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author:("Chen, mingled")
1.  The combination of RAD001 and NVP-BKM120 synergistically inhibits the growth of lung cancer in vitro and in vivo 
Cancer letters  2012;325(2):139-146.
This study focuses on determining whether the combination of NYP-BKM120 (BKM120) and RAD001 exerts enhanced therapeutic effect against lung cancer. The combination of BKM120 and RAD001 exerted synergistic inhibitory effects on the growth of lung cancer cells both in culture and in mouse xenograft model. This combination abrogated RAD001-induced Akt phosphorylation and exerted enhanced suppressive effect on 4EBP1 phosphorylation. Collectively, we suggest that the combination of RAD001 and BKM120 may be an effective regimen for treatment of lung cancer, hence warranting further evaluation of the combination in the clinic.
PMCID: PMC3433638  PMID: 22781393
RAD001; BKM120; PI3 kinase; mTOR; lung cancer
2.  The E3 ubiquitin ligases β-TrCP and FBXW7 cooperatively mediates GSK3-dependent Mcl-1 degradation induced by the Akt inhibitor API-1, resulting in apoptosis 
Molecular Cancer  2013;12:146.
The novel Akt inhibitor, API-1, induces apoptosis through undefined mechanisms. The current study focuses on revealing the mechanisms by which API-1 induces apoptosis.
API-1 rapidly and potently reduced the levels of Mcl-1 primarily in API-1-senstive lung cancer cell lines. Ectopic expression of Mcl-1 protected cells from induction of apoptosis by API-1. API-1 treatment decreased the half-life of Mcl-1, whereas inhibition of the proteasome with MG132 rescued Mcl-1 reduction induced by API-1. API-1 decreased Mcl-1 levels accompanied with a rapid increase in Mcl-1 phosphorylation (S159/T163). Moreover, inhibition of GSK3 inhibited Mcl-1 phosphorylation and reduction induced by API-1 and antagonized the effect of API-1 on induction of apoptosis. Knockdown of either FBXW7 or β-TrCP alone, both of which are E3 ubiquitin ligases involved in Mcl-1 degradation, only partially rescued Mcl-1 reduction induced by API-1. However, double knockdown of both E3 ubiquitin ligases enhanced the rescue of API-1-induced Mcl-1 reduction.
API-1 induces GSK3-dependent, β-TrCP- and FBXW7-mediated Mcl-1 degradation, resulting in induction of apoptosis.
PMCID: PMC3924345  PMID: 24261825
API-1; GSK3; Mcl-1; E3 ubiquitin ligase; Apoptosis; Lung cancer
3.  The novel Akt inhibitor API-1 induces c-FLIP degradation and synergizes with TRAIL to augment apoptosis independent of Akt inhibition 
API-1 is a novel small molecule inhibitor of Akt, which acts by binding to Akt and preventing its membrane translocation, and has promising preclinical antitumor activity. In this study, we reveal a novel function of API-1 in regulation of c-FLIP levels and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, independent of Akt inhibition. API-1 effectively induced apoptosis in tested cancer cell lines including activation of caspase-8 and caspase-9. It reduced the levels of c-FLIP without increasing the expression of DR4 or DR5. Accordingly, it synergized with TRAIL to induce apoptosis. Enforced expression of ectopic c-FLIP did not attenuate API-1-induced apoptosis, but inhibited its ability to enhance TRAIL-induced apoptosis. These data indicate that downregulation of c-FLIP mediates enhancement of TRAIL-induced apoptosis by API-1, but is not sufficient for API-1-induced apoptosis. API-1-induced reduction of c-FLIP could be blocked by the proteasome inhibitor MG132. Moreover, API-1 increased c-FLIP ubiquitination and decreased c-FLIP stability. These data together suggest that API-1 downregulates c-FLIP by facilitating its ubiquitination and proteasome-mediated degradation. Since other Akt inhibitors including API-2 and MK2206 had minimal effects on reducing c-FLIP and enhancement of TRAIL-induced apoptosis, it is likely that API-1 reduces c-FLIP and enhances TRAIL-induced apoptosis independent of its Akt-inhibitory activity.
PMCID: PMC3324640  PMID: 22345097
API-1; Akt; TRAIL; c-FLIP; apoptosis; cancer
4.  A nanoscale co-precipitation approach for property enhancement of Fe-base alloys 
Scientific Reports  2013;3:1327.
Precipitate size and number density are two key factors for tailoring the mechanical behavior of nanoscale precipitate-hardened alloys. However, during thermal aging, the precipitate size and number density change, leading to either poor strength or high strength but significantly reduced ductility. Here we demonstrate, by producing nanoscale co-precipitates in composition-optimized multicomponent precipitation-hardened alloys, a unique approach to improve the stability of the alloy against thermal aging and hence the mechanical properties. Our study provides compelling experimental evidence that these nanoscale co-precipitates consist of a Cu-enriched bcc core partially encased by a B2-ordered Ni(Mn, Al) phase. This co-precipitate provides a more complex obstacle for dislocation movement due to atomic ordering together with interphases, resulting in a high yield strength alloy without sacrificing alloy ductility.
PMCID: PMC3579184  PMID: 23429646
5.  Combining multiple serum biomarkers in tumor diagnosis: A clinical assessment 
Molecular and Clinical Oncology  2012;1(1):153-160.
The present study aimed to assess the diagnostic/prognostic value of various clinical tumor markers, including carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), cytokeratin 19 (CYFRA21-1), α-fetoprotein (AFP), carbohydrate antigen-125 (CA-125), carbohydrate antigen-19.9 (CA-19.9) and ferritin, individually or in combination. The electro-chemiluminescence immunization method was performed to detect the levels of seven tumor markers in 560 cancer patients and 103 healthy subjects for comparison. The serum levels of the seven markers measured in cancer patients were higher compared to healthy subjects (P<0.05 for AFP and P<0.001 for the remaining six markers). Different markers had different sensitivity towards different types of tumors. Combining more markers significantly increased the ratios of positive diagnosis in the tumors. The diagnostic sensitivities of combining seven markers were particularly high in digestive, urinary and skeletal tumors (82, 92 and 83%, respectively). Gynecological tumors have exhibited a constant yet relatively low positive diagnosis irrespective of the use of a single marker or combined markers. However, the increase in sensitivity when combining markers was accompanied by a decrease in specificity. Generally, combining more markers increased the tumor detection rates, while a combination of the seven markers provided the highest detection rate. Combined detection showed a particularly high sensitivity in detecting respiratory, digestive and urinary system tumors, with the lowest sensitivity observed in gynecological tumors. As a result, combining tumor markers may play an important role in early tumor detection/diagnosis while the loss of specificity can be tolerated.
PMCID: PMC3956235  PMID: 24649139
tumor marker; diagnosis; lung cancer; carcinoembryonic antigen; neuron-specific enolase; cytokeratin 19
6.  Descriptive data on cancerous lung lesions detected by auto-fluorescence bronchoscope: A five-year study 
Annals of Thoracic Medicine  2012;7(1):21-25.
Auto-fluorescence bronchoscopy (AFB) has been used for the identification and localization of intra-epithelial pre-neoplastic and neoplastic lesions within the bronchus.
To determine the applicability of AFB for the detection and localization of precancerous and cancerous lesions, in addition to analyzing the morphologic presentation, their association to histological type and the variation between genders.
A five-year study involving 4983 patients, who underwent routine bronchoscopy [B] examination in a local tertiary teaching hospital, was done. The B examination was performed under intratracheal lidocaine, and samples were obtained using suitable approach. One thousand four hundred and eighty-five pathologically confirmed lung cancer patients were included in the study. The following parameters were studied: Morphological presentation, biopsy sites, histology. Differences between the groups were analyzed using Chi square test.
One thousand four hundred and eighty-five patients who had hyperplasia or neoplastic lesions were further confirmed as lung cancer pathologically. Lung cancer was more commonly found in the right lung (51.58% vs. 42.82%). The lesion occurred more frequently in the upper lobe than the lower lobe (44.17% vs. 22.42%). Male patients with squamous cell carcinoma showed upper lobe involvement more commonly, while the left main bronchus was more commonly involved in female patients. Adenocarcinoma mostly involved lesion of the upper lobe. Squamous cell carcinoma and small cell carcinoma were the major proliferative types (80.15% and 76.16% respectively).
AFB is efficient in the detection of pre-invasive and invasive lung lesions. The morphological presentation is associated to the histological type. There is variation in the presentation and histology of cancerous lung lesions between genders.
PMCID: PMC3277036  PMID: 22347346
Auto-fluorescence bronchoscopy; gender; invasive lesion; lung cancer; screening
7.  A Potent and Selective AMPK Activator That Inhibits de Novo Lipogenesis 
ACS Medicinal Chemistry Letters  2010;1(9):478-482.
AMP-activated protein kinase (AMPK) is a heterotrimeric kinase that regulates cellular energy metabolism by affecting energy-consuming pathways such as de novo lipid biosynthesis and glucose production as well as energy-producing pathways such as lipid oxidation and glucose uptake. Accordingly, compounds that activate AMPK represent potential drug candidates for the treatment of hyperlipidemia and type 2 diabetes. Screening of a proprietary library of AMP mimetics identified the phosphonic acid 2 that bears little structural resemblance to AMP but is capable of activating AMPK with high potency (EC50 = 6 nM vs AMP EC50 = 6 μM) and specificity. Phosphonate prodrugs of 2 inhibited de novo lipogenesis in cellular and animal models of hyperlipidemia.
PMCID: PMC4007905  PMID: 24900234
5-(5-Hydroxy-isoxazol-3-yl)-furan-2-phosphonic acid; AMPK activator; lipogenesis; hepatocytes
8.  Gefitinib (IRESSA) sensitive lung cancer cell lines show phosphorylation of Akt without ligand stimulation 
BMC Cancer  2006;6:277.
Phase III trials evaluating the efficacy of gefitinib (IRESSA) in non-small cell lung cancer (NSCLC) lend support to the need for improved patient selection in terms of gefitinib use. Mutation of the epidermal growth factor receptor (EGFR) gene is reported to be associated with clinical responsiveness to gefitinib. However, gefitinib-sensitive and prolonged stable-disease-defined tumors without EGFR gene mutation have also been reported.
To identify other key factors involved in gefitinib sensitivity, we analyzed the protein expression of molecules within the EGFR family, PI3K-Akt and Ras/MEK/Erk pathways and examined the sensitivity to gefitinib using the MTT cell proliferation assay in 23 lung cancer cell lines.
We identified one highly sensitive cell line (PC9), eight cell lines displaying intermediate-sensitivity, and 14 resistant cell lines. Only PC9 and PC14 (intermediate-sensitivity) displayed an EGFR gene mutation including amplification. Eight out of the nine cell lines showing sensitivity had Akt phosphorylation without ligand stimulation, while only three out of the 14 resistant lines displayed this characteristic (P = 0.0059). Furthermore, the ratio of phosphor-Akt/total Akt in sensitive cells was higher than that observed in resistant cells (P = 0.0016). Akt phosphorylation was partially inhibited by gefitinib in all sensitive cell lines.
These results suggest that Akt phosphorylation without ligand stimulation may play a key signaling role in gefitinib sensitivity, especially intermediate-sensitivity. In addition, expression analyses of the EGFR family, EGFR gene mutation, and FISH (fluorescence in situ hybridization) analyses showed that the phosphorylated state of EGFR and Akt might be a useful clinical marker of Akt activation without ligand stimulation, in addition to EGFR gene mutation and amplification, particularly in adenocarcinomas.
PMCID: PMC1698934  PMID: 17150102
9.  In situ atomic-scale observation of continuous and reversible lattice deformation beyond the elastic limit 
Nature Communications  2013;4:2413.
The elastic strain sustainable in crystal lattices is usually limited by the onset of inelastic yielding mediated by discrete dislocation activity, displacive deformation twinning and stress-induced phase transformations, or fracture associated with flaws. Here we report a continuous and gradual lattice deformation in bending nickel nanowires to a reversible shear strain as high as 34.6%, which is approximately four times that of the theoretical elastic strain limit for unconstrained loading. The functioning deformation mechanism was revealed on the atomic scale by an in situ nanowire bending experiments inside a transmission electron microscope. The complete continuous lattice straining process of crystals has been witnessed in its entirety for the straining path, which starts from the face-centred cubic lattice, transitions through the orthogonal path to reach a body-centred tetragonal structure and finally to a re-oriented face-centred cubic structure.
In bulk materials crystal lattices typically have a limited resistance to elastic strain, beyond which yielding and plastic deformation occur. Here, using in situ transmission electron microscopy, a continuous elastic lattice deformation is observed in nickel nanowires, up to a strain of 34.6%.
PMCID: PMC3778763  PMID: 24022231

Results 1-9 (9)