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Background
To date, targeted tyrosine kinase inhibitors have been approved for FGFR2 and FGFR3 fusions (pemigatinib and erdafitinib, respectively), but the importance of FGFR2 mutations for transformation activity and as a druggable gene variant with response to different FGFR inhibitors is poorly understood. FGFR2 inhibitors present a mainstay of treatment for locally advanced or metastatic intrahepatic cholangiocellular carcinoma (iCCA).
Methods
A 74-year-old male was diagnosed with iCCA in liver segments seven and eight with infiltration of the hepatic veins and inferior vena cava revealed a C382R mutation of the intramembrane domain of FGRR2 receptor. We performed an in-silico study to understand the potential mode-of-action of the mutant FGFR2 targets. Based on experimentally determined structures we then used a structure generated by AlphaFold2 as the variation in question is located at a position not determined well in the experiments. This revealed that the C382R mutation is located in the trans-membranal domain at a position crucial for signal transduction, both for activation and inhibition of downstream-signaling. The Molecular Tumor Board decided to start the treatment with 13.5 mg pemigatinib once daily for 14 days, followed by 7 days of free therapy interval resulting in a sustained partial response. The patient continues to be treated of 13.5 mg as described above.
Results
In our case report, we were able to show that the patient in whom an C382R mutation was detected responded to the therapy with pemigatinib. This shows that real-world scenarios differ from the data of the approval studies, thereby illustrating how complex data on patients with FGFR mutations is. One of the main problems of large approval studies is that the functionality of the respective alterations is often disregarded.
Conclusions
Our results suggest that respective mutation may be successfully targeted by FGFR-selective tyrosine-kinase inhibitors, demonstrating the importance of the functional characterization of mutations.
no conflicts of interest.
We present a novel differential relaxation oscillator for inductive power transfer. The proposed oscillator offers an automatic adaption of the oscillation period to a change in the power link impedance, which ensures a high efficient operation for variable loads and coupling factors. A detailed circuit model of the self-oscillation system is provided with analytical design equations. We find a large self-oscillation range for variable coupling factors and loads. The theoretical results are confirmed by circuit simulation and measurements carried out on a low-power demonstrator system. We demonstrate non-resonant and robust self-adaption of the relaxation oscillator to coupling factors ranging from k=0.6-0.9.
A new approach for the friction and wear characterisation of polymer fibres under dry, mixed, and hydrodynamic sliding conditions is developed. The production process of the tested polymer fibres is described and an introduction in fibre-reinforced concrete is given. Tribotesting is done on an optimised tribometer capable of measuring the friction and wear behaviour of polymer fibres with diameters of a few 100 µm under lubricated conditions. Three extruded polypropylene macro fibres with varying diameters are characterised under tribological conditions found in an industrial concrete mixing process. It is shown that detailed friction and wear data of polymer fibres can be gathered.
Point mutations of the fibroblast growth factor receptor (FGFR)2 receptor in intrahepatic cholangiocarcinoma (iCC) are mainly of unknown functional significance compared to FGFR2 fusions. Pemigatinib, a tyrosine kinase inhibitor, is approved for the treatment of cholangiocarcinoma with FGFR2 fusion/rearrangement. Although it is hypothesized that FGFR2 mutations may cause uncontrolled activation of the signaling pathway, the data for targeted therapies for FGFR2 mutations remain unclear. In vitro analyses demonstrated the importance of the p.C382R mutation for ligand-independent constitutive activation of FGFR2 with transforming potential. The following report describes the clinical case of a patient diagnosed with an iCC carrying a FGFR2 p.C382R point mutation which was detected in liquid, as well as in tissue-based biopsies. The patient was treated with pemigatinib, resulting in a sustained complete functional remission in fluorodeoxyglucose-positron emission tomography/computed tomography over 10 months to date. The reported case is the first description of a complete functional remission under the treatment with pemigatinib in a patient with p.C383R mutation.
Adaptable Machining Process Identification based on Expert Knowledge and Artificial Intelligence
(2022)
The demand for product individuality increased enormously in recent years and thus affects directly manufacturers and their employees. Due to the increasing demand for batch-size-one production, every product needs specific manufacturing processes. Usually, employees determine these manufacturing steps with provided product data. This research proposal aims to contribute to the extraction of machining processes from product data and their assignment to suitable machinery. We plan to develop an organic computing system based on artificial intelligence methods to solve these problems by including customer-specific designs and employee expertise. The overall objective is to support employees in manufacturing facilities by simplifying the manufacturer and customer interaction.
In this contribution the frequency domain fluorescence lifetime imaging microscopy (FD-FLIM) technique is evaluated for post-consumer wood sorting. The fluorescence characteristics of several wood samples were determined, whereby two excitation wavelengths (405 and 488 nm) were used. The measured data were processed using algorithmic methods to identify the wood species and post-consumer wood category. With the excitation wavelength of 405 nm, 16 out of 19 samples could be correctly assigned to the corresponding post-consumer wood category by means of the fluorescence lifetimes. Thus, the experimental results revealed the high potential of the FD-FLIM technique for automated post-consumer wood sorting.
Increasing demand for energy-efficient means of transport has steadily intensified the trend towards lightweight components. Thermoplastic glass fiber composites (organo sheets) play a major role in the production of functional automotive components. Organo sheets are cut, shaped and functionalized by injection molding to produce hybrid components, such as those used in car door modules. The cutting process produces a considerable amount of production waste, which has thus far been thermally recycled. This study develops a closed mechanical recycling process and analyzes the different steps of the process. The offcuts were shredded using two shredding methods and implemented directly in the injection-molding process. Using tensile tests and impact bending tests, the material properties of the recycled materials were compared with the virgin material. In addition, fiber length degradation via the injection-molding process and the influence of the waterjet-cutting process on the mechanical properties are investigated. Recycled offcuts are both comparable to new material in terms of mechanical properties and usability, and are also economically and ecologically advantageous. Recycling polypropylene waste with glass fiber reinforcement in a closed loop is an effective way to reduce industrial waste in a sustainable and economical production process.