These analyses demonstrate that first-line erlotinib provides a statistically significant improvement in PFS versus GP in Asian patients with EGFR mutation-positive NSCLC (NCT01342965).

No abstract

The maternal high-E2 environment in the first trimester is correlated with increased risks of LBW and SGA. Evaluation of serum E2 before ET should be adopted to reduce the possibility of high E2 exposure to gamete/embryo.

Dually targeted mitochondrial proteins usually possess an unconventional mitochondrial targeting sequence (MTS), which makes them difficult to predict by current bioinformatics approaches. Human apurinic/apyrimidinic endonuclease (APE1) plays a central role in the cellular response to oxidative stress. It is a dually targeted protein preferentially residing in the nucleus with conditional distribution in the mitochondria. However, the mitochondrial translocation mechanism of APE1 is not well characterized because it harbors an unconventional MTS that is difficult to predict by bioinformatics analysis. Two experimental approaches were combined in this study to identify the MTS of APE1. First, the interactions between the peptides from APE1 and the three purified translocase receptors of the outer mitochondrial membrane (Tom) were evaluated using a peptide array screen. Consequently, the intracellular distribution of green fluorescent protein-tagged, truncated, or mutated APE1 proteins was traced by tag detection. The results demonstrated that the only MTS of APE1 is harbored within residues 289 -318 in the C terminus, which is normally masked by the intact N-terminal structure. As a dually targeted mitochondrial protein, APE1 possesses a special distribution pattern of different subcellular targeting signals, the identification of which sheds light on future prediction of MTSs.Human APE1 (apurinic/apyrimidinic endonuclease) is an important multifunctional protein that plays a central role in the cellular response to oxidative stress. The two major activities of APE1 are DNA repair and redox regulation of transcriptional factors. On one hand, APE1 functions as a critical ratelimiting enzyme in DNA base excision repair and accounts for nearly all of the AP site incision activities in cell extracts (1). On the other hand, APE1 also exerts unique redox activity to regulate the DNA binding affinity of certain transcriptional factors by controlling the redox status of their DNA-binding domain (2). Inhibition of the redox function of APE1 blocks murine endothelial cell growth and angiogenesis and also blocks the growth of human tumor cell lines (3). The biological importance of APE1 is highlighted by the finding that APE1 knockout mice exhibit an embryonic lethal phenotype (4). Although APE1 has long been labeled as a nuclear protein, a growing body of evidence has shown that the subcellular distribution of APE1 can be cytoplasmic in some cell types with high metabolic or proliferative rates, with predominant localization in the mitochondria and the endoplasmic reticulum (5-7). Recent mitochondrial proteomic studies have further confirmed the existence of APE1 in the mitochondria (8). Considering the importance of the mitochondria in cellular response to oxidative stress, the roles of APE1 in the mitochondria have been extensively investigated.

Caffeic acid phenethyl ester, an active component of propolis, has been implicated in the regulation of cell growth and apoptosis, although the exact mechanism of this activity has not been elucidated. In this study, we explored the effects of caffeic acid phenethyl ester on growth, cell cycle, apoptosis and beta-catenin/T-cell factor signaling in human colon cancer cells. Using two human sporadic colon cancer cell lines (HCT116 and SW480), we assayed for cell growth inhibition, cell cycle and apoptosis induction. We also assayed for beta-catenin and downstream target genes (cyclin D1 and c-myc) mRNA and protein expression by reverse transcriptase-polymerase chain reaction and Western blot analysis. Beta-catenin localization was detected by indirect immunofluorescence. Beta-catenin/T-cell factor transcriptional activity was determined by transient transfection and reporter gene assay. Caffeic acid phenethyl ester completely inhibited growth, and induced G1 phase arrest and apoptosis in a dose-dependent manner in both HCT116 and SW480 cells. Treatment of human colon cancer cells with apoptotic concentrations of caffeic acid phenethyl ester resulted in a dose-dependent and time-dependent loss of total beta-Catenin protein, associated with decreased nuclear beta-catenin. Caffeic acid phenethyl ester reduced the expression of cyclin D1 and c-myc in a dose-dependent and time-dependent manner. We proved that caffeic acid phenethyl ester markedly suppressed the transcriptional activity of beta-catenin/T-cell factor in both HCT116 and SW480 cells depending on the concentration of caffeic acid phenethyl ester. These results indicate that caffeic acid phenethyl ester is an excellent inhibitor of beta-catenin/T-cell factor signaling in colon cancer cell lines and suggest that caffeic acid phenethyl ester merits further study as an agent against colorectal cancers.

No abstract

PurposeTo define the role of the DNA repair protein apurinic/apyrimidinic endonuclease 1 (APE1) in predicting the prognosis and chemotherapeutic response of non-small cell lung cancer patients receiving platinum-containing chemotherapy.ResultsOur investigations found that serum APE1 level was significantly elevated in 229 of 412 NSCLC patients and correlated with its level in tissue (r2 = 0.639, p < 0.001). The elevated APE1 level in both tissue and serum of patients prior to chemotherapy was associated with worse progression-free survival (HR: 2.165, p < 0.001, HR: 1.421, p = 0.012), but not with overall survival. After 6 cycles of chemotherapy, a low APE1 serum level was associated with better overall survival (HR: 0.497, p = 0.010).Experimental DesignWe measured APE1 protein levels in biopsy tissue from 172 NSCLC patients and sera of 412 NSCLC patients receiving platinum-based chemotherapy by immunohistochemistry and a newly established sensitive and specific enzyme-linked immunosorbent assay, respectively. APE1 levels in sera of 523 healthy donors were also determined as control.ConclusionsOur studies indicate that APE1 is a biomarker for predicting prognosis and therapeutic efficacy in NSCLC. The chemotherapy-naïve serum APE1 level, which correlated with its tissue level inversely associated with progression-free survival of platinum-containing doublet chemotherapy, whereas post-treatment serum APE1 level was inversely associated with overall survival.

Osteosarcoma is a highly vascular and extremely destructive malignancy, and the survival of patients with osteosarcoma has not improved significantly in recent years. Antiangiogenic therapy currently holds great potential in conjunction with conventional treatment modalities for osteosarcoma. However, there are examples of gradual loss of response, and perhaps acquired resistance to antiangiogenic drugs. The acquired resistance of antiangiogenesis may be associated with a lot of hypoxia-response genes. The human apurinic/apyrimidinic endonuclease (Ape1) protein, a bifunctional redox factor and apurinic/apyrimidinic (AP) endonuclease, plays a crucial role in protecting against cell death due to hypoxia. We therefore hypothesized that Ape1 may contribute to the resistance of antiangiogenic therapy. To investigate the effect of Ape1 on the sensitivity of human osteosarcoma cells to endostatin, we constructed an Ape1 small interfering RNA expression vector, O steosarcoma is the most common malignant bone tumor in children and young people. The peak incidence of osteosarcoma usually occurs in the second and third decade of life, and approximately 1000 new cases a year are diagnosed in the USA. Over the past three decades, advances in treatment have been responsible for improved limb salvage, reduced metastases, and overall higher survival rates.(1) Multiagent doseintensive chemotherapy regimens have resulted in long-term disease-free survival rates of ~60-76% in patients with localized disease.(2) Osteosarcoma patients whose tumors respond poorly to chemotherapy are at a higher risk of relapse and adverse outcome due to the genetic instability and intrinsic concomitant tumor resistance.(3) Angiogenesis inhibitors are new anticancer drugs considered potentially capable of circumventing or significantly delaying acquired drug resistance, because they target the normal -and hence genetically stable -host endothelial cells of a tumor's growing vasculature.(4,5) However, there are examples of gradual loss of response, and perhaps acquired resistance to antiangiogenic drugs or treatment strategies, especially when the drugs are administered as monotherapies. (6) These experiments demonstrate that the genetic background of a tumor cell, in this case the presence or absence of wild-type p53, may be an important determinant of response to antiangiogenic therapy.(7) The acquired resistance to antiangiogenic therapy may be associated with a lot of hypoxia-response genes.(8,9) The human apurinic/apyrimidinic endonuclease (Ape1), a bifunctional redox factor/apurinic/apyrimidinic (AP) endonuclease, plays a crucial role in protecting against cell death due to hypoxia.(10) We therefore hypothesized that Ape1 may contribute to the resistance to antiangiogenic therapy, and the knockdown of Ape1 may enhance tumor sensitivity to antiangiogenic therapy.In the present study, we constructed the specific Ape1 small interfering RNA (siRNA) stable expression vector pSilenceApe1 to knockdown Ape1 expression in the osteosarcoma cells, and to de...