MEK inhibition synergizes with TYK2 inhibitors in NF1-associated malignant peripheral nerve sheath tumors

PURPOSE: Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas with limited treatment options and poor survival rates. About half of MPNST cases are associated with the neurofibromatosis type 1 (NF1) cancer predisposition syndrome. Overexpression of TYK2 occurs in the majority of MPNST, implicating TYK2 as a therapeutic target. EXPERIMENTAL DESIGN: The effects of pharmacologic TYK2 inhibition on MPNST cell proliferation and survival were examined using IncuCyte live cell assays in vitro, and downstream actions were analyzed using RNA-sequencing (RNA-seq), qPCR arrays, and validation of protein changes with the WES automated Western system. Inhibition of TYK2 alone and in combination with MEK inhibition was evaluated in vivo using both murine and human MPNST cell lines, as well as MPNST PDX. RESULTS: Pharmacologic inhibition of TYK2 dose-dependently decreased proliferation and induced apoptosis over time. RNA-seq pathway analysis on TYK2 inhibitor-treated MPNST demonstrated decreased expression of cell cycle, mitotic, and glycolysis pathways. TYK2 inhibition resulted in upregulation of the MEK/ERK pathway gene expression, by both RNA-seq and qPCR array, as well as increased pERK1/2 levels by the WES Western system. The compensatory response was tested with dual treatment with TYK2 and MEK inhibitors, which synergistically decreased proliferation and increased apoptosis in vitro. Finally, combination therapy was shown to inhibit growth of MPNST in multiple in vivo models. CONCLUSIONS: These data provide the preclinical rationale for the development of a phase I clinical trial of deucravacitinib and mirdametinib in NF1-assosciated MPNST

Discutindo a educação ambiental no cotidiano escolar: desenvolvimento de projetos na escola formação inicial e continuada de professores

A presente pesquisa buscou discutir como a Educação Ambiental (EA) vem sendo trabalhada, no Ensino Fundamental e como os docentes desta escola compreendem e vem inserindo a EA no cotidiano escolar., em uma escola estadual do município de Tangará da Serra/MT, Brasil. Para tanto, realizou-se entrevistas com os professores que fazem parte de um projeto interdisciplinar de EA na escola pesquisada. Verificou-se que o projeto da escola não vem conseguindo alcançar os objetivos propostos por: desconhecimento do mesmo, pelos professores; formação deficiente dos professores, não entendimento da EA como processo de ensino-aprendizagem, falta de recursos didáticos, planejamento inadequado das atividades. A partir dessa constatação, procurou-se debater a impossibilidade de tratar do tema fora do trabalho interdisciplinar, bem como, e principalmente, a importância de um estudo mais aprofundado de EA, vinculando teoria e prática, tanto na formação docente, como em projetos escolares, a fim de fugir do tradicional vínculo “EA e ecologia, lixo e horta”.Facultad de Humanidades y Ciencias de la Educació

Implantatkörper mit Wirkstoffträgerschicht und Abgabekontrollschicht

The invention relates to an implant body comprising a substrate (3) and, on the surface thereof, a layer system consisting of an active substance carrier layer (2) and a release control layer (1) arranged on same, said active substance carrier layer having a plurality of open pores (4), and said release control layer (1) being a layer that is deposited from the gas phase and that reduces the area of the pore opening of the pores (4) of the active substance carrier layer (2) without closing them

Antibiotic-loaded amphora-shaped pores on a titanium implant surface enhance osteointegration and prevent infections

Artificial prostheses for joint replacement are indispensable in orthopedic surgery. Unfortunately, the implanted surface is attractive to not only host cells but also bacteria. To enable better osteointegration, a mechanically stable porous structure was created on a titanium surface using laser treatment and metallic silver particles were embedded in a hydrophilic titanium oxide layer on top. The laser structuring resulted in unique amphora-shaped pores. Due to their hydrophilic surface conditions and capillary forces, the pores can be loaded preoperative with the antibiotic of choice/need, such as gentamicin. Cytotoxicity and differentiation assays with primary human osteoblast-like cells revealed no negative effect of the surface modification with or without gentamicin loading. An in vivo biocompatibility study showed significantly enhanced osteointegration as measured by push-out testing and histomorphometry 56 days after the implantation of the K-wires into rat femora. Using a S. aureus infection model, the porous, silver-coated K-wires slightly reduced the signs of bone destruction, while the wires were still colonized after 28 days. Loading the amphora-shaped pores with gentamicin significantly reduced the histopathological signs of bone destruction and no bacteria were detected on the wires. Taken together, this novel surface modification can be applied to new or established orthopedic implants. It enables preoperative loading with the antibiotic of choice/need without further equipment or post-coating, and supports osteointegration without a negative effect of the released dug, such as gentamicin.233123456

Impact of Laser Structuring on Medical-Grade Titanium: Surface Characterization and In Vitro Evaluation of Osteoblast Attachment

Improved implant osteointegration offers meaningful potential for orthopedic, spinal, and dental implants. In this study, a laser treatment was used for the structuring of a titanium alloy (Ti6Al4V) surface combined with a titanium dioxide coating, whereby a porous surface was created. The objective was to characterize the pore structure shape, treatment-related metallographic changes, cytocompatibility, and attachment of osteoblast-like cells (MG-63). The treatment generated specific bottleneck pore shapes, offering the potential for the interlocking of osteoblasts within undercuts in the implant surface. The pore dimensions were a bottleneck diameter of 27 µm (SD: 4 µm), an inner pore width of 78 µm (SD: 6 µm), and a pore depth of 129 µm (SD: 8 µm). The introduced energy of the laser changed the metallic structure of the alloy within the heat-affected region (approximately 66 µm) without any indication of a micro cracking formation. The phase of the alloy (microcrystalline alpha + beta) was changed to a martensite alpha phase in the surface region and an alpha + beta phase in the transition region between the pores. The MG-63 cells adhered to the structured titanium surface within 30 min and grew with numerous filopodia over and into the pores over the following days. Cell viability was improved on the structured surface compared to pure titanium, indicating good cytocompatibility. In particular, the demonstrated affinity of MG-63 cells to grow into the pores offers the potential to provide significantly improved implant fixation in further in vivo studies

Current State of Bone Adhesives—Necessities and Hurdles

The vision of gluing two bone fragments with biodegradable and biocompatible adhesives remains highly fascinating and attractive to orthopedic surgeons. Possibly shorter operation times, better stabilization, lower infection rates, and unnecessary removal make this approach very appealing. After 30 years of research in this field, the first adhesive systems are now appearing in scientific reports that may fulfill the comprehensive requirements of bioadhesives for bone. For a successful introduction into clinical application, special requirements of the musculoskeletal system, challenges in the production of a bone adhesive, as well as regulatory hurdles still need to be overcome. In this article, we will give an overview of existing synthetic polymers, biomimetic, and bio-based adhesive approaches, review the regulatory hurdles they face, and discuss perspectives of how bone adhesives could be efficiently introduced into clinical application, including legal regulations

99mTc-HDP Labeling—A Non-Destructive Method for Real-Time Surveillance of the Osteogenic Differentiation Potential of hMSC during Ongoing Cell Cultures

99-Metastabil Technetium (99mTc) is a radiopharmaceutical widely used in skeletal scintigraphy. Recent publications show it can also be used to determine the osteogenic potential of human mesenchymal stem cells (hMSCs) by binding to hydroxyapatite formed during bone tissue engineering. This field lacks non-destructive methods to track live osteogenic differentiation of hMSCs. However, no data about the uptake kinetics of 99mTc and its effect on osteogenesis of hMSCs have been published yet. We therefore evaluated the saturation time of 99mTc by incubating hMSC cultures for different periods, and the saturation concentration by using different amounts of 99mTc activity for incubation. The influence of 99mTc on osteogenic potential of hMSCs was then evaluated by labeling a continuous hMSC culture three times over the course of 3 weeks, and comparing the findings to cultures labeled once. Our findings show that 99mTc saturation time is less than 0.25 h, and saturation concentration is between 750 and 1000 MBq. Repeated exposure to γ-radiation emitted by 99mTc had no negative effects on hMSC cultures. These new insights can be used to make this highly promising method broadly available to support researchers in the field of bone tissue engineering using this method to track and evaluate, in real-time, the osteogenic differentiation of hMSC, without any negative influence on the cell viability, or their osteogenic differentiation potential

Chemical characterization of the adhesive secretions of the salamander Plethodon shermani (Caudata, Plethodontidae)

Salamanders have developed a wide variety of antipredator mechanisms, including tail autotomy, colour patterns, and noxious skin secretions. As an addition to these tactics, the red-legged salamander (Plethodon shermani) uses adhesive secretions as part of its defensive strategy. The high bonding strength, the fast-curing nature, and the composition of the biobased materials makes salamander adhesives interesting for practical applications in the medical sector. To understand the adhesive secretions of P. shermani, its components were chemically analysed by energy dispersive X-ray spectroscopy (EDX), inductively coupled plasma mass spectrometry (ICP-MS), amino acid analysis, and spectroscopy (ATR-IR, Raman). In addition, proteins were separated by gel-electrophoresis and selected spots were characterised by peptide mass fingerprinting. The salamander secretion contains a high amount of water and predominantly proteins (around 77% in the dry stage). The gel-electrophoresis and peptide mass fingerprint analyses revealed a de novo set of peptides/proteins, largely with a pI between 5.0 and 8.0 and a molecular mass distribution between 10 and 170 kDa. Only low homologies with other proteins present in known databases could be identified. The results indicate that the secretions of the salamander Plethodon clearly differ chemically from those shown for other glue-producing terrestrial or marine species and thus represent a unique glue system