ProTide and cyclic phosphate ester are two successful prodrug technologies to overcome the limitations of nucleoside drugs, among which the cyclic phosphate ester strategy has not been widely used in the optimization of gemcitabine. Herein, we designed a series of novel ProTide and cyclic phosphate ester prodrugs of gemcitabine. Cyclic phosphate ester derivative 18c exhibits much higher anti-proliferative activity than positive control NUC-1031 with IC50s of 3.6–19.2 nM on multiple cancer cells. The metabolic pathway of 18c demonstrates that 18c’s bioactive metabolites prolong its anti-tumor activity. More importantly, we separated the two P chiral diastereomers of gemcitabine cyclic phosphate ester prodrugs for the first time, revealing their similar cytotoxic potency and metabolic profile. 18c displays significant in vivo anti-tumor activity in both 22Rv1 and BxPC-3 xenograft tumor models. These results suggest that compound 18c is a promising anti-tumor candidate for treating human castration-resistant prostate and pancreatic cancer.
Objective: The objective of this research was to search the new ways to reconstruct the immune function. Methods: 200 Kunming mice, 5 to 6 weeks old, divided into 8 Groups: control group bearing tumors (Group B, n=9);observation group for combined transplantation of fetal liver, spleen and thymus cells(Group CI, n=15); observation group(Group CII, n=15; carry on combined transplantation to this group once a week for successive 5 weeks and then execute the mice);treatment group with transplantation of fetal liver cells (Group F);treatment group with transplantation of fetal spleen cells (Group G); treatment group with transplantation of fetal thymus cells (Group H); treatment group with combined transplantation of fetal liver and spleen cells (Group I);treatment group with combined transplantation of fetal liver and thymus cells (Group K), nF=nG=nH=nI=nJ=nK= 12. First, prepare mice of ascitic type after the anabiosis of the root of Ehrlich ascites tumor; when the ascites are formed, draw out the ascites of the cancer cells and collect them to inoculate the experimental mice under the skin of the right hollow viscera to make the subcutaneous solid tumor model bearing Ehrlich Ascites tumor. When the model is prepared, carry out correspondent cell transplantation once a week for each group. After prepared of the suspension of fetal liver, spleen and thymus, they were transplanted into above animal models to record the tumor growth, disappear, survival time, the immune function and the tissue pathology change and compared each experimental group number. Results: The results showed that in three experimental groups the rate which the tumors were completely disappeared is 40% in the early stages and the rate which the tumors were completely disappeared in the later stage is 46.67%. After the tumors completely disappeared, the animals can survive for a long time. The partial disappeared rate is 26.67% in the early group and is 13.33% in the long-term group. In the partial group the average survival time is above one month which the immune function increase and immune organ enlarge. The immune organ histology slides showed that the organ cells proliferation increased. Conclusion: Reconstitution of immune system organ completely and partially can help the host to fight the tumor and to improve the treatment effects. Citation Format: Jie Xu, Ze Xu, Sitthipol Tovanich, Bin Wu. The novel ways to inhibit atrophy of thymus and reconstructing the immune function in preventing the advance of tumor. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr A33.
Shallow-buried and Deep-Excavated large-section tunnels in Urban Metro have many characteristics, such as large span, complex construction procedures, multiple disturbances to surrounding rocks, and difficult to control ground subsidence. In the process of tunnel construction, the surrounding rock geological conditions and construction procedures have a very important impact on the stability and stress distribution of the tunnel. Based on the South limb project of Xiejiacun entrance and exit section of Tiantongyuan East Station of Beijing Metro Line 17, the applicability of dynamic partition method (DPM) and double-sided pilot excavation method is studied by numerical simulation. The ground subsidence, convergence point deformation, surrounding rock stress, initial support stress and extrusion deformation of palm face are taken as the judgment basis for analysis. The conclusions of this paper are as follows: the surface settlement, vault displacement and surrounding rock stress of DPM method are smaller than those of double-sided guide tunnel method, so it is concluded that DPM method is more suitable for this project; however, the difference of displacement and internal force between DPM method and DPM method is even slight, but when DPM (10) and DPM (15) are used in the construction of right guide tunnel, the internal force and displacement will change abruptly and can be strengthened appropriately. Finally, the deformations of the face during the construction of three construction methods are discussed to verify the feasibility and safety of DPM method, which provides a basis and guidance for the smooth implementation of the project and can be used as a reference for similar projects.
While immune checkpoint therapies against CTLA-4, PD-1 and PD-L1 have achieved promising clinical outcome recently, the dynamic therapeutic responses spanning individual patients and different cancer types warrant exploration and validation of additional therapeutic strategies. Since the expression of immune checkpoints in tumor infiltrating lymphocytes (TIL) has been of interest to the field, we attempted to analyze the expression of several checkpoint receptors on TILs in clinical tumor samples. Unexpectedly, a number of markers were subject to time-dependent degradation during the tissue disaggregation process. This degradation could be due to the proteolytic activity of a proteinase, which has been used commonly in various tissue disaggregation protocols. Analysis of the protein sequences verified the presence of the proteinase recognition sequences in the affected receptors. Using PHA-stimulated hPBMCs, we found and demonstrated that a specific protease was responsible for either partial or total degradation of these markers. To overcome this issue, we developed a protease-free tissue disaggregation method, which showed no adverse effect on protease affected cell membrane receptors, thus allowing for more reliable flow cytometric analysis of various TIL subpopulations. With this method, we analyzed these checkpoint receptors positivity of both CD4+ and CD8+ TILs and revealed a high degree of heterogeneity of these immune checkpoints in a number of tumor types, including lung, breast and gastric cancers. Analysis of the magnitude of lymphocyte infiltration to the tumor and expression of prominent immune checkpoints on CD4+ or CD8+ TILs will help understand the subtle interaction between tumor and the immune system in the tumor microenvironment and may provide guidance for clinical trials of novel combinatorial immuno-therapeutic strategies. Citation Format: Norman Zhang, Qiyao Zhang, Yan Liu, Juntao Yu, Jingjing Wang, Jie Xu, Qunsheng Ji, Keith Wilcoxen, Jonathan Graves. Optimization of a method for FACS analysis of checkpoint receptor expression on tumor infiltrating lymphocytes in clinical tumor samples. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3950.
Tyrosine Kinase Inhibitor (TKI) of Epidermal Growth Factor Receptor (EGFR) is a first-line therapy for non-small cell carcinoma lung cancer patients with EGFR mutations, but patients often develop resistance to such a target therapy. Recently several PD-1 and PD-L1 inhibitors were approved for treating NSCLC, however, it remains unclear whether EGFR mutant NSCLC would benefit from PD-1/PD-L1 treatment. PD-1 response in cancer patients is closely associated with oncogenic mutation status, tumor microenvironment, PD-L1 expression and tumor mutation burden (TMB); however, the lack of pre-clinical models limited the investigation of the checkpoint inhibitors in EGFR mutant tumors. Here we use human PBMC reconstitution system for immune-humanization, and established a series of IO-Xenograft models (IO-CDX and IO-PDX) with cancer cell lines (IO-CDX) or patient-derived tissues (IO-PDX) that contain various EGFR mutations, including EGFR 19 del, L858R, T790M, and EGFR over-expression, amplification and fusion. We treated these models with either EGFR TKI (erlotinib, afatinib or osimertinib) or nivolumab, a PD-1 inhibitor. The predictive biomarkers including PD-L1 expression and TMB were analyzed by whole exom sequencing (WES) and FACS for tumor infiltrating lymphocytes (TILs), respectively. We found that 3 TKI-resistant PDX models bearing EGFR T790M mutation exhibited lower TILs than those bearing EGFR wild type or exon 19del mutation. Of the 8 IO-CDX or IO-PDX humanized models we have examined, those exhibiting higher TILs achieved better responses to nivolumab treatment. The 3 most sensitive models are EGFR amplification (wt), EGFR over-expression (wt) and EGFR exon 19del. In contrast, the EGFR T790M model from H1975 cell line was observed with hyper-progressive disease after nivolumab treatment. We will also discuss the contribution of PD-L1 expression and TMB to nivolumab in other models. In summary, these well-established IO-CDX and IO-PDX models can provide a human-resembling immune system for of immune therapeutics and combination with targeted therapies, and help to facilitate the understanding of relationship among tumor microenvironment, driver oncogenic mutations and drug response. Citation Format: Xuzhen Tang, Li Yang, Hui Qi, Xianzhi Zhai, Fuyang Wang, Xiangnan Qiang, Jie Xu, Xiaoran Qin, Qingyang Gu, Shaoyu Yan, Qunsheng Ji. Evaluation of immune checkpoint inhibitor efficacy in EGFR mutant tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1055.
We have established and optimized a robust tumor bone metastasis mouse model, which recapitulates the tumor metastasis progression from circulation to bone colonization, and provides windows for both prophylaxis and treatment. Specifically, we inoculated two breast cancer cell lines, JIMT-1 and MDA-MB-231, each with high metastatic potential, into mouse intra-caudal artery. By detection of steadily incremental bioluminescence signal, prophylaxis was observed to precede metastases, which were found exclusively on mouse hind limbs. These mouse models exhibited swollen hind limbs and even paralysis at late stage. Gross necropsy and pathology analysis confirmed the exclusive hind limb localization, the invasion and spreading of tumor cells to muscles and bone marrows, and the lesions in tibias and femurs. Our robust bone metastases models thus imitate the multiple stages of tumor metastasis, leading to exclusion bone metastasis and opening up windows for prophylaxis and treatment. Citation Format: Yao Shuai, Chaomeng Wang, Ling Tong, Qiao Liu, Jie Xu, Qunsheng Ji. Mouse hind limb tumor metastatic model to evaluate prophylaxis and treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6010.
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