It is increasingly appreciated that 3D cultures are more predictive of
therapeutic efficacy than 2D cultures. Using
3D type I collagen cultures of human colorectal cancer (CRC) cell line HCA-7 ...derivatives CC, SC, and CC-CR, we previously identified that activation of receptor tyrosine kinases (RTKs) MET and RON contributed to resistance to the EGF receptor (EGFR)-directed therapeutic antibody cetuximab. The
mode of cetuximab resistance in SC cells could be overcome by crizotinib, a multi-RTK inhibitor that also targets MET and RON. We now show that crizotinib also overcomes acquired cetuximab resistance in CC-CR cells. Phospho-RTK array analysis showed increased phosphorylation of several RTKs, including MET and RON, in SC and CC-CR cells compared to cetuximab-sensitive CC counterparts. Furthermore, other multi-RTK inhibitors cabozantinib and BMS-777607 helped overcome cetuximab resistance, as measured by 3D colony growth and activation state of key signaling molecules. Conversely, addition of RTK ligands HGF and NRG1 induced cetuximab resistance in CC cells, which could be blocked by addition of crizotinib. We further determined the mechanism of the cooperative effect of cetuximab and crizotinib by FACS analysis and observed increased cell cycle arrest in G1 phase in cetuximab-resistant CRC 3D cultures. Finally, we show that crizotinib overcomes cetuximab resistance
in SC nude mice xenografts. Thus, our work shows that multi-RTK inhibition strategy is a potent, broadly applicable strategy to overcome resistance to EGFR-targeted therapeutics in CRC and highlights the relevance of 3D cultures in these studies. Statement of implication: Using
3D CRC cultures and
CRC xenografts, we show that parallel inhibition of multiple RTKs with small molecule inhibitors overcomes
and acquired resistance to EGFR-directed therapies in CRC.
Global Navigation Satellite Systems (GNSS) have revolutionized land surveying, by determining position coordinates with centimeter-level accuracy in real-time or up to sub-millimeter accuracy in ...post-processing solutions. Although low-cost single-frequency receivers do not meet the accuracy requirements of many surveying applications, multi-frequency hardware is expected to overcome the major issues. Therefore, this paper is aimed at investigating the performance of a u-blox ZED-F9P receiver, connected to a u-blox ANN-MB-00-00 antenna, during multiple field experiments. Satisfactory signal acquisition was noticed but it resulted as >7 dB Hz weaker than with a geodetic-grade receiver, especially for low-elevation mask signals. In the static mode, the ambiguity fixing rate reaches 80%, and a horizontal accuracy of few centimeters was achieved during an hour-long session. Similar accuracy was achieved with the Precise Point Positioning (PPP) if a session is extended to at least 2.5 h. Real-Time Kinematic (RTK) and Network RTK measurements achieved a horizontal accuracy better than 5 cm and a sub-decimeter vertical accuracy. If a base station constituted by a low-cost receiver is used, the horizontal accuracy degrades by a factor of two and such a setup may lead to an inaccurate height determination under dynamic surveying conditions, e.g., rotating antenna of the mobile receiver.
Members of the CD44 family of transmembrane glycoproteins emerge as major signal transduction control units. CD44 isoforms participate in several signaling pathways ranging from growth factor-induced ...signaling to Wnt-regulated pathways. The role of the CD44 family members in tumor progression and metastasis is most likely linked to the function of the various isoforms as signaling hubs. Increasing evidence suggests that these proteins are not solely cancer stem cell (CSC) markers but are directly involved in tumor and metastasis initiation. It is foreseeable that a link between the expression of CD44 isoforms in CSCs and their function as signaling regulators will be drawn in a near future.
A synthesis of two prevailing global navigation satellite system positioning technologies, namely the precise point positioning and the network-based real-time kinematic, results in the emergence of ...the PPP-RTK, enabling single-receiver users to achieve high positioning accuracy with reasonable timeliness through integer ambiguity resolution. The realization of PPP-RTK needs to accomplish two sequential tasks. The first task is to determine a class of corrections including, among others, the satellite phase biases (SPBs) at the network level. With these corrections, the second task, then, is to solve for the ambiguity-fixed, absolute position at the user level. In this contribution, we revisit three variants (geometry-free, geometry-fixed and geometry-plus-satellite-clock-fixed) of the undifferenced and uncombined PPP-RTK network model and then point out their implications for practical use. We also carry out a case study using multi-day, dual-frequency global positioning system data from the crustal movement observation network of China stations, aiming to figure out what are the most appropriate linear combinations of the SPBs to be transmitted to the users from the viewpoint of decorrelation, and to assess the static and kinematic positioning performance.
ABSTRACT
A geophysical exploration employing ground‐penetrating radar (GPR) and electrical resistivity tomography (ERT) was conducted at the Western Cemetery, Giza, Egypt, in 2021–23 by a joint ...research team of Higashi Nippon International University, Tohoku University and the National Research Institute of Astronomy and Geophysics (NRIAG), Helwan, Egypt. We believe we found an anomaly: a combination of a shallow structure connected to a deeper structure. The shallow structure, which is L‐shaped in the horizontal plane, 10 m by 10 m, was clearly imaged by GPR. It seems to have been filled with sand, which means it was backfilled after it was constructed. It may have been an entrance to the deeper structure. Its depth is of up to 2 m, measured from the ground surface. Below this structure, ERT reveals a highly electrically resistive anomaly, which extends over an area of about 10 m by 10 m. The depth of the structure is about 5–10 m below the surface. Electrically resistive material in a sand dune can be a mixture of sand and gravel, including sparse spacing or air voids within it. Neither GPR nor ERT could identify the properties of the anomaly.
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•Receptor tyrosine kinases (RTKs) regulate pivotal cellular processes and are dysregulated in cancer.•RTKs are extensively glycosylated and this modification affects cellular ...functions of these receptors.•Galectins are carbohydrate binding proteins implicated in developmental processes and cancers. Galectins directly and indirectly affect RTKs, modulating RTKs activation, their cross-talk with other cell surface proteins and their cellular trafficking.•Galectins are responsible for oncogenic activation of RTKs.•RTK-galectin interplay constitutes an attractive target for development of anti-cancer therapies.
Receptor tyrosine kinases (RTKs) constitute a large group of cell surface proteins that mediate communication of cells with extracellular environment. RTKs recognize external signals and transfer information to the cell interior, modulating key cellular activities, like metabolism, proliferation, motility, or death. To ensure balanced stream of signals the activity of RTKs is tightly regulated by numerous mechanisms, including receptor expression and degradation, ligand specificity and availability, engagement of co-receptors, cellular trafficking of the receptors or their post-translational modifications. One of the most widespread post-translational modifications of RTKs is glycosylation of their extracellular domains. The sugar chains attached to RTKs form a new layer of information, so called glyco-code that is read by galectins, carbohydrate binding proteins. Galectins are family of fifteen lectins implicated in immune response, inflammation, cell division, motility and death. The versatility of cellular activities attributed to galectins is a result of their high abundance and diversity of their cellular targets. A various sugar specificity of galectins and the differential ability of galectin family members to form oligomers affect the spatial distribution and the function of their cellular targets. Importantly, galectins and RTKs are tightly linked to the development, progression and metastasis of various cancers. A growing number of studies points on the close cooperation between RTKs and galectins in eliciting specific cellular responses. This review focuses on the identified complexes between galectins and RTK members and discusses their relevance for the cell physiology both in healthy tissues and in cancer.
We simulate some scenarios that 2/3 LEO satellites enhance 3/4/5 GPS satellites, to assess LEO-augmented GPS RTK positioning in signal-degraded environment. The effects of LEO-augmented GPS RTK in ...terms of reliability, availability and accuracy are presented, and the DIA algorithm is applied to deal with the poor data quality.
The combination of BRAF and MEK inhibitors (BRAFi/MEKi) has shown promising response rates in treating BRAF-mutant melanoma by inhibiting ERK activation. However, treatment efficacy is limited by the ...emergence of drug-tolerant persister cells (persisters). Here, we show that the magnitude and duration of receptor tyrosine kinase (RTK) activation determine ERK reactivation and persister development. Our single-cell analysis reveals that only a small subset of melanoma cells exhibits effective RTK and ERK activation and develops persisters, despite uniform external stimuli. The kinetics of RTK activation directly influence ERK signaling dynamics and persister development. These initially rare persisters form major resistant clones through effective RTK-mediated ERK activation. Consequently, limiting RTK signaling suppresses ERK activation and cell proliferation in drug-resistant cells. Our findings provide non-genetic mechanistic insights into the role of heterogeneity in RTK activation kinetics in ERK reactivation and BRAFi/MEKi resistance, suggesting potential strategies for overcoming drug resistance in BRAF-mutant melanoma.
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•RTK activation causes ERK reactivation and BRAF/MEK-inhibitor-tolerant persister cells•RTK activation kinetics govern ERK signaling dynamics and persister development•Alterations in ERK signaling dynamics are associated with BRAF/MEK-inhibitor resistance•BRAF/MEK-inhibitor resistance can be reversed by limiting RTK signaling
Kim et al. show that the strength and duration of receptor tyrosine kinase (RTK) activation regulate ERK reactivation and the development of BRAFi/MEKi-tolerant persister cells in BRAF-mutant melanoma. These persister cells eventually become the dominant population in established resistance. Limiting RTK signaling can reverse the BRAFi/MEKi-resistant state.
PPP-RTK which takes full advantages of both Real-Time Kinematic (RTK) and Precise Point Positioning (PPP), is able to provide centimeter-level positioning accuracy with rapid integer Ambiguity ...Resolution (AR). In recent years, with the development of BeiDou Navigation Satellite System (BDS) and Galileo navigation satellite system (Galileo) as well as the modernization of Global Positioning System (GPS) and GLObal NAvigation Satellite System (GLONASS), more than 140 Global Navigation Satellite System (GNSS) satellites are available. Particularly, the new-generation GNSS satellites are capable of transmitting signals on three or more frequencies. Multi-GNSS and multi-frequency observations become available and can be used to enhance the performance of PPP-RTK. In this contribution, we develop a multi-GNSS and multi-frequency PPP-RTK model, which uses all the available GNSS observations, and comprehensively evaluate its performance in urban environments from the perspectives of positioning accuracy, convergence and fixing percentage. In this method, the precise atmospheric corrections are derived from the multi-frequency and multi-GNSS observations of a regional network, and then disseminated to users to achieve PPP rapid AR. Furthermore, a cascade ambiguity fixing strategy using Extra‐Wide‐Lane (EWL), Wide-Lane (WL) and L1 ambiguities is employed to improve the performance of ambiguity fixing in the urban environments. Vehicle experiments in different scenarios such as suburbs, overpasses, and tunnels are conducted to validate the proposed method. In suburbs, an accuracy of within 2 cm in the horizontal direction and 4 cm in the vertical direction, with the fixing percentage of 93.7% can be achieved. Compared to the GPS-only solution, the positioning accuracy is improved by 87.6%. In urban environments where signals are interrupted frequently, a fast ambiguity re-fixing can be achieved within 5 s. Moreover, multi-frequency GNSS signals can further improve the positioning performance of PPP-RTK, particularly in the case of small amount of observations. These results demonstrate that the multi-frequency and multi-GNSS PPP-RTK is a promising tool for supporting precise vehicle navigation.
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•A new critical role of STEAP3 in OA progression.•The functional partners of STEAP3 were identified in rat chondrocytes.•The mechanism of STEAP3 effects was revealed in OA ...progression.•The results provide the potential of new drug for the progression and treatment of OA.
Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation and inflammation. The molecular mechanisms underlying OA progression remain incompletely understood. In this study, we investigated the role of STEAP3 (Six Transmembrane Epithelial Antigen of the Prostate 3) in the development of OA. Our results demonstrated that STEAP3 was upregulated in OA cartilage tissues and contributes to the progression of the disease. To elucidate the mechanism, we employed transcriptomic and interaction proteomics analysis, and identified dysregulated genes and pathways associated with STEAP3 overexpression. Specifically, we found that STEAP3 interacted with Rab7A, a protein involved in intracellular trafficking and autophagy, and suppressed its activity. In addition, STEAP3 interacted with activated C kinase 1 (RACK1) and enhanced its activity. Furthermore, our data indicated that the suppression of Rab7A activity by STEAP3 promoted the activation of receptor tyrosine kinases (RTKs) and the promoting effects of RACK1 by STEAP3, both of which in turn activated the MAPK and JAK/STAT signaling pathways. In conclusion, our findings highlighted the role of STEAP3 in promoting OA progression. By inhibiting Rab7A activity and promoting RACK1 activity, STEAP3 enhanced inflammation through the activation of RTKs and subsequent activation of the MAPK and JAK/STAT signaling pathways. Targeting STEAP3 may provide a potential therapeutic strategy for the treatment of OA by modulating these interconnected pathways.
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