Anti-EGFR antibody cetuximab is secreted by oral squamous cell carcinoma and alters EGF-driven mesenchymal transition

Genetic amplification, overexpression, and increased signaling from the epidermal growth factor receptor (EGFR) are often found in oral squamous cell carcinoma (OSCC) and thus EGFR is frequently targeted molecularly by the therapeutic antibody cetuximab. We assessed effects of cetuximab in control of EGF-driven malignant traits of OSCC cells. EGF stimulation promoted progression level of mesenchymal traits in OSCC cells, which were attenuated by cetuximab but incompletely. We pursued a potential mechanism underlying such incomplete attenuation of OSCC malignant traits. Cetuximab promoted secretion of EGFR-EVs by OSCC cells and failed to inhibit EGF-driven secretion of EGFR-EVs. Cetuximab was also found to be robustly secreted with the EGFR-EVs by the OSCC cells. Thus, EGF promotes the level of mesenchymal traits of OSCC cells and secretion of EGFR-EVs, which involve cetuximab resistance

Evolutionary continuous cellular automaton for the simulation of wet etching of quartz

Anisotropic wet chemical etching of quartz is a bulk micromachining process for the fabrication of micro-electro-mechanical systems (MEMS), such as resonators and temperature sensors. Despite the success of the continuous cellular automaton for the simulation of wet etching of silicon, the simulation of the same process for quartz has received little attention-especially from an atomistic perspective-resulting in a lack of accurate modeling tools. This paper analyzes the crystallographic structure of the main surface orientations of quartz and proposes a novel classification of the surface atoms as well as an evolutionary algorithm to determine suitable values for the corresponding atomistic removal rates. Not only does the presented evolutionary continuous cellular automaton reproduce the correct macroscopic etch rate distribution for quartz hemispheres, but it is also capable of performing fast and accurate 3D simulations of MEMS structures. This is shown by several comparisons between simulated and experimental results and, in particular, by a detailed, quantitative comparison for an extensive collection of trench profiles. © 2012 IOP Publishing Ltd.We are grateful to D Cheng and K Sato (Nagoya University, Japan) for providing part of the experimental data. We acknowledge support by the JAE-Doc grant form the Junta para la Ampliacion de Estudios program co-funded by FSE, the Ramon y Cajal Fellowship Program by the Spanish Ministry of Science and Innovation, NANO-IKER Project (IE11-304) from the ETORTEK program by the Basque Government and the Professor Partnership Program by NVIDIA Corporation.Ferrando Jódar, N.; Gosalvez Ayuso, MA.; Colom Palero, RJ. (2012). Evolutionary continuous cellular automaton for the simulation of wet etching of quartz. Journal of Micromechanics and Microengineering. 22(2). https://doi.org/10.1088/0960-1317/22/2/025021S222Hida, H., Shikida, M., Fukuzawa, K., Murakami, S., Sato, K., Asaumi, K., … Sato, K. (2008). Fabrication of a quartz tuning-fork probe with a sharp tip for AFM systems. Sensors and Actuators A: Physical, 148(1), 311-318. doi:10.1016/j.sna.2008.08.021Oh, H., Kim, G., Seo, H., Song, Y., Lee, K., & Yang, S. S. (2010). Fabrication of micro-lens array using quartz wet etching and polymer. Sensors and Actuators A: Physical, 164(1-2), 161-167. doi:10.1016/j.sna.2010.10.003Xing, Y., Gosálvez, M. A., & Sato, K. (2007). Step flow-based cellular automaton for the simulation of anisotropic etching of complex MEMS structures. New Journal of Physics, 9(12), 436-436. doi:10.1088/1367-2630/9/12/436Zhou, Z., Huang, Q., Li, W., & Deng, W. (2007). A cellular automaton-based simulator for silicon anisotropic etching processes considering high index planes. Journal of Micromechanics and Microengineering, 17(4), S38-S49. doi:10.1088/0960-1317/17/4/s03Gosalvez, M. A., Yan Xing, & Sato, K. (2008). Analytical Solution of the Continuous Cellular Automaton for Anisotropic Etching. Journal of Microelectromechanical Systems, 17(2), 410-431. doi:10.1109/jmems.2008.916339Zhou, Z., Huang, Q., & Li, W. (2009). Modeling and Simulations of Anisotropic Etching of Silicon in Alkaline Solutions with Experimental Verification. Journal of The Electrochemical Society, 156(2), F29. doi:10.1149/1.3031485Rangsten, P., Hedlund, C., Katardjiev, I. V., & Bäcklund, Y. (1998). Etch rates of crystallographic planes inZ-cut quartz - experiments and simulation. Journal of Micromechanics and Microengineering, 8(1), 1-6. doi:10.1088/0960-1317/8/1/001Tellier, C. R., & Leblois, T. G. (2000). Micromachining of quartz plates: determination of a database by combined stereographic analysis and 3-D simulation of etching shapes. IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control, 47(5), 1204-1216. doi:10.1109/58.869067Hedlund, C., Lindberg, U., Bucht, U., & Soderkvist, J. (1993). Anisotropic etching of Z-cut quartz. Journal of Micromechanics and Microengineering, 3(2), 65-73. doi:10.1088/0960-1317/3/2/006Liang, J., Kohsaka, F., Matsuo, T., & Ueda, T. (2007). Wet Etched High Aspect Ratio Microstructures on Quartz for MEMS Applications. IEEJ Transactions on Sensors and Micromachines, 127(7), 337-342. doi:10.1541/ieejsmas.127.337Gosálvez, M. A., Xing, Y., Sato, K., & Nieminen, R. M. (2009). Discrete and continuous cellular automata for the simulation of propagating surfaces. Sensors and Actuators A: Physical, 155(1), 98-112. doi:10.1016/j.sna.2009.08.012Zhenjun Zhu, & Chang Liu. (2000). Micromachining process simulation using a continuous cellular automata method. Journal of Microelectromechanical Systems, 9(2), 252-261. doi:10.1109/84.846706Gosálvez, M. A., Xing, Y., Sato, K., & Nieminen, R. M. (2008). Atomistic methods for the simulation of evolving surfaces. Journal of Micromechanics and Microengineering, 18(5), 055029. doi:10.1088/0960-1317/18/5/055029Ferrando, N., Gosálvez, M. A., Cerdá, J., Gadea, R., & Sato, K. (2011). Octree-based, GPU implementation of a continuous cellular automaton for the simulation of complex, evolving surfaces. Computer Physics Communications, 182(3), 628-640. doi:10.1016/j.cpc.2010.11.004Mühlenbein, H., & Schlierkamp-Voosen, D. (1993). Predictive Models for the Breeder Genetic Algorithm I. Continuous Parameter Optimization. Evolutionary Computation, 1(1), 25-49. doi:10.1162/evco.1993.1.1.25Kohsaka, F., Liang, J., Matsuo, T., & Ueda, T. (2007). High Sensitive Tilt Sensor for Quartz Micromachining. IEEJ Transactions on Sensors and Micromachines, 127(10), 431-436. doi:10.1541/ieejsmas.127.43

A histological and micro-CT investigation in to the effect of NGF and EGF on the periodontal, alveolar bone, root and pulpal healing of replanted molars in a rat model - a pilot study

Background: This study aims to investigate, utilising micro-computed tomography (micro-CT) and histology, whether the topical application of nerve growth factor (NGF) and/or epidermal growth factor (EGF) can enhance periodontal, alveolar bone, root and pulpal tissue regeneration while minimising the risk of pulpal necrosis, root resorption and ankylosis of replanted molars in a rat model. Methods: Twelve four-week-old male Sprague-Dawley rats were divided into four groups: sham, collagen, EGF and NGF. The maxillary right first molar was elevated and replanted with or without a collagen membrane impregnated with either the growth factors EGF or NGF, or a saline solution. Four weeks after replantation, the animals were sacrificed and the posterior maxilla was assessed using histological and micro-CT analysis. The maxillary left first molar served as the control for the corresponding right first molar. Results: Micro-CT analysis revealed a tendency for all replanted molars to have reduced root length, root volume, alveolar bone height and inter-radicular alveolar bone volume. It appears that the use of the collagen membrane had a negative effect while no positive effect was noted with the incorporation of EGF or NGF. Histologically, the incorporation of the collagen membrane was found to negatively affect pulpal, root, periodontal and alveolar bone healing with pulpal inflammation and hard tissue formation, extensive root resorption and alveolar bone fragmentation. The incorporation of EGF and NGF did not improve root, periodontal or alveolar bone healing. However, EGF was found to improve pulp vascularisation while NGF improved pulpal architecture and cell organisation, although not to the level of the control group.Conclusions: Results indicate a possible benefit on pulpal vascularisation and pulpal cell organisation following the incorporation of EGF and NGF, respectively, into the alveolar socket of replanted molars in the rat model. No potential benefit of EGF and NGF was detected in periodontal or root healing, while the use of a collagen membrane carrier was found to have a negative effect on the healing response

The role of CCN2 in cartilage and bone development

CCN2, a classical member of the CCN family of matricellular proteins, is a key molecule that conducts cartilage development in a harmonized manner through novel molecular actions. During vertebrate development, all cartilage is primarily formed by a process of mesenchymal condensation, while CCN2 is induced to promote this process. Afterwards, cartilage develops into several subtypes with different fates and missions, in which CCN2 plays its proper roles according to the corresponding microenvironments. The history of CCN2 in cartilage and bone began with its re-discovery in the growth cartilage in long bones, which determines the skeletal size through the process of endochondral ossification. CCN2 promotes physiological developmental processes not only in the growth cartilage but also in the other types of cartilages, i.e., Meckel’s cartilage representing temporary cartilage without autocalcification, articular cartilage representing hyaline cartilage with physical stiffness, and auricular cartilage representing elastic cartilage. Together with its significant role in intramembranous ossification, CCN2 is regarded as a conductor of skeletogenesis. During cartilage development, the CCN2 gene is dynamically regulated to yield stage-specific production of CCN2 proteins at both transcriptional and post-transcriptional levels. New functional aspects of known biomolecules have been uncovered during the course of investigating these regulatory systems in chondrocytes. Since CCN2 promotes integrated regeneration as well as generation (=development) of these tissues, its utility in regenerative therapy targeting chondrocytes and osteoblasts is indicated, as has already been supported by experimental evidence obtained in vivo

A multi-targeted approach to suppress tumor-promoting inflammation

Cancers harbor significant genetic heterogeneity and patterns of relapse following many therapies are due to evolved resistance to treatment. While efforts have been made to combine targeted therapies, significant levels of toxicity have stymied efforts to effectively treat cancer with multi-drug combinations using currently approved therapeutics. We discuss the relationship between tumor-promoting inflammation and cancer as part of a larger effort to develop a broad-spectrum therapeutic approach aimed at a wide range of targets to address this heterogeneity. Specifically, macrophage migration inhibitory factor, cyclooxygenase-2, transcription factor nuclear factor-κB, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase B, and CXC chemokines are reviewed as important antiinflammatory targets while curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene, and anthocyanins are reviewed as low-cost, low toxicity means by which these targets might all be reached simultaneously. Future translational work will need to assess the resulting synergies of rationally designed antiinflammatory mixtures (employing low-toxicity constituents), and then combine this with similar approaches targeting the most important pathways across the range of cancer hallmark phenotypes

Depletion of Lipid Efflux Pump ABCG1 Triggers the Intracellular Accumulation of Extracellular Vesicles and Reduces Aggregation and Tumorigenesis of Metastatic Cancer Cells

The ATP-binding cassette transporter G1 (ABCG1) is a cholesterol lipid efflux pump whose role in tumor growth has been largely unknown. Our transcriptomics revealed that ABCG1 was powerfully expressed in rapidly metastatic, aggregative colon cancer cells, in all the ABC transporter family members. Coincidently, genetic amplification of ABCG1 is found in 10–35% of clinical samples of metastatic cancer cases. Expression of ABCG1 was further elevated in three-dimensional tumoroids (tumor organoids) within stemness-enhancing tumor milieu, whereas depletion of ABCG1 lowered cellular aggregation and tumoroid growth in vitro as well as hypoxia-inducible factor 1α in cancer cells around the central necrotic areas in tumors in vivo. Notably, depletion of ABCG1 triggered the intracellular accumulation of extracellular vesicles (EVs) and regression of tumoroids. Collectively, these data suggest that ABCG1 plays a crucial role in tumorigenesis in metastatic cancer and that depletion of ABCG1 triggers tumor regression with the accumulation of EVs and their derivatives and cargos, implicating a novel ABCG1-targeting therapeutic strategy by which redundant and toxic substances may be accumulated in tumors leading to their regression

A Case of Unerupted Lower Primary Second Molar Associated with Compound Odontoma

Odontoma is the most common type of benign odontogenic tumor, and often causes disturbances in the eruption of its associated tooth. Odontomas usually occur in the permanent dentition, and rarely occur solely in the primary dentition. This case report documents a six-year-old-child with a compound odontoma located in the mandible, which caused the impaction of the primary second molar

Mdm20 Stimulates PolyQ Aggregation via Inhibiting Autophagy Through Akt-Ser473 Phosphorylation

Mdm20 is an auxiliary subunit of the NatB complex, which includes Nat5, the catalytic subunit for protein N-terminal acetylation. The NatB complex catalyzes N-acetylation during de novo protein synthesis initiation; however, recent evidence from yeast suggests that NatB also affects post-translational modification of tropomyosin, which is involved in intracellular sorting of aggregated proteins. We hypothesized that an acetylation complex such as NatB may contribute to protein clearance and/or proteostasis in mammalian cells. Using a poly glutamine (polyQ) aggregation system, we examined whether the NatB complex or its components affect protein aggregation in rat primary cultured hippocampal neurons and HEK293 cells. The number of polyQ aggregates increased in Mdm20 over-expressing (OE) cells, but not in Nat5-OE cells. Conversely, in Mdm20 knockdown (KD) cells, but not in Nat5-KD cells, polyQ aggregation was significantly reduced. Although Mdm20 directly associates with Nat5, the overall cellular localization of the two proteins was slightly distinct, and Mdm20 apparently co-localized with the polyQ aggregates. Furthermore, in Mdm20-KD cells, a punctate appearance of LC3 was evident, suggesting the induction of autophagy. Consistent with this notion, phosphorylation of Akt, most notably at Ser473, was greatly reduced in Mdm20-KD cells. These results demonstrate that Mdm20, the so-called auxiliary subunit of the translation-coupled protein N-acetylation complex, contributes to protein clearance and/or aggregate formation by affecting the phosphorylation level of Akt indepenently from the function of Nat5