Recent progress in chimeric antigen receptor-modified T-cell (CAR-T cell) technology in cancer therapy is extremely promising, especially in the treatment of patients with B-cell acute lymphoblastic ...leukemia. In contrast, due to the hostile immunosuppressive microenvironment of a solid tumor, CAR T-cell accessibility and survival continue to pose a considerable challenge, which leads to their limited therapeutic efficacy. In this study, we constructed two anti-MUC1 CAR-T cell lines. One set of CAR-T cells contained SM3 single chain variable fragment (scFv) sequence specifically targeting the MUC1 antigen and co-expressing interleukin (IL) 12 (named SM3-CAR). The other CAR-T cell line carried the SM3 scFv sequence modified to improve its binding to MUC1 antigen (named pSM3-CAR) but did not co-express IL-12. When those two types of CAR-T cells were injected intratumorally into two independent metastatic lesions of the same MUC1
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seminal vesicle cancer patient as part of an interventional treatment strategy, the initial results indicated no side-effects of the MUC1 targeting CAR-T cell approach, and patient serum cytokines responses were positive. Further evaluation showed that pSM3-CAR effectively caused tumor necrosis, providing new options for improved CAR-T therapy in solid tumors.
Chimeric antigen receptor (CAR)-T cell therapy is a novel type of immunotherapy. However, the use of CAR-T cells to treat acute myeloid leukaemia (AML) has limitations. B7-H3 is expressed in several ...malignancies, including some types of AML cells. However, its expression in normal tissues is low. Therefore, B7-H3 is ideal for targeted AML therapy.
First, we constructed B7-H3 CAR that can target B7-H3, and then constructed B7-H3-CAR-T cells in vitro, which were co-incubated with six AML cell lines expressing different levels of B7-H3, respectively. The toxicity and cytokines were detected by flow cytometry. In vivo, AML model was established in B-NSG mice to study the toxicity of B7-H3-CAR T on AML cells.
In vitro functional tests showed that B7-H3-CAR-T cells were cytotoxic to B7-H3-positive AML tumor cells and had good scavenging effect on B7-H3-expressing AML cell lines, and the cytokine results were consistent. In vivo, B7-H3-CAR-T cells significantly inhibited tumor cell growth in a mouse model of AML, prolonging mouse survival compared with controls.
B7-H3-CAR-T cells may serve as a novel therapeutic method for the targeted treatment of AML.
Manufacturing error and assembly error should be taken into consideration during evaluation and analysis of accurate product performance in the design phase. Traditional tolerance analysis methods ...establish error propagation model based on dimension chains with tolerance values being regarded as error boundaries, and obtain the limit of target feature error through optimization methods or conducting statistical analysis with the tolerance domain being the boundary. As deviations of the tolerance feature (TF) on degrees of freedom (DOF) have coupling relations, accurate deviations on all DOF may not be obtained, even though these deviations constitute the basis for product performance analysis. Therefore, taking the widely used shaft-hole fit as an example, a pose decoupling model of the axis TF was proposed based on an area coordinate system. This model realized decoupling analysis of any pose of the axis TF within the tolerance domain. As proposed by the authors, by combining a tolerance analysis model based on tracking local coordinate systems, ultimate pose analysis of the closed-loop system, namely the target feature, as well as statistical analysis could be further implemented. This method contributed to analysis of true product performance with arbitrary error in the product design phase from the angle of tolerance, therefore, shortening the product research and development cycle. This method is demonstrated through applying it to a real-life example.
Among current approaches to tolerance analysis in three-dimensional space, the Matrix method based on rigid body kinematics is widely used. However, this method ignores the impact a tolerance feature ...(TF) may get from the variations of TFs before it, therefore showing its demerits when applied to long and complex dimension chains. For this reason, this paper puts forward a new tolerance analysis model where two local coordinate systems are built at each TF: a nominal one based on the datum of current TF and a tracking one based on the variations of the prior TFs. Then the variations of all TFs along the dimension chain are accumulated. Compared with the Matrix method, the new approach generates results with more accuracy and higher efficiency.
•A new more accurate analytical model for calculating the tooth surface contact stress of tip-relieved gears is established based on the accurate tooth profile equations represented by the parameter ...equations, which can be used to calculate both the standard gear and tip-relieved gear.•The solutions of equation with implicit function and singular integral are studied.•The influence of the tip relief on the tooth surface contact stress of gears is measured and compared with the results of the finite element method and Hertzian contact model.
Spur gears with tip relief can effectively improve transmission performance, and accurate determination of their tooth surface contact stress (TSCS) can provide guidance for structure optimization and performance evaluation. However, since the tip-relieved gear profile has not been accurately approximated with a quadratic parabola, the TSCS cannot be calculated using the cylindrical contact model of the Hertzian contact theory (Hertz model). Therefore, a new more accurate analytical model for calculating the non-Hertzian TSCS of tip-relieved gears is proposed in this paper. This model is established based on the accurate tooth profile equations represented by the parameter equations (new model). The solution of the model with an implicit function and a singular integral is also studied. Finally, the TSCS of two gear pairs with and without tip relief are compared for different parameters under different loads according to the new model, the finite element method (FEM model) and Hertz model. The results show that the tip relief will affect the maximum TSCS, location and size of the contact area, whereas the Hertz model cannot quantify these effects. However, the new model, which is validated using the FEM model, can provide accurate and reliable results.
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•A method for calculating the contact stress of gears with misalignment errors.•The method is effectively verified by the finite element method.•Misalignment errors will affect the magnitude and ...distribution of contact stress.•The influence of misalignment errors on contact stress is non-linear.
Misalignment errors (MEs) in multiple degrees of freedom (multi-DOFs) along gear pair axis are unavoidable under actual working conditions. These MEs lead to changes in tooth surface contact stress (TSCS) and make its accurate calculation complicated and difficult. Unlike the traditional methods of obtaining TSCS with MEs in multi-DOFs via experimental tests, finite element methods (FEMs) or coefficient methods following international standards, a new analytical calculation model is proposed in this paper. The profile equation of a gear pair with MEs in multi-DOFs is first established. Then, a new profile equation for meshing pairs of gear and pinion slices with non-standard shapes that are coplanar with the line of action of the meshing force is obtained. On this basis, the correctness of meshing force transmission, as well as the accuracy and speed of calculation, can be guaranteed with the contact analysis of gear pairs. Finally, the magnitude and distribution of the TSCS of a gear pair with MEs in multi-DOFs are obtained. Compared with the results of a FEM model, the new model can accurately and rapidly calculate the TSCS of a gear pair with MEs in multi-DOFs.
•A new analytical model is established to calculate the maximum tooth root stress and critical section location of gear based on mechanics theory.•The new model can determine the critical section ...location accurately and quickly by solving the extreme value.•Both bending moment stress and compressive axial stress are taken into account in the model with the accurate profile equation.•The result of the new model is consistent with that of finite element method and more reliable than international standards.
An accurate calculation of the maximum tooth root stress (TRS) and critical section location (CSL) provides a basis for predicting and improving gear performance. The irregular profile represented by the implicit function may cause the calculation to be more complex. In current research, finite element methods (FEM model) and experimental test methods (ET model) can obtain accurate results but need large computational resources and time. The results from ISO 6336:2006 (ISO model) and AGMA 2101-D04 (AGMA model) are obtained conveniently but sometimes not reliable. Therefore, a new analytical model based on the mechanics theory with an accurate profile equation is established to calculate the maximum TRS and corresponding CSL quickly and accurately by solving the extreme value. Finally, the results of the spur gear in five cases with different parameters are obtained and compared to those of the FEM, ISO and AGMA models. It is shown that the results of the new model are in agreement with those of the FEM model, even under different parametric conditions.
Panax notoginseng saponins (PNS), bioactive compounds, are commonly used to treat ischemic heart and cerebral diseases in China and other Asian countries. Most previous studies of PNS have focused on ...the mechanisms underlying their treatment of ischemic cardiovascular diseases but not cerebral ischemic diseases. This study sought to explore the pharmacological mechanisms underlying the effectiveness of PNS in treating cerebral ischemic diseases. Different experimental cerebral ischemia models (including middle cerebral artery occlusion (MCAO) and the blockade of four arteries in rats, collagen-adrenaline-induced systemic intravascular thrombosis in mice, thrombosis of carotid artery-jugular vein blood flow in the bypass of rats, and hypoxia tolerance in mice) were used to investigate the mechanisms underlying the actions of PNS on cerebral ischemia. The results indicated that (1) PNS improved neurological function and reduced the cerebral ischemia infraction area in MCAO rats; (2) PNS improved motor coordination function in rats with complete cerebral ischemia (blockade of four arteries), decreased Ca2+ levels, and ameliorated energy metabolism in the brains of ischemia rats; (3) PNS reduced thrombosis in common carotid artery-jugular vein blood flow in the bypass of rats; (4) PNS provided significant promise in antistroke hemiplegia and hypoxia tolerance in mice. In conclusion, PNS showed antagonistic effects on ischemic stroke, and pharmacological mechanisms are likely to be associated with the reduction of cerebral pathological damage, thrombolysis, antihypoxia, and improvement in the intracellular Ca2+ overload and cerebral energy metabolism.
Chimeric antigen receptor (CAR) αβ T cell adoptive immunotherapy has shown great promise for improving cancer treatment. However, there are several hurdles to overcome for the wide clinical ...application of CAR-αβ T cells therapy, including side effects and a limited T cells source from cancer patients. Therefore, we sought to identify an alternative T cell subset that could avoid these limitations and improve the effectiveness of CAR-T immunotherapy. γδ T cells are a minor subset of T cells, which share the characteristic of innate immune cells and adaptive immune cells. Vγ9Vδ2 T cells are a predominant γδ T subset in the circulating peripheral blood. In this study, we investigated the antigen-specific antitumor activity of CAR-Vγ9Vδ2 T cells targeting MUC1-Tn antigen. Vγ9Vδ2 T cells were expanded from peripheral blood mononuclear cells of healthy volunteers with zoledronic acid and interleukin-2. CAR-Vγ9Vδ2 T cells were generated by transfection of lentivirus encoding MUC1-Tn CAR. Cytotoxicity assays with various cancer cell lines revealed that CAR-Vγ9Vδ2 T cells could effectively lyse tumor cells in an antigen-specific manner, with similar or stronger effects than CAR-αβ T cells. However, CAR-Vγ9Vδ2 T cells had shorter persistence, which could be improved with the addition of IL-2 to maintain the function of CAR-Vγ9Vδ2 T cells with consecutive stimulation of tumor cells. Using a xenograft mouse model, we further showed that CAR-Vγ9Vδ2 T cells more effectively suppressed tumor growth
than Vγ9Vδ2 T cells. Therefore, MUC1-Tn CAR-modified Vγ9Vδ2 T cells may represent a novel, promising ready-to-use product for cancer allogeneic immunotherapy.
Revealing the atomistic mechanisms for the high-temperature mechanical behavior of materials is important for optimizing their properties for service at high-temperatures and their thermomechanical ...processing. However, due to materials microstructure's dynamic recovery and the absence of available in situ techniques, the high-temperature deformation behavior and atomistic mechanisms of materials are difficult to evaluate. Here, we report the development of a microelectromechanical systems-based thermomechanical testing apparatus that enables mechanical testing at temperatures reaching 1556 K inside a transmission electron microscope for in situ investigation with atomic-resolution. With this unique technique, we first uncovered that tungsten fractures at 973 K in a ductile manner via a strain-induced multi-step body-centered cubic (BCC)-to-face-centered cubic (FCC) transformation and dislocation activities within the strain-induced FCC phase. Both events reduce the stress concentration at the crack tip and retard crack propagation. Our research provides an approach for timely and atomic-resolved high-temperature mechanical investigation of materials at high-temperatures.
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