Adenosine monophosphate-activated protein kinase (AMPK) acts as a major sensor of cellular energy status in cancers and is critically involved in cell sensitivity to anticancer agents. Here, we showed that AMPK was inactivated in lymphoma and related to the upregulation of the mammalian target of rapamycin (mTOR) pathway. AMPK activator metformin potentially inhibited the growth of B- and T-lymphoma cells. Strong antitumor effect was also observed on primary lymphoma cells while sparing normal hematopoiesis ex vivo. Metformin-induced AMPK activation was associated with the inhibition of the mTOR signaling without involving AKT. Moreover, lymphoma cell response to the chemotherapeutic agent doxorubicin and mTOR inhibitor temsirolimus was significantly enhanced when co-treated with metformin. Pharmacologic and molecular knock-down of AMPK attenuated metformin-mediated lymphoma cell growth inhibition and drug sensitization. In vivo, metformin induced AMPK activation, mTOR inhibition and remarkably blocked tumor growth in murine lymphoma xenografts. Of note, metformin was equally effective when given orally. Combined treatment of oral metformin with doxorubicin or temsirolimus triggered lymphoma cell autophagy and functioned more efficiently than either agent alone. Taken together, these data provided first evidence for the growth-inhibitory and drug-sensitizing effect of metformin on lymphoma. Selectively targeting mTOR pathway through AMPK activation may thus represent a promising new strategy to improve treatment of lymphoma patients.

Purpose: Poly(ADP-ribose) polymerase-1 (PARP-1) is the founding member of a family of enzymes that catalyze the addition of ADP-ribose units to proteins that mediate DNA repair pathways. Ionizing radiation induces DNA strand breaks, suggesting that PARP-1inhibition may sensitize tumor cells to radiation. Experimental Design: We investigated the combination of PARP-1 inhibition with radiation in lung cancer models. ABT-888, a novel potent PARP-1 inhibitor, was used to explore the effects of PARP-1inhibition on irradiated tumors and tumor vasculature. Results: ABT-888 reduced clonogenic survival in H460 lung cancer cells, and inhibited DNA repair as shown by enhanced expression of DNA strand break marker histone g-H2AX. Both apoptosis and autophagy contributed to the mechanism of increased cell death. Additionally, ABT-888 increased tumor growth delay at well-tolerated doses in murine models. For a 5-fold increase in tumor volume, tumor growth delay was 1day for ABT-888 alone, 7 days for radiation alone, and 13.5 days for combination treatment. Immunohistochemical staining of tumor sections revealed an increase in terminal deoxyribonucleotide transferase^mediated nick-end labeling apoptotic staining, and a decrease in Ki-67 proliferative staining after combination treatment. Matrigel assay showed a decrease in in vitro endothelial tubule formation with ABT-888/radiation combination treatment, and von Willebrand factor staining of tumor sections revealed decreased vessel formation in vivo, suggesting that this strategy may also target tumor angiogenesis. Conclusions: We conclude that PARP-1 inhibition shows promise as an effective means of enhancing tumor sensitivity to radiation, and future clinical studies are needed to determine the potential of ABT-888 as a radiation enhancer.

The landscape of genetic alterations in lung adenocarcinoma derived from Asian patients is largely uncharacterized. Here we present an integrated genomic and transcriptomic analysis of 335 primary lung adenocarcinomas and 35 corresponding lymph node metastases from Chinese patients. Altogether 13 significantly mutated genes are identified, including the most commonly mutated gene TP53 and novel mutation targets such as RHPN2, GLI3 and MRC2. TP53 mutations are furthermore significantly enriched in tumours from patients harbouring metastases. Genes regulating cytoskeleton remodelling processes are also frequently altered, especially in metastatic samples, of which the high expression level of IQGAP3 is identified as a marker for poor prognosis. Our study represents the first large-scale sequencing effort on lung adenocarcinoma in Asian patients and provides a comprehensive mutational landscape for both primary and metastatic tumours. This may thus form a basis for personalized medical care and shed light on the molecular pathogenesis of metastatic lung adenocarcinoma.

Background: Albumin and globulin are main components of serum protein. The level of albumin and globulin partially represents the nutrition status and immune system. Albumin-to-globulin ratio (AGR) has been reported as a prognostic factor in various cancers. We therefore performed a meta-analysis to elucidate the prognosis effect of AGR on survival outcomes in solid tumors.Method: Six electronic database were searched for the relevant articles that assessing the prognostic value of pre-treatment AGR in solid tumor patients. The primary outcome was overall survival (OS) and the secondary outcomes were cancer-specific survival (CSS), disease-free survival (DFS) and disease-metastasis-free survival (DMFS). The time-to-event outcomes were summarized in hazard ratio (HR) and 95% confidence interval (CI).Result: A total of 13890 solid tumor patients in 24 studies were included. The AGR higher than the cut-off values ranging from 1.15-1.75 was related to better OS (HR=0.58, 95%CI 0.537-0.626, p<0.0001), CSS (HR=0.287, 95%CI 0.187-0.438, p<0.0001), DFS (HR=0.792, 95%CI 0.715-0.878, p<0.0001) and DMFS (HR=0.595, 95%CI 0.447-0.792, p<0.0001). According to the cut-off values, subgroup analysis showed that AGR had significant prognostic effect on OS in each cut-off intervals (≤1.20, 1.20-1.40 and ≥1.40).Conclusion: Pre-treatment AGR is an effective prognostic factor and high AGR represents an ideal clinical outcome in the solid tumor patients.

BackgroundGamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the adult mammalian brain, but exerts physiologic effects other than that on neurotransmitter in non-neuronal peripheral tissues and organs. GABA may affect cancer growth through activation GABA receptors. We investigated the gene expression of GABA receptors in tissue of non-small cell lung cancers (NSCLC) and non-cancerous tissues, and found that the gene expression of GABA receptor phenotypes was correlated with tumorigenesis and clinical prognosis.MethodsSixty-one snap-frozen human samples of NSCLC tissues and paired non-cancerous tissues (5cm away from tumor) were analyzed. Gene expression of GABA receptors was detected by Real-time quantitative PCR (RT-qPCR). Survival times in relation to the expression of GABA receptor phenotypes were analyzed. Human NSCLC cell lines H1299, A549, H520, H460 and human bronchial epithelial cell line BEAS-2B were used to determine the phenotypes of GABA inhibitory effects on cancer cell growth. The effects of exogenous administration of GABA on H1299 cell growth were examined.ResultsThe gene expressions were significantly higher in NSCLC tissues than in the paired non-cancerous tissues for GABAA receptor subunit α3 (GABRA3, P = 0.030); for GABAA receptor subunit epsilon (GABRE, P = 0.036); and GABAB receptor subunit 2 (GABBR2, P = 0.005). Kaplan-Meier curves showed that patients with high expression of GABBR2 gene and low expression of GABRA3 gene had a better prognosis (P < 0.05). The administration of GABA resulted in suppressed proliferation of NSCLC cell lines in a dose- and time-dependent manner. The use of the GABA receptor antagonist CGP35348 could reverse the inhibitory effect.ConclusionsThe pattern of GABA receptor gene phenotype expression may be involved in the regulation of tumorigenesis. A high expression of GABBR2 with a low expression of GABRA3 may predict a better outcome. The treatment with GABA attenuates cancer cell growth in vitro. The expression of GABA receptor may be not only promising genetic therapeutic targets but may also serve as valuable prognostic markers for NSCLC.

A treatment strategy that combines arsenic trioxide (ATO) with the tyrosine kinase inhibitor imatinib mesylate (STI571, Gleevec) appears to induce markedly more cell apoptosis than imatinib mesylate alone in chronic myeloid leukemia (CML). To understand the mechanisms underlying the synergistic/additive action of these agents, we applied cDNA microarrays, component plane presentation integrated self-organizing map (CPP-SOM), and methods of protein biochemistry to study cell apoptosis induced by imatinib mesylate, ATO, and the combination of the 2 agents in the CML cell line K562. Numerous features with temporospatial relationships were revealed, indicating the coordinated regulation of molecular networks from various aspects of proapoptotic and apoptotic activities in CML. Imatinib mesylate appears to induce mainly the intrinsic pathway of cell apoptosis, whereas ATO induces the endoplasmic reticulum (ER) stress-mediated pathway of cell apoptosis, and the combination of the 2 agents seems to more effectively induce the intrinsic, extrinsic, and ER stress-mediated pathways of cell apoptosis, which results in a more effective and efficient induction of programmed cell death in K562 cells. This finding appears to be supported also by data de- IntroductionAdvances in molecular pathogenesis have facilitated the development of therapeutic strategies targeted to molecular events critical for human malignancies. This is represented by the treatment of chronic myeloid leukemia (CML) with imatinib mesylate (STI571), a specifically designed inhibitor that targets the tyrosine kinase activity of the BCR-ABL protein and consequently induces apoptosis in vitro as well as in vivo in CML cells. [1][2][3][4][5][6] Recent clinical trials in the chronic phase of CML have also demonstrated the remarkable efficacy of this molecularly targeted agent to patients with CML. 7 However, a significant proportion of the treated patients with previously failed experiences of interferon therapy remained predominantly BCR-ABL ϩ , suggesting a risk of later relapse. 8 Furthermore, patients in the accelerated and blast-crisis phase revealed a high frequency of relapse or resistance to imatinib mesylate. 9-11 As a result, much interest is now focused on the development of combination therapies to improve response rates and prevent resistance or relapse. 12 Arsenic, the oldest and also the newest form of antileukemia drug, may promote apoptosis and exert anti-CML effects. 13 A treatment strategy that combines arsenic compounds that lower BCR-ABL levels, with imatinib mesylate that inhibits BCR-ABL tyrosine kinase activity, has indeed shown promising potential in inducing more apoptosis in BCR-ABL ϩ cells. [14][15][16] Clinical applications of similar strategies may potentially strengthen the curative effects of imatinib mesylate. To better evaluate additive or synergistic effects of the combination of ATO with imatinib mesylate in CML cells, and to develop more sophisticated clinical protocols, we treated the CML cell line K562 with ATO, imatinib...

Background: Small cell lung cancer (SCLC) is a subtype of lung cancer with poor prognosis. In this study, we aimed to build a nomogram to predict the survival of individual with SCLC by incorporating significant clinical parameters. Methods:The patients with SCLC were enrolled from the First Affiliated Hospital of Guangzhou Medical University (GMUFAH) between 2009 and 2013. We identified and incorporated the independent prognostic factors to build a nomogram to predict the survival of SCLC patients. The predictive accuracy and discriminative ability of the nomogram were evaluated by concordance index (C-index) and calibration curve.We also compared the accuracy of the built model with the 7 th AJCC TNM and VALSG staging system. The nomogram was further validated in an independent cohort of 80 patients with SCLC from Cancer Center of Guangzhou Medical University (GMUCC) between 2009 and 2013.Results: A total of 275 patients with SCLC were included in the primary cohort, and seven independent prognostic factors were identified including age, N stage, metastasis status, histology, platelets to lymphocyte ratio (PLR), neuron specific enolase (NSE) and CYFRA21-1 as independent prognostic factors after using Cox regression model. A nomogram incorporating these prognostic factors was subsequently built. The calibration curves for possibilities of 1-, 2-year overall survival (OS) revealed optimal agreement between nomogram prediction and actual observation. The C-index of this nomogram was higher than that of TNM Conclusions:In this study, we established and validated a novel nomogram for the prediction of OS for the patients with SCLC. This model could provide more accurate individual prediction of survival probability of SCLC than the existing staging systems.

Gender-associated difference in incidence and clinical outcomes of lung cancer have been established, but the biological mechanisms underlying these gender-associated differences are less studied. Recently we have characterized the genomic landscape of lung adenocarcinoma derived from Chinese population (Reference [1]). In this study we evaluated the clinical significance of mutation burden in lung adenocarcinoma and found that the male tumors harbored statistically greater burden of genetic alterations than female counterparts (Male median 3 (range 0–34) vs female median = 2 (0–24), male to female ratio = 1.636, 95% CI = 1.343–1.992) after adjustment of age at surgery, stage, smoking status. Kaplan-Meier survival analysis revealed that greater burden of genetic alterations was associated with worse overall survival. Moreover, multivariable analysis demonstrated mutation burden was an independent prognostic factor for the patients. Taken together, our analysis demonstrated gender disparity of mutation burden and their prognostic value in lung adenocarcinoma. This gender difference in mutation burden might provide an explanation for the distinct difference in the clinical outcomes between sexes in lung adenocarcinoma.