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In this article, 3-(3,5-di-tert-butyl-4-hydroxyphenyl) propionic acid (DBHP)-functionalized ZnO (DBHP–ZnO) nanoparticles were synthesized by decomposing the organometallic precursor Zn(DBHP)2under alkaline conditions. This in situ surface modification method can induce small-sized ZnO nanoparticles (5 nm) and form strong linkage between DBHP and ZnO nanoparticles. DBHP as an organic compound hindered phenol antioxidant that not only improved the dispersion stability of the prepared DBHP–ZnO nanoparticles in the lubrication oil but also scavenged free radicals produced during the oxidation process of oil. Compared with DBHP, the thermal stability of the prepared composite antioxidant was greatly enhanced by introducing inorganic ZnO nanoparticles, which was proved by the results of the thermogravimetric analysis test. A rotary oxygen bomb test, pressurized differential scanning calorimetry, and free-radical-scavenging method all showed that DBHP–ZnO nanoparticles had better antioxidant properties than DBHP under high temperature in the base oil of di-iso-octylsebacate (DIOS). The activation energy of the oxidation process was used to analyze this result by the model-free methods, including the Flynn–Wall–Ozawa method and the Kissinger equation. The calculated results showed that DIOS containing DBHP–ZnO nanoparticles have the lowest reaction constant and the longest half-life period compared to those of individual DBHP and ZnO nanoparticles, which is attributed to the combined action of the organic–inorganic composites. Besides, DBHP–ZnO nanoparticles as the additive are able to improve the antiwear ability of DIOS to some extent. Therefore, the as-prepared DBHP–ZnO nanoparticles with desired dispersibility as well as better thermal stability and antioxidant ability than DBHP in the DIOS base oil could be a potential high-performance nanocomposite additive for a synthetic lubricant base oil like DIOS.

Previous studies have revealed that the activation of the epithelial-mesenchymal transition (EMT) endows metastatic properties upon cancer cells to promote invasion and migration. In this study, immunohistochemical analysis was performed in 50 cases of clear cell renal cell carcinoma (RCC) and paired normal kidney tissues. We detected the expression of vascular endothelial growth inhibitor (VEGI) and EMT markers (E-cadherin, fibronectin, and Slug) and recorded the clinical, pathologic, and follow-up (median follow-up: 79.0 mo) information. The expression of VEGI and E-cadherin was significantly lower in RCC tissues compared with normal kidney tissues (P<0.001). However, the expression of fibronectin and Slug was higher in RCC tissues (P<0.05). VEGI and EMT marker expression marginally differed in tumor size and stage. Significant differences were found in the pathologic grade (P<0.05). The Spearman correlation analysis suggested a positive correlation between VEGI and E-cadherin (r=0.451, P<0.01). A negative correlation was shown between VEGI and fibronectin (r=−0.465, P<0.01). There was also a negative correlation between VEGI and Slug (r=−0.758, P<0.01). During the 79.0 months (range, 7 to 119 mo) of follow-up, 6 patients died due to RCC, and the tumor-free survival rate was 88% (44/50). We did not find a significant correlation between VEGI/EMT markers (E-cadherin, fibronectin, and Slug) and overall survival (P>0.05). Our findings indicate that VEGI plays an important role in EMT in RCC. It suggests that VEGI may be investigated as a disease biomarker and therapeutic target in RCC.

Human epidermal growth factor receptor 2 (HER2) is frequently overexpressed and activated in metastatic breast cancers. Monoclonal antibodies targeting Her2, such as trastuzumab and pertuzumab, have become important targeted therapies for patients with HER2-positive breast cancer. Both trastuzumab and pertuzumab can reduce Her2 positive tumor burden by inhibiting Her2 signaling and inducing ADCC activities (antibody dependent cell-mediated cytotoxicity). In this study, we have generated a bispecific antibody, Her2(Per)-S-Fab, by linking the pertuzumab Fab to an anti-CD16 single domain antibody. The Her2(Per)-S-Fab can be expressed and purified efficiently from Escherichia coli. In vitro and in vivo experiments showed Her2(Per)-S-Fab had potent cytotoxicity against Her2-positive tumor cells. Thus, Her2(Per)-S-Fab may provide an alternative to treat Her2-positive cancer patients.

Among different cancer immunotherapy approaches, bispecific antibodies (BsAbs) are of great interest due to their ability to recruit immune cells to kill tumor cells directly. Various BsAbs against Her2 tumor cells have been proposed with potent cytotoxic activities. However, most of these formats require extensive processing to obtain heterodimeric bispecific antibodies. In this study, we describe a bispecific antibody, BiHC (bispecific Her2-CD3 antibody), constructed with a single-domain anti-Her2 and a single-chain Fv (variable fragment) of anti-CD3 in an IgG-like format. In contrast to most IgG-like BsAbs, the two arms in BiHC have different molecular weights, making it easier to separate hetero- or homodimers. BiHC can be expressed in Escherichia coliand purified viaProtein A affinity chromatography. The purified BiHC can recruit T cells and induce specific cytotoxicity of Her2-expressing tumor cells in vitro. The BiHC can also efficiently inhibit the tumor growth in vivo. Thus, BiHC is a promising candidate for the treatment of Her2-positive cancers.

ABSTRACTBispecific antibodies have emerged as powerful therapeutic agents given their high specificity and ability to induce a potent immune response. Various bispecific antibody formats have been designed and studied regarding their applications in cancer therapy, though associated with issues of short half-life or manufacturing difficulties. Herein, a novel bispecific antibody, SS-Fc, was constructed by pairing 2 single-domain antibodies, anti-CD16 and anti-CEA, which were fused with CH3 “knobs into holes” mutations individually. SS-Fc was expressed and purified from E.coli. In vitroand in vivoexperiments confirmed that SS-Fc can form a heterodimeric bispecific antibody when expressed and purified from E. coli. By engaging natural killer (NK) cells through an anti-CD16 single domain antibody, the SS-Fc bispecific antibody exhibited potent in vitroand in vivocytotoxicity against cancer cells with carcinoembryonic antigen (CEA) expression. Thus, SS-Fc represents a novel bispecific antibody format that can be applied to a wide range of both discovery and clinical applications.

ABSTRACTOne of the most active fields in cancer immunotherapy is the study of bispecific antibodies, which engage immune cells to kill cancer cells. However, a variety of issues are associated with most of current bispecific antibody formats. In this study, we present a novel bispecific antibody, BiSS (Bispecific antibody with Single domain, Single domain antibodies), which was constructed by linking 2 single domain antibodies, anti-CEA and anti-CD16, in tandem. Unlike most other bispecific antibodies, the BiSS antibody can be expressed and purified from E.coliin large quantities. By recruiting natural killer cells (NK cells) to CEA-positive cancer cells, BiSS led to cancer cell death in vitro. In xenograft models, the BiSS protein blocked cancer progression. The data suggested that the single domain-based bispecific antibody BiSS was functional and can be potentially applied to a broad range of immunotherapies.

Bispecific antibodies that engage immune cells to kill cancer cells have been actively studied in cancer immunotherapy. In this study, we present a novel bispecific format, S-Fab, fabricated by linking a single-domain anti-carcinoembryonic antigen VHH to a conventional anti-CD3 Fab. In contrast to most bispecific antibodies, the S-Fab bispecific antibody can be efficiently expressed and purified from bacteria. The purified S-Fab is stable in serum and is able to recruit T cells to drive potent cancer cell killing. In xenograft models, the S-Fab antibody suppresses tumor growth in the presence of human immune cells. Our study suggested that the bispecific S-Fab format can be applied to a wide range of immunotherapies.

This work reports the fabrication of a luminescent planar plate based on stable aqueous quantum dots (QDs) and poly(diallyldimethylammonium chloride) (PDDA) via a layer-by-layer (LBL) assembly technique. Preparation of aqueous QDs with facile monoalkyl maleate amphiphilic surfactants as the coating agent is conducted by a robust and efficient phase-transfer method. The as-prepared aqueous QDs exhibit bright emission, and their surface has very large negative zeta potential values, which are useful for electrostatic LBL assembly. Red, green, and blue luminescent planar plates are successfully fabricated via LBL assembly of the monocolor QDs, respectively. Through accurately adjusting the relative proportion of each monocolor luminescent component, we obtain an inspiring luminescent planar plate, which emits bright white light with a color coordinate of (0.3509, 0.3483), a correlated color temperature (CCT) of 4766 K, and a high color rendering index (CRI, Ra) of 89.5 under the irradiation of UV light. Therefore, this paper reports a facile process for the design and preparation of luminescent planar plates, which have potential applications in display and solid-state lighting devices.

The evolution of optical properties of two types of core/multishell nanocrystals (NCs)–type A (CdSe/CdS/Zn0.5Cd0.5S/ZnS) and type B (CdSe/CdS/ZnxCd1–xS/ZnS)with an increase of shell thickness from 3.5 to 15.5 monolayers (MLs) has been studied. When the shell thickness was 9.5 MLs and more, the stability would be greatly improved and the quantum yields (QYs) almost did not change during the process of purification. Even after phase transfer experiment, the QYs of the water-soluble NCs were still kept 70–99% of their initial level. The as-prepared water-soluble NCs with 9.5 MLs and more also exhibited high stability in varying physiological conditions under PBS buffer and continuous UV radiation. For type B core/multishell NCs, due to a consecutive change of lattice parameters from core to shells, there were almost no defects induced between the CdSe core and ZnS shell. As a result, they had higher QYs and stability than type A core/multishell NCs at the same test condition.

Despite intensive study of the mechanisms of chemotherapeutic drug resistance in human breast cancer, few reports have systematically investigated the mechanisms that underlie resistance to the chemotherapy-sensitizing agent tumor necrosis factor (TNF)-α. Additionally, the relationship between TNF-α resistance mediated by MEK5/Erk5 signaling and epithelial-mesenchymal transition (EMT), a process associated with promotion of invasion, metastasis, and recurrence in breast cancer, has not previously been investigated. To compare differences in the proteome of the TNF-α resistant MCF-7 breast cancer cell line MCF-7-MEK5 (in which TNF-α resistance is mediated by MEK5/Erk5 signaling) and its parental TNF-a sensitive MCF-7 cell line MCF-7-VEC, two-dimensional gel electrophoresis and high performance capillary liquid chromatography coupled with tandem mass spectrometry approaches were used. Differential protein expression was verified at the transcriptional level using RT-PCR assays. An EMT phenotype was confirmed using immunofluorescence staining and gene expression analyses. A short hairpin RNA strategy targeting Erk5 was utilized to investigate the requirement for the MEK/Erk5 pathway in EMT. Proteomic analyses and PCR assays were used to identify and confirm differential expression of proteins. In MCF-7-MEK5 versus MCF-7-VEC cells, vimentin (VIM), glutathione-S-transferase P (GSTP1), and creatine kinase B-type (CKB) were upregulated, and keratin 8 (KRT8), keratin 19 (KRT19) and glutathione-S-transferase Mu 3 (GSTM3) were downregulated. Morphology and immunofluorescence staining for E-cadherin and vimentin revealed an EMT phenotype in the MCF-7-MEK5 cells. Furthermore, EMT regulatory genes SNAI2 (slug), ZEB1 (δ-EF1), and N-cadherin (CDH2) were upregulated, whereas E-cadherin (CDH1) was downregulated in MCF-7-MEK5 cells versus MCF-7-VEC cells. RNA interference targeting of Erk5 reversed MEK5-mediated EMT gene expression. This study demonstrates that MEK5 over-expression promotes a TNF-α resistance phenotype associated with distinct proteomic changes (upregulation of VIM/vim, GSTP1/gstp1, and CKB/ckb; and downregulation of KRT8/krt8, KRT19/krt19, and GSTM3/gstm3). We further demonstrate that MEK5-mediated progression to an EMT phenotype is dependent upon intact Erk5 and associated with upregulation of SNAI2 and ZEB1 expression.

【Abstract】 Objective To investigate the efficacy and safety of CD19-targeted chimeric antigen receptor T cell (CAR-T cell) for refractory/relapsed B-cell lymphoma. Methods The efficacy and safety of CD19-CAR-T cells(4-1BB costimulatory domain) in treatment of 12 patients with relapsed/refractory B-cell lymphoma from March 2018 to December 2019 in the Department of Hematology of Guangdong Second Province Hospital were collected analyzed retrospectively. There were 9 patients (75%) with diffuse large B cell lymphoma, 1 patient with blastic variant of mantle cell lymphoma, 1 patient(8.3%) with Burkitt lymphoma, 1 patient with B cell non-Hodgkin lymphoma that cannot be classified. 3 patients (25%) with large mass (≥7.5cm) and 9 patients (75%) with ECOG score ≥2. The number of chemotherapy courses received before transfusion was 4-9, the median number of chemotherapy courses was 7. All 12 patients were autogenous mouse CAR-T cells. Fludarabine + Cyclophosphamide (FC) regimen was used for pretreatment before transfusion, and the number of CAR-T cells was 1 ~ 3.69×10 6/kg. Results All 12 patients received CD19-targeted CAR-T cell therapy. There were 9 patients had treatment response, and the total effective rate was 75%. Among them, there were 3 patients with complete response (CR), with CR rate of 25%, and 6 patients with partial response (PR), with PR rate of 50%. Among the 3 patients with CR remained CR at the follow-up date. Among the 6 patients with PR, 4 showed disease progression in the second month after transfusion, and 2 showed disease progression in the third month after transfusion. All the 9 patients with effective treatment had different degrees of cytokine release syndrome (CRS), including 3 level-1 CRS, 4 level-2 CRS, and 2 level-3 CRS. Two of them had grade 2 CRES, and all CRS and CRES were controlled after treatment with IL-6 receptor antagonists and glucocorticoids. None of the 3 patients failed to respond to treatment had CRS. Conclusion CD19-targeted CAR-T cell immunotherapy has been shown to be effective in CD19-antigen positive B-cell lymphoma, and adverse CRS reactions during treatment can be controlled after treatment. Patients who obtained CR seemed to be able to maintain long-term CR status, while patients who failed to obtain CR showed disease progression within a short period of 3 months, suggesting that patients who obtained CR at an early stage could achieve better efficacy. Therefore, how to identify patients who receive CR at an early stage may be a research direction for the clinical application of CAR-T cell immunotherapy in B-cell lymphoma.

No relevant conflicts of interest to declare.