Operative Therapie von akral lokalisierten Melanomen

Zusammenfassung: Akrolentiginöse Melanome (ALM) umfassen 4-10% der kutanen Melanome bei Hellhäutigen. Patienten mit ALM wird oft eine schlechtere Prognose zugeschrieben, meist aufgrund zu später Diagnosestellung. Unter Einsatz der 3D-Histologie können akral lokalisierte Melanome mit kontinuierlichem Ausbreitungsmuster lokal chirurgisch mit kleineren Sicherheitsabständen und einem guten funktionellen und kosmetischen Ergebnis behandelt werden. In einer Studie wurden bei 244Patienten mit ALM die konventionelle Histologie vs. 3D-Histologie neben anderen prognostischen Parametern verglichen. Klinische und chirurgische Risikofaktoren beeinflussen die Prognose des ALM. Tumordicke und Ulzeration sind die wichtigsten Risikofaktoren. Die 3D-Histologie in Paraffintechnik ermöglicht es, Sicherheitsabstände zu reduzieren und Lokalrezidive zu vermeiden. Subunguale Melanome machen nur etwa 2-3% der kutanen Melanome beim kaukasischen und etwa 20% der Melanome beim afrikanischen oder asiatischen Hauttyp aus und werden klinisch häufig fehldiagnostiziert. Sie sind oft an Daumen und Großzehe lokalisiert. Die Entfernung von subungualen Melanomen mit 3D-Histologie und tumorfreien Schnitträndern unter Einschluss der Nagelmatrix kann als sichere Strategie angesehen werden, welche die Prognose nicht beeinträchtigt. Funktion und Kosmetik eines Fingers oder Zehs bleiben erhalten. Amputationen bei subungualen Melanomen sollten fortgeschrittenen Verläufen mit Knochen- oder Gelenkbefall vorbehalten bleibe

Model-informed target product profiles of long-acting-injectables for use as seasonal malaria prevention

Seasonal malaria chemoprevention (SMC) has proven highly efficacious in reducing malaria incidence. However, the continued success of SMC is threatened by the spread of resistance against one of its main preventive ingredients, Sulfadoxine-Pyrimethamine (SP), operational challenges in delivery, and incomplete adherence to the regimens. Via a simulation study with an individual-based model of malaria dynamics, we provide quantitative evidence to assess long-acting injectables (LAIs) as potential alternatives to SMC. We explored the predicted impact of a range of novel preventive LAIs as a seasonal prevention tool in children aged three months to five years old during late-stage clinical trials and at implementation. LAIs were co-administered with a blood-stage clearing drug once at the beginning of the transmission season. We found the establishment of non-inferiority of LAIs to standard 3 or 4 rounds of SMC with SP-amodiaquine was challenging in clinical trial stages due to high intervention deployment coverage. However, our analysis of implementation settings where the achievable SMC coverage was much lower, show LAIs with fewer visits per season are potential suitable replacements to SMC. Suitability as a replacement with higher impact is possible if the duration of protection of LAIs covered the duration of the transmission season. Furthermore, optimising LAIs coverage and protective efficacy half-life via simulation analysis in settings with an SMC coverage of 60% revealed important trade-offs between protective efficacy decay and deployment coverage. Our analysis additionally highlights that for seasonal deployment for LAIs, it will be necessary to investigate the protective efficacy decay as early as possible during clinical development to ensure a well-informed candidate selection process

Разработка метода темплатного синтеза наноструктур в алюмооксидных матрицах

Объектом исследования является разработка метода темплатного синтеза наноструктур в алюмооксидных матрицах. Цель работы являются синтез матрицы АОА методом двухступенчатого анодирования и разработка методики темплатного синтеза металлических наноструктур в матрице АОА. Область применения: мембранные технологии, оптика, микроэлектронные устройства, матрицы для темплатного синтеза. В будущем планируется проведение исследования нанокомпозитов на основе кобальта, полученных в матрице АОА, изучение режима формирования наноструктуры и применения таких материалов.The object of research is the development of a template synthesis method for nanostructures in alumina matrices. The aim of the work is the synthesis of the AOA matrix by the method of two-stage anodization and the development of a template synthesis technique for metal nanostructures in the AOA matrix. Scope: membrane technologies, optics, microelectronic devices, matrices for template synthesis. In the future, it is planned to conduct research on cobalt-based nanocomposites obtained in the AOA matrix, to study the regime of nanostructure formation and the use of such materials.In the future, it is planned to conduct research on cobalt-base

New in vitro interaction-parasite reduction ratio assay for early derisk in clinical development of antimalarial combinations

The development and spread of drug-resistant phenotypes substantially threaten malaria control efforts. Combination therapies have the potential to minimize the risk of resistance development but require intensive preclinical studies to determine optimal combination and dosing regimens. To support the selection of new combinations, we developed a novel in vitro-in silico combination approach to help identify the pharmacodynamic interactions of the two antimalarial drugs in a combination which can be plugged into a pharmacokinetic/pharmacodynamic model built with human monotherapy parasitological data to predict the parasitological endpoints of the combination. This makes it possible to optimally select drug combinations and doses for the clinical development of antimalarials. With this assay, we successfully predicted the endpoints of two phase 2 clinical trials in patients with the artefenomel-piperaquine and artefenomel-ferroquine drug combinations. In addition, the predictive performance of our novel in vitro model was equivalent to that of the humanized mouse model outcome. Last, our more informative in vitro combination assay provided additional insights into the pharmacodynamic drug interactions compared to the in vivo systems, e.g., a concentration-dependent change in the maximum killing effect (Emax) and the concentration producing 50% of the killing maximum effect (EC50) of piperaquine or artefenomel or a directional reduction of the EC50 of ferroquine by artefenomel and a directional reduction of Emax of ferroquine by artefenomel. Overall, this novel in vitro-in silico-based technology will significantly improve and streamline the economic development of new drug combinations for malaria and potentially also in other therapeutic areas

Parasite viability as a measure of in vivo drug activity in preclinical and early clinical antimalarial drug assessment

The rate at which parasitemia declines in a host after treatment with an antimalarial drug is a major metric for assessment of antimalarial drug activity in preclinical models and in early clinical trials. However, this metric does not distinguish between viable and nonviable parasites. Thus, enumeration of parasites may result in underestimation of drug activity for some compounds, potentially confounding its use as a metric for assessing antimalarial activity in vivo. Here, we report a study of the effect of artesunate on Plasmodium falciparum viability in humans and in mice. We first measured the drug effect in mice by estimating the decrease in parasite viability after treatment using two independent approaches to estimate viability. We demonstrate that, as previously reported in humans, parasite viability declines much faster after artesunate treatment than does the decline in parasitemia (termed parasite clearance). We also observed that artesunate kills parasites faster at higher concentrations, which is not discernible from the traditional parasite clearance curve and that each subsequent dose of artesunate maintains its killing effect. Furthermore, based on measures of parasite viability, we could accurately predict the in vivo recrudescence of infection. Finally, using pharmacometrics modeling, we show that the apparent differences in the antimalarial activity of artesunate in mice and humans are partly explained by differences in host removal of dead parasites in the two hosts. However, these differences, along with different pharmacokinetic profiles, do not fully account for the differences in activity. (This study has been registered with the Australian New Zealand Clinical Trials Registry under identifier ACTRN12617001394336.)

Repositioning: the fast track to new anti-malarial medicines?

Repositioning of existing drugs has been suggested as a fast track for developing new anti-malarial agents. The compound libraries of GlaxoSmithKline (GSK), Pfizer and AstraZeneca (AZ) comprising drugs that have undergone clinical studies in other therapeutic areas, but not achieved approval, and a set of US Food and Drug Administration (FDA)-approved drugs and other bio-actives were tested against Plasmodium falciparum blood stages. Repositioning of existing therapeutics in malaria is an attractive proposal. Compounds active in vitro at muM concentrations were identified. However, therapeutic concentrations may not be effectively achieved in mice or humans because of poor bio-availability and/or safety concerns. Stringent safety requirements for anti-malarial drugs, given their widespread use in children, make this a challenging area in which to reposition therapy.This work was supported by the Medicines Malaria Venture, St Jude Children's Research Hospital, GlaxoSmithKline Plc and Pfizer Inc

Symmetry breaking in dynamical systems

Symmetry breaking bifurcations and dynamical systems have obtained a lot of attention over the last years. This has several reasons: real world applications give rise to systems with symmetry, steady state solutions and periodic orbits may have interesting patterns, symmetry changes the notion of structural stability and introduces degeneracies into the systems as well as geometric simplifications. Therefore symmetric systems are attractive to those who study specific applications as well as to those who are interested in a the abstract theory of dynamical systems. Dynamical systems fall into two classes, those with continuous time and those with discrete time. In this paper we study only the continuous case, although the discrete case is as interesting as the continuous one. Many global results were obtained for the discrete case. Our emphasis are heteroclinic cycles and some mechanisms to create them. We do not pursue the question of stability. Of course many studies have been made to give conditions which imply the existence and stability of such cycles. In contrast to systems without symmetry heteroclinic cycles can be structurally stable in the symmetric case. Sometimes the various solutions on the cycle get mapped onto each other by group elements. Then this cycle will reduce to a homoclinic orbit if we project the equation onto the orbit space. Therefore techniques to study homoclinic bifurcations become available. In recent years some efforts have been made to understand the behaviour of dynamical systems near points where the symmetry of the system was perturbed by outside influences. This can lead to very complicated dynamical behaviour, as was pointed out by several authors. We will discuss some of the technical difficulties which arise in these problems. Then we will review some recent results on a geometric approach to this problem near steady state bifurcation points