magnetic fluid, composed of iron oxide nanoparticles dispersed in water, must be distributed in the tumour and is subsequently heated by exposing to an alternating magnetic field in the applicator. We performed a feasibility study with 22 patients suffering from heavily pretreated recurrences of different tumour entities, where hyperthermia in conjunction with irradiation and/or chemotherapy was an option. The potential to estimate (by post-implantation analyses) and to achieve (by improving the technique) a satisfactory temperature distribution was evaluated in dependency on the implantation technique.Three implantation methods were established: Infiltration under CT fluoroscopy (group A), TRUS (transrectal ultrasound)--guided implantation with X-fluoroscopy (group B) and intra-operative infiltration under visual control (group C). In group A and B the distribution of the nanoparticles can be planned prior to implantation on the basis of three-dimensional image datasets. The specific absorption rates (SAR in W/kg) can be derived from the particle distribution imaged via CT together with the actual H-field strength (in kA/m). The temperature distribution in the tumour region is calculated using the bioheat-transfer equation assessing a mean perfusion value, which is determined by matching calculated temperatures to direct (invasive or endoluminal) temperature measurements in reference points in or near the target region.Instillation of the magnetic fluid and the thermotherapy treatments were tolerated without or with only moderate side effects, respectively. Using tolerable H-field-strengths of 3.0-6.0 kA/m in the pelvis, up to 7.5 kA/m in the thoracic and neck region and10.0 kA/m for the head, we achieved SAR of 60-380 W/kg in the target leading to a 40 degrees C heat-coverage of 86%. However, the coverage withor =42 degrees C is unsatisfactory at present (30% of the target volume in group A and only 0.2% in group B).Further improvement of the temperature distribution is required by refining the implantation techniques or simply by increasing the amount of nanofluid or elevation of the magnetic field strength. From the actual nanoparticle distribution and derived temperatures we can extrapolate, that already a moderate increase of the H-field by only 2 kA/m would significantly improve the 42 degrees C coverage towards 100% (98%). This illustrates the great potential of the nanofluid-based heating technology.

The purpose of the present study was to examine whether single human carcinoma cells labeled with iron oxide nanoparticles could be detected by magnetic resonance (MR) imaging on a clinical 3-T scanner using a surface coil only. WiDr human colon carcinoma cells were loaded with two kinds of iron oxide nanoparticles differing by coating and size: aminosilan-coated (MagForce) and carboxy-dextran-coated particles (Resovist). The latter were preferred by the colon carcinoma cell line used here and taken up much faster (12 h) than the smaller carboxydextran-coated Resovist (48 h). Labeled single carcinoma cells, distributed in an agarose gel in a monodisperse layer as controlled by light microscopy, became detectable as punctuate signal extinctions when using a small circularly polarized surface coil in conjunction with a T2*-weighted GE sequence at 3 T. The threshold for the detectability of labeled colon carcinoma cells ranged at a load of 4 –5 g iron/10 6 cells. Obviating the need for special hardware additions, this study opens a new lane for single-cell tracking on clinical 3-T MR scanners amenable to patient studies. Magn Reson Med 53:1187–1192, 2005. © 2005 Wiley-Liss, Inc.

Imatinib mesylate is a small molecule inhibitor of the c-Abl, platelet-derived growth factor (PDGF) receptor and c-Kit tyrosine kinases that is approved for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML) and gastrointestinal stromal tumors. Glioblastoma multiforme is a highly malignant primary brain tumor that is usually treated with surgery and/or radiotherapy. Previous studies implicate an autocrine loop caused by high expression of PDGF and its receptor, PDGFR, in the proliferation of some glioblastomas. Here, we demonstrate that pretreatment of a human glioblastoma cell line, RuSi RS1, with imatinib significantly enhanced the cytotoxic effect of ionizing radiation. This effect was not seen in human breast cancer (BT20) and colon cancer (WiDr) cell lines. Whereas c-Abl and c-Kit were expressed about equally in the three cell lines, RuSi RS1 cells showed significantly higher expression of PDGFR-beta protein in comparison to BT20 and WiDr. Imatinib treatment of RuSi RS1 cells decreased overall levels of cellular tyrosine phosphorylation and specifically inhibited phosphorylation of PDGFR-beta, while c-Abl was not prominently activated in these cells. These results suggest that imatinib may have clinical utility as a radiosensitizer in the treatment of human glioblastoma, possibly through disruption of an autocrine PDGF/PDGFR loop.

Magnetic fluid hyperthermia (MFH) is a new approach to deposit heat power in deep tissues by overcoming limitations of conventional heat treatments. After infiltration of the target tissue with nanosized magnetic particles, the power of an alternating magnetic field is transformed into heat. The combination of the 100 kHz magnetic field applicator MFH 300F and the magnetofluid (MF), which both are designed for medical use, is investigated with respect to its dosage recommendations and clinical applicability. We found a magnetic field strength of up to 18 kA/m in a cylindrical treatment area of 20 cm diameter and aperture height up to 300 mm. The specific absorption rate (SAR) can be controlled directly by the magnetic field strength during the treatment. The relationship between magnetic field strength and the iron normalized SAR (SAR(Fe)) is only slightly depending on the concentration of the MF and can be used for planning the target SAR. The achievable energy absorption rates of the MF distributed in the tissue is sufficient for either hyperthermia or thermoablation. The fluid has a visible contrast in therapeutic concentrations on a CT scanner and can be detected down to 0.01 g/l Fe in the MRI. The system has proved its capability and practicability for heat treatment in deep regions of the human body.

Magnetic fractionation was applied to a common magnetic fluid based on superparamagnetic iron-oxide nano-particles with core radius of 5nm. The fractions collected were investigated with respect to particle-sizes and the influence of fractionation on the specific absorption rate, in order to optimize magnetic fluids for the application in hyperthermia.

The design process for large systems, e.g., industrial plants, involves large multi-disciplinary teams. Since each discipline has its own specialised concerns, the common thread is describing the functional requirements of an artefact. In the oil and gas industry, Engineering, Procurement & Construction (EPC) companies are responsible for designing industrial plants whose later use requires exchange of information which is often based on different formats and leads to huge costs due to interoperability overhead. One contender in this space is the ISO15926 standard used for industrial design data interchange. We examine several challenges the standard poses for the conceptual and detailed design phases, and provide an alternative framework grounded on a firm ontological foundation incorporating advanced modelling concepts such as multi-level models and roles that provide a basis for the effective development of meta-model mappings, a novel approach for organisations needing to map to ISO15926.

One of the most significant challenges in information system design is the constant and increasing need to establish interoperability between heterogeneous software systems at increasing scale. The automated translation of data between the data models and languages used by information ecosystems built around official or de facto standards is best addressed using model-driven engineering techniques, but requires handling both data and multiple levels of metadata within a single model. Standard modelling approaches are generally not built for this, compromising modelling outcomes. We establish the SLICER conceptual framework built on multilevel modelling principles and the differentiation of basic semantic relations that dynamically structure the model and can capture existing multilevel notions. Moreover, it provides a natural propagation of constraints over multiple levels of instantiation. Refereed/Peer-reviewed

The GMT-Consortium Large Earth Finder (G-CLEF) is a fiber fed, optical echelle spectrograph that has been selected as a first light instrument for the Giant Magellan Telescope (GMT) currently under construction at the Las Campanas Observatory in Chile’s Atacama desert region. We designed G-CLEF as a general-purpose echelle spectrograph with precision radial velocity (PRV) capability used for exoplanet detection. The radial velocity (RV) precision goal of GCLEF is 10 cm/sec, necessary for detection of Earth-sized planets orbiting stars like our Sun in the habitable zone. This goal imposes challenging stability requirements on the optical mounts and the overall spectrograph support structures. Stability in instruments of this type is typically affected by changes in temperature, orientation, and air pressure as well as vibrations caused by telescope tracking. For these reasons, we have chosen to enclose G-CLEF’s spectrograph in a thermally insulated, vibration isolated vacuum chamber and place it at a gravity invariant location on GMT’s azimuth platform. Additional design constraints posed by the GMT telescope include: a limited space envelope, a thermal emission ceiling, and a maximum weight allowance. Other factors, such as manufacturability, serviceability, available technology and budget are also significant design drivers. All of the previously listed considerations must be managed while ensuring that performance requirements are achieved. In this paper, we discuss the design of G-CLEF’s optical mounts and support structures including technical choices made to minimize the system’s sensitivity to thermal gradients. A more general treatment of the properties of G-CLEF can be found elsewhere in these proceedings1. We discuss the design of the vacuum chamber which houses the irregularly shaped optical bench and optics while conforming to a challenging space envelope on GMT’s azimuth platform. We also discuss the design of G-CLEF’s insulated enclosure and thermal control systems which maintain the spectrograph at milli-Kelvin level stability while simultaneously limiting the maximum thermal emission into the telescope dome environment. Finally, we discuss G-CLEF’s front-end assembly and fiber-feed system as well as other interface challenges presented by the telescope, enclosure and neighboring instrumentation.

Magnetic fluid hyperthermia (MFH) selectively heats up tissue by coupling alternating current (AC) magnetic fields to targeted magnetic fluids, so that boundaries of different conductive tissues do not interfere with power absorption. In this paper, a new AC magnetic field therapy system for clinical application of MFH is described. With optimized magnetic nanoparticle preparations it will be used for target-specific glioblastoma and prostate carcinoma therapy.

In vitro, tumor-selective Hsp70 plasma membrane localization correlates with increased sensitivity to lysis mediated by a subpopulation of human natural killer (NK) cells that adhere to plastic following cytokine stimulation. In the present study, we analyzed the capacity of adoptively transferred human NK cells in SCID/beige mice for local tumor control and prevention of metastatic dissemination of Hsp70-expressing CX(+) and non-expressing CX(-) tumors following orthotopic (o.t.) injection. Both tumor sublines were derived by cell sorting of the original cell line, CX2, and thus exhibit an identical MHC and adhesion molecule expression pattern but differ with respect to Hsp70 plasma membrane expression. Viability of adherent, human NK cells in SCID/beige mice up to 18 days and the capacity to migrate have been demonstrated. Growth of Hsp70-expressing and non-expressing CX(+) and CX(-) tumor cells was completely suppressed when 10 x 10(6) NK cells were injected into the i.p. cavity on day 4 after inoculation of 2.5 x 10(6) tumor cells. Although a single injection of 5 or 2.5 x 10(6) NK cells was not sufficient to suppress tumor growth completely in all mice, the reduction in size of CX(+) tumors was significantly greater than that of CX(-) tumors. To mimic the clinical situation, ex vivo stimulated NK cells were injected i.v. on day 4 after o.t. injection of tumor cells. Under these conditions, growth of Hsp70-expressing primary tumors and metastases was suppressed. If CX(-) tumor cells were injected, 3 of 9 mice developed Hsp70-negative primary tumors. However, none of these mice developed distant metastases. In summary, our data indicate that Hsp70 acts as a recognition structure for adherent NK cells in a SCID/beige mouse model.

The story of hyperthermia with small particles in AC magnetic "elds started in the late 1950s, but most of the studies were unfortunately conducted with inadequate animal systems, inexact thermometry and poor AC magnetic "eld parameters, so that any clinical implication was far behind the horizon. More than three decades later, it was found, that colloidal dispersions of superparamagnetic (subdomain) iron oxide nanoparticles exhibit an extraordinary speci"c absorption rate (SAR [=/g]), which is much higher at clinically tolerable H 0 f combinations in comparison to hysteresis heating of larger multidomain particles. This was the renaissance of a cancer treatment method, which has gained more and more attention in the last few years. Due to the increasing number of randomized clinical trials preferentially in Europe with conventional E-"eld hyperthermia systems, the general medical and physical experience in hyperthermia application is also rapidly growing. Taking this increasing clinical experience carefully into account together with the huge amount of new biological data on heat response of cells and tissues, the approach of magnetic #uid hyperthermia (MFH) is nowadays more promising than ever before. The present contribution reviews the current state of the art and some of the future perspectives supported by advanced methods of the so-called nanotechnology. ( 1999 Elsevier Science B.V. All rights reserved.

Thermotherapy using magnetic nanoparticles, also termed nanotherapy, is a new therapeutic concept in which tumor cells are damaged via local heat application. The principle of this method is direct injection of a magnetic fluid into a tumor and its subsequent heating in an alternating magnetic field. The heat created this way (thermotherapy) causes either direct damage to the tumor cells (depending on temperature and reaction time) or make cells more susceptible to accompanying radio- or chemotherapy. The results of a feasibility trial (phase I) on the treatment of brain tumors (glioblastoma multiforme) are presented.

Magnetic fluids (MF) have a potential for hyperthermia due to their good power absorption capabilities. Recent in vitro experiments with the so-called 'Magnetic Fluid Hyperthermia (MFH)' have shown that human tumours cells are homogeneously inactivated after AC magnetic field excitation of extracellular MF. The aim of the present study was the evaluation of a high dose MFH on intramuscularly implanted mammary carcinoma of the mouse. The tumours originated from initial in vivo passages of a spontaneous parent tumour. Because of larger variations of tumour growth in this rather primary model, logistic regression of non-averaged volumes was performed for each treatment modality. All growing tumours were randomized 30 days after transplantation (day of treatment) with an overall size distribution between 120-400 mm3. An intratumoural steady state temperature of 47 +/- 1.0 degrees C was maintained for 30 minutes with whole-body AC magnetic fields of 6-12.5 kA/m at 520 kHz. The magnetic fluid was #P6, which is a high biocompatible dextran magnetite. #P6 was given intratumourally (1.5 x 10(-2) mg ferrite/mm3) 20-30 minutes before excitation and was combined with magnetic targeting (50 mT), which yielded a 2.5-fold enhancement of the intratumoural iron concentration. Histological examinations of tumour tissue after intralesional ferrofluid administration alone indicated deep infiltration of the fluid into the carcinoma tissue, but no evidence of tissue damage as compared with untreated controls. In contrast, widespread tumour necrosis was observed after MFH. After application of either dextran or ferrofluid alone (no difference, p = 0.665), tumour growth was slightly delayed in comparison with untreated controls (p0.001). In contrast to the good fit of the controls (R = 0.92-0.87), tumour growth after MFH was much more heterogeneous; some tumours showed no evidence for regrowth at 50 days whereas others had grown quite readily. This most probably reflected the critical problem of homogeneity of the intratumoural MF distribution, which was also confirmed qualitatively by Magnetic Resonance Imaging (MRI), heterogeneous pigmentation of MFH treated tumours, and up to 1 degree C differences between temperature probes in the same tumour during AC magnetic field application. However, a quantitative comparison between intratumoural MF-heterogeneity and tumour response could not be performed in this study. Despite these current limitations, the regression analysis of the MFH data yielded a smaller tumour volume of about 1000 mm3 at 50 days growth time in contrast to all three controls. In conclusion, encouraging results have been obtained, which show, that one single high dose MFH is already able to induce local tumour control in many cases within 30 days after treatment. To overcome the uncertainties of intratumoural MF heterogeneity, advanced intralesional application methods are currently under development.

Suspensions of coated superparamagnetic particles (magnetic fluids, MF) in AC magnetic fields have a pronounced specific absorption rate (SAR) per mass compared to multidomain particles. The aim of the present study was to investigate cellular uptake and the biological effects of AC magnetic field excited bio-compatible magnetic fluids on human carcinoma cells in vitro. One of the fluids tested was a dextran magnetite, which has a very low cyto-toxicity with survival fractions (SF) between 0.8 and 0.9 at concentrations of up to 5 mg ferrite per ml. Human carcinoma cells intracellularly accumulate up to 1 pg ferrite/cell which has been demonstrated by electron microscopy (TEM), X-ray spectroscopy and measurements of intracellular iron. It has been shown that the ferrite core is not altered intracellularly, but many of the dextran shells are degraded which yields particle chains and other aggregates observed in TEM. Semi-solid pellets of the tumour cells were treated with AC magnetic fields (520 kHz, 4-12.5 kA/m) or waterbath hyperthermia at 43 and 45 degrees C, in presence of extracellular and/or intracellular magnetic fluid particles. Although MF heating is produced from individual particles, the survival fractions of MF heated and water bath heated cells are equal. In fact, the extracellular MF particle distribution is homogeneous enough to obtain similar inactivation. In contrast to earlier reports intracellular dextran magnetite particles in AC magnetic fields did not induce cell inactivation. Since the amount of intracellular ferrite should be indeed large enough for cell inactivation, the loss of dextran shells is most probably the main cause of limited effectiveness of the intracellular magnetite particles. The present work has demonstrated that: (1) MFH is able to inactivate tumour cells in vitro to at least the same extent as water bath hyperthermia; and (2) that there is a sensitizer effect of ferrofluids at 43 degrees C probably caused by free ferric ions which induce oxidative stress; and (3) that there is no cytotoxic effect of intracellular dextran magnetite particles 30-180 min excited with AC magnetic fields used in this study. For the new method the term 'magnetic fluid hyperthermia (MFH)' is proposed.

Flexible integration of information systems with heterogeneous data structures and interfaces has been an important IT research goal for decades. It is a fundamental requirement for enterprise transformation that the business knowledge captured in form of data and business processes can be integrated and adapted within and across enterprise boundaries. In this paper we present results of a model-driven interoperability approach in the asset management domain. The approach builds on multi-domain modeling principles and has been applied in three large use cases over the last 5 years. We show how information interoperability and enterprise transformation can benefit from multi-domain modeling and how it fits together with a design science approach. Refereed/Peer-reviewed