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Haisheng Guo,1,* Yunhui Xing,2,* Ailan Mu,1 Xia Li,3 Tingshan Li,4 Xia Bian,1 Chunmei Yang,1 Xiaolei Zhang,1 Yuefen Liu,1 Xunguo Wang1 1Department of Oncology, Dongying People’s Hospital, 2Department of Tuberculosis, Shengli Hospital ofShengli Oil Field, 3Department of Health, 4Personnel Department, Dongying People’s Hospital, Dongying, Shandong, People’s Republic of China *These authors contributed equally tothis work Abstract: Proliferation, growth, and differentiation of cells are strictly controlled by the signal system of epidermal growth factor receptor (EGFR). If any link of the EGFR signals system is interfered with or damaged, the proliferation, growth, and differentiation of cells would become uncontrolled. EGFR is overexpressed in a variety of malignant tumors, such as non-small-cell lung cancer, colorectal cancer and breast cancer. Results of the study have proved that EGFR overexpression is closely associated with mutations and variants of the EGFR genes, whose mutations and variants are associated with occurrence, metastasis, and prognosis of different types of tumors, including lung cancer. This study is aimed at investigating whether the polymorphisms of CA simple sequence repeat in intron 1 (CA-SSR1), -216G/T, and R497K in the EGFR are able to induce EGFR activation and whether overexpression is associated with pleural metastasisof lung adenocarcinoma. A total of 432 lung adenocarcinoma patientswith pleural metastasis (metastasis group) and 424patients with lung adenocarcinoma but without pleuralmetastasis (nonmetastasis group) were enrolled in this study. For all patients, the CA-SSR1 genotypeswere determined by capillary electrophoresis, polymerase chain reaction amplification, and direct DNA sequencing, and the R497K and -216G/T genotypes were determined by polymerase chain reaction amplification and direct DNA sequencing. EGFR expression was evaluated by immunohistochemical staining in primary tumor tissues with different -216G/T, R497K, and CA-SSR1 genotypes. Our results showed significant differences between pleural metastasis and nonmetastasis groups in the genotype and allele distribution of -216G/T, R497K, and CA-SSR1 polymorphisms of the EGFR gene. The -216T allele, Arg allele, and shorter CA-SSR1 (

Xinyu Bian,* Puyuan Wu,* Huizi Sha, Hanqing Qian, Qing Wang, Lei Cheng, Yang Yang, Mi Yang, Baorui LiuComprehensive Cancer Center of Drum-Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, People’s Republic of China*These authors contributed equally to this workAbstract: In this study, we report a novel kind of targeting with paclitaxel (PTX)-loaded silk fibroin nanoparticles conjugated with iRGD–EGFR nanobody recombinant protein (anti-EGFR-iRGD). The new nanoparticles (called A-PTX-SF-NPs) were prepared using the carbodiimide-mediated coupling procedure and their characteristics were evaluated. The cellular cytotoxicity and cellular uptake of A-PTX-SF-NPs were also investigated. The results in vivo suggested that NPs conjugated with the recombinant protein exhibited more targeting and anti-neoplastic property in cells with high EGFR expression. In the in vivo antitumor efficacy assay, the A-PTX-SF-NPs group showed slower tumor growth and smaller tumor volumes than PTX-SF-NPs in a HeLa xenograft mouse model. A real-time near-infrared fluorescence imaging study showed that A-PTX-SF-NPs could target the tumor more effectively. These results suggest that the anticancer activity and tumor targeting of A-PTX-SF-NPs were superior to those of PTX-SF-NPs and may have the potential to be used for targeted delivery for tumor therapies. Keywords: EGFR, nanobody, iRGD, recombinant protein, targeting drug carriers, antitumor efficiency

This paper aims to propose a procedure for calculating separately the resistance factors for ultimate base and shaft resistances for the reliability-based design of piles. The proposed procedure can clearly explain the different sources of uncertainties of the bearing capacity, including those from ultimate base and shaft resistances. The study evaluates the convergence of the proposed procedure, and the effects of relevant parameters on resistance factors. Finally, two examples are used for comparison and application of the presented method for determining ultimate base and shaft resistance factors. Convergence analysis proves that the final resistance factors can be rapidly obtained, and maintain good stability using the iteration algorithm included in the proposed procedure. A parametric study indicates that the ratio of dead load to live load and initial values of the ultimate shaft (or base) resistance factor, have a limited effect on the final convergence values of ultimate shaft (and base) resistance factors. However, the target reliability index has significant influence on the ultimate shaft and base resistance factors. The validation example shows that the ultimate shaft and base resistance factors, as calculated in this paper, are conservative compared to the results by Kim et al (2011), due to the consideration of more uncertainties. The recommended ultimate shaft and base resistance factors for the reliability-based design of piles can be obtained conveniently using the proposed procedure in the application example.

Lei Cheng,1,* Zuguang Xia,2,3,* Xinyu Bian,1 Guangchao Li,4 Jing Hu,1 Ya Cao,5 Qing Wang,1 Xiaoping Qian1 1Comprehensive Cancer Center of Drum-Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, 2Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 3Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 4School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, Guangdong, 5Department of Biological Science and Technology and State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, People’s Republic of China *These authors contributed equally tothis work Abstract: Mammalian target of rapamycin (mTOR) has been shown to be overactive in human colorectal cancer, but the first-generation mTOR inhibitor, rapamycin, has failed to show clinical efficacy against colorectal cancer. On the other hand, although the second-generation mTOR inhibitor, PP242, has exerted substantial efficacy, it was revealed that independent inhibition by PP242 was transient, which could lead to positive-feedback loop to EGFR. Using wild-type KRAS colorectal cancer cells as models, we investigate the treatment efficacy of a widely used anti-EGFR monoclonal antibody, cetuximab, and PP242, alone or in combination in vitro and in vivo. Results of cell viability assays confirmed the synergistic inhibitory effect of PP242 and cetuximab on the survival of Caco-2 and HT-29 cells. Moreover, the ability of cancer-cell invasion and proliferation was also significantly inhibited by the combination therapy when compared with cetuximab or PP242 alone. Interestingly, the percentage of CD44-positive cancer cells was substantially decreased by the combination therapy in comparison with PP242 alone through fluorescence-activated cell sorting. The growth of cancer stem-like cell spheres in vitro was also maximally inhibited by combination therapy, in terms of either diameter or number. More importantly, the efficacy of combination therapy was more prominent than either drug alone in established tumor xenografts. These findings supported the potential use of combination therapy of PP242 and cetuximab against wild-type KRAS colorectal carcinomas. Keywords: colorectal cancer, cancer stem-like cells, anti-EGFR treatment