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Maize grain yield can be greatly reduced when flowering time coincides with drought conditions, which delays silking and consequently increases the anthesis-silking interval. Although the genetic basis of delayed flowering time under water-stressed conditions has been elucidated in maize-maize populations, little is known in this regard about maize-teosinte populations. Here, 16 quantitative trait loci (QTL) for three flowering-time traits, namely days to anthesis, days to silk, and the anthesis-silking interval, were identified in a maize-teosinte introgression population under well-watered and water-stressed conditions; these QTL explained 3.98–32.61% of phenotypic variations. Six of these QTL were considered to be sensitive to drought stress, and the effect of any individual QTL was small, indicating the complex genetic nature of drought resistance in maize. To resolve which genes underlie the six QTL, 11 candidate genes were identified via colocalization analysis of known associations with flowering-time-related drought traits. Among the 11 candidate genes, five were found to be differentially expressed in response to drought stress or under selection during maize domestication, and thus represented the most likely candidates underlying the drought-sensitive QTL. The results lay a foundation for further studies of the genetic mechanisms of drought resistance and provide valuable information for improving drought resistance during maize breeding. [ABSTRACT FROM AUTHOR]

Lung cancer is the most common incident cancer and the leading cause of cancer death. In recent years, the development of tumor immunotherapy especially chimeric antigen receptor T (CAR-T) cell has shown a promising future. Epidermal growth factor receptor variant III (EGFRvIII) is a tumor-specific mutation expressed in various types of tumors and has been detected in non-small cell lung cancer with a mutation rate of 10%. Thus, EGFRvIII is a potential antigen for targeted lung cancer therapy. In this study, CAR vectors were constructed and transfected into virus-packaging cells. Then, activated T cells were infected with retrovirus harvested from stable virus-producing single clone cell lines. CAR expression on the surfaces of the T cells was detected by flow cytometry and Western blot. The function of CAR-T targeting EGFRvIII was then evaluated. The EGFRvIII-CAR vector was successfully constructed and confirmed by DNA sequencing. A stable virus-producing cell line was produced from a single clone by limited dilution. The culture conditions for the cell line, including cell density, temperature, and culture medium were optimized. After infection with retrovirus, CAR was expressed on more than 90% of the T cells. The proliferation of CAR-T cells were induced by cytokine and specific antigen in vitro. More importantly, EGFRvIII-CART specifically and efficiently recognized and killed A549-EGFRvIII cells with an effector/target ratio of 10:1 by expressing and releasing cytokines, including perforin, granzyme B, IFN-γ, and TNF-α. The in vivo study indicated that the metastasis of A549-EGFRvIII cells in mice were inhibited by EGFRvIII-CART cells, and the survival of the mice was significantly prolonged with no serious side effects. EGFRvIII-CART showed significantly efficient antitumor activity against lung cancer cells expressing EGFRvIII in vivo and in vitro. Therefore, CAR-T targeting EGFRvIII is a potential therapeutic strategy in preventing recurrence and metastasis of lung cancer after surgery. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. This malignancy is associated with poor prognosis and high mortality. Novel approaches for prolonging the overall survival of patients with advanced HCC are urgently needed. The antitumor activities of adoptive cell transfer therapy (ACT), such as strategies based on tumor-infiltrating lymphocytes and cytokine-induced killer cells, are more effective than those of traditional strategies. Currently, chimeric antigen receptor T-cell (CAR-T) immunotherapy has achieved numerous breakthroughs in the treatment of hematological malignancies, including relapsed or refractory lymphoblastic leukemia and refractory large B-cell lymphoma. Nevertheless, this approach only provides a modest benefit in the treatment of solid tumors. The clinical results of CAR-T immunotherapy for HCC that could be obtained at present are limited. Some published studies have demonstrated that CAR-T could inhibit tumor growth and cause severe side effects. In this review, we summarized the current application of ACT, the challenges encountered by CAR-T technology in HCC treatment, and some possible strategies for the future direction of immunotherapeutic research. [ABSTRACT FROM AUTHOR]

Key message: Genetic relationships among Chinese maize germplasms reveal historical trends in heterotic patterns from Chinese breeding programs and identify line Dan340 as a potential genome donor for elite inbred line Zheng58.Abstract: The characterization of the genetic relationships, heterotic patterns and breeding history of lines in maize breeding programs allows breeders to efficiently use maize germplasm for line improvement over time. In this study, 269 temperate inbred lines, most of which have been widely used in Chinese maize breeding programs since the 1970s, were genotyped using the Illumina MaizeSNP50 BeadChip, which contains 56,110 single-nucleotide polymorphisms. The STRUCTURE analysis, cluster analysis and principal coordinate analysis results consistently revealed seven groups, of which five were consistent with known heterotic groups within the Chinese maize germplasm—Domestic Reid, Lancaster, Zi330, Tang SPT and Tem-tropic I (also known as “P”). These genetic relationships also allowed us to determine the historical trends in heterotic patterns during the three decades from 1970 to 2000, represented by Mo17 from Lancaster, HuangZaoSi (HZS) from Tang SPT, Ye478 from Domestic Reid and P178 from Tem-tropic I heterotic groups. Mo17-related commercial hybrids were widely used in the 1970s and 1980s, followed by the release of HZS- and Ye478-related commercial hybrids in the 1980s and 1990s, and the introduction of Tem-tropic I group in the 1990s and 2000s. Additionally, we identified inbred line Dan340 as a potential genome donor for Zheng58, which is the female parent of the most widely grown commercial hybrid ZhengDan958 in China. We also reconstructed the recombination events of elite line HZS and its 14 derived lines. These findings provide useful information to direct future maize breeding efforts. [ABSTRACT FROM AUTHOR]

Purpose: To prepare acylated exenatide analogues and investigate their biological properties for guiding the development of PLGA formulations of exenatide. Methods: The acylated exenatide analogues were prepared by reaction with glycolic acid (GA), one constitutional unit of PLGA, and characterized by HPLC-MS/MS and Circular Dichroism (CD). The pharmacokinetic properties and anti-diabetic activities were studied in SD rats and db/db mice, respectively. Results: Structural characterizations of the acylated products showed that one to four glycolic acids (GAs) were connected to the primary amine groups of exenatide, and there was a conversion of α-helix to β-sheet to some extent. Pharmacokinetic studies in SD rats revealed that acylated exenatides had a similar Tmax with that of the prototype drug, whereas the Cmax and the AUC values of the adducts were significantly decreased. Biological activity tests demonstrated that exenatide and acylated exenatide analogues had similar in vivo antidiabetic activities in terms of controlling blood glucose concentration, HbA1c level, body weight and food intake. Conclusions: These findings suggest that GA conjugated exenatide had no influence on the peptide efficacy, therefore it's not necessary to inhibit exenatide acylation in PLGA formulations during the peptide release process. [ABSTRACT FROM AUTHOR]

A composite micelle of ionic complex encapsulated into poly(ethylene glycol)-poly( d, l-lactide) (PEG-PLA) di-block copolymeric micelles was used for protein drug delivery to improve its pharmacokinetic performance. In this study, recombinant human erythropoietin (rhEPO, as a model protein) was formulated with lysine into composite micelles at a diameter of 71.5 nm with narrow polydispersity indices (PDIs < 0.3). Only a trace amount of protein was in aggregate form. The zeta potential of the spherical micelles was ranging from −0.54 to 1.39 mv, and encapsulation efficiency is high (80 %). The stability of rhEPO was improved significantly in composite micelles in vitro. Pharmacokinetic studies in rats showed significant, enhanced plasma retention of the composite micelles in comparison with native rhEPO. Areas under curve (AUCs) of the rhEPO released from the composite micelles were 4.5- and 2.3-folds higher than those of the native rhEPO and rhEPO-loaded PEG-PLA micelle, respectively. In addition, the composite micelles exhibited good biocompatibility using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay with human embryonic kidney (HEK293T) cells. All these features are preferable for utilizing the composite micelles as a novel protein delivery system. [ABSTRACT FROM AUTHOR]