MHC class I restricted and antigen-specific TCRs against viral and tumor-associated antigens (TAAs) for future biological therapy

Adoptive cellular immunotherapy (ACT) refers to the process of transferring immune cells (autologous or allogeneic) directly to the host as a treatment for cancer or infectious diseases. The effector cells could be antigen-specific, like T cells, or non-specific, such as NK cells or lymphokine-activated killer (LAK) cells. A substantial amount of evidence shows that T cells play an important role in controlling pathogens and tumor growth. Controlling pathogens and orchestrating the function of immune cells depends on engagement of the nominal TCR (T- cell receptor) with its ligand (the MHC class I or -II peptide complex), the structure and function of T cell receptor (TCR) and the subsequent immune effector functions upon TCR triggering (cytotoxicity, proliferation, cytokine production). Tumor-infiltrating T-cells (TILs) represent a source of T-cells for the immunotherapy of patients with tumors of the central nervous system and pancreas. According to the results of paper I and II, we successfully established a rapid TIL expansion protocol for patients with brain tumors or pancreatic cancer. TILs were shown to produce Th1-cytokines and were able to recognize autologous tumor cells defined by cytokine production or cytoxicity. In paper III, we found that tumor associated antigens (TAAs)-reactive T-cells could be successfully expanded from patients with glioma with IL-2, IL-15 and IL-21; they exhibit a Th1 cytokine pattern and a central memory phenotype. NY-ESO-1 expression was found in 15/38 cases and survivin expression in 20/40 cases in glioblastoma, defined by immunohisto- chemistry. Thus, NY-ESO-1 or survivin represent a potential target for anti-NY-ESO-1 or anti-survivin directed T-cells for the biological therapy of patients with glioblastoma (GBM). Mesothelin was first identified to be overexpressed in ovarian cancer. It is constitutively expressed in normal tissue, e.g. pericardium, pleura or peritoneum. This 40kDa protein could serve as a tumor marker and as a target of immunotherapy for anti-cancer directed T-cells. In paper IV, mesothelin was found to be expressed in 4 out of 11 GBM tissues, by immune- fluorescence staining. Mesothelin directed T cell reactions were also observed in a whole blood assay (WBA) measured in 293 patients with brain tumors. Mesothelin immunogenic epitopes were also identified using a peptide mapping assay; mesothelin-specific TILs could be expanded from glioma samples. We analyzed in detail potential prospective factors in patients with GBM (n=145) and non- GBM (n=60) which refers to glioma (WHO grade II or III). In paper V, we performed univariate Kaplan-Meier (K-M) survival analysis by setting of groups based on demographic, clinical, immunological parameters and immunological reactivity patterns, then we defined factor(s) with a cut-off strategy. We performed further multivariate analysis with a Cox proportional hazards model (forward and backward stepwise analysis) to determine the key factor related with patient’s survival by considering (and omitting) interactions between employed factors. We found that T-cell reactivity to an individual survivin epitope (97-111) is positively related (P=0.024) with survival of patients with GBM. The same was found to be true for the serum cytokine pattern of IL-4/IL-5/IL-6 (P=0.052) and IFN-γ/TNF-α/IL-17A (P=0.003) which could serve as ‘predictor’ for prognosis in clinical settings. The cytokine serum profile as well as the immune reactivity to survivin may serve as a clinically relevant indicator for the clinical follow up of patients with GBM after surgery and provide a viable option to offer tailored immunological therapy

Shear thickening effects of drag-reducing nanofluids for low permeability reservoir

Drag-reducing nanofluids are complex non-Newtonian fluids. Their constitutive characteristics are the basis of flow mechanism analysis in porous media. However, the rheological effects of drag-reducing nanofluids have not been thoroughly studied. In the present work, rheological properties of several nanofluids were measured, and the shear thickening mechanism was investigated experimentally. The results show that all the nanofluids examined have complex characteristics and critical shear rates. The viscosity exhibits a slow linear increase with the shear rate below the critical shear rate, while the shear thickening power-law fluid behaviour appears above the critical shear rate. The critical shear rate increases with the increase of particle concentration, which indicates the injection rate needs to be controlled to avoid significant increase of nanofluids viscosity. The rheological curve of increasing shear rate nearly coincides with that of decreasing shear rate, which indicates that the shear thickening of nanofluids studied in this work is transient and reversible. A constant index constitutive equation with an exponent of 0.5 is obtained from test results by the fixed index method, and its coefficient k(c) is a linear function of the concentration, which can replace a set of conventional constitutive equations with different concentrations. The constant index constitutive equation also clarifies the coefficient dimension. Similar results have been obtained by analysing several other nanofluids using the fixed index method, which validates the new effective method for constructing the constitutive equations of non-Newtonian nanofluids.Cited as: Gu, C., Qiu, R., Liu, S., You, Z., Qin, R. Shear thickening effects of drag-reducing nanofluids for low permeability reservoir. Advances in Geo-Energy Research, 2020, 4(3): 317-325, doi: 10.46690/ager.2020.03.0

What experiments on pinned nanobubbles can tell about the critical nucleus for bubble nucleation.

The process of homogeneous bubble nucleation is almost impossible to probe experimentally, except near the critical point or for liquids under large negative tension. Elsewhere in the phase diagram, the bubble nucleation barrier is so high as to be effectively insurmountable. Consequently, there is a severe lack of experimental studies of homogenous bubble nucleation under conditions of practical importance (e.g., cavitation). Here we use a simple geometric relation to show that we can obtain information about the homogeneous nucleation process from Molecular Dynamics studies of bubble formation in solvophobic nanopores on a solid surface. The free energy of pinned nanobubbles has two extrema as a function of volume: one state corresponds to a free-energy maximum ("the critical nucleus"), the other corresponds to a free-energy minimum (the metastable, pinned nanobubble). Provided that the surface tension does not depend on nanobubble curvature, the radius of the curvature of the metastable surface nanobubble is independent of the radius of the pore and is equal to the radius of the critical nucleus in homogenous bubble nucleation. This observation opens the way to probe the parameters that determine homogeneous bubble nucleation under experimentally accessible conditions, e.g. with AFM studies of metastable nanobubbles. Our theoretical analysis also indicates that a surface with pores of different sizes can be used to determine the curvature corrections to the surface tension. Our conclusions are not limited to bubble nucleation but suggest that a similar approach could be used to probe the structure of critical nuclei in crystal nucleation

Global μ

The impulsive complex-valued neural networks with three kinds of time delays including leakage delay, discrete delay, and distributed delay are considered. Based on the homeomorphism mapping principle of complex domain, a sufficient condition for the existence and uniqueness of the equilibrium point of the addressed complex-valued neural networks is proposed in terms of linear matrix inequality (LMI). By constructing appropriate Lyapunov-Krasovskii functionals, and employing the free weighting matrix method, several delay-dependent criteria for checking the global μ-stability of the complex-valued neural networks are established in LMIs. As direct applications of these results, several criteria on the exponential stability, power-stability, and log-stability are obtained. Two examples with simulations are provided to demonstrate the effectiveness of the proposed criteria

Global μ

The complex-valued neural networks with unbounded time-varying delays are considered. By constructing appropriate Lyapunov-Krasovskii functionals, and employing the free weighting matrix method, several delay-dependent criteria for checking the global μ-stability of the addressed complex-valued neural networks are established in linear matrix inequality (LMI), which can be checked numerically using the effective LMI toolbox in MATLAB. Two examples with simulations are given to show the effectiveness and less conservatism of the proposed criteria

Regulation of COL1A2, AKT3 genes, and related signaling pathway in the pathology of congenital talipes equinovarus

Congenital talipes equinovarus (CTEV) is one of the most common congenital limb defects in children, which is a multifactorial and complex disease that associates with many unknown genetic, social-demographic, and environmental risk factors. Emerging evidence proved that gene expression or mutation might play an important role in the occurrence and development of CTEV. However, the underlying reasons and involved mechanisms are still not clear. Herein, to probe the potential genes and related signaling pathways involved in CTEV, we first identified the differentially expressed genes (DEGs) by mRNA sequencing in pediatric patients with CTEV compared with normal children. The gene of COL1A2 was upregulated, and AKT3 was downregulated at the transcriptional level. Western blot and quantitative polymerase chain reaction (qRT-PCR) results also showed that the expression of COL1A2 in CTEV was enhanced, and the AKT3 was decreased. Furthermore, the COL1A2 Knock-in (+COL1A2) and AKT3 Knock-out (-AKT3) transgenic mice were used to verify the effects of these two genes in the CTEV, and the results of which showed that both COL1A2 and AKT3 were closely related to the CTEV. We also investigated the effect of the PI3K-AKT3 signaling pathway in CTEV by measuring the relative expression of several key genes using Western blot and qRT-PCR. In line with the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis data, the PI3K-AKT3 signaling pathway might play a potentially important role in the regulation of pathological changes of CTEV. This study will provide new ideas for the mechanism investigation and prenatal diagnosis of CTEV

Bone-targeted polymeric nanoparticles as alendronate carriers for potential osteoporosis treatment

Bone-targeted polymeric nanoparticles for alendronate delivery based on Poly (lactic-co-glycolic acid) conjugated chitosan (CS-PLGA) and alendronate conjugated PLGA (Alen-PLGA) are fabricated and their superior performances are evaluated. The nanoparticles exhibited sustained Alen release without obvious burst release and good cytocompatibility against MC3T3 cells. Alen-modified nanoparticles demonstrated a high affinity to hydroxyapatite, which is the main mineral component of bone, indicating their feasibility for bone-targeted delivery. In addition, unlike nanoparticles without Alen, Alen-modified nanoparticles were preferentially taken up by MC3T3 cells, compared to HDF cells, revealing their specific uptake for osteoblast-like cells. Thus, the Alen-modified nanoparticles can potentially be developed as bone-targeted carriers for osteoporosis treatment