Gingival-derived mesenchymal stem cells (GMSCs) have strong self-renewal, multilineage differentiation, and immunomodulatory properties and are expected to be applied in anti-inflammatory and tissue regeneration. However, achieving the goal of using endogenous stem cells to treat diseases and even regenerate tissues remains a challenge. Resveratrol is a natural compound with multiple biological activities that can regulate stem cell immunomodulation when acting on them. This study found that resveratrol can reduce inflammation in human gingival tissue and upregulate the stemness of GMSCs in human gingiva. In cell experiments, it was found that resveratrol can reduce the expression of TLR4, TNFα, and NFκB and activate ERK/Wnt crosstalk, thereby alleviating inflammation, promoting the proliferation and osteogenic differentiation ability of GMSCs, and enhancing their immunomodulation. These results provide a new theoretical basis for the application of resveratrol to activate endogenous stem cells in the treatment of diseases in the future.
Background:Adoptive NK cells infusion is a promising immunotherapy for acute myeloid leukemia (AML) patients.Aims:The aim of this study was to explore that two weeks of clinical grade expansion could provide sufficient numbers and purity of NK cells for clinical application with an enhanced ant‐leukemia response in vitro.Methods:NK cells were expanded in the large‐scale expansion platform based on membrane‐bound interleukin‐21/4–1BBL K562 feeder cells (mbIL21/4‐1BBL). The phenotype as well as responsitveness of NKcells were evaluated before and post NK cells expansion. NCG mouse model were used to assess the in vivo persistence and in vivo anti‐leukemia effect of NK products. Finally, 20 minimal residual disease persistent or relapse (MRD+) AML were enrolled to evaluate the safety of adoptive expanded NK products infusion.Results:In this study, using the large‐scale expansion platform, we first demonstrated that 2 weeks of expansion could satisfy clinical use in number (∼4.1 × 109 NK cell) and purity (median 81%) from 2 × 107 peripheral blood mononuclear cells based on membrane‐bound interleukin‐21/4‐1BBL K562 feeder cells (mbIL21/4‐1BBL), with expansion folds of 1318 and 2876 at 2 and 3 weeks, respectively. The CD107α production as well as TNF‐α secretion capacity of NK products against AML cell lines, or primary AML blasts, were comparable between 2 weeks and 3 weeks expanded NK products, both of which were higher than those resting NK cells before expansion. The MbIL21/4‐1BBL expanded NK product xenografted into immunodeficient leukemia mice could be found in bone marrow, spleen, liver, lung and peripheral blood, persisting for at least 2 weeks and reducing the AML burden in vivo. NK cells infusions once, or three times every other days exhibited similar tumor control. Compared with the case‐paired 20 minimal residual disease persistent or relapse (MRD+) AML patients with regular consolidation therapy, 20 AML MRD+ patients who accepted the expanded NK treatment showed better leukemia‐free survival and overall survival.Summary/Conclusion:In conclusion, this study demonstrated that mbIL‐21/4‐1BBL expanded NK cells exhibited anti‐leukemia activity against AML in vitro and in a mouse model, and the infusion of expanded NK product was potentially efficacious for AML patient without adverse effects.
The association between the activating mutations of K-ras gene and poor clinical response to current targeted therapies against epidermal growth factor receptor (EGFR ) such as cetuximab (Erbitux®) and panitumumab (Vectibix®) in colorectal cancer (CRC) has been well documented. Therefore detection of K-ras mutation status will guide effective therapeutical options for patients with CRC. Here we developed a new method for the rapid and reliable detection of K-ras mutations by using a combination of the modified mutation-specific ARMS primers, peptide nucleic acid (PNA) clamping and taqman-MGB probes, named ARMS-PM system. In the ARMS-PM system, the wild-type K-ras DNA is completely blocked by PNA at a higher annealing temperature, and the mutant gene is selectively amplified by the modified ARMS primers and the amplicon extending signals are collected by the taqman-MGB probe at the same time. The ARMS-PM system can detect approximately 10 copies of the mutant gene stably in somatic cells at the background of 10ng genomic DNA. In addition, the premixed reaction was introduced into this system to allow the assay to be completed in only one step of sample loading, which minimizes the potential contamination significantly. By using this assay, we analyzed the K-ras mutations in 1014 Chinese CRC and 205 Chinese lung cancer FFPE samples in comparison with Sanger sequencing. Our results showed that the positive rates were 38.6% and 10.2% 38.0% in CRC and lung cancer samples respectively, which were higher than that measured by Sanger sequencing (38.0% and 7.1%). The coincidence rates of the two methods were 97.3% for the positive samples and 97.7 for the negative samples. The total coincidence rate was 97.8%. In conclusion, our study provides a basis for the detection of somatic mutations in K-ras in a routine clinical setting. The ARMS-PM assay allows the detection of the activating K-ras mutations in FFPE samples with better sensitivity and feasibility than the current assays used in clinic. <!–EndFragment–> Citation Format: Wei-Tao Duan, Xiujuan Wang, Lihong Hu, Feng Zhu, Dehua Yu. A highly sensitive and reliable methodology (ARMS-PM system) for detection of K-ras mutations in FFPE samples. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1508. doi:10.1158/1538-7445.AM2014-1508
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