Search

Background/Purpose Deregulation of metabolic pathways is one of the hallmarks of cancer progression. Connective tissue growth factor (CTGF/CCN2) acts as a tumor suppressor in oral squamous cell carcinoma (OSCC). However, the role of CTGF in modulating cancer metabolism is still unclear. Methods OSCC cells stably overexpressing CTGF (SAS/CTGF) and shRNA against CTGF (TW2.6/shCTGF) were established. Oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) were examined by the Seahorse XF24 analyzer. The expression of CTGF and mitochondrial biogenesis related genes was measured by real-time polymerase chain reaction or Western blot analysis. Results CTGF decreased OCR, ECAR, adenosine triphosphate (ATP) generation, mitochondrial DNA (mtDNA), and mitochondrial transcription factor A (mtTFA) protein expression in OSCC cells. Overexpression of mtTFA restored CTGF-decreased OCR, ECAR, mtDNA copy number, migration and invasion of SAS/CTGF cells. Immunoprecipitation assay showed a higher level of ubiquitinated mtTFA protein after CTGF treatment. MG132, an inhibitor of proteasomal degradation, reversed the effect of CTGF on mtTFA protein expression in SAS cells. Conclusion CTGF can decrease glycolysis, mitochondrial oxidative phosphorylation, ATP generation, and mtDNA copy number by increasing mtTFA protein degradation through ubiquitin proteasome pathway and in turn reduces migration and invasion of OSCC cells. Therefore, CTGF may be developed as a potential additive therapeutic drug for oral cancer in the near future.

Abnormalities in the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway are commonly observed in human cancers and contribute to chemotherapy resistance. Combination therapy, involving the use of molecular targeted agents and traditional cytotoxic drugs, may represent a promising strategy to lower resistance and enhance cytotoxicity. Here, we demonstrate the efficacy of an Akt inhibitor, MK-2206, in increasing the cytotoxic effect of either paclitaxel (Taxol) or cisplatin against the ovarian cancer cell lines SKOV3 (with constitutively active Akt) and ES2 (with inactive Akt). Sequential treatment of Taxol or cisplatin, followed by MK-2206, induced a synergistic inhibition of cell proliferation and effectively promoted cell death, either by inhibiting the phosphorylation of Akt and its downstream effectors 4E-BP1 and p70S6K in SKOV3 cells or by restoring p53 levels, which were downregulated after Taxol or cisplatin treatment, in ES2 cells. Combination treatment also downregulated the pro-survival protein Bcl-2 in both SKOV3 and ES2 cells, which may have contributed to cell death. In addition, we discovered that Taxol/MK-2206 or cisplatin/MK-2206 combination treatment resulted in significant enhancement of intracellular reactive oxygen species (ROS) induced by MK-2206, in both SKOV3 and ES2 cells; however, MK-2206-induced growth inhibition was reversed by a ROS scavenger only in ES2 cells. MK-2206 also suppressed DNA repair, particularly in SKOV3 cells. Taken together, our results demonstrate that the Akt inhibitor MK-2206 enhances the efficacy of cytotoxic agents in both Akt-active and Akt-inactive ovarian cancer cells but through different mechanisms.

We reported previously that a hemiasterlin derivative BF65 is a potent anticancer agent that can inhibit microtubule assembly. Here we show that a more potent stereospecific diastereomer (R)(S)(S)-BF65 can synergize with an allosteric Akt inhibitor MK-2206 to suppress the growth of SKOV3 ovarian cancer cells with constitutively active Akt. (R)(S)(S)-BF65 induced mitotic arrest and MK-2206 caused G0/G1 arrest, while the combination of both induced simultaneous G0/G1 and G2/M cell cycle arrest. (R)(S)(S)-BF65 induced phosphorylation and inactivation of Bcl-2, and downregulated Mcl-1, consequently may lead to apoptosis. (R)(S)(S)-BF65 inhibited mitogen-activated protein kinases (MAPKs), which may stimulate cell proliferation upon activation. (R)(S)(S)-BF65 also induced DNA damage after long-term treatment. MK-2206 is known to inhibit phosphorylation and activation of Akt and suppress cancer cell growth. The combination of (R)(S)(S)-BF65 and MK-2206 also inhibited the Akt pathway. Interestingly, MK-2206 upregulated Bcl-2 and induced activation of MAPKs in SKOV3 cells; however, when combined with (R)(S)(S)-BF65, these prosurvival effects were reversed. The combination also more significantly decreased Mcl-1 protein, increased PARP cleavage, and induced γ-H2AX, a DNA damage marker. Remarkably, MK-2206 enhanced the microtubule depolymerization effect of (R)(S)(S)-BF65. The combination of (R)(S)(S)-BF65 and MK-2206 also markedly inhibited cell migration. Thus, MK-2206 synergizes with (R)(S)(S)-BF65 to inhibit SKOV3 cell growth via downregulating the Akt signaling pathway, and enhancing the microtubule disruption effect of (R)(S)(S)-BF65. (R)(S)(S)-BF65 in turn suppresses Bcl-2 and MAPKs induced by MK-2206. (R)(S)(S)-BF65 and MK-2206 compensate each other leading to increased apoptosis and enhanced cytotoxicity, and may also suppress cancer cell invasion.

We demonstrated the controlled placement of a Ge quantum dot (QD) along with tunnel-junction engineering in a self-organized approach for the effective management of single charge tunneling. In this approach, a single-Ge-QD ( ~ 11 nm) self-aligning with nickel-polycide electrodes is realized by thermally oxidizing a SiGe nanorod that bridges a 15-nm-wide nanotrench in close proximity to electrodes via a spacer bilayer of Si3N4/SiO2. The fabricated Ge-QD single-hole transistor exhibits clear Coulomb oscillation and Coulomb diamond behaviors at T = 77 K-150 K, providing a way to analyze the electronic structure of the Ge QD.

We demonstrate a CMOS-compatible scheme, selective oxidation of SiGe pillars, for creating well-organized 3-D Ge quantum dot (QD) array by guiding QDs migration along the oxidation path and thus placing them on targeted locations where the ultimate oxidation occurs. Stacked QDs exhibit tunable luminescence over the visible and possess low thermal conductivity, showing promise for nanophotonic and energy conversion devices.

Controlled heterogeneous nucleation and growth of Ge quantum dots (QDs) are demonstrated on SiO_2/Si_3N_4 substrates by means of a novel fabrication process of thermally oxidizing nanopatterned SiGe layers. The otherwise random self-assembly process for QDs is shown to be strongly influenced by the nanopatterning in determining both the location and size of the QDs. Ostwald ripening processes are observed under further annealing at the oxidation temperature. Both nanopattern oxidation and Ostwald ripening offer additional mechanisms for lithography for controlling the size and placement of the QDs.

Trigate Si nanowire (NW) MOSFETs have been fabricated and characterized at temperature between 77 and 300 K in the dark and under light pumping. The NW width W and height H, the gate length Lg, and the gate oxide thickness tox, respectively, were 7-25, 16, 34-52, and 7 nm. The interesting aspects of Si NW MOSFETs with W/Lg = 25 nm /52 nm, 24 nm/34 nm, 7 nm/47 nm, and 10 nm/37 nm measured at low drain voltage are that the drain current exhibited not only inverse temperature dependence in strong accumulation but also clear current plateaus/oscillations near the threshold regime at temperature up to 300 K. Notably, such current plateaus diminished or were invisible in the device of W/Lg = 24 nm/42 nm. The observed current behaviors are inferred from the interplay of quantum interference and intersubband scattering effects. Additional current plateaus due to photogenerated excitons were also observed in the studied devices, evidencing photoexcitation effects on quantum transports through a Si NW.

Liquid-phase and solid-phase extractions (SPE) in combination with a simple micellar electrokinetic chromatography (MEKC) method were used to investigate human very low-density lipoprotein (VLDL) lipids for two healthy donors. At absorbance 200 nm, the effective mobilities and peak areas of the MEKC profiles showed good reproducibility and precisions. A major peak and several minor peaks appeared for the total lipids of native VLDL, but both the peak numbers and areas reduced for the in vitro oxidized VLDL. Two chloroform and two methanol fractions were obtained from SPE of VLDL total lipids. Significant differences were observed for the first methanol fraction between native and in vitro oxidized VLDL lipids. The first methanol fraction showed a major peak and several minor peaks for native VLDL, but both the peak numbers and areas reduced for oxidized VLDL. Oxidation of VLDL caused decomposition of lipids, and thus the reduction of peak numbers and areas.

A simple capillary zone electrophoresis (CZE) method was used to characterize human very low-density lipoprotein (VLDL) particles for four healthy donors. One major peak was observed for native, in vitro oxidized and glycated VLDL particles. The effective mobilities and peak areas of the capillary electrophoresis (CE) profiles showed good reproducibility and precision. The mobility of the oxidized VLDL peak was higher than that of the native VLDL. The mobility of the glycated VLDL peak was similar to that of the native VLDL. Phospholipids isolated from VLDL particles were analyzed by our recently developed micellar electrokinetic chromatography (MEKC) with a high-salt stacking method. At absorbance 200 nm, the native VLDL phospholipids showed a major peak and a minor peak for each donor. For oxidized VLDL phospholipids, the area of the major peak reduced for three donors, possibly due to phospholipid decomposition. For glycated VLDL phospholipids, the peak mobilities were more positive than native VLDL phospholipids for two donors, possibly due to phospholipid-linked advanced glycation end products (AGEs). Very interestingly, at absorbance 234 nm, the major peak of oxidized VLDL phospholipids was resolved as two peaks for each donor, possibly due to conjugated dienes formed upon oxidation.

A single Ge quantum-dot (~10 nm) forms and self-aligns with source/drain electrodes via SiO2 tunneling barriers using thermal oxidation of a SiGe-on-insulator nanowire. Thereby, a Ge single-hole transistor with self-aligned electrodes is experimentally realized based on FinFET technology and features with clear Coulomb staircase/negative differential conductance and large Coulomb-blockade oscillation behaviors at room temperature. This work provides a simple approach to alleviate this nanofabrication bottleneck and thereby reduce series resistances and increase design freedom for SETs.

A single electron transistor (SET) is an ultimate scheme of electronic devices for the purpose of controlling current with one charge precision based on Coulomb blockade effect. A SET could be used as a highly sensitive electrometer and might provide great potential applications for quantum information technology. For RT operation, the size of a Si-based QD should be less than 10 nm to prevent errors caused by thermal fluctuation. Nevertheless, control of nanometer-scaled thickness, area, and volume is not easy even when state of the art lithography and/or self-organization techniques are used. The solution we propose to alleviate this problem is to form Ge QDs by selective oxidation of Si1-xGexSi-on-insulator (SOI) (Li et al., 2004). Using this method, Ge QDs are comparatively uniform and thermodynamically stable since Ge QDs are confined by the insulating layers. The proposed process is compatible to CMOS technology and can be easily adapted in the fabrication of embedded circuits

We reported experimental observations of strong quantum confinement and coulomb blockade effects in germanium (Ge) quantum dots (QDs)/SiO/sub 2/ system. With a CMOS-compatible method, nanometer-scale Ge QDs (less than 10 nm) could be controllably formed for novel optoelectronic device applications such as single-electron transistors (SETs) as well as light emitter or detectors. Distinguishable photoemission from Ge QDs and relevant blueshifts of the emission peaks are observed from room-temperature cathodoluminescence spectra. Ge QD SETs were also experimentally realized with a large single-electron addition energy and an energy level separation of 125 meV and 50 meV, respectively.

The purpose of this study was to study the morphology and cytokeratin expression in the epithelia of pterygia. Impression cytology and immunohistochemical staining with antikeratin antibodies were performed in 32 eyes of 16 patients with pterygia. TUNEL stain and electron microscopy were also performed in surgical specimens of pterygium. Squamous metaplasia-like epithelial cells were found in all specimens of impression cytology, especially in the head part. These specimens had positive immunostaining by antipancytokeratin antibodies, but not by anti-K12 AK2 mAb. Goblet cells were found around the area of these abnormal epithelial cells. TUNEL-positive cells were found in the epithelia of the pterygial head, but not in the body of pterygia and normal conjunctiva. The expressional patterns of keratin by these epithelial cells of pterygia are consistent with the notion that they are derived from conjunctival epithelium and mimic the process of squamous metaplasia.