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目的 探讨脾切除联用环孢素对协调性异种移植心脏存活时间的影响及其机制。方法 建立协调性异种心脏移植模型。分别采用不同时间脾切除联用环孢素，观察异种移植物的生存时间。用CH50法检测各组动物血清中总补体活性。应用流式细胞技术检测动物血清中异种反应性抗体IgG、IgM的滴度变化。移植物标本HE染色观察病理学改变。免疫组化染色观察各实验组不同时间移植物组织中IgG、IgM抗体的沉积。结果 脾切除联用环孢素能够显著延长移植物的生存时间（P〈0．05），降低受者体内异种反应性抗体的滴度。结论 脾切除联用环孢素可以减少移植术后早期受者体内异种反应性抗体的产生，延长异种移植物的生存时间。

Wenshen ZhuanggLi formula （WSZG） is a traditional Chinese medicine used as an adjuvant for the prevention of bone metastases in breast cancer patients. In this study we investigated the efficacy of WSZG in preventing bone metastases and the potential mechanisms in a mouse xenograft model of breast cancer bone metastases. This model was established by injection of human MDA- MB-231BO-Luc breast cancer cells alone or a mixture of the cancer cells with bone marrow-derived mesenchymat stem cells （BMSCs） into left ventricle of the heart in female nude mice. Then the mice were treated with WSZG （3.25, 6.5 or 13.0 mg-kEl.d1, ig） for four weeks, whereas zo{edronic acid （100 pg/kg per week, ig） was used as a positive control. The occurrence and development of bone metastases were monitored via bioluminescent imaging, and bone lesions were assessed using micro-CT. Intracardiac injection of the mixture of MDA-MB-231BO-Luc breast cancer cells with BMSCs significantly facilitated the bone metastatic capacity of the breast cancer cells, and aggravated bone lesions in the mouse xenograft model of breast cancer bone metastases. Administration of WSZG dose-dependently inhibited the incidence and intensity of bone metastases and protected against bone lesions by suppressing osteoclast formation and tumor cell infiltration. Furthermore, administration of WSZG caused a marked reduction in the expression of CCLS/CCR5 and IL-17B/IL-17BR in bone metastatic tissues. The results demonstrate thatWSZG exerts potential therapeutic effects in a mouse xenograft model of breast cancer bone metastases, which are partially mediated by weakening the interaction between BMSCs and breast cancer ceils in the tumor microenvironment.

Aim： To investigate whether the conjugation of magainin II （MG2）, an antimicrobial peptides （AMPs）, to the tumor-homing peptide bombesin could enhance its cytotoxicity in tumor cells. Methods： A magainin II-bombesin conjugate （MG2B） was constructed by attaching magainin II （MG2） to bombesin at its N-terminus. The peptides were synthesized using Fmoc-chemistry. The in vitro cytotoxicity of the peptide in cancer cells was quantitatively deter- mined using the CCK-8 cell counting kit. Moreover, the in vivo antitumor effect of the peptide was determined in tumor xenograft mod- els. Results： The IC5o of MG2B for cancer cells （10-15 pmol/L） was at least 10 times lower than the IC50 of unconjugated MG2 （125 μmol/L）. Moreover, the binding affinity of MG2B for cancer cells was higher than that of unconjugated MG2. in contrast, conjugation to a bombesin analog lacking the receptor-binding domain failed to increase the cytotoxicity of MG2, suggesting that bombesin conjugation enhances the cytotoxicity of MG2 in cancer cells through improved binding. Indeed, MG2B selectively induced cell death in cancer cells in vitro with the IC50 ranging from 10 to 15 pmol/L, which was about 6-10 times lower than the IC5o for normal cells. MG2B （20 mp=/kg per day, intratumorally injected for 5 d） also exhibited antitumor effects in mice bearing MCF-7 tumor grafts. The mean weights of tumor grafts in MG2B- and PBS-treated mice were 0.21±0.05 g and 0.59±0.12 g, respectively. Conclusion： The results suggest that conjugation of AMPs to bombesin might be an alternative approach for targeted cancer therapy.

There is a critical need for more effective therapeutic approaches for prostate cancer. Research in this area, however, has been seriously hampered by a lack of clinically relevant, experimental in vivo models of the disease. This review particularly focuses on the development of prostate cancer xenograft models based on subrenal capsule grafting of patients＇ tumor tissue into nonobese diabetic/ severe combined immunodeficient （NOD/ SCID） mice. This technique allows successful development of transplantable, patient-derived cancer tissue xenograft lines not only from aggressive metastatic, but also from localized prostate cancer tissues. The xenografts have been found to retain key biological properties of the original malignancies, including histopathological and molecular characteristics, tumor heterogeneity, response to androgen ablation and metastatic ability. As such, they are highly clinically relevant and provide valuable tools for studies of prostate cancer progression at cellular and molecular levels, drug screening for personalized cancer therapy and preclinical drug efficacy testing; especially when a panel of models is used to cover a broader spectrum of the disease. These xenograft models could therefore be viewed as next-generation models of prostate cancer.

FXYD6, FXYD domain containing ion transport regulator 6, has been reported to affect the activity of Na＋/K＋-ATP- ase and be associated with mental diseases. Here, we demonstrate that FXYD6 is up-regulated in hepatocellular carcinoma （HCC） and enhances the migration and prolif- eration of HCC cells. Up-regulation of FXYD6 not only positively correlates with the increase of Na＋IK＋-ATPase but also coordinates with the activation of its downstream Src-ERK signaling pathway. More importantly, blocking FXYD6 by its functional antibody significantly inhibits the growth potential of the xenografted HCC tumors in mice, indicating that FXYD6 represents a potential therapeutic target toward HCC. Altogether, our results establish a critical role of FXYD6 in HCC progression and suggest that the therapy targeting FXYD6 can benefit the clinical treatment toward HCC patients.

Aim： Erlotinib is used to treat non-small-cell lung cancer （NSCLC）, which targets epidermal growth factor receptor （EGFR） tyrosine kinase. The aim of this study was to investigate the relationship between erlotinib plasma concentrations and phosphorylated EGFR （pEGFR） levels, as well as the relationship between pEGFR levels and tumor growth inhibition in a human non-small-cell lung cancer xenograft mouse model. Methods： Female BALB/c nude mice were implanted with the human NSCLC cell line SPC-A-1. The animals were given via gavage a single dose of erlotinib （4, 12.5, or 50 mg/kg）. Pharmacokinetics of erlotinib was determined using LC-MS/MS. Tumor volume and pEGFR levels in tumor tissues were measured at different time points after erlotinib administration, The levels of pEGFR in tumor tissues was detected using Western blotting and ELISA assays. Results： The pharmacokinetics of erlotinib was described by a two-compartment model with first order extravascular absorption kinetics. There was a time delay of approximately 2 h between erlotinib plasma concentrations and pEGFR degradation. The time course of pEGFR degradation was reasonably fit by the indirect response model with a calculated IC~o value of 1.80 pg/mL. The relationship between pEGFR levels and tumor volume was characterized by the integrated model with a Kbio value of 0.507 cm3/week which described the impact of pEGFR degradation on tumor growth. Conclusion： The pharmacokinetic/pharmacodynamic properties of erlotinib in a human tumor xenograft model were described by the indirect response model and integrated model, which will be helpful in understanding the detailed processes of erlotinib activity and determining an appropriate dosing regimen in clinical studies.

Dear Editor, We examined myelin formation by oligodendrocytes co-transplanted with immunosuppressive mesenchymal stem cells （MSCs）. Oligodendrocyte precursor cells （OPCs） were grafted into the mouse retina, and graft survival and maturation was determined with or without adjunctive MSCs. Green fluorescent protein （GFP）-labeled MSCs were present at 2 but not 6 weeks post transplant,

Chronic myeloid leukemia （CML） is a clonal hemato poietic stem cell disorder characterized by the oncogenic BCR-ABL fusion gene with increased ABL tyrosine ki- nase （TK） activity [1]. Transduction of primitive hematopoietic cells with the BCR-ABL oncoprotein creates cells that display many features of their BCR-ABL＋ coun- terparts in CML patients. Inhibition of the TK activity of BCR-ABL by small molecule inhibitors （imatinib mesyl- ate （IM）, dasatinib and nilotinib） [2] causes impressive responses in chronic phase CML patients. Nevertheless, response failures, early relapses and the later emergence of IM-resistant disease remain significant problems for many patients. In particular, CML stem cells are insensi- tive to IM and other ABL inhibitors and are not eradi- cated by currently available agents [1, 3]. These findings underscore the importance of understanding the biology of CML stem/progenitor cells and their unique properties in vivo, in guiding the development of strategies to per- manently cure CML. We have used a new xenograft model that exploits the advantages of a long-living, large animal host, the goat, which can be transplanted in a preimmune state in utero and then followed for several years after birth [4]. We transplanted fetal goats in utero with BCR-ABL- transduced lin-CD34＋ human cord blood （CB） cells and analyzed 6 liveborn goats for persistent engraftment of GFP＋BCR-ABL＋ cells in multiple tissues and for initia- tion of early phase CML. Twenty-eight fetuses were injected intraperitoneally at 45-55 days of gestation with 2 x l04 to l0s transduced lin human CB cells （-85% were CD34＋, 20%-30% were GFP＋BCR-ABL＋）. Another 14 fetuses were similarly transplanted with control GFP- vector-transduced cells （MIG）. Both groups displayed a high rate of abortion （〉 50%）. Therefore, only 6 goats transplanted with BCR-ABL-transduced cells （all recipi- ents of 2 x 104 cells, hereafter referred to as BCR-ABL goats for brevity） and 5 goats transplanted with MIG-transduced cells （2-5 x 104 cells, hereafter referred to as MIG goats for brevity） were born alive and thus avail- able for follow-up studies. A group of 3 BCR-ABL goats and 2 MIG goats were sacrificed 3 weeks after birth. Fluorescence microscopy and confocal laser scanning microscopy revealed a large number of GFP＋ （BCR-ABL＋） cells in liver, kidney and lung from all three BCR-ABL goats （Supplementary in- formation, Figure S1A-S 1C）. FACS analysis also detect- ed GFP＋ （BCR-ABL＋） cells in suspensions prepared from multiple tissues including liver, kidney, smooth muscle, heart and lung of all three BCR-ABL goats （1%-49% of all the viable cells from these tissues, Supplementary information, Figure $2）. These results were confirmed by fluorescence in situ hybridization （FISH） analyses performed on cells isolated from the bone marrow （BM） or liver of a BCR-ABL goat using the P17H8 probe that specifically identifies the unique a-satellite DNA se- quences on human chromosome 17, and a specific probe for human BCR-ABL （Figure 1A and Supplementary information, Figure S3A）. Neither of these probes gave any signal in the control BM cells from a normal goat （unmanipulated） （Figure 1A）. Immunohistochemical staining of liver tissue sections obtained from all three of the 3-week-old BCR-ABL goats showed frequent coinci- dence of GFP fluorescence and the expression of human proliferating cell nuclear antigen （PCNA） （Supplementary information, Figure S1D）.Don A Baldwin