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The current study evaluated the efficacy and safety of a denosumab biosimilar, QL1206 (60 mg), compared to placebo in postmenopausal Chinese women with osteoporosis and high fracture risk. At 31 study centers in China, a total of 455 postmenopausal women with osteoporosis and high fracture risk were randomly assigned to receive QL1206 (60 mg subcutaneously every 6 months) or placebo. From baseline to the 12-month follow-up, the participants who received QL1206 showed significantly increased bone mineral density (BMD) values (mean difference and 95% CI) in the lumbar spine: 4.780% (3.880%, 5.681%), total hip :3.930% (3.136%, 4.725%), femoral neck 2.733% (1.877%, 3.589%) and trochanter: 4.058% (2.791%, 5.325%) compared with the participants who received the placebo. In addition, QL1206 injection significantly decreased the serum levels of C-terminal crosslinked telopeptides of type 1 collagen (CTX): -77.352% (-87.080%, -66.844%), and N-terminal procollagen of type l collagen (P1NP): -50.867% (-57.184%, -45.217%) compared with the placebo over the period from baseline to 12 months. No new or unexpected adverse events were observed. We concluded that compared with placebo, QL1206 effectively increased the BMD of the lumbar spine, total hip, femoral neck and trochanter in postmenopausal Chinese women with osteoporosis and rapidly decreased bone turnover markers. This study demonstrated that QL1206 has beneficial effects on postmenopausal Chinese women with osteoporosis and high fracture risk.

To protect vessels and components against local fracture, fracture initiation strain limits are used as acceptance criteria. Based on the fracture strain model established from the Unified Strength Theory, this paper proposes fracture strain limits with only three model parameters to be calibrated. To avoid large sensitivity of an elastic-plastic analysis to the intermediate principal stress and also the Lode angle due to assumptions and simplifications used for analysis, the lower-bound fracture initiation strain limits with respect to the Lode angle are proposed. The model parameters are determined directly using the material constants defined in the ASME BPVC VIII-2. The proposed strain limit model is validated against available experimental results of aluminum alloys and low to medium carbon steels. Accuracy and applicability of the ASME VIII-2 and III specified strain limits are examined and discussed. Non-conservatism and over-conservatism in the ASME code specified strain limits can be removed. The proposed lower-bound strain limits retain simple forms and provide practical and enhanced acceptance criteria against local fracture.

Kai-Yi Tao,1 Xian-Xing Li,2 Wei-Zhen Xu,3 Yin Wang,4 Shuang-Mei Zhu,5 Hua-Xia Xie,3 Wen-Hua Luo,6 Yan-Jun Xu,7 Xiao-Ling Xu3,7 1Department of Thoracic Surgery, 2Department of Radiology, 3Key Laboratory on Diagnosis and Treatment Technology on Thoracic Cancer, Zhejiang Cancer Hospital (Zhejiang Cancer Research Institute), 4Physical Examination Center, Zhejiang Provincial People’s Hospital, Hangzhou, 5Department of Radio-Chemotherapy Oncology, Lishui People’s Hospital, Sixth Affiliated Hospital of Wenzhou Medical University, 6Department of Radio-Chemotherapy Oncology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 7Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, People’s Republic of China Background: Single-nucleotide polymorphisms in apoptosis-related genes have been shown to play a role in the efficacy of platinum-based chemotherapy and may influence clinical outcomes. Our study aimed to evaluate the correlations of four functional single-nucleotide polymorphisms – FAS −670 A>G, FAS ligand −844 T>C, survivin −31 G>C, and survivin 9386 C>T – with drug response and clinical outcomes in advanced non-small-cell lung cancer patients who received platinum-based chemotherapy. Materials and methods: Polymorphisms were evaluated using the polymerase chain reaction-based restriction fragment-length polymorphism technique.Results: Patients with the CC genotype of FAS −670 A>G had worse overall survival (OS) than those with the CT or TT genotype (P=0.044), with median OS values of 20.1 months, 22.8 months, and 26.0 months, respectively. Furthermore, progression-free survival was associated with the FAS −670 A>G polymorphism (P=0.032). In addition, patients with the TC and CC genotypes of survivin 9386 C>T experienced improved survival compared with patients with the TT genotype (median OS 31.4 months and 22.8 months, respectively).Conclusion: The functional FAS −670 A>G and survivin 9386 C>T polymorphisms are potential independent prognostic factors in advanced non-small-cell lung cancer patients treated with platinum-based chemotherapy. Keywords: lung cancer, FAS −670 A>G, survivin 9386 C>T, polymorphism, chemotherapy response

The lateral–torsional buckling behavior of general prismatic and tapered steel members with doubly and singly symmetric sections are investigated based on the general forms of differential equilibrium equations for minor-axis bending and torsion. Fundamental lateral–torsional buckling moments are derived for general tapered steel members that are in forms similar to those for prismatic members. The factor accounting for the effects of level loading application is derived and incorporated into the moment diagram modification factor that is generalized for the prismatic and tapered steel members. American Institute of Steel Construction-type equations for calculating the inelastic lateral–torsional capacity are proposed by using straight-line transition, and limiting unbraced member lengths are explicitly derived. The analytical procedure presented can give reasonable results with consistent accuracy for general design consideration and follows the same philosophy as for prismatic doubly symmetric wide-flan...

Topoisomerase 2α (Topo2A) is a key enzyme in replication. It functions as a cell proliferation and cell cycle-specific marker and it is identified mainly in the interphase nuclei of proliferating cells. Many studies have shown that Topo2A protein expression is up-regulated in various cancers including esophageal cancer. However, to date, no studies have adequately addressed the prognostic value of Topo2A in patients with resectable esophageal squamous cell carcinoma (ESCC). Therefore, we conducted a large-scale retrospective study investigating the expression of Topo2A and the clinicopathological characteristics or prognosis of ESCC patients. Eight hundred and twenty-nine specimens of ESCC from patients who underwent complete esophageal cancer resection were evaluated using an immunohistochemical assay. Among them, 404 (48.7 %) cases with a score >2 were determined to be positive for Topo2A expression. Topo2A overexpression was significantly associated with poorer differentiation (P = 0.007) and perineural invasion (P = 0.046). The median progression-free survival (PFS) of 319 patients with Topo2A-positive expression and 336 patients with Topo2A-negative expression was 19.5 and 26.5 months, respectively (P = 0.000). The overall survival (OS) in patients with and without Topo2A expression was 34.0 and 44.5 months, respectively (P = 0.002). In the multivariate analysis, Topo2A overexpression was identified as an independent prognostic factor for PFS (P = 0.001) and OS (P = 0.009). We determined that Topo2A overexpression was not only associated with poorer differentiation and perineural invasion, but it could also act as an independent risk factor for ESCC.

The p53 protein is involved in many biological functions in cancer, such as cell cycle arrest, DNA repair, apoptosis, senescence, DNA metabolism, angiogenesis, and cellular differentiation. However, the association between p53 expression and clinicopathological findings or prognosis in esophageal squamous cell carcinoma (ESCC) is controversial. We designed a large-scale study of 830 operable ESCC patients with a long follow-up to investigate the relationship between p53 expression and the clinicopathological characteristics and prognosis of patients. Immunohistochemistry was used to detect p53 protein expression. When the patients were divided into two groups, a positive expression group and a negative expression group, p53-positive expression positively correlated with a poorer differentiation level (P = 0.044). The overexpression of p53 was associated with a more advanced clinical stage (P = 0.015). A total of 775 patients were available for survival analysis. The median OS of 160 patients who had p53-positive expression and 486 patients who had p53-negative expression were 58.8 and 46.3 months, respectively (P = 0.021); the median PFS of the two groups were 39.6 and 27.5 months, respectively (P = 0.015). Lymph node metastasis, gender, differentiation, depth of invasion, and p53 protein expression were proven to have an influence on both OS and PFS in a univariate analysis. In the multivariate analysis, p53-positive expression maintained its independent prognostic impact on OS (P = 0.048) and PFS (P = 0.039), as did lymph node metastasis, differentiation, and depth of invasion. We identified that p53 protein-positive expression can serve as an independent, unfavorable prognosis biomarker in ESCC.

The amount of drug remaining after previous doses, or drug accumulation, is closely related to drug efficacy and safety. An accurate calculation of the accumulation index or ratio (R(ac)) is crucial for dose finding. However, in drug accumulation studies little consensus exists with regard to experimental design or data analysis. We conducted a systematic review of the literature to produce a detailed profile of drug accumulation studies of the last 30 years (1980-2011). Ninety-six articles comprising 122 studies were analyzed. A typical drug accumulation study enrolled 10 to 20 subjects randomly assigned into treatment groups of 1 or 2 dose levels to observe pharmacokinetic behaviors. The median washout period between single and multiple dosing was 7 days, and the dose interval was 1-2 elimination half-lives in non- or one-compartmental models. Generally, the number of repeated times of administration for multiple dosing was 7-14, and the median number of sampling time points was 11. Eight different methods were used to calculate R(ac). The most frequently used method, in 72.9% of the studies, was to set R(ac) equal to the ratio of the area under a plasma concentration-time curve (AUC) during a dosage interval at steady state to the AUC of a dosage interval after the first dose, i.e., R(ac) = AUC(0-τ,ss) / AUC(0-τ,1). The values of R(ac) in the included studies ranged from 0.85 to 18.8, and 68.03% were

Comparative pharmacokinetic (PK) analysis is often carried out throughout the entire period of drug development, the common approach for the assessment of pharmacokinetics between different treatments requires that the individual PK parameters, which employs estimation of 90% confidence intervals for the ratio of average parameters, such as AUC and Cmax, these 90% confidence intervals then need to be compared with the pre-specified equivalent interval, and last we determine whether the two treatments are equivalent. Unfortunately in many clinical circumstances, some or even all of the individuals can only be sparsely sampled, making the individual evaluation difficult by the conventional non-compartmental analysis. In such cases, nonlinear mixed effect model (NONMEM) could be applied to analyze the sparse data. In this article, we simulated a sparsely sampling design trial based on the dense sampling data from a truly comparative PK study. The sparse data were analyzed with NONMEM method, and the original dense data were analyzed with non-compartment analysis. Although the trial design and analysis methods are different, the 90% confidence intervals for the ratio of PK parameters based on 1000 Bootstrap are very similar, indicated that the analysis based on NONMEM is a reliable method to treat with the sparse data in the comparative pharmacokinetic study.

To compare p27 interfering effect on the proliferation and hematopoietic potential of hematopoietic progenitor cells (HPC) derived from human bone marrow (BM) and umbilical cord blood (UCB), and investigate the related mechanism.CD34(+) cells sorted from human BM by flow cytometry and isolated from UCB by a magnetic isolation system were infected with retrovirus-p27 antisense cDNA (p27AS) and cultured with cocktail-cytokines. The cell proliferation capacities were detected by cell growth curve and DNA content analysis, and the hematopoietic potential by colony formation assay. The protein expression of p27 and CDK2 were measured with Western blot. CD34(+) cells infected with retrovirus-p27 sense cDNA (p27SE) and virus-green fluorescence protein (GFP) were used as the control.Comparing with groups of GFP and p27SE, p27AS showed to accelerate the expansion of UCB HPC significantly (P0.01), the cell number of p27AS, p27SE and GFP increased by 197.3 +/- 47.7-, 12.7 +/- 8.1- and 41.8 +/- 30.6- fold respectively by the end of the 9-day culture, the BM HPC increased by 36.0 +/- 22.3-, 8.7 +/- 6.8- and 14.1 +/- 10.4-fold respectively in the same time as UCB HPC. Cell cycle analysis showed p27AS mainly promoted S phase of BM and UCB HPC. S phase cell percentages of UCB HPC infected with p27AS, p27SE and GFP were (17.0 +/- 4.8)%, (2.0 +/- 0.8)% and (4.1 +/- 1.8)% and that of BM HPC were (8.4 +/- 4.4)%, (1.0 +/- 0.7)% and (3.8 +/- 1.4)% respectively. The yields of colony formation of p27AS for BM and UCB was higher than that for GFP (P0.05). Western blot demonstrated the expression of p27 reduced in the p27AS group, while CDK2 increased in the group. The virus infection rate, cell growth rate and colony forming yields of BM HPC was inferior to that of UCB HPC.p27 gene interfering could promote HPC proliferation, hematopoietic potential and the response to stimulations of UCB HPC is higher than that of BM HPC ex vivo. It seems that cell cycle controlled by p27 was related to CDK2.