Inhibition of FLT3: A Prototype for Molecular Targeted Therapy in Acute Myeloid Leukemia

Modern therapy of acute myeloid leukemia (AML) began in 1973 with the first report of the successful combination of daunorubicin and cytarabine, which led to complete remission in approximately 45% of patients. Accurate AML diagnosis was dependent on morphology, aided initially only by cytochemistry. Unlike acute lymphoblastic leukemia (ALL), immunophenotyping offered little in the diagnosis of AML, at least during the 1970s and 1980s. The advent of reliable cytogenetics changed the entire prognostic outlook of AML. With karyotypic analysis, different groups of AML could be classified and stratified for various therapies. Unique mutational profiling was a major advance in further categorizing AML patients, aided by the immunophenotypic identification of antigenic markers on the cells. All these advances were occurring as the understanding of the importance of the tumor burden—known as minimal residual disease (MRD)—became crucial for the management of AML patients. The efficacy of MRD has rapidly progressed in the past decade, from a specificity of 10⁻³ with immunophenotyping to 10⁻⁴ with polymerase chain reaction (PCR), which is only appropriate for some patients with AML, and finally to 10⁻⁵ or even 10⁻⁶ cells with the extraordinary sensitivity of next-generation sequencing (NGS). All of these advances have promoted the concept of personalized medicine, which has led to the advent of targeted agents that can accurately be used for specific diagnostic subtypes. Responses can be predicted and measured accurately. Such targeted agents have now become a cornerstone in the management of AML, increasing efficacy and dramatically reducing toxicity. The focus of this review is on one of the most well-studied targeted agents in AML: the FMS-like tyrosine kinase 3 (FLT3) inhibitors, which have impacted the prognostication and therapeutics of AML. This review selectively discusses the FLT3 inhibitors in detail, as a model for the other burgeoning targeted agents that have already been approved, as well as those that are currently in development.     

Designing on-site: Facilitating participatory contextual architecture with mobile phones

Some movements within modern architecture particularly emphasise the importance of matching buildings to their surroundings. However, practicing such “contextual architecture” is highly challenging and typically not something the future inhabitants of a building are well equipped for participating in. This paper explores the potentials of using mobile phone technology for facilitating such client participation in the parts of an architecture process that take place on the building site. For this we introduce ArchiLens, a mobile system for interactive on-site 3D visualisation of houses, and findings from a field study with 40 participants in the process of building or modifying their home. The study showed that using the system helped evoke people’s imagination of the look and feel of their future house, and envision it in context. This enabled them to participate more closely in the design process on-site by iteratively reviewing design alternatives and exploring, for example, other placements and materials.     

Gecko‐Inspired Dry Adhesive for Robotic Applications

Most geckos can rapidly attach and detach from almost any kind of surface. This ability is attributed to the hierarchical structure of their feet (involving toe pads, setal arrays, and spatulae), and how they are moved (articulated) to generate strong adhesion and friction forces on gripping that rapidly relax on releasing. Inspired by the gecko's bioadhesive system, various structured surfaces have been fabricated suitable for robotic applications. In this study, x–y–z asymmetric, micrometer‐sized rectangular flaps composed of polydimethylsiloxane (PDMS) were fabricated using massively parallel micro‐electromechanical systems (MEMS) techniques with the intention of creating directionally responsive, high‐to‐low frictional‐adhesion toe pads exhibiting properties similar to those found in geckos. Using a surface forces apparatus (SFA), the friction and adhesion forces of both vertical (symmetric) and angled/tilted (x–y–z asymmetric) microflaps under various loading, unloading and shearing conditIons were investigated. It was found that the anisotropic structure of tilted microflaps gives very different adhesion and tribological forces when articulated along different x–y–z directions: high friction and adhesion forces when articulated in the y–z plane along the tilt (+y) direction, which is also the direction of motion, and weak friction and adhesion forces when articulated against the tilt (–y) direction. These results demonstrate that asymmetric angled structures, as occur in geckos, are required to enable the gecko to optimize the requirements of high friction and adhesion on gripping, and low frictional‐adhesion on releasing. These properties are intimately coupled to a (also optimum) articulation mechanism. We discuss how both of these features can be simultaneously optimized in the design of robotic systems that can mimic the gecko adhesive system.     

Effect of Microstructural Parameters on the Relative Densities of Metal Foams

A detailed quantitative microstructural analyses of primarily open cell FeCrAlY and 314 stainless steel metal foams with different relative densities and pores per inch (p.p.i.) were undertaken in the present investigation to determine the effect of microstructural parameters on the relative densities of metal foams. Several elements of the microstructure, such as major and minor cell sizes, cell areas and perimeters, ligament dimensions, cell shapes, and area fractions of closed and open cells, were measured. The cross-sections of the foam ligaments showed numerous pores, and their circularity factors and average sizes were determined. The area fractions of the open cells and ligaments decreased, whereas that of the closed cells increased linearly with increasing relative density. The relative densities and p.p.i. were not significantly dependent on cell size, cell perimeter, and ligament dimensions within the limits of experimental scatter. A phenomenological model is proposed to rationalize the present microstructural observations.     

Hydrogenation of dinitriles on Raney-type Ni catalysts: kinetic and mechanistic aspects

The mechanism of the hydrogenation of aliphatic C₄–C₆ dinitriles (succinonitrile, glutaronitrile, and adiponitrile) over Raney-type Ni catalysts was investigated in a fed-batch autoclave at 350 K and 5.0 MPa. The results are interpreted based on the strength of adsorption, the interaction with the solvent and intramolecular interactions. The kinetics of the hydrogenation of aliphatic dinitriles is highly dependent on the hydrocarbon chain length. Short dinitriles like succinonitrile adsorb stronger on the catalyst surface than longer dinitriles like adiponitrile. The yield of the intermediate aminonitriles decreases with increasing hydrocarbon chain length, due to the enhanced competitiveness of dinitrile and aminonitrile for the same active sites. It is proposed that the reactivity of dinitriles and aminonitriles is caused by difference in solvent interaction. It is remarkable that the stronger the adsorption, the higher the reactivity. The reactivity decreases in the order: succinonitrile > glutaronitrile > adiponitrile. In contrast, the reaction rate of the aminonitriles is fairly independent of the hydrocarbon chain length. The formation of undesired secondary amines in the form of cyclic compounds is under kinetic control and increases with decreasing chain length. It is found that adiponitrile can be very selectively hydrogenated to primary diamines. Promoting Raney-type Ni catalysts with traces of Mo, Cr or Fe enhances the performance in the hydrogenation of dinitriles. This gives the best opportunity for process improvement towards the desired primary amines.     

Mitochondrial Processing Peptidases—Structure,Function and the Role in Human Diseases

Mitochondrial proteins are encoded by both nuclear and mitochondrial DNA. While some of the essential subunits of the oxidative phosphorylation (OXPHOS) complexes responsible for cellular ATP production are synthesized directly in the mitochondria, most mitochondrial proteins are first translated in the cytosol and then imported into the organelle using a sophisticated transport system. These proteins are directed mainly by targeting presequences at their N-termini. These presequences need to be cleaved to allow the proper folding and assembly of the pre-proteins into functional protein complexes. In the mitochondria, the presequences are removed by several processing peptidases, including the mitochondrial processing peptidase (MPP), the inner membrane processing peptidase (IMP), the inter-membrane processing peptidase (MIP), and the mitochondrial rhomboid protease (Pcp1/PARL). Their proper functioning is essential for mitochondrial homeostasis as the disruption of any of them is lethal in yeast and severely impacts the lifespan and survival in humans. In this review, we focus on characterizing the structure, function, and substrate specificities of mitochondrial processing peptidases, as well as the connection of their malfunctions to severe human diseases.