Experimental assessment of skull aberration and transmission loss at 270 kHz for focused ultrasound stimulation of the primary visual cortex

Transcranial focused ultrasound is a rapidly emerging method for non-invasive neuromodulation and stimulation. However, the skull causes a significant acoustic barrier and can reduce the focal intensity and alter the position and shape of the focus compared to free-field. In this study, the insertion loss and focal distortion due to the skull bone were quantified using three ex vivo human skulls and a focused ultrasound transducer operating at 270 kHz targeted on the approximate positions of the left and right primary visual cortex. Compared to free-field, the average insertion loss was -9.8 dB (± 2.2 dB), while the average focal shift was 1.7 mm (± 0.56 mm) in the lateral direction and 2.8 mm (±4.2 mm) in the axial direction. Overall, the acoustic aberrations were small compared to the size of the focal volume, meaning effective stimulation at this frequency can likely be achieved without patient-specific targeting. However, the insertion loss was significant and should be considered when selecting the target focal intensity for human studies

Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe toxicity.

The majority of chimeric antigen receptor (CAR) T-cell research has focused on attacking cancer cells. Here, we show that targeting the tumor-promoting, nontransformed stromal cells using CAR T cells may offer several advantages. We developed a retroviral CAR construct specific for the mouse fibroblast activation protein (FAP), comprising a single-chain Fv FAP [monoclonal antibody (mAb) 73.3] with the CD8α hinge and transmembrane regions, and the human CD3ζ and 4-1BB activation domains. The transduced muFAP-CAR mouse T cells secreted IFN-γ and killed FAP-expressing 3T3 target cells specifically. Adoptively transferred 73.3-FAP-CAR mouse T cells selectively reduced FAP(hi) stromal cells and inhibited the growth of multiple types of subcutaneously transplanted tumors in wild-type, but not FAP-null immune-competent syngeneic mice. The antitumor effects could be augmented by multiple injections of the CAR T cells, by using CAR T cells with a deficiency in diacylglycerol kinase, or by combination with a vaccine. A major mechanism of action of the muFAP-CAR T cells was the augmentation of the endogenous CD8(+) T-cell antitumor responses. Off-tumor toxicity in our models was minimal following muFAP-CAR T-cell therapy. In summary, inhibiting tumor growth by targeting tumor stroma with adoptively transferred CAR T cells directed to FAP can be safe and effective, suggesting that further clinical development of anti-human FAP-CAR is warranted

IL-21 promotes the expansion of CD27+CD28+ tumor infiltrating lymphocytes with high cytotoxic potential and low collateral expansion of regulatory T cells

Contains fulltext : 118572.pdf (publisher's version ) (Open Access)BACKGROUND: Adoptive cell transfer of tumor infiltrating lymphocytes has shown clinical efficacy in the treatment of melanoma and is now also being explored in other tumor types. Generation of sufficient numbers of effector T cells requires extensive ex vivo expansion, often at the cost of T cell differentiation and potency. For the past 20 years, IL-2 has been the key cytokine applied in the expansion of TIL for ACT. However, the use of IL-2 has also led to collateral expansion of regulatory T cells (Tregs) and progressive T cell differentiation, factors known to limit in vivo persistence and activity of transferred TIL. The use of alternative T cell growth factors is therefore warranted. Here, we have compared the effects of IL-2, -15 and -21 cytokines on the expansion and activation of TIL from single-cell suspensions of non-small cell lung cancer, ovarian cancer and melanoma. METHODS: We applied the K562-based artificial APC (aAPC) platform for the direct and rapid expansion of tumor infiltrating lymphocytes isolated from primary cancer specimens. These aAPC were engineered to express the Fc-gamma receptor CD32 (for anti-CD3 antibody binding), the co-stimulatory molecule 4-1BBL, and to secrete either IL-2, IL-15 or IL-21 cytokine. RESULTS: Although IL-2 aAPC induced the greatest overall TIL expansion, IL-21 aAPC induced superior expansion of CD8+ T cells with a CD27+CD28+ "young" phenotype and superior functional cytotoxic effector characteristics, without collateral expansion of Tregs. CONCLUSION: Our data rationalize the clinical application of IL-21-secreting aAPC as a standardized cell-based platform in the expansion of "young" effector TIL for ACT

The effect of an external magnetic force on cell adhesion and proliferation of magnetically labeled mesenchymal stem cells

<p>Abstract</p> <p>Background</p> <p>As the strategy for tissue regeneration using mesenchymal stem cells (MSCs) for transplantation, it is necessary that MSCs be accumulated and kept in the target area. To accumulate MSCs effectively, we developed a novel technique for a magnetic targeting system with magnetically labeled MSCs and an external magnetic force. In this study, we examined the effect of an external magnetic force on magnetically labeled MSCs in terms of cell adhesion and proliferation.</p> <p>Methods</p> <p>Magnetically labeled MSCs were plated at the bottom of an insert under the influence of an external magnetic force for 1 hour. Then the inserts were turned upside down for between 1 and 24 hours, and the number of MSCs which had fallen from the membrane was counted. The gene expression of MSCs affected magnetic force was analyzed with microarray. In the control group, the same procedure was done without the external magnetic force.</p> <p>Results</p> <p>At 1 hour after the inserts were turned upside down, the average number of fallen MSCs in the magnetic group was significantly smaller than that in the control group, indicating enhanced cell adhesion. At 24 hours, the average number of fallen MSCs in the magnetic group was also significantly smaller than that in control group. In the magnetic group, integrin alpha2, alpha6, beta3 BP, intercellular adhesion molecule-2 (ICAM-2), platelet/endothelial cell adhesion molecule-1 (PECAM-1) were upregulated. At 1, 2 and 3 weeks after incubation, there was no statistical significant difference in the numbers of MSCs in the magnetic group and control group.</p> <p>Conclusions</p> <p>The results indicate that an external magnetic force for 1 hour enhances cell adhesion of MSCs. Moreover, there is no difference in cell proliferation after using an external magnetic force on magnetically labeled MSCs.</p

Efficient finite element methodology based on cartesian grids: application to structural shape optimization

This work presents an analysis methodology based on the use of the Finite Element Method (FEM) nowadays considered one of the main numerical tools for solving Boundary Value Problems (BVPs). The proposed methodology, so-called cg-FEM (Cartesian grid FEM), has been implemented for fast and accurate numerical analysis of 2D linear elasticity problems. The traditional FEM uses geometry-conforming meshes; however, in cg-FEM the analysis mesh is not conformal to the geometry. This allows for defining very efficient mesh generation techniques and using a robust integration procedure, to accurately integrate the domain's geometry. The hierarchical data structure used in cg-FEM together with the Cartesian meshes allow for trivial data sharing between similar entities. The cg-FEM methodology uses advanced recovery techniques to obtain an improved solution of the displacement and stress fields (for which a discretization error estimator in energy norm is available) that will be the output of the analysis. All this results in a substantial increase in accuracy and computational efficiency with respect to the standard FEM. cg-FEM has been applied in structural shape optimization showing robustness and computational efficiency in comparison with FEM solutions obtained with a commercial code, despite the fact that cg-FEM has been fully implemented in MATLAB.This work has been developed within the framework of research project DPI2010-20542 of the Ministerio de Economia y Competitividad (Spain). The financial support of the FPU program (AP2008-01086), the funding from Universitat Politecnica de Valencia, and Generalitat Valenciana (PROMETEO/2012/023) are also acknowledged. The authors also thank the support of the Framework Programme 7 Initial Training Network Funding under Grant no. 289361 "Integrating Numerical Simulation and Geometric Design Technology."Nadal, E.; Ródenas, J.; Albelda Vitoria, J.; Tur Valiente, M.; Tarancón Caro, JE.; Fuenmayor Fernández, FJ. (2013). Efficient finite element methodology based on cartesian grids: application to structural shape optimization. Abstract and Applied Analysis. 2013:1-19. https://doi.org/10.1155/2013/953786S1192013Moés, N., Dolbow, J., & Belytschko, T. (1999). A finite element method for crack growth without remeshing. International Journal for Numerical Methods in Engineering, 46(1), 131-150. doi:10.1002/(sici)1097-0207(19990910)46:13.0.co;2-jSukumar, N., & Prévost, J.-H. (2003). Modeling quasi-static crack growth with the extended finite element method Part I: Computer implementation. 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Topology design for multiple loading conditions of continuum structures using isolines and isosurfaces. Finite Elements in Analysis and Design, 46(3), 229-237. doi:10.1016/j.finel.2009.09.003Parussini, L., & Pediroda, V. (2009). Fictitious Domain approach with hp-finite element approximation for incompressible fluid flow. Journal of Computational Physics, 228(10), 3891-3910. doi:10.1016/j.jcp.2009.02.019Bishop, J. (2003). Rapid stress analysis of geometrically complex domains using implicit meshing. Computational Mechanics, 30(5-6), 460-478. doi:10.1007/s00466-003-0424-5Zhang, L., Gerstenberger, A., Wang, X., & Liu, W. K. (2004). Immersed finite element method. Computer Methods in Applied Mechanics and Engineering, 193(21-22), 2051-2067. doi:10.1016/j.cma.2003.12.044Roma, A. M., Peskin, C. S., & Berger, M. J. (1999). An Adaptive Version of the Immersed Boundary Method. Journal of Computational Physics, 153(2), 509-534. doi:10.1006/jcph.1999.6293García‐Ruíz, M. J., & Steven, G. P. 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Equilibrated patch recovery error estimates: simple and accurate upper bounds of the error. International Journal for Numerical Methods in Engineering, 69(10), 2075-2098. doi:10.1002/nme.1837Ródenas, J. J., González-Estrada, O. A., Díez, P., & Fuenmayor, F. J. (2010). Accurate recovery-based upper error bounds for the extended finite element framework. Computer Methods in Applied Mechanics and Engineering, 199(37-40), 2607-2621. doi:10.1016/j.cma.2010.04.010Ainsworth, M., & Oden, J. T. (2000). A Posteriori Error Estimation in Finite Element Analysis. doi:10.1002/9781118032824Xiao, Q. Z., & Karihaloo, B. L. (2006). Improving the accuracy of XFEM crack tip fields using higher order quadrature and statically admissible stress recovery. International Journal for Numerical Methods in Engineering, 66(9), 1378-1410. doi:10.1002/nme.1601Bordas, S., & Duflot, M. (2007). Derivative recovery and a posteriori error estimate for extended finite elements. 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Propuesta metodológica para la evaluación de competencias transversales en el Máster en Ingeniería Mecánica de la Universitat Politècnica de València

[ES] En esta comunicación se presentan los trabajos desarrollados en el marco de un proyecto de innovación y mejora educativa llevado a cabo durante los dos últimos cursos en el Máster Universitario en Ingeniería Mecánica de la Universitat Politècnica de València. Uno de los principales objetivos de este proyecto es el desarrollo y puesta en marcha de nuevas metodologías para la evaluación de competencias transversales. Entre estas nuevas metodologías está una aproximación mediante el aprendizaje basado en proyectos, que permite incorporar la evaluación de algunas competencias transversales que no se hacía de forma adecuada con anterioridad. En esta línea se han coordinado varias asignaturas, se ha planteado un nuevo tipo de Trabajo Fin de Máster, con la colaboración de una empresa, y se han diseñado nuevas herramientas de evaluación.[EN] This contribution presents the work carried out within the framework of an educational innovation and improvement project developed during the last two years in the Master's Degree in Mechanical Engineering at the Technical University of Valencia. One of the main objectives of this project is the development and implementation of new methodologies for the evaluation of generic competences. Among these new methodologies, there is an approach through projectbased learning, which allows for the incorporation of the assessment of some generic competences that was not done previously in a proper way. Therefore, several subjects have been coordinated, a new type of Master’s Thesis has been proposed, with the collaboration of a company, and new assessment tools have been designedCarballeira, J.; Tur, M.; Besa, AJ.; Albelda J.; Tarancón, JE.; Martínez-Casas, J.; Denia, FD.... (2021). Propuesta metodológica para la evaluación de competencias transversales en el Máster en Ingeniería Mecánica de la Universitat Politècnica de València. En IN-RED 2020: VI Congreso de Innovación Educativa y Docencia en Red. Editorial Universitat Politècnica de València. 11332-1138. https://doi.org/10.4995/INRED2020.2020.11998OCS11332113

Peer assessing individual contributions in a group project

Graduates are expected to have good academic knowledge but also the professional skills required in the workplace. One such ‘soft’ skill is the ability to give constructive criticism and provide meaningful but professional feedback. This is particularly relevant when working in a team within industry, where peers need to influence each other to improve their project outcomes and chances of success. The development of student’s skills to generate such feedback should be supported within higher education. Specifically the IPAC Consortium investigates the use of Individual Peer Assessed Contribution to group work. In this context, students create an output directed to their own peers (i.e. a form of external-facing assessment), and prepares students for similar practices in industry. This paper, linked to the roundtable session on external-facing assessments proposed by Grindle and Tong, investigates staff and student perceptions on such practice. Insights gained to this date are presented

The dopamine D2/D3 receptor agonist quinpirole increases checking-like behaviour in an operant observing response task with uncertain reinforcement: a novel possible model of OCD.

Excessive checking is a common, debilitating symptom of obsessive-compulsive disorder (OCD). In an established rodent model of OCD checking behaviour, quinpirole (dopamine D2/3-receptor agonist) increased checking in open-field tests, indicating dopaminergic modulation of checking-like behaviours. We designed a novel operant paradigm for rats (observing response task (ORT)) to further examine cognitive processes underpinning checking behaviour and clarify how and why checking develops. We investigated i) how quinpirole increases checking, ii) dependence of these effects on D2/3 receptor function (following treatment with D2/3 receptor antagonist sulpiride) and iii) effects of reward uncertainty. In the ORT, rats pressed an 'observing' lever for information about the location of an 'active' lever that provided food reinforcement. High- and low-checkers (defined from baseline observing) received quinpirole (0.5mg/kg, 10 treatments) or vehicle. Parametric task manipulations assessed observing/checking under increasing task demands relating to reinforcement uncertainty (variable response requirement and active-lever location switching). Treatment with sulpiride further probed the pharmacological basis of long-term behavioural changes. Quinpirole selectively increased checking, both functional observing lever presses (OLPs) and non-functional extra OLPs (EOLPs). The increase in OLPs and EOLPs was long-lasting, without further quinpirole administration. Quinpirole did not affect the immediate ability to use information from checking. Vehicle and quinpirole-treated rats (VEH and QNP respectively) were selectively sensitive to different forms of uncertainty. Sulpiride reduced non-functional EOLPs in QNP rats but had no effect on functional OLPs. These data have implications for treatment of compulsive checking in OCD, particularly for serotonin-reuptake-inhibitor treatment-refractory cases, where supplementation with dopamine receptor antagonists may be beneficial

Peripheral Immune Cell Gene Expression Predicts Survival of Patients with Non-Small Cell Lung Cancer

Prediction of cancer recurrence in patients with non-small cell lung cancer (NSCLC) currently relies on the assessment of clinical characteristics including age, tumor stage, and smoking history. A better prediction of early stage cancer patients with poorer survival and late stage patients with better survival is needed to design patient-tailored treatment protocols. We analyzed gene expression in RNA from peripheral blood mononuclear cells (PBMC) of NSCLC patients to identify signatures predictive of overall patient survival. We find that PBMC gene expression patterns from NSCLC patients, like patterns from tumors, have information predictive of patient outcomes. We identify and validate a 26 gene prognostic panel that is independent of clinical stage. Many additional prognostic genes are specific to myeloid cells and are more highly expressed in patients with shorter survival. We also observe that significant numbers of prognostic genes change expression levels in PBMC collected after tumor resection. These post-surgery gene expression profiles may provide a means to re-evaluate prognosis over time. These studies further suggest that patient outcomes are not solely determined by tumor gene expression profiles but can also be influenced by the immune response as reflected in peripheral immune cells